Emotionally arousing pictures increase blood glucose levels and enhance recall.

PubMed

Blake, T M; Varnhagen, C K; Parent, M B

2001-05-01

Arousal enhances memory in human participants and this enhancing effect is likely due to the release of peripheral epinephrine. As epinephrine does not readily enter the brain, one way that peripheral epinephrine may enhance memory is by increasing circulating blood glucose levels. The present study investigated the possibility that emotionally arousing color pictures would improve memory and elevate blood glucose levels in human participants. Blood glucose levels were measured before, 15 min, and 30 min after male university students viewed 60 emotionally arousing or relatively neutral pictures. Participants viewed each picture for 6 s and then had 10 s to rate the arousal (emotional intensity) and valence (pleasantness) of each picture. A free-recall memory test was given 30 min after the last picture was viewed. Although the emotionally arousing and neutral picture sets were given comparable valence ratings, participants who viewed the emotionally arousing pictures rated the pictures as being more arousing, recalled more pictures, and had higher blood glucose levels after viewing the pictures than did participants who viewed the neutral pictures. These findings indicate that emotionally arousing pictures increase blood glucose levels and enhance memory, and that this effect is not due to differences in the degree of pleasantness of the stimuli. These findings support the possibility that increases in circulating blood glucose levels in response to emotional arousal may be part of the biological mechanism that allows emotional arousal to enhance memory. Copyright 2001 Academic Press.

Renal glucose metabolism in normal physiological conditions and in diabetes.

PubMed

Alsahli, Mazen; Gerich, John E

2017-11-01

The kidney plays an important role in glucose homeostasis via gluconeogenesis, glucose utilization, and glucose reabsorption from the renal glomerular filtrate. After an overnight fast, 20-25% of glucose released into the circulation originates from the kidneys through gluconeogenesis. In this post-absorptive state, the kidneys utilize about 10% of all glucose utilized by the body. After glucose ingestion, renal gluconeogenesis increases and accounts for approximately 60% of endogenous glucose release in the postprandial period. Each day, the kidneys filter approximately 180g of glucose and virtually all of this is reabsorbed into the circulation. Hormones (most importantly insulin and catecholamines), substrates, enzymes, and glucose transporters are some of the various factors influencing the kidney's role. Patients with type 2 diabetes have an increased renal glucose uptake and release in the fasting and the post-prandial states. Additionally, glucosuria in these patients does not occur at plasma glucose levels that would normally produce glucosuria in healthy individuals. The major abnormality of renal glucose metabolism in type 1 diabetes appears to be impaired renal glucose release during hypoglycemia. Copyright © 2017 Elsevier B.V. All rights reserved.

Myostatin and carbohydrate disturbances.

PubMed

Assyov, Yavor S; Velikova, Tsvetelina V; Kamenov, Zdravko A

2017-05-01

Purpose/aim of the study: Myostatin is a myokine that has been shown to inhibit muscle growth and to have potentially deleterious effects on metabolism. The aim of the current study was to compare its circulating serum levels in subjects from the whole spectrum of carbohydrate disturbances leading to diabetes. A total of 159 age-, sex-, and BMI-matched subjects participated in the study - 50 had normal glucose tolerance (NGT), 60 had prediabetes (PreDM), and 49 had type 2 diabetes mellitus (T2D). Oral glucose tolerance testing was used to determine glucose tolerance. Serum myostatin was quantified by means of ELISA. Circulating serum myostatin levels were highest in patients with T2D, lower in subjects with prediabetes, and lowest in subjects with normoglycemia (all p < 0.05). Myostatin was shown to be positively associated with fasting plasma glucose, HOMA-IR, hepatic enzymes, uric acid, and FINDRISC questionnaire scores in both sexes. ROC analyses determined circulating myostatin levels to be of value for differentiating subjects with T2D (AUC = 0.72, p = 0.002 in men; AUC = 0.70, p = 0.004 in women) in the study population. After adjustment for potential confounders, in a multiple binary logistic regression model, serum myostatin added further information to traditional risk estimates in distinguishing subjects with T2D. Serum myostatin levels are higher with deterioration of carbohydrate tolerance. Furthermore, circulating myostatin is positively associated with traditional biochemical estimates of poor metabolic health. These data add to evidence of the involvement of this myokine in the pathogenesis of T2D.

Circulating Prolactin Associates With Diabetes and Impaired Glucose Regulation

PubMed Central

Wang, Tiange; Lu, Jieli; Xu, Yu; Li, Mian; Sun, Jichao; Zhang, Jie; Xu, Baihui; Xu, Min; Chen, Yuhong; Bi, Yufang; Wang, Weiqing; Ning, Guang

2013-01-01

OBJECTIVE Prolactin is a major stimulus for the β-cell adaptation during gestation and guards postpartum women against gestational diabetes. Most studies of the role of prolactin on glucose metabolism have been conducted in humans and animals during pregnancy. However, little is known concerning the association between circulating prolactin and glucose metabolism outside pregnancy in epidemiological studies. We aimed to determine whether the variation of circulating prolactin concentration associates with diabetes and impaired glucose regulation (IGR) in a cross-sectional study. RESEARCH DESIGN AND METHODS We recruited 2,377 participants (1,034 men and 1,343 postmenopausal women) without hyperprolactinemia, aged 40 years and older, in Shanghai, China. Diabetes and IGR were determined by an oral glucose tolerance test. Multinomial logit analyses were performed to evaluate the relationship of prolactin with diabetes and IGR. RESULTS Prolactin levels decreased from normal glucose regulation to IGR to diabetes. Multinomial logit analyses, adjusted for potential confounding factors, showed that high circulating prolactin was associated with lower prevalence of diabetes and IGR. The adjusted odds ratios (95% CI) for IGR and diabetes for the highest compared with the lowest quartile of prolactin were 0.54 (95% CI 0.33–0.89) and 0.38 (0.24–0.59) in men and 0.54 (0.36–0.81) and 0.47 (0.32–0.70) in women. CONCLUSIONS High circulating prolactin associates with lower prevalence of diabetes and IGR in the current study. Further studies are warranted to confirm this association. PMID:23340889

Influence of a ketogenic diet, fish-oil, and calorie restriction on plasma metabolites and lipids in C57BL/6J mice

PubMed Central

2014-01-01

Background Diet therapies including calorie restriction, ketogenic diets, and fish-oil supplementation have been used to improve health and to treat a variety of neurological and non-neurological diseases. Methods We investigated the effects of three diets on circulating plasma metabolites (glucose and β-hydroxybutyrate), hormones (insulin and adiponectin), and lipids over a 32-day period in C57BL/6J mice. The diets evaluated included a standard rodent diet (SD), a ketogenic diet (KD), and a standard rodent diet supplemented with fish-oil (FO). Each diet was administered in either unrestricted (UR) or restricted (R) amounts to reduce body weight by 20%. Results The KD-UR increased body weight and glucose levels and promoted a hyperlipidemic profile, whereas the FO-UR decreased body weight and glucose levels and promoted a normolipidemic profile, compared to the SD-UR. When administered in restricted amounts, all three diets produced a similar plasma metabolite profile, which included decreased glucose levels and a normolipidemic profile. Linear regression analysis showed that circulating glucose most strongly predicted body weight and triglyceride levels, whereas calorie intake moderately predicted glucose levels and strongly predicted ketone body levels. Conclusions These results suggest that biomarkers of health can be improved when diets are consumed in restricted amounts, regardless of macronutrient composition. PMID:24910707

Testicular glucose and its transporter GLUT 8 as a marker of age-dependent variation and its role in steroidogenesis in mice.

PubMed

Banerjee, Arnab; Anuradha; Mukherjee, Kaustab; Krishna, Amitabh

2014-11-01

The present study evaluates the hypothesis, that glucose is essential for steroidogenesis and inadequate supply of glucose to the testis may be responsible for decline in steroidogenesis in mice during aging. Mice of different age groups (birth, weaning, puberty, reproductively active, and senescence) were utilized for this study. The changes in glucose, glucose transporter (GLUT), and insulin receptor (IR) level in the testis were evaluated and compared with the testicular steroidogenic parameters such as steroidogenic acute regulatory protein (StAR), 3β-hydroxy steroid dehydrogenase (3β-HSD) and circulating testosterone levels. The result showed significant correlation between changes in GLUT 8 and glucose levels with changes in StAR level in the testis and circulating testosterone level in the mice from birth to senescence. Immunohistochemical analysis showed intense immunostaining of GLUT 8 and IR in the interstitial cells, most likely Leydig cells, in testis of pubertal and reproductively active mice suggesting their relevance in steroidogenesis. The in vitro study showed a significant positive correlation between luteinizing hormone (LH)-induced increase in GLUT 8 and StAR (r = 0.82; P < 0.05) proteins level in the testes with increase in testosterone (r = 0.97; P < 0.05) synthesis of reproductively active mice. This study also showed increased release of lactate with increased uptake of glucose by the testis. Further, intra-testicular treatment of 2-deoxy glucose, to reproductively active mice caused a significant decrease in 3β-HSD enzyme activity in the testis. Based on these findings, it may be concluded that the changes in glucose level either directly or indirectly lead to changes in testicular steroidogenesis during aging. © 2014 Wiley Periodicals, Inc.

Wholegrain barley β-glucan fermentation does not improve glucose tolerance in rats fed a high-fat diet.

PubMed

Belobrajdic, Damien P; Jobling, Stephen A; Morell, Matthew K; Taketa, Shin; Bird, Anthony R

2015-02-01

Fermentation of oat and barley β-glucans is believed to mediate in part their metabolic health benefits, but the exact mechanisms remain unclear. In this study, we sought to test the hypothesis that barley β-glucan fermentation raises circulating incretin hormone levels and improves glucose control, independent of other grain components. Male Sprague-Dawley rats (n = 30) were fed a high-fat diet for 6 weeks and then randomly allocated to 1 of 3 dietary treatments for 2 weeks. The low- (LBG, 0% β-glucan) and high- (HBG, 3% β-glucan) β-glucan diets contained 25% wholegrain barley and similar levels of insoluble dietary fiber, available carbohydrate, and energy. A low-fiber diet (basal) was included for comparison. Immediately prior to the dietary intervention, gastric emptying rate (using the (13)C-octanoic breath test) and postprandial glycemic response of each diet were determined. At the end of the study, circulating gut hormone levels were determined; and a glucose tolerance test was performed. The rats were then killed, and indices of cecal fermentation were assessed. Diet did not affect live weight; however, the HBG diet, compared to basal and LBG, reduced food intake, tended to slow gastric emptying, increased cecal digesta mass and individual and total short-chain fatty acid pools, and lowered digesta pH. In contrast, circulating levels of glucose, insulin, gastric-inhibitory peptide, and glucagon-like peptide-1, and glucose tolerance were unaffected by diet. In conclusion, wholegrain barley β-glucan suppressed feed intake and increased cecal fermentation but did not improve postprandial glucose control or insulin sensitivity. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Evidence of extensive plasma glucose recycling following a glucose load in seabass.

PubMed

Rito, João; Viegas, Ivan; Pardal, Miguel A; Jones, John G

2017-09-01

Seabass and other carnivorous fish are highly dependent on gluconeogenesis from dietary amino acids to maintain glycemia. Glucose recycling (glucose→C3-intermediate→glucose) may potentiate the effects of glucose administration in sparing amino acid gluconeogenesis. To date, very few measurements of glucose recycling have been reported in fish. Thus, to determine the extent of glucose recycling following a glycemic challenge, juvenile seabass were given an intraperitoneal glucose load (2gkg -1 ) enriched with [U- 13 C]glucose. 13 C NMR analysis of plasma glucose 13 C-isotopomers was used to determine the fractional contributions of glucose derived directly from the load versus that from glucose recycling at 48h after the load. Both fed and 21-day fasted fish (20 per condition) were studied. In fasted fish, 18±4% of plasma glucose was directly derived from the load while 13±2% was derived from glucose recycling. In fed fish, the load accounted for 6±1% of plasma glucose levels while glucose recycling contributed 16±4%. 13 C NMR analysis of plasma lactate revealed 13 C-isotopomers corresponding to the expected C3-intermediates of peripheral [U- 13 C]glucose catabolism indicating that circulating lactate was a key intermediate in glucose carbon recycling under these conditions. In conclusion, glucose recycling was shown to contribute a significant portion of plasma glucose levels in both fed and fasted seabass 48h after an intraperitoneal glucose challenge and circulating lactate was shown to be an intermediate of this pathway. Copyright © 2017. Published by Elsevier Inc.

Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism

NASA Astrophysics Data System (ADS)

Lam, Tony K. T.; Gutierrez-Juarez, Roger; Pocai, Alessandro; Rossetti, Luciano

2005-08-01

The brain keenly depends on glucose for energy, and mammalians have redundant systems to control glucose production. An increase in circulating glucose inhibits glucose production in the liver, but this negative feedback is impaired in type 2 diabetes. Here we report that a primary increase in hypothalamic glucose levels lowers blood glucose through inhibition of glucose production in rats. The effect of glucose requires its conversion to lactate followed by stimulation of pyruvate metabolism, which leads to activation of adenosine triphosphate (ATP)-sensitive potassium channels. Thus, interventions designed to enhance the hypothalamic sensing of glucose may improve glucose homeostasis in diabetes.

Jejunal administration of glucose enhances acyl ghrelin suppression in obese humans

PubMed Central

Sidani, Reem M.; Garcia, Anna E.; Antoun, Joseph; Isbell, James M.; Abumrad, Naji N.

2016-01-01

Ghrelin is a gastric hormone that stimulates hunger and worsens glucose metabolism. Circulating ghrelin is decreased after Roux-en-Y gastric bypass (RYGB) surgery; however, the mechanism(s) underlying this change is unknown. We tested the hypothesis that jejunal nutrient exposure plays a significant role in ghrelin suppression after RYGB. Feeding tubes were placed in the stomach or jejunum in 13 obese subjects to simulate pre-RYGB or post-RYGB glucose exposure to the gastrointestinal (GI) tract, respectively, without the confounding effects of caloric restriction, weight loss, and surgical stress. On separate study days, the plasma glucose curves obtained with either gastric or jejunal administration of glucose were replicated with intravenous (iv) infusions of glucose. These “isoglycemic clamps” enabled us to determine the contribution of the GI tract and postabsorptive plasma glucose to acyl ghrelin suppression. Plasma acyl ghrelin levels were suppressed to a greater degree with jejunal glucose administration compared with gastric glucose administration (P < 0.05). Jejunal administration of glucose also resulted in a greater suppression of acyl ghrelin than the corresponding isoglycemic glucose infusion (P ≤ 0.01). However, gastric and isoglycemic iv glucose infusions resulted in similar degrees of acyl ghrelin suppression (P > 0.05). Direct exposure of the proximal jejunum to glucose increases acyl ghrelin suppression independent of circulating glucose levels. The enhanced suppression of acyl ghrelin after RYGB may be due to a nutrient-initiated signal in the jejunum that regulates ghrelin secretion. PMID:27279247

Circulating miR-192 and miR-193b are markers of prediabetes and are modulated by an exercise intervention.

PubMed

Párrizas, Marcelina; Brugnara, Laura; Esteban, Yaiza; González-Franquesa, Alba; Canivell, Sílvia; Murillo, Serafín; Gordillo-Bastidas, Elizabeth; Cussó, Roser; Cadefau, Joan A; García-Roves, Pablo M; Servitja, Joan-Marc; Novials, Anna

2015-03-01

Diabetes is frequently diagnosed late, when the development of complications is almost inevitable, decreasing the quality of life of patients. However, early detection of affected individuals would allow the implementation of timely and effective therapies. Here we set to describe the profile of circulating microRNAs (miRNAs) in prediabetic patients with the intention of identifying novel diagnostic and therapeutic tools. We used real-time RT-PCR to measure the abundance of 176 miRNAs in serum of a cohort of 92 control and prediabetic individuals with either impaired fasting glucose or impaired glucose tolerance, as well as newly diagnosed diabetic patients. We validated the results in a second cohort of control and prediabetic subjects undergoing a therapeutic exercise intervention, as well as in a mouse model of glucose intolerance. We identified two miRNAs, miR-192 and miR-193b, whose abundance is significantly increased in the prediabetic state but not in diabetic patients. Strikingly, these miRNAs are also increased in plasma of glucose-intolerant mice. Moreover, circulating levels of miR-192 and miR-193b return to baseline in both prediabetic humans and glucose-intolerant mice undergoing a therapeutic intervention consisting in chronic exercise, which succeeded in normalizing metabolic parameters. Our data show that the pattern of circulating miRNAs is modified by defects in glucose metabolism in a similar manner in mice and humans. This circulating miRNA signature for prediabetes could be used as a new diagnostic tool, as well as to monitor response to intervention.

Joint Analysis of Individual Participants’ Data from 17 Studies on the Association of the IL6 Variant -174G>C with Circulating Glucose Levels, Interleukin-6 Levels, and Body-Mass Index

PubMed Central

Huth, Cornelia; Illig, Thomas; Herder, Christian; Gieger, Christian; Grallert, Harald; Vollmert, Caren; Rathmann, Wolfgang; Hamid, Yasmin H.; Pedersen, Oluf; Hansen, Torben; Thorand, Barbara; Meisinger, Christa; Döring, Angela; Klopp, Norman; Gohlke, Henning; Lieb, Wolfgang; Hengstenberg, Christian; Lyssenko, Valeriya; Groop, Leif; Ireland, Helen; Stephens, Jeffrey W.; Asterholm, Ingrid Wernstedt; Jansson, John-Olov; Boeing, Heiner; Möhlig, Matthias; Stringham, Heather M.; Boehnke, Michael; Tuomilehto, Jaakko; Fernandez-Real, Jose-Manuel; Lopez-Bermejo, Abel; Gallart, Luis; Vendrell, Joan; Humphries, Steve E.; Kronenberg, Florian; Wichmann, H.-Erich; Heid, Iris M.

2013-01-01

Background Several studies have investigated associations between the -174G>C polymorphism (rs1800795) of the IL6-gene, but presented inconsistent results. Aims This joint analysis aimed to clarify whether IL6 -174G>C was associated with type 2 diabetes mellitus (T2DM) related quantitative phenotypes. Methods Individual-level data from all studies of the IL6-T2DM consortium on Caucasian subjects with available BMI were collected. As study-specific estimates did not show heterogeneity (P>0.1), they were combined by using the inverse-variance fixed-effect model. Results The main analysis included 9440, 7398, 24,117, or 5659 nondiabetic and manifest T2DM subjects for fasting glucose, 2-hour glucose, BMI or circulating interleukin-6 levels, respectively. IL6 -174 C-allele carriers had significantly lower fasting glucose (−0.091mmol/L, P=0.014). There was no evidence for association between IL6 -174G>C and BMI or interleukin-6. In an additional analysis of 641 subjects known to develop T2DM later on, the IL6 -174 CC-genotype was associated with higher baseline interleukin-6 (+0.75pg/mL, P=0.004), which was consistent with higher interleukin-6 in the 966 manifest T2DM subjects (+0.50pg/mL, P=0.044). Conclusions Our data suggest association between IL6 -174G>C and quantitative glucose, and exploratory analysis indicated modulated interleukin-6 levels in pre-diabetic subjects, being in-line with this SNP’s previously reported T2DM association and a role of circulating interleukin-6 as intermediate phenotype. PMID:18752089

Circulating Irisin Levels Are Not Regulated by Nutritional Status, Obesity, or Leptin Levels in Rodents.

PubMed

Quiñones, Mar; Folgueira, Cintia; Sánchez-Rebordelo, Estrella; Al-Massadi, Omar

2015-01-01

Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5) that is mainly released by skeletal muscle and was proposed to mediate the beneficial effects of exercise on metabolism. In the present study we aim to investigate the regulation of the circulating levels of irisin in obese animal models (diet-induced obese (DIO) rats and leptin-deficient (ob/ob) mice), as well as the influence of nutritional status and leptin. Irisin levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA) and Radioimmunoassay (RIA). Serum irisin levels remained unaltered in DIO rats and ob/ob mice. Moreover, its circulating levels were also unaffected by fasting, leptin deficiency, and exogenous leptin administration in rodents. In spite of these negative results we find a negative correlation between irisin and insulin in DIO animals and a positive correlation between irisin and glucose under short-term changes in nutritional status. Our findings indicate that serum irisin levels are not modulated by different physiological settings associated to alterations in energy homeostasis. These results suggest that in rodents circulating levels of irisin are not involved in the pathophysiology of obesity and could be unrelated to metabolic status; however, further studies should clarify its precise role in states of glucose homeostasis imbalance.

Blood glucose may condition factor VII levels in diabetic and normal subjects.

PubMed

Ceriello, A; Giugliano, D; Quatraro, A; Dello Russo, P; Torella, R

1988-12-01

Increased factor VII levels have been reported in Type 1 (insulin-dependent) diabetic subjects. A direct correlation between fasting plasma glucose and factor VII level was found to exist in both diabetic and normal subjects. Induced-hyperglycaemia was able to increase factor VII levels in both diabetic patients and normal control subjects while, when euglycaemia was achieved in diabetic patients, factor VII values returned to normal range. This study shows that the level of factor VII may be directly conditioned by circulating blood glucose and, therefore, stresses the role of hyperglycaemia in conditioning coagulation abnormalities in diabetes mellitus.

Somatostatin-14 modulates postprandial glucose levels and release of gastrointestinal and pancreatic hormones.

PubMed

O'Shaughnessy, D J; Long, R G; Adrian, T E; Christofides, N D; Ghatei, M A; Sarson, D L; Bloom, S R

1985-01-01

Ingestion of a 4,500-kcal mixed meal by healthy volunteers resulted in a significant rise of plasma somatostatin-14-like immunoreactivity (9 +/- 1 pmol l-1. Whether this peptide has a role as a humoral agent or not is still controversial and, until recently, most studies investigating its effects by exogenous administration have produced vastly supraphysiological circulating plasma levels. In order to reproduce the rise obtained following the large meal, synthetic somatostatin-14 was infused at a dose of 0.8 pmol kg-1 min-1 before and during a 530-kcal test breakfast. This resulted in a rise of 8 + 2 pmol l-1 in the peripheral circulation. This infusion produced a significant reduction in the postprandial release of insulin, gastric inhibitory polypeptide, pancreatic polypeptide and in the preprandial motilin levels. In contrast, blood glucose levels following the breakfast were elevated when compared to the control saline infusion. This suggests that somatostatin possesses true endocrine functions and is capable of profoundly altering the postprandial glucose and hormone response.

Effects of glucose ingestion on circulating inflammatory mediators: Influence of sex and weight excess.

PubMed

Escobar-Morreale, Héctor F; Martínez-García, M Ángeles; Montes-Nieto, Rafael; Fernández-Durán, Elena; Temprano-Carazo, Sara; Luque-Ramírez, Manuel

2017-04-01

Low-grade chronic inflammation is involved in the pathophysiology of obesity. However, little is known about the influence of sex and sex hormones on surrogate inflammatory markers and mediators, particularly after glucose ingestion. Observational study. We measured the circulating concentrations of interleukin-6, interleukin-18, macrophage migration inhibitory factor, matrix metallopeptidase-9, monocyte chemotactic protein-1 and pentraxin-3, in the fasting state and during a 75 g oral glucose tolerance test, in 24 women and 25 men. Eleven men and 11 women were lean whereas 14 men and 13 women had weight excess. Anti-inflammatory cytokines (interleukin-6 and interleukin-18) were increased in the fasting state and/or decreased in some women during the oral glucose tolerance test, as opposed to inflammatory mediators such as macrophage migration inhibitory factor and matrix metallopeptidase-9 that increased during the oral glucose tolerance test especially in subjects with weight excess. Body mass index and waist circumference were the main determinants of these changes. Fasting pentraxin-3 levels were especially increased in lean women in parallel to a decrease in free testosterone levels, and decreased during the oral glucose tolerance test as opposed to the increase in insulin concentrations. The circulating concentrations of markers of low-grade chronic inflammation in young healthy adults are not only influenced by obesity but also by abdominal adiposity, fasting and glucose ingestion and, in some cases, by sex and sex hormones. These influences should be considered when these markers are used as surrogate markers of the inflammatory milieu associated with obesity. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Induction of the 72 kDa heat shock protein by glucose ingestion in black pregnant women.

PubMed

Jaffe, Shirlee; Doulaveris, Georgios; Orfanelli, Theofano; Arantes, Mariana; Damasceno, Débora; Calderon, Iracema; Rudge, Marilza V C; Witkin, Steven S

2013-07-01

Obese Black women are at increased risk for development of gestational diabetes mellitus and have worse perinatal outcomes than do obese women of other ethnicities. Since hsp72 has been associated with the regulation of obesity-induced insulin resistance, we evaluated associations between glucose ingestion, hsp72 release and insulin production in Black pregnant women. Specifically, the effect of a 50-g glucose challenge test (GCT) on heat shock protein and insulin levels in the circulation 1 h later was evaluated. Hsp27 and hsp60 levels remained unchanged. In contrast, serum levels of hsp72 markedly increased after glucose ingestion (p = 0.0054). Further analysis revealed that this increase was limited to women who were not obese (body mass index <30). Insulin levels pre-GCT were positively correlated with body mass index (p = 0.0189). Median insulin concentrations also increased post GCT in non-obese women but remained almost unchanged in obese women. Post-GCT serum hsp72 concentrations were inversely correlated with post GCT insulin concentrations (p = 0.0111). These observations suggest that glucose intake during gestation in Black women rapidly leads to an elevation in circulating hsp72 only in non-obese Black women. The release of hsp72 may regulate the extent of insulin production in response to a glucose challenge and, thereby, protect the mother and/or fetus from development of hyperglycemia, hyperinsulinemia, and/or immune system alterations.

Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels.

PubMed

Herman, Mark A; She, Pengxiang; Peroni, Odile D; Lynch, Christopher J; Kahn, Barbara B

2010-04-09

Whereas the role of adipose tissue in glucose and lipid homeostasis is widely recognized, its role in systemic protein and amino acid metabolism is less well-appreciated. In vitro and ex vivo experiments suggest that adipose tissue can metabolize substantial amounts of branched chain amino acids (BCAAs). However, the role of adipose tissue in regulating BCAA metabolism in vivo is controversial. Interest in the contribution of adipose tissue to BCAA metabolism has been renewed with recent observations demonstrating down-regulation of BCAA oxidation enzymes in adipose tissue in obese and insulin-resistant humans. Using gene set enrichment analysis, we observe alterations in adipose-tissue BCAA enzyme expression caused by adipose-selective genetic alterations in the GLUT4 glucose-transporter expression. We show that the rate of adipose tissue BCAA oxidation per mg of tissue from normal mice is higher than in skeletal muscle. In mice overexpressing GLUT4 specifically in adipose tissue, we observe coordinate down-regulation of BCAA metabolizing enzymes selectively in adipose tissue. This decreases BCAA oxidation rates in adipose tissue, but not in muscle, in association with increased circulating BCAA levels. To confirm the capacity of adipose tissue to modulate circulating BCAA levels in vivo, we demonstrate that transplantation of normal adipose tissue into mice that are globally defective in peripheral BCAA metabolism reduces circulating BCAA levels by 30% (fasting)-50% (fed state). These results demonstrate for the first time the capacity of adipose tissue to catabolize circulating BCAAs in vivo and that coordinate regulation of adipose-tissue BCAA enzymes may modulate circulating BCAA levels.

Different responses of circulating ghrelin, obestatin levels to fasting, re-feeding and different food compositions, and their local expressions in rats.

PubMed

Guo, Zhi-Fu; Ren, An-Jing; Zheng, Xing; Qin, Yong-Wen; Cheng, Fang; Zhang, Jing; Wu, Hong; Yuan, Wen-Jun; Zou, Lin

2008-07-01

Obestatin, a sibling of ghrelin derived from preproghrelin, opposes several physiological actions of ghrelin. Our previous study has demonstrated that both plasma ghrelin and obestatin levels were decreased significantly 2h after food intake in human. To further expand current knowledge, we investigated the temporal profiles of their levels in ad libitum fed rats, 48h fasted rats and 48h fasted rats refed 2h with a standard chow, crude fiber, 50% glucose or water, and their expressions in stomach, liver and pancreatic islets immunohistochemically. Plasma ghrelin and obestatin levels were measured by EIA. Plasma leptin, insulin and glucose levels were also evaluated. Both plasma ghrelin and obestatin levels increased significantly in fasted rats compared with ad libitum fed rats. The ingestion of standard chow produced a profound and sustained suppression of ghrelin levels, whereas plasma obestatin levels decreased significantly but recovered quickly. Intake of crude fiber or 50% glucose, however, produced a more profound and sustained suppression of obestatin levels, though they had relatively less impact on ghrelin levels. Plasma glucose was the only independent predictor of ghrelin levels, obestatin levels, and ghrelin to obestatin ratios. Obestatin immunoreactivity was detected in the fundus of stomach, liver and pancreatic islets, with roughly similar patterns of distribution to ghrelin. These data show quantitative and qualitative differences in circulating ghrelin and obestatin responses to the short-term feeding status and nutrient composition, and may support a role for obestatin in regulating metabolism and energy homeostasis.

Differential Responses of Plasma Adropin Concentrations To Dietary Glucose or Fructose Consumption In Humans.

PubMed

Butler, Andrew A; St-Onge, Marie-Pierre; Siebert, Emily A; Medici, Valentina; Stanhope, Kimber L; Havel, Peter J

2015-10-05

Adropin is a peptide hormone encoded by the Energy Homeostasis Associated (ENHO) gene whose physiological role in humans remains incompletely defined. Here we investigated the impact of dietary interventions that affect systemic glucose and lipid metabolism on plasma adropin concentrations in humans. Consumption of glucose or fructose as 25% of daily energy requirements (E) differentially affected plasma adropin concentrations (P < 0.005) irrespective of duration, sex or age. Glucose consumption reduced plasma adropin from 3.55 ± 0.26 to 3.28 ± 0.23 ng/ml (N = 42). Fructose consumption increased plasma adropin from 3.63 ± 0.29 to 3.93 ± 0.34 ng/ml (N = 45). Consumption of high fructose corn syrup (HFCS) as 25% E had no effect (3.43 ± 0.32 versus 3.39 ± 0.24 ng/ml, N = 26). Overall, the effect of glucose, HFCS and fructose on circulating adropin concentrations were similar to those observed on postprandial plasma triglyceride concentrations. Furthermore, increases in plasma adropin levels with fructose intake were most robust in individuals exhibiting hypertriglyceridemia. Individuals with low plasma adropin concentrations also exhibited rapid increases in plasma levels following consumption of breakfasts supplemented with lipids. These are the first results linking plasma adropin levels with dietary sugar intake in humans, with the impact of fructose consumption linked to systemic triglyceride metabolism. In addition, dietary fat intake may also increase circulating adropin concentrations.

Circulating metabolite predictors of glycemia in middle-aged men and women.

PubMed

Würtz, Peter; Tiainen, Mika; Mäkinen, Ville-Petteri; Kangas, Antti J; Soininen, Pasi; Saltevo, Juha; Keinänen-Kiukaanniemi, Sirkka; Mäntyselkä, Pekka; Lehtimäki, Terho; Laakso, Markku; Jula, Antti; Kähönen, Mika; Vanhala, Mauno; Ala-Korpela, Mika

2012-08-01

Metabolite predictors of deteriorating glucose tolerance may elucidate the pathogenesis of type 2 diabetes. We investigated associations of circulating metabolites from high-throughput profiling with fasting and postload glycemia cross-sectionally and prospectively on the population level. Oral glucose tolerance was assessed in two Finnish, population-based studies consisting of 1,873 individuals (mean age 52 years, 58% women) and reexamined after 6.5 years for 618 individuals in one of the cohorts. Metabolites were quantified by nuclear magnetic resonance spectroscopy from fasting serum samples. Associations were studied by linear regression models adjusted for established risk factors. Nineteen circulating metabolites, including amino acids, gluconeogenic substrates, and fatty acid measures, were cross-sectionally associated with fasting and/or postload glucose (P < 0.001). Among these metabolic intermediates, branched-chain amino acids, phenylalanine, and α1-acid glycoprotein were predictors of both fasting and 2-h glucose at 6.5-year follow-up (P < 0.05), whereas alanine, lactate, pyruvate, and tyrosine were uniquely associated with 6.5-year postload glucose (P = 0.003-0.04). None of the fatty acid measures were prospectively associated with glycemia. Changes in fatty acid concentrations were associated with changes in fasting and postload glycemia during follow-up; however, changes in branched-chain amino acids did not follow glucose dynamics, and gluconeogenic substrates only paralleled changes in fasting glucose. Alterations in branched-chain and aromatic amino acid metabolism precede hyperglycemia in the general population. Further, alanine, lactate, and pyruvate were predictive of postchallenge glucose exclusively. These gluconeogenic precursors are potential markers of long-term impaired insulin sensitivity that may relate to attenuated glucose tolerance later in life.

27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation

PubMed Central

Mateos, Laura; Maioli, Silvia; Ali, Zeina; Gulyás, Balázs; Winblad, Bengt; Savitcheva, Irina

2017-01-01

Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced 18F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)–mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders. PMID:28213512

Plasma ANGPTL-4 is Associated with Obesity and Glucose Tolerance: Cross-Sectional and Longitudinal Findings.

PubMed

Barja-Fernandez, Silvia; Moreno-Navarrete, José María; Folgueira, Cintia; Xifra, Gemma; Sabater, Mònica; Castelao, Cecilia; FernØ, Johan; Leis, Rosaura; Diéguez, Carlos; Casanueva, Felipe F; Ricart, Wifredo; Seoane, Luisa M; Fernandez-Real, José Manuel; Nogueiras, Rubén

2018-05-01

Angiopoietin-like protein 4 (ANGPTL-4) regulates plasma lipoprotein levels, but its relevance in human obesity and type 2 diabetes (T2D) is largely unknown. We aim to investigate the regulation of circulating ANGPTL-4 levels in obesity, T2D, and after changes in body weight. Circulating ANGPTL-4 levels were measured in two different cohorts. First, in a cross-sectional study, we evaluated ANGPTL-4 levels in lean and obese patients with normoglycemia or with altered glucose tolerance (AGT; n = 282). Second, in a longitudinal intervention study, 51 obese participants were evaluated. A hypocaloric diet was prescribed, with follow-up 2 years later. ANGPTL-4 levels were significantly increased in obese patients with AGT compared to lean participants. Moreover, ANGPTL-4 was positively correlated with BMI, waist circumference, fat mass, HbA1c, HOMA-IR, fasting triglycerides, and with inflammatory markers. Participants gaining weight after the follow-up showed increased ANGPTL-4 levels in parallel to increased BMI, fat mass, and fasting glucose, while ANGPTL-4 levels were reduced in participants losing weight. Our data support a relevant role of ANGPTL-4 in human obesity and its involvement in long-term body weight changes. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gestational glucocorticoid exposure disrupts glucose homeostasis that is accompanied by increased endoglin and DPP-4 activity instead of GSK-3 in rats.

PubMed

Badmus, Olufunto O; Michael, Olugbenga S; Rabiu, Saheed; Olatunji, Lawrence A

2018-04-13

Gestational glucocorticoid (GC) treatment has been associated with cardiometabolic disorder (CMD) in offspring's in later life. Elevated dipeptidyl peptidase-4 (DPP-4) activity, endoglin and glycogen synthase kinase-3 (GSK-3) has also been implicated in the development of insulin resistance (IR) and/or vascular inflammation. We aimed to investigate the impact of GC exposure on glucose metabolism and the circulating levels of inflammatory biomarkers, DPP-4 activity and GSK-3 in pregnant rats. Pregnant Wistar rats received either vehicle or dexamethasone (DEX; 0.2 mg/kg; po) between gestational days 14 and 19. Gestational GC exposure resulted in impaired glucose homeostasis that is accompanied with elevated circulating levels of inflammatory biomarkers (endoglin, uric acid, and platelet/lymphocyte ratio), oxidative stress (malondialdehyde), blood viscosity, reduced NO level and increased DPP-4 activity. However, these effects were associated with atherogenic dyslipidemia and reduced GSK-3.We conclude that plasma endoglin, a marker of vascular inflammation, and plasma DPP-4 activity are increased in pregnant rats treated with GC during late gestation. Therefore, glucose deregulation associated with gestational GC exposure is through endoglin-/DPP-4-dependent but GSK-3-independent pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes.

PubMed

Yamada, Hodaka; Saito, Tomoyuki; Aoki, Atsushi; Asano, Tomoko; Yoshida, Masashi; Ikoma, Aki; Kusaka, Ikuyo; Toyoshima, Hideo; Kakei, Masafumi; Ishikawa, San-E

2015-01-01

There is evidence that betatrophin, a hormone derived from adipose tissue and liver, affects the proliferation of pancreatic beta cells in mice. The aim of this study was to examine circulating betatrophin concentrations in Japanese healthy controls and patients with type 1 and type 2 diabetes. A total of 76 subjects (12 healthy controls, 34 type 1 diabetes, 30 type 2 diabetes) were enrolled in the study. Circulating betatrophin was measured with an ELISA kit and clinical parameters related to betatrophin were analyzed statistically. Circulating betatrophin (Log transformed) was significantly increased in patients with diabetes compared with healthy subjects (healthy controls, 2.29 ± 0.51; type 1 diabetes, 2.94 ± 0.44; type 2 diabetes, 3.17 ± 0.18; p<0.001, 4.1 to 5.4 times in pg/mL order). Age, HbA1c, fasting plasma glucose and Log triglyceride were strongly associated with Log betatrophin in all subjects (n=76) in correlation analysis. In type 1 diabetes, there was a correlation between Log betatrophin and Log CPR. These results provide the first evidence that circulating betatrophin is significantly elevated in Japanese patients with diabetes. The findings of this pilot study also suggest a possibility of association between the level of betatrophin and the levels of glucose and triglycerides.

Assessment of circulating betatrophin concentrations in lean glucose-tolerant women with polycystic ovary syndrome.

PubMed

Erol, Onur; Özel, Mustafa Kemal; Ellidağ, Hamit Yaşar; Toptaş, Tayfun; Derbent, Aysel Uysal; Yılmaz, Necat

2017-07-01

The aims of the current study were to investigate the betatrophin levels in lean glucose-tolerant women with polycystic ovary syndrome (PCOS), and to explore the relationships between these levels and antropometric, hormonal and metabolic parameters. The study population consisted of 50 lean (body mass index [BMI] < 25 kg/m 2 ) women diagnosed with PCOS using the Rotterdam criteria, and 60 age- and BMI-matched healthy controls without any features of clinical or biochemical hyperandrogenism. Before recruitment, glucose tolerance was evaluated in all of the subjects using the 2-h 75 g oral glucose-tolerance test, and only those exhibiting normal glucose tolerance were enrolled. Serum betatrophin levels were significantly higher in women with PCOS (median 322.3; range 44.7-1989.3 ng/L) compared to the controls (median 199.9; range 6.2-1912.9 ng/L; p = .005). In the control group, no significant correlation was evident between betatrophin levels and clinical or biochemical parameters. In the PCOS group, betatrophin levels were positively correlated with prolactin levels (r = .286, p = .046) and negatively correlated with BMI (r = -.283, p = .049), waist/hip ratio (r = -.324, p = .023), and low-density lipoprotein cholesterol levels (r = -.385, p = .006). Impact statement What is already known on this subject: Several studies have suggested that primary alteration in beta-cell function is a pathophysiological feature of PCOS, and insulin resistance is the most significant predictor of beta-cell dysfunction independent of obesity. Betatrophin is a circulating protein that is primarily expressed in the liver in humans. Early experimental investigations demonstrated that overexpression of betatrophin significantly promoted pancreatic beta-cell proliferation, insulin production and improved glucose tolerance. Few studies have investigated the association between PCOS and betatrophin. However, in contrast to our study, the authors included overweight/obese patients and glucose tolerance was not evaluated before recruitment. What the results of this study add: Our results showed that serum betatrophin levels were significantly higher in lean glucose-tolerant PCOS women than in age- and BMI-matched healthy controls. What are the implications of these findings for clinical practice and/or further research: Elevated betatrophin levels in PCOS women, in the absence of obesity and glucose intolerance, may reflect a compensatory mechanism in order to counteract metabolic syndrome-related risk factors.

Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects: effects of hyperglycemia and hypoglycemia.

PubMed

Abi-Saab, Walid M; Maggs, David G; Jones, Tim; Jacob, Ralph; Srihari, Vinod; Thompson, James; Kerr, David; Leone, Paola; Krystal, John H; Spencer, Dennis D; During, Matthew J; Sherwin, Robert S

2002-03-01

Brain levels of glucose and lactate in the extracellular fluid (ECF), which reflects the environment to which neurons are exposed, have never been studied in humans under conditions of varying glycemia. The authors used intracerebral microdialysis in conscious human subjects undergoing electrophysiologic evaluation for medically intractable epilepsy and measured ECF levels of glucose and lactate under basal conditions and during a hyperglycemia-hypoglycemia clamp study. Only measurements from nonepileptogenic areas were included. Under basal conditions, the authors found the metabolic milieu in the brain to be strikingly different from that in the circulation. In contrast to plasma, lactate levels in brain ECF were threefold higher than glucose. Results from complementary studies in rats were consistent with the human data. During the hyperglycemia-hypoglycemia clamp study the relationship between plasma and brain ECF levels of glucose remained similar, but changes in brain ECF glucose lagged approximately 30 minutes behind changes in plasma. The data demonstrate that the brain is exposed to substantially lower levels of glucose and higher levels of lactate than those in plasma; moreover, the brain appears to be a site of significant anaerobic glycolysis, raising the possibility that glucose-derived lactate is an important fuel for the brain.

Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations

PubMed Central

Chen, Brian H.; Hivert, Marie-France; Peters, Marjolein J.; Pilling, Luke C.; Hogan, John D.; Pham, Lisa M.; Harries, Lorna W.; Fox, Caroline S.; Bandinelli, Stefania; Dehghan, Abbas; Hernandez, Dena G.; Hofman, Albert; Hong, Jaeyoung; Joehanes, Roby; Johnson, Andrew D.; Munson, Peter J.; Rybin, Denis V.; Singleton, Andrew B.; Uitterlinden, André G.; Ying, Saixia; Melzer, David; Levy, Daniel; van Meurs, Joyce B.J.; Ferrucci, Luigi; Florez, Jose C.; Dupuis, Josée

2016-01-01

Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes–imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis. PMID:27625022

Proportional Insulin Infusion in Closed-Loop Control of Blood Glucose

PubMed Central

Grasman, Johan

2017-01-01

A differential equation model is formulated that describes the dynamics of glucose concentration in blood circulation. The model accounts for the intake of food, expenditure of calories and the control of glucose levels by insulin and glucagon. These and other hormones affect the blood glucose level in various ways. In this study only main effects are taken into consideration. Moreover, by making a quasi-steady state approximation the model is reduced to a single nonlinear differential equation of which parameters are fit to data from healthy subjects. Feedback provided by insulin plays a key role in the control of the blood glucose level. Reduced β-cell function and insulin resistance may hamper this process. With the present model it is shown how by closed-loop control these defects, in an organic way, can be compensated with continuous infusion of exogenous insulin. PMID:28060898

Metabolic Evidence of Diminished Lipid Oxidation in Women With Polycystic Ovary Syndrome

PubMed Central

Whigham, Leah D.; Butz, Daniel E.; Dashti, Hesam; Tonelli, Marco; Johnson, LuAnn K.; Cook, Mark E.; Porter, Warren P.; Eghbalnia, Hamid R.; Markley, John L.; Lindheim, Steven R.; Schoeller, Dale A.; Abbott, David H.; Assadi-Porter, Fariba M.

2014-01-01

Polycystic ovary syndrome (PCOS), a common female endocrinopathy, is a complex metabolic syndrome of enhanced weight gain. The goal of this pilot study was to evaluate metabolic differences between normal (n=10) and PCOS (n=10) women via breath carbon isotope ratio, urinary nitrogen and nuclear magnetic resonance (NMR)-determined serum metabolites. Breath carbon stable isotopes measured by cavity ring down spectroscopy (CRDS) indicated diminished (p<0.030) lipid use as a metabolic substrate during overnight fasting in PCOS compared to normal women. Accompanying urinary analyses showed a trending correlation (p<0.057) between overnight total nitrogen and circulating testosterone in PCOS women, alone. Serum analyzed by NMR spectroscopy following overnight, fast and at 2 h following an oral glucose tolerance test showed that a transient elevation in blood glucose levels decreased circulating levels of lipid, glucose and amino acid metabolic intermediates (acetone, 2-oxocaporate, 2-aminobutyrate, pyruvate, formate, and sarcosine) in PCOS women, whereas the 2 h glucose challenge led to increases in the same intermediates in normal women. These pilot data suggest that PCOS-related inflexibility in fasting-related switching between lipid and carbohydrate/protein utilization for carbon metabolism may contribute to enhanced weight gain. PMID:24765590

Pregnancy and pentobarbital anaesthesia modify hepatic synthesis of acylglycerol glycerol and glycogen from gluconeogenic precursors during fasting in rats.

PubMed Central

Zorzano, A; Herrera, E

1988-01-01

1. Incorporation of gluconeogenic precursors into blood glucose and hepatic glycogen and acylglycerol glycerol was examined in 24 h-fasted virgin rats by using a flooding procedure for substrate administration. At 10 min after their intravenous injection, the conversion of alanine or glycerol into liver glycogen or acylglycerol glycerol was proportional to glucose synthesis. 2. In 24 h-fasted 21-day-pregnant rats, the incorporation of alanine and glycerol into hepatic acylglycerol glycerol was markedly enhanced compared with the control group. In addition, during fasting at late pregnancy, the proportion of substrates directed to acylglycerol glycerol as compared with the fraction incorporated into glucose was augmented. 3. In pentobarbital-treated fasted rats, the incorporation of both alanine and pyruvate into circulating glucose and into hepatic glycogen and acylglycerol glycerol was increased. Pentobarbital treatment increased the proportion of substrates incorporated into liver glycogen, compared with the fraction appearing in circulating glucose. These changes were concomitant with a marked accumulation of glycogen. 4. The data indicate that, during fasting, gluconeogenesis provides glucose as well as hepatic glycogen and acylglycerol glycerol, independently of whether the substrates enter gluconeogenesis at the level of pyruvate or dihydroxyacetone phosphate. PMID:3223926

Endocan is a predictor of increased cardiovascular risk in women with polycystic ovary syndrome.

PubMed

Bicer, Merve; Guler, Aslı; Unal Kocabas, Gokcen; Imamoglu, Cetin; Baloglu, Ali; Bilgir, Oktay; Yuksel, Arif; Bozkaya, Giray; Calan, Mehmet

2017-05-01

Endocan is a proteoglycan secreted mainly from endothelial cells. It has been implicated that there is a link between endocan and endothelial dysfunction. Polycystic ovary syndrome (PCOS) is a reproductive and metabolic disease associated with increased risk of cardiovascular events. The aims of this study were to ascertain whether circulating endocan levels are altered in women with PCOS, and whether there is an association between endocan and carotid intima media thickness (cIMT). This cross-sectional study included 80 women with PCOS and 80 age- and BMI-matched controls without PCOS. Circulating endocan levels were measured using ELISA. Metabolic, hormonal parameters and cIMT were determined. 2-h oral glucose tolerance test (2-h OGTT) was performed on all women. Circulating endocan levels were significantly elevated in women with PCOS compared with controls (5.99 ± 2.37 vs. 3.66 ± 1.79 ng/ml, P < 0.001). Endocan levels positively correlated with BMI, homeostasis model assessment of insulin resistance (HOMA-IR), free androgen index (FAI), high-sensitivity C-reactive protein (hs-CRP), and cIMT in both PCOS and control groups. Endocan levels did not correlate with fasting blood glucose, 2-h OGTT, A1 C and lipid parameters. Multiple linear regression analysis revealed that endocan is an independent predictor for cIMT (β = 0.128, 95% CI = 0.118-0.138, P = 0.011). Circulating endocan levels are significantly higher in women with PCOS and endocan is independently associated with cIMT. Elevated endocan levels can be a predictor of increased cardiovascular risk in PCOS subjects.

Hypoglycemia-Induced Changes in the Electroencephalogram

PubMed Central

Blaabjerg, Lykke; Juhl, Claus B.

2016-01-01

Hypoglycemia is defined by an abnormally low blood glucose level. The condition develops when rates of glucose entry into the systematic circulation are reduced relative to the glucose uptake by the tissues. A cardinal manifestation of hypoglycemia arises from inadequate supply of glucose to the brain, where glucose is the primary metabolic fuel. The brain is one of the first organs to be affected by hypoglycemia. Shortage of glucose in the brain, or neuroglycopenia, results in a gradual loss of cognitive functions causing slower reaction time, blurred speech, loss of consciousness, seizures, and ultimately death, as the hypoglycemia progresses. The electrical activity in the brain represents the metabolic state of the brain cells and can be measured by electroencephalography (EEG). An association between hypoglycemia and changes in the EEG has been demonstrated, although blood glucose levels alone do not seem to predict neuroglycopenia. This review provides an overview of the current literature regarding changes in the EEG during episodes of low blood glucose. PMID:27464753

Brain-derived neurotrophic factor in the nucleus tractus solitarii modulates glucose homeostasis after carotid chemoreceptor stimulation in rats.

PubMed

Montero, Sergio; Cuéllar, Ricardo; Lemus, Mónica; Avalos, Reyes; Ramírez, Gladys; de Álvarez-Buylla, Elena Roces

2012-01-01

Neuronal systems, which regulate energy intake, energy expenditure and endogenous glucose production, sense and respond to input from hormonal related signals that convey information from body energy availability. Carotid chemoreceptors (CChr) function as sensors for circulating glucose levels and contribute to glycemic counterregulatory responses. Brain-derived neurotrophic factor (BDNF) that plays an important role in the endocrine system to regulate glucose metabolism could play a role in hyperglycemic glucose reflex with brain glucose retention (BGR) evoked by anoxic CChr stimulation. Infusing BDNF into the nucleus tractus solitarii (NTS) before CChr stimulation, showed that this neurotrophin increased arterial glucose and BGR. In contrast, BDNF receptor (TrkB) antagonist (K252a) infusions in NTS resulted in a decrease in both glucose variables.

Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue

PubMed Central

Youn, Byung-Soo; Bang, Sa-Ik; Klöting, Nora; Park, Ji Woo; Lee, Namseok; Oh, Ji-Eun; Pi, Kyung-Bae; Lee, Tae Hee; Ruschke, Karen; Fasshauer, Mathias; Stumvoll, Michael; Blüher, Matthias

2009-01-01

OBJECTIVE—Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown. RESEARCH DESIGN AND METHODS—For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1–based cell migration assays. RESULTS—Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Gα. Moreover, in type 2 diabetes, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels. CONCLUSIONS—Elevated progranulin serum concentrations are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. We identified progranulin as a novel marker of chronic inflammation in obesity and type 2 diabetes that closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes. PMID:19056610

Circulating Zinc-α2-glycoprotein levels and Insulin Resistance in Polycystic Ovary Syndrome

PubMed Central

Lai, Yerui; Chen, Jinhua; Li, Ling; Yin, Jingxia; He, Junying; Yang, Mengliu; Jia, Yanjun; Liu, Dongfang; Liu, Hua; Liao, Yong; Yang, Gangyi

2016-01-01

The aim of study was to assess the relationship between zinc-α2-glycoprotein (ZAG) and androgen excess with insulin resistance in polycystic ovary syndrome (PCOS) women. 99 PCOS women and 100 healthy controls were recruited. Euglycemic-hyperinsulinemic clamp (EHC) was preformed to assess their insulin sensitivity. Circulating ZAG was determined with an ELISA kit. In healthy subjects, circulating ZAG levels exhibited a characteristic diurnal rhythm in humans, with a major nocturnal rise occurring between midnight and early morning. Circulating ZAG and M-value were much lower in PCOS women than in the controls. In all population, overweight/obese subjects had significantly lower circulating ZAG levels than lean individuals. Multiple linear regression analysis revealed that only M-value and the area under the curve for glucose were independently related factors to circulating ZAG in PCOS women. Multivariate logistic regression analysis showed that circulating ZAG was significantly associated with PCOS even after controlling for anthropometric variables, blood pressure, lipid profile and hormone levels. The PCOS women with high ZAG had fewer MetS, IGT and polycystic ovaries as compared with the low ZAG PCOS women. Taken together, circulating ZAG levels are reduced in women with PCOS and ZAG may be a cytokine associated with insulin resistance in PCOS women. PMID:27180914

Omentin, an adipokine with insulin-sensitizing properties, is negatively associated with insulin resistance in normal gestation.

PubMed

Brandt, Benny; Mazaki-Tovi, Shali; Hemi, Rina; Yinon, Yoav; Schiff, Eyal; Mashiach, Roy; Kanety, Hannah; Sivan, Eyal

2015-05-01

Omentin, a newly identified adipokine, enhances insulin mediated glucose uptake in human adipocytes, thus, inducing systemic insulin-sensitizing effect. The aims of this study were to determine whether circulating maternal omentin levels are associated with insulin resistance indices and to assess which compartment, maternal, fetal, or placental, is the source of omentin in maternal circulation. Fasting serum glucose, insulin, and omentin were determined in 25 healthy pregnant women at the third trimester, before and 3 days after elective cesarean section. Cord blood omentin was measured in the 25 term neonates. Homeostasis model assessment (HOMA) was used to evaluate insulin sensitivity before and after delivery. Antepartum maternal omentin levels were negatively correlated with insulin levels (r=-0.41, P=0.04) and positively correlated with insulin sensitivity (HOMA%S; r=0.4, P=0.04). Postpartum omentin levels were negatively correlated with maternal body mass index (r=-0.44, P=0.02). Median maternal omentin levels was comparable before and after delivery (57.2, inter-quartile range: 38.2-76.2 ng/mL vs. 53.4, 39.8-69.4 ng/mL, respectively, P=0.25) and highly correlated (r=0.83, P<0.001). Antepartum maternal and neonatal omentin levels did not differ significantly (fetal: 62.2, 44.3-74.2 ng/mL, P=0.77) and did not correlate (P=0.6). Circulating maternal omentin levels are correlated with insulin resistance indices, suggesting that this adipokine may play a role in metabolic adaptations of normal gestation. The strong correlation between anteparum and postpartum maternal omentin levels, as well as the lack of association between maternal and neonatal omentin levels, suggest that placental or fetal compartments are unlikely as the main source of circulating maternal omentin.

An increase level of acylation stimulating protein is correlated with metabolic risk markers in North Indian obese women.

PubMed

Mishra, Supriya; Gupta, Vani; Mishra, Sameeksha; Gupta, Vandana; Mahdi, Abbas Ali; Sachan, Rekha

2017-12-01

The present study was to investigate the association between serum acylation stimulating protein (ASP) level with metabolic risk factors in North Indian obese women. This is a case control study, total n=322 women aged between 20 and 45 years (n=162 with metabolic syndrome & n=160 without metabolic syndrome) were recruited for the study according to National Cholesterol Education Program Treatment Panel (NCEPATP) guidelines. Serum ASP level were determined by enzyme linked immunosorbent assay. Results indicated that circulating ASP and other metabolic risk factors (waist circumference, triglycerides, fasting plasma glucose etc) were significantly higher in women with metabolic syndrome (WmetS) than in women without syndrome (WometS) (p<0.001). Furthermore circulating ASP was significantly higher possitively correlated with waist circumference (r=0.51, p<0.001), triglyceride (r=0.56, p<0.001), glucose (r=0.70, p<0.001), and negatively correlated with high density lipoprotein(r=-0.56, p<0.001) in women with metabolic syndrome. Conclusively circulating ASP was found to be significantly associated with hyperlipidemia, obesity and obesity related disorders in North Indian obese women. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Reduced circulating stem cells associate with excess fasting and post-load NEFA exposure in healthy adults with normal glucose tolerance.

PubMed

Fadini, Gian Paolo; Tura, Andrea; Pacini, Giovanni; Avogaro, Angelo; Vigili de Kreutzenberg, Saula

2017-06-01

Reduced levels of circulating stem cells (CSCs) predict cardiovascular events and death, but the factors underlying variability of CSCs in healthy adults are mostly unknown. Previous studies detected associations of CSCs with glucose tolerance or insulin resistance, while the role of fatty acids has been overlooked. We herein aimed to describe in better detail the metabolic abnormalities associated with a reduced CSC level. This was a cross-sectional study on 94 healthy male and female individuals with normal glucose tolerance, aged 18-65 years. All participants underwent an oral glucose tolerance test (OGTT) with blood samples collected at 0, 10, 20, 30, 60, 90 and 120 min. Mathematical models were applied to plasma glucose, insulin, C-peptide and non-esterified fatty acids (NEFA) concentrations. CSCs were defined as CD34 + or CD133 + . Participants (mean ± SEM age 43.8 ± 0.7; 41% males) were divided according to CSC levels below (low) or above (high) the median value and metabolic parameters were compared. There was no significant baseline difference between groups except for higher concentrations of fasting NEFA in subjects with low CSCs. Upon OGTT, individuals with low CSCs had higher area under curve (AUC) of NEFA (p < 0.001) and no significant differences in glucose, insulin and C-peptide. Several insulin sensitivity and beta cell function indexes were not significantly different, except for a decrease in the disposition index (DI) in subjects with low CSCs. CSCs were associated with excess NEFA levels independently from age and DI. We show for the first time that, in healthy adults with normal glucose tolerance, low CSCs are strongly associated with excess NEFA exposure. The pathophysiological consequence of this association needs to be interpreted in view of the prognostic role of CSCs. Future studies should explore whether excess NEFA and low CSCs and are causally interconnected. Copyright © 2017 Elsevier B.V. All rights reserved.

EJE PRIZE 2018: A gut feeling about glucagon.

PubMed

Knop, Filip K

2018-06-01

Hyperglucagonaemia (in the fasting as well as in the postprandial state) is considered a core pathophysiological component of diabetes and is found to contribute substantially to the hyperglycaemic state of diabetes. Hyperglucagonaemia is usually viewed upon as a consequence of pancreatic alpha cell insensitivity to the glucagon-suppressive effects of glucose and insulin. Since we observed that the well-known hyperglucagonaemic response to oral glucose in patients with type 2 diabetes is exchanged by normal suppression of plasma glucagon levels following isoglycaemic intravenous glucose administration in these patients, we have been focusing on the gut and gut-derived factors as potential mediators of diabetic hyperglucagonaemia. In a series of clinical experiments, we have elucidated the role of gut-derived factors in diabetic hyperglucagonaemia and shown that glucose-dependent insulinotropic polypeptide promotes hyperglucagonaemia and that glucagon, hitherto considered a pancreas-specific hormone, may also be secreted from extrapancreatic tissues - most likely from proglucagon-producing enteroendocrine cells. Furthermore, our observation that fasting hyperglucagonaemia is unrelated to the diabetic state, but strongly correlates with obesity, liver fat content and circulating amino acids, has made us question the common 'pancreacentric' and 'glucocentric' understanding of hyperglucagonaemia and led to the hypothesis that steatosis-induced hepatic glucagon resistance (and reduced amino acid turnover) and compensatory glucagon secretion mediated by increased circulating amino acids constitute a complete endocrine feedback system: the liver-alpha cell axis. This article summarises the physiological regulation of glucagon secretion in humans and considers new findings suggesting that the liver and the gut play key roles in determining fasting and postabsorptive circulating glucagon levels. © 2018 European Society of Endocrinology.

Progesterone receptor knockout mice have an improved glucose homeostasis secondary to -cell proliferation

NASA Astrophysics Data System (ADS)

Picard, Frédéric; Wanatabe, Mitsuhiro; Schoonjans, Kristina; Lydon, John; O'Malley, Bert W.; Auwerx, Johan

2002-11-01

Gestational diabetes coincides with elevated circulating progesterone levels. We show that progesterone accelerates the progression of diabetes in female db/db mice. In contrast, RU486, an antagonist of the progesterone receptor (PR), reduces blood glucose levels in both female WT and db/db mice. Furthermore, female, but not male, PR-/- mice had lower fasting glycemia than PR+/+ mice and showed higher insulin levels on glucose injection. Pancreatic islets from female PR-/- mice were larger and secreted more insulin consequent to an increase in -cell mass due to an increase in -cell proliferation. These findings demonstrate an important role of progesterone signaling in insulin release and pancreatic function and suggest that it affects the susceptibility to diabetes.

Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations.

PubMed

Chen, Brian H; Hivert, Marie-France; Peters, Marjolein J; Pilling, Luke C; Hogan, John D; Pham, Lisa M; Harries, Lorna W; Fox, Caroline S; Bandinelli, Stefania; Dehghan, Abbas; Hernandez, Dena G; Hofman, Albert; Hong, Jaeyoung; Joehanes, Roby; Johnson, Andrew D; Munson, Peter J; Rybin, Denis V; Singleton, Andrew B; Uitterlinden, André G; Ying, Saixia; Melzer, David; Levy, Daniel; van Meurs, Joyce B J; Ferrucci, Luigi; Florez, Jose C; Dupuis, Josée; Meigs, James B; Kolaczyk, Eric D

2016-12-01

Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis. © 2016 by the American Diabetes Association.

Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery.

PubMed

Wu, Q; Li, J V; Seyfried, F; le Roux, C W; Ashrafian, H; Athanasiou, T; Fenske, W; Darzi, A; Nicholson, J K; Holmes, E; Gooderham, N J

2015-07-01

Bariatric surgery offers sustained marked weight loss and often remission of type 2 diabetes, yet the mechanisms of establishment of these health benefits are not clear. We mapped the coordinated systemic responses of gut hormones, the circulating miRNAome and the metabolome in a rat model of Roux-en-Y gastric bypass (RYGB) surgery. The response of circulating microRNAs (miRNAs) to RYGB was striking and selective. Analysis of 14 significantly altered circulating miRNAs within a pathway context was suggestive of modulation of signaling pathways including G protein signaling, neurodegeneration, inflammation, and growth and apoptosis responses. Concomitant alterations in the metabolome indicated increased glucose transport, accelerated glycolysis and inhibited gluconeogenesis in the liver. Of particular significance, we show significantly decreased circulating miRNA-122 levels and a more modest decline in hepatic levels, following surgery. In mechanistic studies, manipulation of miRNA-122 levels in a cell model induced changes in the activity of key enzymes involved in hepatic energy metabolism, glucose transport, glycolysis, tricarboxylic acid cycle, pentose phosphate shunt, fatty-acid oxidation and gluconeogenesis, consistent with the findings of the in vivo surgery-mediated responses, indicating the powerful homeostatic activity of the miRNAs. The close association between energy metabolism, neuronal signaling and gut microbial metabolites derived from the circulating miRNA, plasma, urine and liver metabolite and gut hormone correlations further supports an enhanced gut-brain signaling, which we suggest is hormonally mediated by both traditional gut hormones and miRNAs. This transomic approach to map the crosstalk between the circulating miRNAome and metabolome offers opportunities to understand complex systems biology within a disease and interventional treatment setting.

Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery

PubMed Central

Wu, Q; Li, J V; Seyfried, F; le Roux, C W; Ashrafian, H; Athanasiou, T; Fenske, W; Darzi, A; Nicholson, J K; Holmes, E; Gooderham, N J

2015-01-01

Background/Objectives: Bariatric surgery offers sustained marked weight loss and often remission of type 2 diabetes, yet the mechanisms of establishment of these health benefits are not clear. Subjects/Methods: We mapped the coordinated systemic responses of gut hormones, the circulating miRNAome and the metabolome in a rat model of Roux-en-Y gastric bypass (RYGB) surgery. Results: The response of circulating microRNAs (miRNAs) to RYGB was striking and selective. Analysis of 14 significantly altered circulating miRNAs within a pathway context was suggestive of modulation of signaling pathways including G protein signaling, neurodegeneration, inflammation, and growth and apoptosis responses. Concomitant alterations in the metabolome indicated increased glucose transport, accelerated glycolysis and inhibited gluconeogenesis in the liver. Of particular significance, we show significantly decreased circulating miRNA-122 levels and a more modest decline in hepatic levels, following surgery. In mechanistic studies, manipulation of miRNA-122 levels in a cell model induced changes in the activity of key enzymes involved in hepatic energy metabolism, glucose transport, glycolysis, tricarboxylic acid cycle, pentose phosphate shunt, fatty-acid oxidation and gluconeogenesis, consistent with the findings of the in vivo surgery-mediated responses, indicating the powerful homeostatic activity of the miRNAs. Conclusions: The close association between energy metabolism, neuronal signaling and gut microbial metabolites derived from the circulating miRNA, plasma, urine and liver metabolite and gut hormone correlations further supports an enhanced gut-brain signaling, which we suggest is hormonally mediated by both traditional gut hormones and miRNAs. This transomic approach to map the crosstalk between the circulating miRNAome and metabolome offers opportunities to understand complex systems biology within a disease and interventional treatment setting. PMID:25783038

Differential Responses of Plasma Adropin Concentrations To Dietary Glucose or Fructose Consumption In Humans

PubMed Central

Butler, Andrew A.; St-Onge, Marie-Pierre; Siebert, Emily A.; Medici, Valentina; Stanhope, Kimber L.; Havel, Peter J.

2015-01-01

Adropin is a peptide hormone encoded by the Energy Homeostasis Associated (ENHO) gene whose physiological role in humans remains incompletely defined. Here we investigated the impact of dietary interventions that affect systemic glucose and lipid metabolism on plasma adropin concentrations in humans. Consumption of glucose or fructose as 25% of daily energy requirements (E) differentially affected plasma adropin concentrations (P < 0.005) irrespective of duration, sex or age. Glucose consumption reduced plasma adropin from 3.55 ± 0.26 to 3.28 ± 0.23 ng/ml (N = 42). Fructose consumption increased plasma adropin from 3.63 ± 0.29 to 3.93 ± 0.34 ng/ml (N = 45). Consumption of high fructose corn syrup (HFCS) as 25% E had no effect (3.43 ± 0.32 versus 3.39 ± 0.24 ng/ml, N = 26). Overall, the effect of glucose, HFCS and fructose on circulating adropin concentrations were similar to those observed on postprandial plasma triglyceride concentrations. Furthermore, increases in plasma adropin levels with fructose intake were most robust in individuals exhibiting hypertriglyceridemia. Individuals with low plasma adropin concentrations also exhibited rapid increases in plasma levels following consumption of breakfasts supplemented with lipids. These are the first results linking plasma adropin levels with dietary sugar intake in humans, with the impact of fructose consumption linked to systemic triglyceride metabolism. In addition, dietary fat intake may also increase circulating adropin concentrations. PMID:26435060

Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21.

PubMed

Iglesias, Pedro; Selgas, Rafael; Romero, Sara; Díez, Juan J

2012-09-01

Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as renal function deteriorates. Circulating FGF21 levels seem to be related to insulin resistance and inflammation in dialysis patients. In summary, FGF21 is a recently identified hormone with antihyperglycemic, antihyperlipidemic, and thermogenic properties. Direct or indirect potentiation of its effects might be a potential therapeutic target in insulin-resistant states.

Physiology and role of irisin in glucose homeostasis

PubMed Central

Perakakis, Nikolaos; Triantafyllou, Georgios A.; Fernández-Real, José Manuel; Huh, Joo Young; Park, Kyung Hee; Seufert, Jochen; Mantzoros, Christos S.

2018-01-01

Irisin is a myokine that leads to increased energy expenditure by stimulating the ‘browning’ of white adipose tissue. In the first description of this hormone, increased levels of circulating irisin, which is cleaved from its precursor fibronectin type III domain-containing protein 5, were associated with improved glucose homeostasis by reducing insulin resistance. Consequently, several studies attempted to characterize the role of irisin in glucose regulation, but contradictory results have been reported, and even the existence of this hormone has been questioned. In this Review, we present the current knowledge on the physiology of irisin and its role in glucose homeostasis. We describe the mechanisms involved in the synthesis, secretion, circulation and regulation of irisin, and the controversies regarding the measurement of irisin. We also discuss the direct effects of irisin on glucose regulatory mechanisms in different organs, the indirect effects and interactions with other hormones, and the important open questions with regard to irisin in those organs. Finally, we present the results from animal interventional studies and from human clinical studies investigating the association of irisin with obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome. PMID:28211512

The role of glucose, insulin and NEFA in regulating tissue triglyceride accumulation: Substrate cooperation in adipose tissue versus substrate competition in skeletal muscle.

PubMed

Guzzardi, M A; Hodson, L; Guiducci, L; La Rosa, F; Salvadori, P A; Burchielli, S; Iozzo, P

2017-11-01

Metabolic factors initiating adipose tissue expansion and ectopic triglyceride accumulation are not completely understood. We aimed to investigate the independent role of circulating glucose, NEFA and insulin on glucose and NEFA uptake, and lipogenesis in skeletal muscle and subcutaneous adipose tissue (SCAT). Twenty-two pigs were stratified according to four protocols: 1) and 2) low NEFA + high insulin ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia-euglycaemia), 3) high NEFA + low insulin (fasting), 4) low NEFA + low insulin (nicotinic acid). Positron emission tomography with [ 18 F]fluoro-2-deoxyglucose and [ 11 C]acetate, was combined with [ 14 C]acetate and [U- 13 C]palmitate enrichment techniques to assess glucose and lipid metabolism. Hyperinsulinaemia increased glucose extraction, whilst hyperglycaemia enhanced glucose uptake in skeletal muscle and SCAT. In SCAT, during hyperglycaemia, elevated glucose uptake was accompanied by greater [U- 13 C]palmitate-TG enrichment compared to the other groups, and by a 39% increase in de novo lipogenesis (DNL) compared to baseline, consistent with a 70% increment in plasma lipogenic index. Conversely, in skeletal muscle, [U- 13 C]palmitate-TG enrichment was higher after prolonged fasting. Our data show the necessary role of hyperglycaemia-hyperinsulinaemia vs euglycaemia-hyperinsulinaemia in promoting expansion of TG stores in SCAT, by the consensual elevation in plasma NEFA and glucose uptake and DNL. In contrast, skeletal muscle NEFA uptake for TG synthesis is primarily driven by circulating NEFA levels. These results suggest that a) prolonged fasting or dietary regimens enhancing lipolysis might promote muscle steatosis, and b) the control of glucose levels, in association with adequate energy balance, might contribute to weight loss. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Glucose-dependent insulinotropic polypeptide lowers branched chain amino acids in hyperglycemic rats.

PubMed

Spégel, Peter; Lindqvist, Andreas; Sandberg, Monica; Wierup, Nils

2014-02-10

Hypersecretion of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) has been associated with obesity and glucose intolerance. This condition has been suggested to be linked to GIP resistance. Besides its insulinotropic effect, GIP also directly affects glucose uptake and lipid metabolism. This notwithstanding, effects of GIP on other circulating metabolites than glucose have not been thoroughly investigated. Here, we examined effects of infusion of various concentrations of GIP in normo- and hyperglycemic rats on serum metabolite profiles. We found that, despite a decrease in serum glucose levels (-26%, p<0.01), the serum metabolite profile was largely unaffected by GIP infusion in normoglycemic rats. Interestingly, levels of branched chain amino acids and the ketone body β-hydroxybutyrate were decreased by 21% (p<0.05) and 27% (p<0.001), respectively, in hyperglycemic rats infused with 60 ng/ml GIP. Hence, our data suggest that GIP provokes a decrease in BCAA levels and ketone body production. Increased concentrations of these metabolites have been associated with obesity and T2D. Copyright © 2014. Published by Elsevier B.V.

Euglycemic Hyperinsulinemia Increases Blood Pressure in Pregnant Rats Independent of Placental Antiangiogenic and Inflammatory Factors

PubMed Central

2013-01-01

BACKGROUND Although pregnancies associated with hyperinsulinemia and altered placental angiogenic and inflammatory factors are at increased risk for developing preeclampsia, the effects of euglycemic hyperinsulinemia on placental factors and blood pressure regulation during pregnancy are unclear. We hypothesized that chronic hyperinsulinemia results in increased placental soluble fms-like tyrosine kinase 1(sFlt-1) and tumor necrosis factor α (TNF- α) levels and hypertension in pregnant rats. METHODS On gestational day (GD) 14, Sprague-Dawley rats were assigned as normal pregnant or pregnant + insulin. Insulin was infused subcutaneously by osmotic minipump for 5 days at a dose of 1.5 mU/kg/min. Those rats receiving insulin were supplemented with 20% glucose in drinking water to maintain euglycemia. On GD 19, mean arterial pressure (MAP) and heart rate (HR) were assessed in conscious rats by indwelling carotid catheters, followed by collections of blood, placentas, and fetuses. In addition to pl acental sFlt-1 and TNF-α levels, circulating insulin, glucose, leptin, cholesterol, triglyceride, and free fatty acid concentrations were measured. RESULTS MAP was higher in pregnant + insulin vs. normal pregnant rats; however, HR was similar between groups. Although litter size and placental weight were comparable, fetuses from pregnant + insulin rats were heavier. Importantly, circulating insulin concentration was elevated in the pregnant + insulin group, with no change in glucose level. Moreover, circulating leptin, cholesterol, triglyceride, and free fatty acid concentrations were increased in the pregnant + insulin group. There were no differences in placental sFlt-1 and TNF-α concentrations between groups. CONCLUSIONS In summary, sustained euglycemic hyperinsulinemia, comparable with insulin levels in preeclamptic women, can raise blood pressure in pregnancy independent of recognized placental factors associated with preeclampsia. PMID:23955606

β-Cell–Specific Protein Kinase A Activation Enhances the Efficiency of Glucose Control by Increasing Acute-Phase Insulin Secretion

PubMed Central

Kaihara, Kelly A.; Dickson, Lorna M.; Jacobson, David A.; Tamarina, Natalia; Roe, Michael W.; Philipson, Louis H.; Wicksteed, Barton

2013-01-01

Acute insulin secretion determines the efficiency of glucose clearance. Moreover, impaired acute insulin release is characteristic of reduced glucose control in the prediabetic state. Incretin hormones, which increase β-cell cAMP, restore acute-phase insulin secretion and improve glucose control. To determine the physiological role of the cAMP-dependent protein kinase (PKA), a mouse model was developed to increase PKA activity specifically in the pancreatic β-cells. In response to sustained hyperglycemia, PKA activity potentiated both acute and sustained insulin release. In contrast, a glucose bolus enhanced acute-phase insulin secretion alone. Acute-phase insulin secretion was increased 3.5-fold, reducing circulating glucose to 58% of levels in controls. Exendin-4 increased acute-phase insulin release to a similar degree as PKA activation. However, incretins did not augment the effects of PKA on acute-phase insulin secretion, consistent with incretins acting primarily via PKA to potentiate acute-phase insulin secretion. Intracellular calcium signaling was unaffected by PKA activation, suggesting that the effects of PKA on acute-phase insulin secretion are mediated by the phosphorylation of proteins involved in β-cell exocytosis. Thus, β-cell PKA activity transduces the cAMP signal to dramatically increase acute-phase insulin secretion, thereby enhancing the efficiency of insulin to control circulating glucose. PMID:23349500

Glucosensing capacity in rainbow trout liver displays day-night variations possibly related to melatonin action.

PubMed

Conde-Sieira, Marta; Patiño, Marcos A López; Míguez, Jesús M; Soengas, José L

2012-09-01

To assess whether the glucosensing capacity in peripheral (liver and Brockmann bodies) and central (hypothalamus and hindbrain) locations of rainbow trout displays day-night variations in its response to changes in circulating glucose levels, we evaluated the response of parameters related to glucosensing [glucose, glycogen and glucose 6-phosphate levels, activities of glucokinase (GK), glycogen synthetase (GSase) and pyruvate kinase (PK), and mRNA abundance of GK, glucose transporter 2 (GLUT2), and K(ATP) channel subunits Kir6.x-like and sulfonylurea receptor (SUR)-like] in fish subjected to hyperglycemic treatment under night or day conditions. No day-night significant variations were noticed in the glucosensing capacity of the hypothalamus, hindbrain and Brockmann bodies. In contrast, a clear differential response was noticed in the liver, where glucose levels, GK activity (and mRNA levels) and GSase activity displayed increased values during the day in hyperglycemic fish compared with controls, and lower (GK mRNA levels) or non-existent (glucose, GK and GSase activities, and Kir6.x-like mRNA levels) values during the night. A similar decrease in parameters related to glucosensing in the liver was observed when fish under day conditions were treated with melatonin, suggesting a modulatory role of melatonin in day-night changes of the glucosensing response in the same tissue.

UCP2 regulates mitochondrial fission and ventromedial nucleus control of glucose responsiveness

PubMed Central

Toda, Chitoku; Kim, Jung Dae; Impellizzeri, Daniela; Cuzzocrea, Salvatore; Liu, Zhong-Wu; Diano, Sabrina

2016-01-01

Summary The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill-defined. Here we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH, and, that this process regulates systemic glucose homoeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis. PMID:26919426

UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness.

PubMed

Toda, Chitoku; Kim, Jung Dae; Impellizzeri, Daniela; Cuzzocrea, Salvatore; Liu, Zhong-Wu; Diano, Sabrina

2016-02-25

The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill defined. Here, we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH and that this process regulates systemic glucose homeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis. Copyright © 2016 Elsevier Inc. All rights reserved.

HBA1C AND MEAN GLUCOSE DERIVED FROM SHORT-TERM CONTINUOUS GLUCOSE MONITORING ASSESSMENT DO NOT CORRELATE IN PATIENTS WITH HBA1C >8.

PubMed

Yamada, Eijiro; Okada, Shuichi; Nakajima, Yasuyo; Bastie, Claire C; Vatish, Manu; Tagaya, Yuko; Osaki, Aya; Shimoda, Yoko; Shibusawa, Ryo; Saito, Tsugumichi; Okamura, Takashi; Ozawa, Atsushi; Yamada, Masanobu

2017-01-01

Optimum therapy for patients with diabetes depends on both acute and long-term changes in plasma glucose, generally assessed by glycated hemoglobin (HbA1c) levels. However, the correlation between HbA1c and circulating glucose has not been fully determined. Therefore, we carefully examined this correlation when glucose levels were assessed by continuous glucose monitoring (CGM). Fifty-one patients (70% female, 30% male) were examined; among them were 28 with type 1 diabetes and 23 with type 2 diabetes. Clinically determined HbA1c levels were compared with blood glucose determined by CGM during a short time period. Changes in HbA1c levels up to 8.0% showed a clear and statistically strong correlation (R = 0.6713; P<.0001) with mean blood glucose levels measured by CGM, similar to that observed in the A1c-derived Average Glucose study in which patients were monitored for a longer period. However, we found no statistical correlation (R = 0.0498; P = .83) between HbA1c and CGM-assessed glucose levels in our patient population when HbA1c was >8.0%. Short-term CGM appears to be a good clinical indicator of long-term glucose control (HbA1c levels); however, cautions should be taken while interpreting CGM data from patients with HbA1c levels >8.0%. Over- or underestimation of the actual mean glucose from CGM data could potentially increase the risks of inappropriate treatment. As such, our results indicate that a more accurate analysis of CGM data might be useful to adequately tailor clinical treatments. ADAG = A1c-Derived Average Glucose CGM = continuous glucose monitoring %CV = percent coefficient of variation HbA1c = glycated hemoglobin.

Role of Extracellular miR-122 in Breast Cancer Metastasis

DTIC Science & Technology

2015-02-01

endothelial, lung fibroblasts, and brain astrocyte niche cells through secreting exosomal miR-122, a miRNA whose level in the circulation predicts metastasis...Our results demonstrate that cancer cells are capable of influencing how niche cells metabolize glucose through exosome secretion of miR-122 and the... exosome , miRNA, glucose metabolism, PKM2, GLUT1, niche adaption 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES

The Infant Born to a Woman with Gestational Diabetes.

PubMed

Povinelli, Theresa; Lim, Caitlin; Raines, Deborah A

2017-07-01

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset during pregnancy. During pregnancy, women with GDM develop insulin resistance, which results in altered glucose tolerance. As a result, there are frequent episodes of hyperglycemia and high levels of circulating amino acids, increasing the transfer of nutrients to the fetus. This article discusses the role of the mother-baby nursing in the care of neonates born to women with gestational diabetes.

Elevated circulating irisin is associated with lower risk of insulin resistance: association and path analyses of obese Chinese adults.

PubMed

Shi, Xiulin; Lin, Mingzhu; Liu, Changqin; Xiao, Fangsen; Liu, Yongwen; Huang, Peiying; Zeng, Xin; Yan, Bing; Liu, Suhuan; Li, Xiaoying; Yang, Shuyu; Li, Xuejun; Li, Zhibin

2016-07-29

Evidence on the role of irisin in insulin resistance is limited and controversial, and pathways between them remain unknown. We aimed to examine the independent effects of circulating irisin and different adiposity measurements, as well as their potential interactions, on insulin resistance. We also aimed to explore possible pathways among circulating irisin, adiposity, glucose and insulin levels and insulin resistance. A cross-sectional study of 1,115 community- living obese Chinese adults, with data collection on clinical characteristics, glucose and lipid metabolic parameters and circulating irisin levels. Among the 1,115 subjects, 667 (59.8 %) were identified as insulin-resistance, and showed significantly decreased serum irisin than their controls (log-transformed irisin: 1.19 ± 2.34 v.s. 1.46 ± 2.05 ng/ml, p = 0.042). With adjustment for potential confounders, elevated circulating irisin was significantly associated with reduced risk of insulin resistance, with adjusted odds ratio per standard deviation increase of irisin of 0.871 (0.765-0.991, p = 0.036). As for different adiposity measurements, body fat percentage, but neither BMI nor waist, was significantly associated with increased risk of insulin resistance (OR: 1.152 (1.041-1.275), p = 0.006). No significant interaction effect between serum irisin and adiposity on insulin resistance was found. A one pathway model about the relationship between serum irisin and insulin resistance fits well (χ (2) = 44.09, p < 0.001; CFI-0.994; TLI =0.986; and RMSEA = 0.067), and shows that elevated circulating irisin might improve insulin resistance indirectly through lowering fasting insulin levels (standardized path coefficient = -0.046, p = 0.032). Elevated circulating irisin is associated with lower risk of insulin resistance indirectly through lowering fasting insulin.

Reduction of Syndecan Transcript Levels in the Insulin-Producing Cells Affects Glucose Homeostasis in Adult Drosophila melanogaster.

PubMed

Warren, Jonathan L; Hoxha, Eneida; Jumbo-Lucioni, Patricia; De Luca, Maria

2017-11-01

Signaling by direct cell-matrix interactions has been shown to impact the transcription, secretion, and storage of insulin in mammalian β cells. However, more research is still needed in this area. Syndecans are transmembrane heparan sulfate proteoglycans that function independently and in synergy with integrin-mediated signaling to mediate cell adhesion to the extracellular matrix. In this study, we used the model organism Drosophila melanogaster to determine whether knockdown of the Syndecan (Sdc) gene expression specifically in the insulin-producing cells (IPCs) might affect insulin-like peptide (ILP) production and secretion. IPCs of adult flies produce three ILPs (ILP2, ILP3, and ILP5), which have significant homology to mammalian insulin. We report that flies with reduced Sdc expression in the IPCs did not show any difference in the expression of ilp genes compared to controls. However, they had significantly reduced levels of the circulating ILP2 protein, higher circulating carbohydrates, and were less glucose tolerant than control flies. Finally, we found that IPCs-specific Sdc knockdown led to reduced levels of head Glucose transporter1 gene expression, extracellular signal-regulated kinase phosphorylation, and reactive oxygen species. Taken together, our findings suggest a cell autonomous role for Sdc in insulin release in D. melanogaster.

Role of endogenously released cholecystokinin in determining postprandial insulin levels in man: effects of loxiglumide, a specific cholecystokinin receptor antagonist.

PubMed

Baum, F; Nauck, M A; Ebert, R; Cantor, P; Hoffmann, G; Choudhury, A R; Schmidt, W E; Creutzfeldt, W

1992-01-01

To estimate the contribution of postprandial cholecystokinin (CCK) responses to circulating insulin concentrations and insulin secretion, a specific CCK receptor antagonist (loxiglumide; 10 mg/kg body weight/h) or saline were infused intravenously in normal volunteers, beginning 90 min before insulin secretion was stimulated on separate occasions by the intraduodenal administrations of glucose, glucose and protein, and glucose plus protein with the admixture of pancreatin. The release of CCK (radioimmunoassay) was stimulated by the protein component of the nutrients from basal 2.4 +/- 0.4 to 8.0 +/- 1.2 pmol/l. CCK plasma levels were significantly higher with loxiglumide (p < 0.05). Glucose-dependent insulinotropic polypeptide (GIP) was also released by all nutrient mixtures. Loxiglumide significantly inhibited the amount of bilirubin and pancreatic enzymes recovered from duodenal aspirates. In contrast, in none of the experiments, C-peptide increments and hence insulin secretion rates were altered by loxiglumide. With glucose and protein as intraduodenal stimulus (no pancreatin added), the plasma amino acids rose significantly less (by approximately 50% of the control experiment) and the increment in insulin (but not C-peptide) concentrations was significantly reduced by loxiglumide. This is most likely explained by a change in insulin metabolic clearance. This effect cannot be a primary action of CCK because there was no similar effect of loxiglumide with the same intraduodenal stimulus plus added pancreatin. Pancreatic enzymes reduced maldigestion secondary to loxiglumide effects on pancreatic exocrine secretion: The increment in circulating amino acid concentrations was similar with and without loxiglumide. In conclusion, CCK does not alter insulin secretion and, therefore, is not an incretin hormone in man. Blocking CCK actions on the exocrine pancreas by loxiglumide, however, can secondarily cause reductions in postprandial insulin profiles by altering insulin clearance. These changes are possibly related to reductions in circulating amino acid concentrations.

Hyperandrogenism Accompanies Increased Intra-Abdominal Fat Storage in Normal Weight Polycystic Ovary Syndrome Women.

PubMed

Dumesic, Daniel A; Akopians, Alin L; Madrigal, Vanessa K; Ramirez, Emmanuel; Margolis, Daniel J; Sarma, Manoj K; Thomas, Albert M; Grogan, Tristan R; Haykal, Rasha; Schooler, Tery A; Okeya, Bette L; Abbott, David H; Chazenbalk, Gregorio D

2016-11-01

Normal weight polycystic ovary syndrome (PCOS) women may have altered adipose structure-function underlying metabolic dysfunction. This study examines whether adipose structure-functional changes exist in normal weight PCOS women and correlate with hyperandrogenism and/or hyperinsulinemia. This is a prospective cohort study. The setting was an academic medical center. Six normal weight PCOS women and 14 age- and body mass index-matched normoandrogenic ovulatory (NL) women were included. All women underwent circulating hormone and metabolic measurements; frequently sampled intravenous glucose tolerance testing; total body dual-energy x-ray absorptiometry; abdominal magnetic resonance imaging; and SC abdominal fat biopsy. Circulating hormones and metabolites, body fat and its distribution, and adipocyte size were compared between PCOS and NL women, and were correlated with each other in all women. Circulating LH and androgen levels were significantly greater in PCOS than NL women, as were fasting insulin levels, pancreatic β-cell responsiveness to glucose, and total abdominal fat mass. Intra-abdominal fat mass also was significantly increased in PCOS women and was positively correlated with circulating androgen, fasting insulin, triglyceride, and non-high-density lipoprotein cholesterol levels in all women. SC abdominal fat mass was not significantly increased in PCOS women, but contained a greater proportion of small SC abdominal adipocytes that positively correlated with serum androgen levels in all women. Hyperandrogenism in normal weight PCOS women is associated with preferential intra-abdominal fat deposition and an increased population of small SC abdominal adipocytes that could constrain SC adipose storage and promote metabolic dysfunction.

Whole cinnamon and aqueous extracts ameliorate sucrose-induced blood pressure elevations in spontaneously hypertensive rats.

PubMed

Preuss, Harry G; Echard, Bobby; Polansky, Marilyn M; Anderson, Richard

2006-04-01

Many agents (nutrients, nutraceuticals, and drugs) that enhance insulin sensitivity and/or reduce circulating insulin concentrations lower blood pressure (BP). Recently, it was reported that cinnamon has the potential to favorably influence the glucose/insulin system. Accordingly, the purpose of the present study was to examine the effects of dietary cinnamon on systolic BP (SBP), and various glucose- and insulin-related parameters in spontaneously hypertensive rats (SHR). In a series of three experiments, treated SHR eating sucrose and non sucrose containing diets were given various amounts of cinnamon, cinnamon extracts, or chromium. Then various parameters such as: body weight, systolic blood pressure, hematology and blood chemistries were followed for three to four weeks. Diets high in sucrose content are associated with insulin resistance and the elevation of SBP. Addition to diets of cinnamon (8% w/w) reduced the SBP of rats eating sucrose containing diets to virtually the same levels as SHR consuming non sucrose containing (only starch) diets. The presence of cinnamon in the diet also decreased the SBP of SHR consuming a non sucrose-containing diet, suggesting that cinnamon reduces more than just sucrose-induced SBP elevations--perhaps a genetic component(s) of the elevated BP as well. The effects of cinnamon on SBP tended to be dose-dependent. Cinnamon did not decrease the levels of blood glucose, but did lower circulating insulin concentrations. Aqueous extracts of cinnamon also decreased SBP and lowered the circulating levels of fructosamine. Cinnamon is used for flavor and taste in food preparation, but cinnamon may have additional roles in glucose metabolism and BP regulation. Therefore, BP regulation may not only be influenced favorably by limiting the amounts of dietary substances that have negative effects on BP and insulin function but also by the addition of beneficial ones, such as cinnamon, that have positive effects.

Hypoglycaemia of the newborn: a review.

PubMed Central

Williams, A. F.

1997-01-01

It is almost a century since hypoglycaemia (a reduction in the glucose concentration of circulating blood) was first described in children, and over 50 years since the condition was first recognized in infants. Nevertheless, controversy still surrounds the definition, significance, and management of neonatal hypoglycaemia. Technological developments such as bedside glucose monitoring have, paradoxically, exacerbated rather than eased the situation. This article reviews the literature on hypoglycaemia of the newborn, and covers the following: historical aspects; glucose homeostasis and metabolic adaptation at birth; the effect of low blood glucose levels on the central nervous system; the definition of hypoglycaemia; screening; prevention; treatment; research needs; and concludes with recommendations for prevention and management. PMID:9277014

Response of circulating ghrelin levels to insulin therapy in children with newly diagnosed type 1 diabetes mellitus.

PubMed

Soriano-Guillén, Leandro; Barrios, Vicente; Lechuga-Sancho, Alfonso; Chowen, Julie A; Argente, Jesús

2004-05-01

Ghrelin is secreted primarily by the stomach, although other tissues such as the pancreas synthesize a minor proportion. The discovery of a new cell type that produces ghrelin in the human pancreas and that this organ expresses GHS-R opens new perspectives in the understanding of the control of glucose metabolism. We have studied 22 children with newly diagnosed type 1 diabetes mellitus at four different points: at diagnosis before insulin therapy, after 48-60 h of insulin therapy, and after 1 and 4 mo of insulin treatment. At each point circulating levels of ghrelin, leptin, IGF-I, IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, and glucose were determined. Ghrelin levels were significantly decreased at diagnosis (573 +/- 68 pg/mL, p < 0.01) compared with controls (867 +/- 38 pg/mL) and remained decreased after insulin therapy (d 2: 595 +/- 68 pg/mL; 1 mo: 590 +/- 61 pg/mL; 4 mo: 538 +/- 67 pg/mL) with no differences before or after insulin treatment. There was a negative correlation between ghrelin levels and body mass index at all of the study points, whereas a negative correlation between ghrelin and glucose concentrations was only observed after insulin therapy. No correlation between ghrelin and HbA1c was found at any point. A positive correlation between ghrelin and IGFBP-1 was found after insulin therapy, but no correlation with other members of the IGF system or leptin was found. In conclusion, these data could indicate a possible link between glucose concentrations and ghrelin; hence, the persisting low ghrelin levels in diabetic children may suggest a defensive mechanism against hyperglycemia.

Rapid fluctuations in extracellular brain glucose levels induced by natural arousing stimuli and intravenous cocaine: fueling the brain during neural activation

PubMed Central

Lenoir, Magalie

2012-01-01

Glucose, a primary energetic substrate for neural activity, is continuously influenced by two opposing forces that tend to either decrease its extracellular levels due to enhanced utilization in neural cells or increase its levels due to entry from peripheral circulation via enhanced cerebral blood flow. How this balance is maintained under physiological conditions and changed during neural activation remains unclear. To clarify this issue, enzyme-based glucose sensors coupled with high-speed amperometry were used in freely moving rats to evaluate fluctuations in extracellular glucose levels induced by brief audio stimulus, tail pinch (TP), social interaction with another rat (SI), and intravenous cocaine (1 mg/kg). Measurements were performed in nucleus accumbens (NAcc) and substantia nigra pars reticulata (SNr), which drastically differ in neuronal activity. In NAcc, where most cells are powerfully excited after salient stimulation, glucose levels rapidly (latency 2–6 s) increased (30–70 μM or 6–14% over baseline) by all stimuli; the increase differed in magnitude and duration for each stimulus. In SNr, where most cells are transiently inhibited by salient stimuli, TP, SI, and cocaine induced a biphasic glucose response, with the initial decrease (−20–40 μM or 5–10% below baseline) followed by a reboundlike increase. The critical role of neuronal activity in mediating the initial glucose response was confirmed by monitoring glucose currents after local microinjections of glutamate (GLU) or procaine (PRO). While intra-NAcc injection of GLU transiently increased glucose levels in this structure, intra-SNr PRO injection resulted in rapid, transient decreases in SNr glucose. Therefore, extracellular glucose levels in the brain change very rapidly after physiological and pharmacological stimulation, the response is structure specific, and the pattern of neuronal activity appears to be a critical factor determining direction and magnitude of physiological fluctuations in glucose levels. PMID:22723672

Glucagon receptor antagonists for the treatment of type II diabetes: current prospects.

PubMed

Djuric, Stevan W; Grihalde, Nelson; Lin, Chun Wel

2002-11-01

As the incidence of Type II diabetes (T2DM) will increase to 200 million cases worldwide by 2010, the search for new, effective agentsfor its treatment has been pushed into overdrive. According to Unger's bihormonal hypothesis, elevated levels of circulating glucagon in T2DM patients results in increased rates of hepatic glucose synthesis and glycogen metabolism, translating to excessive plasma glucose levels. In this context, considerable efforts have been made to identify glucagon antagonists for the treatment of T2DM. This review reflects research in this area from 1999 to 2002.

Circulating MiRNAs of ‘Asian Indian Phenotype’ Identified in Subjects with Impaired Glucose Tolerance and Patients with Type 2 Diabetes

PubMed Central

Prabu, Paramasivam; Rome, Sophie; Sathishkumar, Chandrakumar; Aravind, Sankaramoorthy; Mahalingam, Balakumar; Shanthirani, Coimbatore Subramanian; Gastebois, Caroline; Villard, Audrey; Mohan, Viswanathan; Balasubramanyam, Muthuswamy

2015-01-01

Several omics technologies are underway worldwide with an aim to unravel the pathophysiology of a complex phenotype such as type 2 diabetes mellitus (T2DM). While recent studies imply a clinically relevant and potential biomarker role of circulatory miRNAs in the etiology of T2DM, there is lack of data on this aspect in Indians—an ethnic population characterized to represent ‘Asian Indian phenotype’ known to be more prone to develop T2DM and cardiovascular disease than Europeans. We performed global serum miRNA profiling and the validation of candidate miRNAs by qRT-PCR in a cohort of subjects comprised of normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and patients with T2DM. Our study revealed 4 differentially expressed miRNAs (miR-128, miR-130b-3p, miR-374a-5p, miR-423-5p) in subjects with IGT and T2DM patients compared to control subjects. They were positively or negatively correlated to cholesterol levels, HbA1C, HOMA-IR and fasting insulin. Interestingly, circulating level of miR-128 and miR-130b-3p were also altered in serum of diet-induced diabetic mice compared to control animals. Among the altered circulating miRNAs, miR-128 had never been described in previous studies/populations and appeared to be a ‘New Lead’ in Indians. It was positively correlated with cholesterol both in prediabetic subjects and in diet-induced diabetic mice, suggesting that its increased level might be associated with the development of dyslipedemia associated with T2DM. Our findings imply directionality towards biomarker potential of miRNAs in the prevention/diagnosis/treatment outcomes of diabetes. PMID:26020947

Circulating MiRNAs of 'Asian Indian Phenotype' Identified in Subjects with Impaired Glucose Tolerance and Patients with Type 2 Diabetes.

PubMed

Prabu, Paramasivam; Rome, Sophie; Sathishkumar, Chandrakumar; Aravind, Sankaramoorthy; Mahalingam, Balakumar; Shanthirani, Coimbatore Subramanian; Gastebois, Caroline; Villard, Audrey; Mohan, Viswanathan; Balasubramanyam, Muthuswamy

2015-01-01

Several omics technologies are underway worldwide with an aim to unravel the pathophysiology of a complex phenotype such as type 2 diabetes mellitus (T2DM). While recent studies imply a clinically relevant and potential biomarker role of circulatory miRNAs in the etiology of T2DM, there is lack of data on this aspect in Indians--an ethnic population characterized to represent 'Asian Indian phenotype' known to be more prone to develop T2DM and cardiovascular disease than Europeans. We performed global serum miRNA profiling and the validation of candidate miRNAs by qRT-PCR in a cohort of subjects comprised of normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and patients with T2DM. Our study revealed 4 differentially expressed miRNAs (miR-128, miR-130b-3p, miR-374a-5p, miR-423-5p) in subjects with IGT and T2DM patients compared to control subjects. They were positively or negatively correlated to cholesterol levels, HbA1C, HOMA-IR and fasting insulin. Interestingly, circulating level of miR-128 and miR-130b-3p were also altered in serum of diet-induced diabetic mice compared to control animals. Among the altered circulating miRNAs, miR-128 had never been described in previous studies/populations and appeared to be a 'New Lead' in Indians. It was positively correlated with cholesterol both in prediabetic subjects and in diet-induced diabetic mice, suggesting that its increased level might be associated with the development of dyslipedemia associated with T2DM. Our findings imply directionality towards biomarker potential of miRNAs in the prevention/diagnosis/treatment outcomes of diabetes.

Elevated Medium-Chain Acylcarnitines Are Associated With Gestational Diabetes Mellitus and Early Progression to Type 2 Diabetes and Induce Pancreatic β-Cell Dysfunction.

PubMed

Batchuluun, Battsetseg; Al Rijjal, Dana; Prentice, Kacey J; Eversley, Judith A; Burdett, Elena; Mohan, Haneesha; Bhattacharjee, Alpana; Gunderson, Erica P; Liu, Ying; Wheeler, Michael B

2018-05-01

Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type 2 diabetes (T2D) and linked to peripheral insulin resistance. However, the effect of acylCs on pancreatic β-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: 1 ) women with gestational diabetes mellitus (GDM) and 2 ) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D, or returned to normoglycemia within a 2-year follow-up period. We observed a specific elevation in serum medium-chain (M)-acylCs, particularly hexanoyl- and octanoylcarnitine, among women with GDM and individuals with T2D without alteration in long-chain acylCs. Mice treated with M-acylCs exhibited glucose intolerance, attributed to impaired insulin secretion. Murine and human islets exposed to elevated levels of M-acylCs developed defects in glucose-stimulated insulin secretion and this was directly linked to reduced mitochondrial respiratory capacity and subsequent ability to couple glucose metabolism to insulin secretion. In conclusion, our study reveals that an elevation in circulating M-acylCs is associated with GDM and early stages of T2D onset and that this elevation directly impairs β-cell function. © 2018 by the American Diabetes Association.

Normal adiponectin levels despite abnormal glucose tolerance (or diabetes) and inflammation in adult patients with cystic fibrosis.

PubMed

Hammana, I; Malet, A; Costa, M; Brochiero, E; Berthiaume, Y; Potvin, S; Chiasson, J-L; Coderre, L; Rabasa-Lhoret, R

2007-06-01

Circulating adiponectin levels are negatively associated with glucose intolerance, inflammation and central adiposity. Since these conditions are common in cystic fibrosis (CF), we examined whether adiponectin values are altered in these patients. To determine if CF patients have altered adiponectin levels and if these levels correlate with glucose tolerance categories (normal, impaired glucose tolerance (IGT) and cystic fibrosis-related diabetes (CFRD)), insulin resistance or inflammatory markers such as fibrinogen and C-reactive protein (CRP). Oral glucose tolerance tests (OGTTs) were performed and adiponectin levels were measured in 90 CF patients not known to be diabetic and 15 healthy controls matched for age, sex and body mass index (BMI). Inflammatory markers, serum albumin concentrations and the clinical status of CF patients (i.e. pulmonary function) were also examined. CF pathology was characterized by a high prevalence (43.5%) of glucose tolerance abnormalities: 26.5% of IGT and 17.0% of newly diagnosed CFRD. CF patients also presented systemic inflammation as revealed by a significant increase of fibrinogen (P=0.029) in all patients and higher CRP levels in CFRD patients compared to the controls (P<0.05). On the other hand, CF and control subjects had similar albumin serum concentration. While CF patients and controls had similar serum adiponectin values, women had significantly higher hormone levels than men (P<0.001). Adiponectin levels did not correlate with glucose tolerance, inflammatory markers or insulin resistance. On the other hand, they correlated positively with both total and HDL-cholesterol (P<0.001). CF patients did not show any alterations in adiponectin levels despite insulin resistance, glucose intolerance and sub clinical chronic inflammation. Thus, CF appears to be one of the rare conditions in which discordance between adiponectin values and insulin resistance or inflammation is evident.

Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat.

PubMed

Holness, M J; Greenwood, G K; Smith, N D; Sugden, M C

2005-11-01

Hyperthyroidism modifies lipid dynamics (increased oxidation), impairs insulin action and can suppress insulin secretion. We therefore examined the impact of hyperthyroidism on the relationship between glucose-stimulated insulin secretion (GSIS) and insulin action, using late pregnancy as a model of physiological insulin resistance that is associated with compensatory insulin hypersecretion to maintain glucose tolerance. Our aim was to examine whether hyperthyroidism compromises the regulation of insulin secretion and the ability of insulin to modulate circulating lipid concentrations in late pregnancy. Hyperthyroidism was induced by tri-iodothyronine (T(3)) administration from day 17 to 19 of pregnancy. GSIS was assessed during an IVGTT and during hyperglycaemic clamps in vivo and in vitro, using step-up and -down islet perifusions. Hyperthyroidism in pregnancy elevated the glucose threshold for GSIS and impaired GSIS at low and high glucose concentrations in islet perifusions. In the intact animal, insulin secretion (after bolus glucose) was more rapidly curtailed following removal of the glucose stimulus to secretion. In contrast, GSIS was maintained during protracted hyperglycaemia (hyperglycaemic clamps) in the hyperthyroid pregnant state in vivo. Hyperthyroidism in vivo during late pregnancy blunts GSIS in subsequently isolated and perifused islets at low and high glucose concentrations. It also adversely affects GSIS under conditions of an acute glucose challenge in vivo. In contrast, GSIS is maintained during sustained hyperglycaemia in vivo, suggesting that in vivo factors can rescue GSIS. The ability of insulin to suppress systemic lipid levels during hyperglycaemic clamps was impaired. We therefore suggest that higher circulating lipids may preserve GSIS under conditions of sustained hyperglycaemia in the hyperthyroid pregnancy.

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

PubMed

Stijnen, Pieter; Ramos-Molina, Bruno; O'Rahilly, Stephen; Creemers, John W M

2016-08-01

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

Complement factor H is expressed in adipose tissue in association with insulin resistance.

PubMed

Moreno-Navarrete, José María; Martínez-Barricarte, Rubén; Catalán, Victoria; Sabater, Mònica; Gómez-Ambrosi, Javier; Ortega, Francisco José; Ricart, Wifredo; Blüher, Mathias; Frühbeck, Gema; Rodríguez de Cordoba, Santiago; Fernández-Real, José Manuel

2010-01-01

Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances.

Hyperandrogenism Accompanies Increased Intra-Abdominal Fat Storage in Normal Weight Polycystic Ovary Syndrome Women

PubMed Central

Akopians, Alin L.; Madrigal, Vanessa K.; Ramirez, Emmanuel; Margolis, Daniel J.; Sarma, Manoj K.; Thomas, Albert M.; Grogan, Tristan R.; Haykal, Rasha; Schooler, Tery A.; Okeya, Bette L.; Abbott, David H.; Chazenbalk, Gregorio D.

2016-01-01

Context: Normal weight polycystic ovary syndrome (PCOS) women may have altered adipose structure-function underlying metabolic dysfunction. Objective: This study examines whether adipose structure-functional changes exist in normal weight PCOS women and correlate with hyperandrogenism and/or hyperinsulinemia. Design: This is a prospective cohort study. Setting: The setting was an academic medical center. Patients: Six normal weight PCOS women and 14 age- and body mass index-matched normoandrogenic ovulatory (NL) women were included. Intervention(s): All women underwent circulating hormone and metabolic measurements; frequently sampled intravenous glucose tolerance testing; total body dual-energy x-ray absorptiometry; abdominal magnetic resonance imaging; and SC abdominal fat biopsy. Main Outcome Measure(s): Circulating hormones and metabolites, body fat and its distribution, and adipocyte size were compared between PCOS and NL women, and were correlated with each other in all women. Results: Circulating LH and androgen levels were significantly greater in PCOS than NL women, as were fasting insulin levels, pancreatic β-cell responsiveness to glucose, and total abdominal fat mass. Intra-abdominal fat mass also was significantly increased in PCOS women and was positively correlated with circulating androgen, fasting insulin, triglyceride, and non-high-density lipoprotein cholesterol levels in all women. SC abdominal fat mass was not significantly increased in PCOS women, but contained a greater proportion of small SC abdominal adipocytes that positively correlated with serum androgen levels in all women. Conclusion: Hyperandrogenism in normal weight PCOS women is associated with preferential intra-abdominal fat deposition and an increased population of small SC abdominal adipocytes that could constrain SC adipose storage and promote metabolic dysfunction. PMID:27571186

Regulation of gonadotropin-releasing hormone neurons by glucose

PubMed Central

Roland, Alison V.; Moenter, Suzanne M.

2011-01-01

Reproduction is influenced by energy balance, but the physiological pathways mediating their relationship have not been fully elucidated. As the central regulators of fertility, gonadotropin-releasing hormone (GnRH) neurons integrate numerous physiological signals, including metabolic cues. Circulating glucose levels regulate GnRH release and may in part mediate the effects of negative energy balance on fertility. Existing evidence suggests that neural pathways originating in the hindbrain, as well as in the hypothalamic feeding nuclei, transmit information concerning glucose availability to GnRH neurons. Here we review recent evidence suggesting that GnRH neurons may directly sense changes in glucose availability by a mechanism involving adenosine monophosphate-activated protein kinase (AMPK). These findings expand our understanding of how metabolic signaling in the brain regulates reproduction. PMID:21855365

Cultured 3T3L1 adipocytes dispose of excess medium glucose as lactate under abundant oxygen availability

NASA Astrophysics Data System (ADS)

Sabater, David; Arriarán, Sofía; Romero, María Del Mar; Agnelli, Silvia; Remesar, Xavier; Fernández-López, José Antonio; Alemany, Marià

2014-01-01

White adipose tissue (WAT) produces lactate in significant amount from circulating glucose, especially in obesity;Under normoxia, 3T3L1 cells secrete large quantities of lactate to the medium, again at the expense of glucose and proportionally to its levels. Most of the glucose was converted to lactate with only part of it being used to synthesize fat. Cultured adipocytes were largely anaerobic, but this was not a Warburg-like process. It is speculated that the massive production of lactate, is a process of defense of the adipocyte, used to dispose of excess glucose. This way, the adipocyte exports glucose carbon (and reduces the problem of excess substrate availability) to the liver, but the process may be also a mechanism of short-term control of hyperglycemia. The in vivo data obtained from adipose tissue of male rats agree with this interpretation.

Nesfatin-1 and other hormone alterations in polycystic ovary syndrome.

PubMed

Deniz, Rulin; Gurates, Bilgin; Aydin, Suleyman; Celik, Husnu; Sahin, Ibrahim; Baykus, Yakup; Catak, Zekiye; Aksoy, Aziz; Citil, Cihan; Gungor, Sami

2012-12-01

Polycystic ovary syndrome (PCOS) is commonly characterised by obesity, insulin resistance (IR), hyperandrogenemia and hirsutism. Nesfatin-1 a recently discovered hormone, acts upon energy balance, glucose metabolism, obesity and probably gonadal functions. This study was to evaluate the circulating levels of nesfatin-1 in patients with PCOS (n = 30) and in age and body mass index (BMI)-matched controls (n = 30). PCOS patients had significantly lower levels of nesfatin-1 (0.88 ± 0.36 ng/mL) than healthy controls (2.22 ± 1.14 ng/mL). PCOS patients also had higher gonadotropin and androgen plasma concentrations, Ferriman-Gallwey scores, blood glucose levels and a homeostasis model of assessment-IR index (HOMA-IR) index than in healthy women. Correlation tests in PCOS subjects detected a negative correlation between nesfatin-1 levels and BMI, fasting blood glucose, insulin levels and a HOMA-IR index. Lower nesfatin-1 concentration may plays a very important role in the development of PCOS.

Altered ghrelin secretion in mice in response to diet-induced obesity and Roux-en-Y gastric bypass

PubMed Central

Uchida, Aki; Zechner, Juliet F.; Mani, Bharath K.; Park, Won-mee; Aguirre, Vincent; Zigman, Jeffrey M.

2014-01-01

The current study examined potential mechanisms for altered circulating ghrelin levels observed in diet-induced obesity (DIO) and following weight loss resulting from Roux-en-Y gastric bypass (RYGB). We hypothesized that circulating ghrelin levels were altered in obesity and after weight loss through changes in ghrelin cell responsiveness to physiological cues. We confirmed lower ghrelin levels in DIO mice and demonstrated elevated ghrelin levels in mice 6 weeks post-RYGB. In both DIO and RYGB settings, these changes in ghrelin levels were associated with altered ghrelin cell responsiveness to two key physiological modulators of ghrelin secretion – glucose and norepinephrine. In DIO mice, increases in ghrelin cell density within both the stomach and duodenum and in somatostatin-immunoreactive D cell density in the duodenum were observed. Our findings provide new insights into the regulation of ghrelin secretion and its relation to circulating ghrelin within the contexts of obesity and weight loss. PMID:25353000

Retinal lipid and glucose metabolism dictates angiogenesis through lipid sensor Ffar1

PubMed Central

Joyal, Jean-Sébastien; Sun, Ye; Gantner, Marin L.; Shao, Zhuo; Evans, Lucy P.; Saba, Nicholas; Fredrick, Thomas; Burnim, Samuel; Kim, Jin Sung; Patel, Gauri; Juan, Aimee M.; Hurst, Christian G.; Hatton, Colman J.; Cui, Zhenghao; Pierce, Kerry A.; Bherer, Patrick; Aguilar, Edith; Powner, Michael B.; Vevis, Kristis; Boisvert, Michel; Fu, Zhongjie; Levy, Emile; Fruttiger, Marcus; Packard, Alan; Rezende, Flavio A.; Maranda, Bruno; Sapieha, Przemyslaw; Chen, Jing; Friedlander, Martin; Clish, Clary B.; Smith, Lois E.H.

2016-01-01

Tissues with high metabolic rates often use lipid as well as glucose for energy, conferring a survival advantage during feast and famine.1 Current dogma suggests that high-energy consuming photoreceptors depend on glucose.2,3 Here we show that retina also uses fatty acids (FA) β-oxidation for energy. Moreover, we identify a lipid sensor Ffar1 that curbs glucose uptake when FA are available. Very low-density lipoprotein receptor (VLDLR), expressed in tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived FA.4,5 Vldlr is present in photoreceptors.6 In Vldlr−/− retinas, Ffar1, sensing high circulating lipid levels despite decreased FA uptake5, suppresses glucose transporter Glut1. This impaired glucose entry into photoreceptors results in a dual lipid/glucose fuel shortage and reduction in the Krebs cycle intermediate α-ketoglutarate (KG). Low α-KG levels promote hypoxia-induced factor-1α (Hif1a) stabilization and vascular endothelial growth factor (Vegfa) secretion by starved Vldlr−/− photoreceptors, attracting neovessels to supply fuel. These aberrant vessels invading normally avascular photoreceptors in Vldlr−/− retinas are reminiscent of retinal angiomatous proliferation (RAP), a subset of neovascular age-related macular degeneration (AMD)7, associated with high vitreous VEGF levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in neovascular AMD and other retinal diseases. PMID:26974308

Circulating catecholamine and glucose concentrations in Japanese toads (Bufo japonicus) during the breeding season.

PubMed

Wilson, J X; Sawai, H; Kikuchi, M; Kubokawa, K; Ishii, S

1995-06-01

We investigated the relationship between catecholamine neurohormones and glucose during seasonal reproductive activity in Japanese toads (Bufo japonicus). Field studies found that plasma epinephrine concentration increased as toads migrated to their breeding ponds, where amplexus most frequently took place. Blood glucose concentration also increased as toads arrived at the ponds, even though these animals did not eat during the breeding season, and there was a positive correlation between epinephrine and glucose levels. Blood glucose concentration was higher in amplectic than in solitary males, whereas this relationship did not occur in females. For both males and females, plasma epinephrine concentration was elevated during amplexus. The plasma concentration of norepinephrine was lower than that of epinephrine and did not correlate with either the proximity of the animal to the breeding ponds or the blood glucose concentration. Laboratory experiments showed that systemic injection of [Trp7,Leu8]gonadotropin-releasing hormone (sGnRH) increased plasma epinephrine to levels characteristic of amplectic feral toads. These results suggest that a physiological role of GnRH-like peptides may be to stimulate epinephrine secretion and consequently to increase glucose production in toads under the starvation conditions associated with the breeding migration.

Fructose utilization during exercise in men: rapid conversion of ingested fructose to circulating glucose.

PubMed

Jandrain, B J; Pallikarakis, N; Normand, S; Pirnay, F; Lacroix, M; Mosora, F; Pachiaudi, C; Gautier, J F; Scheen, A J; Riou, J P

1993-05-01

The aim of the present study was to compare the metabolic fate of repeated doses of fructose or glucose ingested every 30 min during long-duration moderate-intensity exercise in men. Healthy volunteers exercised for 3 h on a treadmill at 45% of their maximal oxygen consumption rate. "Naturally labeled" [13C]glucose or [13C]fructose was given orally at 25-g doses every 30 min (total feeding: 150 g; n = 6 in each group). Substrate utilization was evaluated by indirect calorimetry, and exogenous sugar oxidation was measured by isotope ratio mass spectrometry on expired CO2. Results were corrected for baseline drift in 13C/12C ratio in expired air due to exercise alone. Fructose conversion to plasma glucose was measured combining gas chromatography and isotope ratio mass spectrometry. Most of the ingested glucose was oxidized: 81 +/- 4 vs. 57 +/- 2 g/3 h for fructose (2P < 0.005). Exogenous glucose covered 20.8 +/- 1.4% of the total energy need (+/- 6.7 MJ) compared with 14.0 +/- 0.6% for fructose (2P < 0.005). The contribution of total carbohydrates was significantly higher and that of lipids significantly lower with glucose than with fructose. The blood glucose response was similar in both protocols. From 90 to 180 min, 55-60% of circulating glucose was derived from ingested fructose. In conclusion, when ingested repeatedly during moderate-intensity prolonged exercise, fructose is metabolically less available than glucose, despite a high rate of conversion to circulating glucose.

Circulating milk fat globule-epidermal growth factor 8 levels are increased in pregnancy and gestational diabetes mellitus.

PubMed

Li, Yuanyuan; Ran, Wenzhuo; Zhang, Jiaqiang; Chen, Shi; Li, Yihang; Luo, Deng; Wang, Chen; Jia, Weiping

2017-07-01

Milk fat globule-epidermal growth factor 8 (MFG-E8) is the key mediator in anti-inflammatory responses that facilitate phagocytosis of apoptotic cells, and play an essential role in type 2 diabetes and pregnancy, both of which are under a low-grade inflammatory state. However, the action of MFG-E8 in gestational diabetes mellitus (GDM) is unclear. We measured plasma MFG-E8 levels in pregnancy and GDM for the first time, and elucidated possible relationships between its plasma levels and various metabolic parameters. Plasma MFG-E8 levels were quantified by enzyme-linked immunosorbent assay in 66 women with GDM, 70 with normal pregnancy (p-NGT) and 44 healthy non-pregnant controls (CON), who were matched for age and body mass index. Inflammatory factors tumor necrosis factor-α (TNF-α) and C-reactive protein levels were measured, oral glucose tolerance test was carried out and β-cell function was evaluated. Plasma MFG-E8 levels were remarkably higher in p-NGT than in CON (P = 0.024), and were further elevated in GDM vs p-NGT (P = 0.016). MFG-E8 concentrations correlated positively with hemoglobin A1c, glucose levels and insulin resistance (homeostasis model assessment for insulin resistance), and correlated inversely with TNF-α and insulin secretion evaluated by disposition indices in pregnancies. Fasting glucose levels, disposition index of first phase insulin secretion and TNF-α were independent predictors of MFG-E8 levels in pregnancies. Logistic regression analyses showed that women in the third tertile of MFG-E8 levels had a markedly elevated risk of GDM. Circulating MFG-E8 levels are dramatically elevated in pregnancy, and are significantly higher in GDM vs p-NGT. MFG-E8 concentrations are significantly associated with TNF-α, fasting glucose levels, homeostasis model assessment for insulin resistance and disposition indices. However, further studies are required to elucidate the regulation mechanism of MFG-E8 during pregnancy and GDM. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose.

PubMed

Powell, David R; Smith, Melinda; Greer, Jennifer; Harris, Angela; Zhao, Sharon; DaCosta, Christopher; Mseeh, Faika; Shadoan, Melanie K; Sands, Arthur; Zambrowicz, Brian; Ding, Zhi-Ming

2013-05-01

LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.

Chronic benzylamine administration in the drinking water improves glucose tolerance, reduces body weight gain and circulating cholesterol in high-fat diet-fed mice.

PubMed

Iffiú-Soltész, Zsuzsa; Wanecq, Estelle; Lomba, Almudena; Portillo, Maria P; Pellati, Federica; Szöko, Eva; Bour, Sandy; Woodley, John; Milagro, Fermin I; Alfredo Martinez, J; Valet, Philippe; Carpéné, Christian

2010-04-01

Benzylamine is found in Moringa oleifera, a plant used to treat diabetes in traditional medicine. In mammals, benzylamine is metabolized by semicarbazide-sensitive amine oxidase (SSAO) to benzaldehyde and hydrogen peroxide. This latter product has insulin-mimicking action, and is involved in the effects of benzylamine on human adipocytes: stimulation of glucose transport and inhibition of lipolysis. This study examined whether chronic, oral administration of benzylamine could improve glucose tolerance and the circulating lipid profile without increasing oxidative stress in overweight and pre-diabetic mice. The benzylamine diffusion across the intestine was verified using everted gut sacs. Then, glucose handling and metabolic markers were measured in mice rendered insulin-resistant when fed a high-fat diet (HFD) and receiving or not benzylamine in their drinking water (3600micromol/(kgday)) for 17 weeks. HFD-benzylamine mice showed lower body weight gain, fasting blood glucose, total plasma cholesterol and hyperglycaemic response to glucose load when compared to HFD control. In adipocytes, insulin-induced activation of glucose transport and inhibition of lipolysis remained unchanged. In aorta, benzylamine treatment partially restored the nitrite levels that were reduced by HFD. In liver, lipid peroxidation markers were reduced. Resistin and uric acid, surrogate plasma markers of metabolic syndrome, were decreased. In spite of the putative deleterious nature of the hydrogen peroxide generated during amine oxidation, and in agreement with its in vitro insulin-like actions found on adipocytes, the SSAO-substrate benzylamine could be considered as a potential oral agent to treat metabolic syndrome. Copyright 2010 Elsevier Ltd. All rights reserved.

Impaired brain energy gain upon a glucose load in obesity.

PubMed

Wardzinski, Ewelina K; Kistenmacher, Alina; Melchert, Uwe H; Jauch-Chara, Kamila; Oltmanns, Kerstin M

2018-03-06

There is evidence that the brain's energy status is lowered in obesity despite of chronic hypercaloric nutrition. The underlying mechanisms are unknown. We hypothesized that the brain of obese people does not appropriately generate energy in response to a hypercaloric supply. Glucose was intravenously infused in 17 normal weights and 13 obese participants until blood glucose concentrations reached the postprandial levels of 7 mmol/L and 10 mmol/L. Changes in cerebral adenosine triphosphate (ATP) and phosphocreatine (PCr) content were measured by 31 phosphorus magnetic resonance spectroscopy and stress hormonal measures regulating glucose homeostasis were monitored. Because vitamin C is crucial for a proper neuronal energy synthesis we determined circulating concentrations during the experimental testing. Cerebral high-energy phosphates were increased at blood glucose levels of 7 mmol/L in normal weights, which was completely missing in the obese. Brain energy content moderately raised only at blood glucose levels of 10 mmol/L in obese participants. Vitamin C concentrations generally correlated with the brain energy content at blood glucose concentrations of 7 mmol/L. Our data demonstrate an inefficient cerebral energy gain upon a glucose load in obese men, which may result from a dysfunctional glucose transport across the blood-brain barrier or a downregulated energy synthesis in mitochondrial oxidation processes. Our finding offers an explanation for the chronic neuroenergetic deficiency and respectively missing satiety perception in obesity. Copyright © 2018. Published by Elsevier Inc.

Metabolic adaptations to HFHS overfeeding: how whole body and tissues postprandial metabolic flexibility adapt in Yucatan mini-pigs.

PubMed

Polakof, Sergio; Rémond, Didier; Bernalier-Donadille, Annick; Rambeau, Mathieu; Pujos-Guillot, Estelle; Comte, Blandine; Dardevet, Dominique; Savary-Auzeloux, Isabelle

2018-02-01

In the present study, we aimed to metabolically characterize the postprandial adaptations of the major tissues involved in energy, lipids and amino acids metabolisms in mini-pigs. Mini-pigs were fed on high-fat-high-sucrose (HFHS) diet for 2 months and several tissues explored for metabolic analyses. Further, the urine metabolome was followed over the time to picture the metabolic adaptations occurring at the whole body level following overfeeding. After 2 months of HFHS consumption, mini-pigs displayed an obese phenotype characterized by high circulating insulin, triglycerides and cholesterol levels. At the tissue level, a general (muscle, adipose tissue, intestine) reduction in the capacity to phosphorylate glucose was observed. This was also supported by the enhanced hepatic gluconeogenesis potential, despite the concomitant normoglycaemia, suggesting that the high circulating insulin levels would be enough to maintain glucose homoeostasis. The HFHS feeding also resulted in a reduced capacity of two other pathways: the de novo lipogenesis, and the branched-chain amino acids transamination. Finally, the follow-up of the urine metabolome over the time allowed determining breaking points in the metabolic trajectory of the animals. Several features confirmed the pertinence of the animal model, including increased body weight, adiposity and porcine obesity index. At the metabolic level, we observed a perturbed glucose and amino acid metabolism, known to be related to the onset of the obesity. The urine metabolome analyses revealed several metabolic pathways potentially involved in the obesity onset, including TCA (citrate, pantothenic acid), amino acids catabolism (cysteine, threonine, leucine).

Diet-induced hyperinsulinemia differentially affects glucose and protein metabolism: a high-throughput metabolomic approach in rats.

PubMed

Etxeberria, U; de la Garza, A L; Martínez, J A; Milagro, F I

2013-09-01

Metabolomics is a high-throughput tool that quantifies and identifies the complete set of biofluid metabolites. This "omics" science is playing an increasing role in understanding the mechanisms involved in disease progression. The aim of this study was to determine whether a nontargeted metabolomic approach could be applied to investigate metabolic differences between obese rats fed a high-fat sucrose (HFS) diet for 9 weeks and control diet-fed rats. Animals fed with the HFS diet became obese, hyperleptinemic, hyperglycemic, hyperinsulinemic, and resistant to insulin. Serum samples of overnight-fasted animals were analyzed by (1)H NMR technique, and 49 metabolites were identified and quantified. The biochemical changes observed suggest that major metabolic processes like carbohydrate metabolism, β-oxidation, tricarboxylic acid cycle, Kennedy pathway, and folate-mediated one-carbon metabolism were altered in obese rats. The circulating levels of most amino acids were lower in obese animals. Serum levels of docosahexaenoic acid, linoleic acid, unsaturated n-6 fatty acids, and total polyunsaturated fatty acids also decreased in HFS-fed rats. The circulating levels of urea, six water-soluble metabolites (creatine, creatinine, choline, acetyl carnitine, formate, and allantoin), and two lipid compounds (phosphatidylcholines and sphingomyelin) were also significantly reduced by the HFS diet intake. This study offers further insight of the possible mechanisms implicated in the development of diet-induced obesity. It suggests that the HFS diet-induced hyperinsulinemia is responsible for the decrease in the circulating levels of urea, creatinine, and many amino acids, despite an increase in serum glucose levels.

Circulating PCSK9 in patients with type 2 diabetes and related metabolic disorders.

PubMed

Ibarretxe, Daiana; Girona, Josefa; Plana, Núria; Cabré, Anna; Ferré, Raimón; Amigó, Núria; Guaita, Sandra; Mallol, Roger; Heras, Mercedes; Masana, Luis

2016-01-01

PCSK9 is a pivotal molecule in the regulation of lipid metabolism. Previous studies have suggested that PCSK9 expression and its function in LDL receptor regulation could be altered in the context of diabetes. The aim was to assess PCSK9 plasma levels in patients with type 2 diabetes (T2DM) and other related metabolic disorders as well as its relation to the metabolomic profile generated by nuclear magnetic resonance (NMR) and glucose homeostasis. There were recruited a total of 457 patients suffering from T2DM and other metabolic disorders (metabolic syndrome (MetS), obesity and atherogenic dyslipidaemia (AD) and other disorders). Anamnesis, anthropometry and physical examinations were conducted, and vascular and abdominal adiposity imaging were carried out. Biochemical studies were performed to determine PCSK9 plasma levels 6 weeks after lipid lowering drug wash-out in treated patients. A complete metabolomic lipid profile was also generated by NMR. The rs505151 and rs11591147 genetic variants of PCSK9 gene were identified in patients. The results showed that PCSK9 levels are increased in patients with T2DM and MetS (14% and 13%; p<0.005, respectively). Circulating PCSK9 levels were correlated with an atherogenic lipid profile and with insulin resistance parameters. PCSK9 levels were also positively associated with AD, as defined by lipoprotein particle number and size. The rs11591147 genetic variant resulted in lower levels of circulating PCSK9 and LDL cholesterol (LDL-C). PCSK9 plasma levels are increased in T2DM and MetS patients and are associated with LDL-C and other parameters of AD and glucose metabolism. Copyright © 2015 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus.

PubMed

Vallon, Volker

2015-01-01

The kidneys in normoglycemic humans filter 160-180 g of glucose per day (∼30% of daily calorie intake), which is reabsorbed and returned to the systemic circulation by the proximal tubule. Hyperglycemia increases the filtered and reabsorbed glucose up to two- to three-fold. The sodium glucose cotransporter SGLT2 in the early proximal tubule is the major pathway for renal glucose reabsorption. Inhibition of SGLT2 increases urinary glucose and calorie excretion, thereby reducing plasma glucose levels and body weight. The first SGLT2 inhibitors have been approved as a new class of antidiabetic drugs in type 2 diabetes mellitus, and studies are under way to investigate their use in type 1 diabetes mellitus. These compounds work independent of insulin, improve glycemic control in all stages of diabetes mellitus in the absence of clinically relevant hypoglycemia, and can be combined with other antidiabetic agents. By lowering blood pressure and diabetic glomerular hyperfiltration, SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control.

Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans.

PubMed

List, James F; Whaley, Jean M

2011-03-01

Glucose is freely filtered in the glomeruli before being almost entirely reabsorbed into circulation from the proximal renal tubules. The sodium-glucose cotransporter 2 (SGLT2), present in the S1 segment of the proximal tubule, is responsible for the majority of glucose reabsorption. SGLT2 inhibitors reduce glucose reabsorption and increase urinary glucose excretion. In animal models and humans with type 2 diabetes, this effect is associated with reduced fasting and postprandial blood glucose levels, and reduced hemoglobin A1c. Animal studies suggest that reduction of hyperglycemia with SGLT2 inhibitors may also improve insulin sensitivity and preserve β-cell function. Urinary excretion of excess calories with SGLT2 inhibitors is also associated with reduction in body weight. Modest reductions in blood pressure have been noted with SGLT2 inhibitors, consistent with a mild diuretic action. Some C-glucoside SGLT2 inhibitors, such as dapagliflozin, have pharmacokinetic properties that make them amenable to once-daily dosing.

Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents

PubMed Central

Sinha, Rajita; Arora, Jagriti; Giannini, Cosimo; Kubat, Jessica; Malik, Saima; Van Name, Michelle A.; Santoro, Nicola; Savoye, Mary; Duran, Elvira J.; Pierpont, Bridget; Cline, Gary; Constable, R. Todd; Sherwin, Robert S.

2016-01-01

Increased sugar-sweetened beverage consumption has been linked to higher rates of obesity. Using functional MRI, we assessed brain perfusion responses to drinking two commonly consumed monosaccharides, glucose and fructose, in obese and lean adolescents. Marked differences were observed. In response to drinking glucose, obese adolescents exhibited decreased brain perfusion in brain regions involved in executive function (prefrontal cortex [PFC]) and increased perfusion in homeostatic appetite regions of the brain (hypothalamus). Conversely, in response to drinking glucose, lean adolescents demonstrated increased PFC brain perfusion and no change in perfusion in the hypothalamus. In addition, obese adolescents demonstrated attenuated suppression of serum acyl-ghrelin and increased circulating insulin level after glucose ingestion; furthermore, the change in acyl-ghrelin and insulin levels after both glucose and fructose ingestion was associated with increased hypothalamic, thalamic, and hippocampal blood flow in obese relative to lean adolescents. Additionally, in all subjects there was greater perfusion in the ventral striatum with fructose relative to glucose ingestion. Finally, reduced connectivity between executive, homeostatic, and hedonic brain regions was observed in obese adolescents. These data demonstrate that obese adolescents have impaired prefrontal executive control responses to drinking glucose and fructose, while their homeostatic and hedonic responses appear to be heightened. Thus, obesity-related brain adaptations to glucose and fructose consumption in obese adolescents may contribute to excessive consumption of glucose and fructose, thereby promoting further weight gain. PMID:27207544

Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota.

PubMed

Serena, Carolina; Ceperuelo-Mallafré, Victoria; Keiran, Noelia; Queipo-Ortuño, Maria Isabel; Bernal, Rosa; Gomez-Huelgas, Ricardo; Urpi-Sarda, Mireia; Sabater, Mónica; Pérez-Brocal, Vicente; Andrés-Lacueva, Cristina; Moya, Andres; Tinahones, Francisco J; Fernández-Real, Jose Manuel; Vendrell, Joan; Fernández-Veledo, Sonia

2018-02-12

Gut microbiota-related metabolites are potential clinical biomarkers for cardiovascular disease (CVD). Circulating succinate, a metabolite produced by both microbiota and the host, is increased in hypertension, ischemic heart disease, and type 2 diabetes. We aimed to analyze systemic levels of succinate in obesity, a major risk factor for CVD, and its relationship with gut microbiome. We explored the association of circulating succinate with specific metagenomic signatures in cross-sectional and prospective cohorts of Caucasian Spanish subjects. Obesity was associated with elevated levels of circulating succinate concomitant with impaired glucose metabolism. This increase was associated with specific changes in gut microbiota related to succinate metabolism: a higher relative abundance of succinate-producing Prevotellaceae (P) and Veillonellaceae (V), and a lower relative abundance of succinate-consuming Odoribacteraceae (O) and Clostridaceae (C) in obese individuals, with the (P + V/O + C) ratio being a main determinant of plasma succinate. Weight loss intervention decreased (P + V/O + C) ratio coincident with the reduction in circulating succinate. In the spontaneous evolution after good dietary advice, alterations in circulating succinate levels were linked to specific metagenomic signatures associated with carbohydrate metabolism and energy production with independence of body weight change. Our data support the importance of microbe-microbe interactions for the metabolite signature of gut microbiome and uncover succinate as a potential microbiota-derived metabolite related to CVD risk.

Hyper-G stress-induced hyperglycemia in rats mediated by glucoregulatory hormones

NASA Technical Reports Server (NTRS)

Daligcon, B. C.; Oyama, J.

1985-01-01

The present investigation is concerned with possible relations of the hyperglycemic response of rats exposed to hyper-G stress to (1) alterations in blood levels of the glucoregulatory hormones and gluconeogenic substrates, and (2) changes in insulin response on muscle glucose uptake. Male Sprague-Dawley rats weighing 250-300 g were used in the study. The results of the experiments indicate that the initial rapid rise in blood glucose of rats exposed to hyper-G stress is mediated by increases in circulating catecholamines and glucagon, both potent stimulators of hepatic gluconeogenesis. Lactate, derived from epinephrine stimulation of muscle glycogenolysis, appears to be a major precursor for the initial rise in blood glucose. The inhibition of the insulin-stimulated glucose uptake by muscle tissues may be a factor in the observed sustained hyperglycemia.

Complement Factor H Is Expressed in Adipose Tissue in Association With Insulin Resistance

PubMed Central

Moreno-Navarrete, José María; Martínez-Barricarte, Rubén; Catalán, Victoria; Sabater, Mònica; Gómez-Ambrosi, Javier; Ortega, Francisco José; Ricart, Wifredo; Blüher, Mathias; Frühbeck, Gema; Rodríguez de Cordoba, Santiago; Fernández-Real, José Manuel

2010-01-01

OBJECTIVE Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. RESEARCH DESIGN AND METHODS Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. RESULTS Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. CONCLUSIONS Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances. PMID:19833879

Physical and mathematical aspects of blood-glucose- and insulin-level kinetics in patients with coronary heart disease and high risk of its development

NASA Astrophysics Data System (ADS)

Denisova, Tatyana P.; Malinova, Lidia I.; Malinov, Igor A.

2001-05-01

The intravenous glucose tolerance test was performed to estimate the kinetics of blood glucose and insulin levels. Glucose was injected in individual standardized dose (0.5 g. per 1 kg of body weight). Three groups of patients were checked up: 1) patients with coronary heart disease verified by cicatricial alterations in myocardium found by electrocardiographic and echocardiographic methods; 2) children of patients with transmural myocardial infarction practically healthy at the moment of study; 3) persons practically healthy at the moment of study without any indications on cardiovascular diseases and non-insulin dependent diabetes mellitus among all ancestors and relatives who frequently were long-livers. Last groups didn't differ by age and sex. Peripheral blood glucose level, immunoreactive and free insulin (tested by muscular tissue) were studied just before glucose injection (on an empty stomach) and 4 times after it. The received discrete data were approximated by high degree polynomials, the estimation of blood glucose and insulin time functions symmetric was performed. The deceleration of degradation of insulin circulating in peripheral blood and the time decrease of second phase of insulin secretion were analytically established. This fact proves the complicated mechanism of insulin alterations in atherosclerosis, consisting not only of insulin resistance of peripheral tissues but of decrease of plastic processes in insulin- generating cells.

Peptide YY kinetics and effects on blood pressure and circulating pancreatic and gastrointestinal hormones and metabolites in man.

PubMed

Adrian, T E; Sagor, G R; Savage, A P; Bacarese-Hamilton, A J; Hall, G M; Bloom, S R

1986-10-01

Peptide YY (PYY) is a 36 amino acid peptide produced by mucosal endocrine cells of the ileum and colon which inhibits acid secretion and intestinal transit in man. To assess its effects on metabolites and digestive hormones PYY was infused into 18 fasting normal subjects at three dose levels (0.06, 0.19, and 0.57 pmol kg-1 min-1), each for a period of 1 h. During the infusions mean plasma PYY levels increased by 8, 25, and 73 pmol/liter, respectively. The mean disappearance half-time on stopping the infusions was 9.2 +/- 0.4 (SEM) min. The mean MCR was 7.3 +/- 0.7 ml kg-1 min-1 and the apparent volume of distribution was calculated to be 94 +/- 9 ml kg-1. During the highest dose infusion there was a significant increase in both systolic and diastolic blood pressure, of 8.6 +/- 3.7 mmHg (P less than 0.05) and 10.9 +/- 3.0 mmHg (P less than 0.01), respectively. PYY caused a significant 50% reduction in plasma pancreatic polypeptide concentrations (P less than 0.05) and a 55% reduction in circulating motilin levels (P less than 0.05). PYY had no significant effect on circulating concentrations of insulin, glucagon, gastrin, gastric inhibitory peptide, neurotensin, enteroglucagon, or vasoactive intestinal peptide. PYY also had no significant effect on circulating concentrations of glucose, lactate, glycerol, or nonesterified fatty acids. This recently discovered human intestinal hormonal peptide thus has significant effects both on gastrointestinal hormones (motilin and pancreatic polypeptide) and blood pressure in man, but appears not to influence glucose or lipid metabolism.

Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1.

PubMed

Joyal, Jean-Sébastien; Sun, Ye; Gantner, Marin L; Shao, Zhuo; Evans, Lucy P; Saba, Nicholas; Fredrick, Thomas; Burnim, Samuel; Kim, Jin Sung; Patel, Gauri; Juan, Aimee M; Hurst, Christian G; Hatton, Colman J; Cui, Zhenghao; Pierce, Kerry A; Bherer, Patrick; Aguilar, Edith; Powner, Michael B; Vevis, Kristis; Boisvert, Michel; Fu, Zhongjie; Levy, Emile; Fruttiger, Marcus; Packard, Alan; Rezende, Flavio A; Maranda, Bruno; Sapieha, Przemyslaw; Chen, Jing; Friedlander, Martin; Clish, Clary B; Smith, Lois E H

2016-04-01

Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine. Current dogma suggests that high-energy-consuming photoreceptors depend on glucose. Here we show that the retina also uses fatty acid β-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid. In the retinas of Vldlr(-/-) mice with low fatty acid uptake but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG). Low α-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr(-/-) photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr(-/-) retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD), which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases.

Adiponectin gene therapy ameliorates high-fat, high-sucrose diet-induced metabolic perturbations in mice

PubMed Central

Kandasamy, A D; Sung, M M; Boisvenue, J J; Barr, A J; Dyck, J R B

2012-01-01

Background and Design: Adiponectin is an adipokine secreted primarily from adipose tissue that can influence circulating plasma glucose and lipid levels through multiple mechanisms involving a variety of organs. In humans, reduced plasma adiponectin levels induced by obesity are associated with insulin resistance and type 2 diabetes, suggesting that low adiponectin levels may contribute the pathogenesis of obesity-related insulin resistance. Methods and Results: The objective of the present study was to investigate whether gene therapy designed to elevate circulating adiponectin levels is a viable strategy for ameliorating insulin resistance in mice fed a high-fat, high-sucrose (HFHS) diet. Electroporation-mediated gene transfer of mouse adiponectin plasmid DNA into gastrocnemius muscle resulted in elevated serum levels of globular and high-molecular weight adiponectin compared with control mice treated with empty plasmid. In comparison to HFHS-fed mice receiving empty plasmid, mice receiving adiponectin gene therapy displayed significantly decreased weight gain following 13 weeks of HFHS diet associated with reduced fat accumulation, and exhibited increased oxygen consumption and locomotor activity as measured by indirect calorimetry, suggesting increased energy expenditure in these mice. Consistent with improved whole-body metabolism, mice receiving adiponectin gene therapy also had lower blood glucose and insulin levels, improved glucose tolerance and reduced hepatic gluconeogenesis compared with control mice. Furthermore, immunoblot analysis of livers from mice receiving adiponectin gene therapy showed an increase in insulin-stimulated phosphorylation of insulin signaling proteins. Conclusion: Based on these data, we conclude that adiponectin gene therapy ameliorates the metabolic abnormalities caused by feeding mice a HFHS diet and may be a potential therapeutic strategy to improve obesity-mediated impairments in insulin sensitivity. PMID:23446660

Serum levels of fractalkine are associated with markers of insulin resistance in gestational diabetes.

PubMed

Ebert, T; Hindricks, J; Kralisch, S; Lossner, U; Jessnitzer, B; Richter, J; Blüher, M; Stumvoll, M; Fasshauer, M

2014-08-01

Fractalkine has recently been introduced as an adipokine that improves glucose tolerance. Regulation of fractalkine in gestational diabetes, as well as its association with markers of obesity, glucose and lipid metabolism, inflammation and renal function, has not been elucidated. Circulating fractalkine was quantified by enzyme-linked immunosorbent assay in 74 women with gestational diabetes and 74 healthy, pregnant control subjects matched for age, BMI, and gestational age. Median (interquartile range) levels of fractalkine were not significantly different between the two groups [gestational diabetes: 2.24 (2.16) μg/l; control: 2.45 (1.38) μg/l] (P = 0.461). In multivariate linear regression analysis, fractalkine remained independently associated with homeostasis model assessment of insulin resistance (β = -0.253, P = 0.002) and the proinflammatory adipokine progranulin (β = 0.218, P = 0.007). Circulating fractalkine is not different between women with gestational diabetes and control subjects, but the adipokine is independently associated with markers of insulin resistance and proinflammatory progranulin in pregnancy. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial.

PubMed

Takebayashi, Kohzo; Hara, Kenji; Terasawa, Tomoko; Naruse, Rika; Suetsugu, Mariko; Tsuchiya, Takafumi; Inukai, Toshihiko

2017-09-30

Canagliflozin has a robust inhibitory effect on sodium glucose transporter (SGLT)-2 and a mild inhibitory effect on SGLT1. The main purpose of this study was to investigate the effect of canagliflozin on circulating active glucagon-like peptide 1 (GLP-1) levels in patients with type 2 diabetes. Patients were randomly divided into a control group (n =15) and a canagliflozin-treated group (n =15). After hospitalization, the canagliflozin-treated group took 100 mg/day canagliflozin for the entire study, and after 3 days both groups took 20 mg/day teneligliptin for an additional 3 days. In a meal test, canagliflozin significantly decreased the area under curve (AUC) (0-120 min) for plasma glucose (PG) after 3 days when compared with that at baseline, and addition of teneligliptin to the canagliflozin-treated group further decreased it. A significant decrease in the AUC (0-120 min) for serum insulin by canagliflozin was obtained, but the addition of teneligliptin elevated the AUC, and thus abolished the significant difference from baseline. A significant increase in the AUC (0-120 min) of plasma active GLP-1 by canagliflozin-treatment compared with that at baseline was observed, and the addition of teneligliptin resulted in a further increase. However, canagliflozin-treatment did not change the AUC (0-120 min) of plasma active glucose-dependent insulinotropic peptide (GIP). In conclusions, canagliflozin-administration before meals decreased PG and serum insulin, and increased plasma active GLP-1 levels in patients with type 2 diabetes. Canagliflozin did not greatly influence plasma active GIP levels.

General Lack of Correlations between Age and Signs of the Metabolic Syndrome in Subjects with Non-diabetic Fasting Glucose Values.

PubMed

Preuss, Harry G; Mrvichin, Nate; Clouatre, Dallas; Bagchi, Debasis; Preuss, Jeffrey M; Perricone, Nicholas V; Swaroop, Anand; Kaats, Gilbert R

2017-01-01

Insulin resistance and advancing age are well-recognized risk factors for metabolic syndrome. Recent reports indicate that fasting glucose levels in non-diabetic patients correlate appropriately with the development of certain elements in metabolic syndrome, which suggest a cause-effect relationship with insulin resistance. The present investigation assessed whether a significant association exists between chronological age and various elements of metabolic syndrome in this same group of subjects possessing non-diabetic fasting glucose levels. Baseline data were taken from 288 subjects (age 17-87 years) with fasting glucose levels ≤ 125 mg/dl. Correlations between chronological age and different metabolic parameters were assessed to determine any statistically significant relationships and compare these with previously demonstrated metabolic parameters. With the exception of systolic blood pressure, the following correlations between age and components of metabolic syndrome were not significant or even significant in the opposite direction compared to those found in the same population using fasting glucose as the independent variable: body weight, body fat, diastolic blood pressure, white blood cell count (WBC)/neutrophil count, and circulating levels of insulin, high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hs-CRP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Although systolic blood pressure still increased, it was to a lesser extent than might be expected. In the present investigation, a cross-sectional analysis was carried out over a wide age range of subjects. It is noteworthy that fasting glucose levels and the other major elements of metabolic syndrome did not change significantly with advancing age. These results demonstrate that decreasing insulin resistance and fasting glucose levels may be an important way to overcome the adverse effects and perturbations of advancing age-induced consequences of metabolic syndrome.

Obese mice on a high-fat alternate-day fasting regimen lose weight and improve glucose tolerance.

PubMed

Joslin, P M N; Bell, R K; Swoap, S J

2017-10-01

Alternate-day fasting (ADF) causes body weight (BW) loss in humans and rodents. However, it is not clear that ADF while maintaining a high-fat (HF) diet results in weight loss and the accompanying improvement in control of circulating glucose. We tested the hypotheses that a high-fat ADF protocol in obese mice would result in (i) BW loss, (ii) improved glucose control, (iii) fluctuating phenotypes on 'fasted' days when compared to 'fed' days and (iv) induction of torpor on 'fasted days'. We evaluated the physiological effects of ADF in diet-induced obese mice for BW, heart rate (HR), body temperature (T b ), glucose tolerance, insulin responsiveness, blood parameters (leptin, insulin, free fatty acids) and hepatic gene expression. Diet-induced obese male C57BL/6J mice lost one-third of their pre-diet BW while on an ADF diet for 10 weeks consisting of HF food. The ADF protocol improved glucose tolerance and insulin sensitivity, although mice on a fast day were less glucose tolerant than the same mice on a fed day. ADF mice on a fast day had low circulating insulin, but had an enhanced response to an insulin-assisted glucose tolerance test, suggesting the impaired glucose tolerance may be a result of insufficient insulin production. On fed days, ADF mice were the warmest, had a high HR and displayed hepatic gene expression and circulating leptin that closely mimicked that of mice fed an ad lib HF diet. ADF mice never entered torpor as assessed by HR and T b . However, on fast days, they were the coolest, had the slowest HR, and displayed hepatic gene expression and circulating leptin that closely mimicked that of Chow-Fed mice. Collectively, the ADF regimen with a HF diet in obese mice results in weight loss, improved blood glucose control, and daily fluctuations in selected physiological and biochemical parameters in the mouse. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

Analytical interferences in point-of-care testing glucometers by icodextrin and its metabolites: an overview.

PubMed

Floré, Katelijne M J; Delanghe, Joris R

2009-01-01

Current point-of-care testing (POCT) glucometers are based on various test principles. Two major method groups dominate the market: glucose oxidase-based systems and glucose dehydrogenase-based systems using pyrroloquinoline quinone (GDH-PQQ) as a cofactor. The GDH-PQQ-based glucometers are replacing the older glucose oxidase-based systems because of their lower sensitivity for oxygen. On the other hand, the GDH-PQQ test method results in falsely elevated blood glucose levels in peritoneal dialysis patients receiving solutions containing icodextrin (e.g., Extraneal; Baxter, Brussels, Belgium). Icodextrin is metabolized in the systemic circulation into different glucose polymers, but mainly maltose, which interferes with the GDH-PQQ-based method. Clinicians should be aware of this analytical interference. The POCT glucometers based on the GDH-PQQ method should preferably not be used in this high-risk population and POCT glucose results inconsistent with clinical suspicion of hypoglycemic coma should be retested with another testing system.

Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes.

PubMed

von Geldern, Thomas W; Tu, Noah; Kym, Philip R; Link, James T; Jae, Hwan-Soo; Lai, Chunqiu; Apelqvist, Theresa; Rhonnstad, Patrik; Hagberg, Lars; Koehler, Konrad; Grynfarb, Marlena; Goos-Nilsson, Annika; Sandberg, Johnny; Osterlund, Marie; Barkhem, Tomas; Höglund, Marie; Wang, Jiahong; Fung, Steven; Wilcox, Denise; Nguyen, Phong; Jakob, Clarissa; Hutchins, Charles; Färnegårdh, Mathias; Kauppi, Björn; Ohman, Lars; Jacobson, Peer B

2004-08-12

Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes. Copyright 2004 American Chemical Society

Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats.

PubMed

Miller, Desinia B; Snow, Samantha J; Henriquez, Andres; Schladweiler, Mette C; Ledbetter, Allen D; Richards, Judy E; Andrews, Debora L; Kodavanti, Urmila P

2016-09-01

Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25ppm or 1.00ppm ozone, 5h/day, 3 consecutive days/week (wk) for 13wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13wk or following a 1wk recovery period (13wk+1wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13wk, however, these responses were largely reversible following a 1wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced beta-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism. Published by Elsevier Inc.

Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats☆,☆☆

PubMed Central

Miller, Desinia B.; Snow, Samantha J.; Henriquez, Andres; Schladweiler, Mette C.; Ledbetter, Allen D.; Richards, Judy E.; Andrews, Debora L.; Kodavanti, Urmila P.

2017-01-01

Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25 ppm or 1.00 ppm ozone, 5 h/day, 3 consecutive days/week (wk) for 13 wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13 wk or following a 1 wk recovery period (13 wk + 1 wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13 wk, however, these responses were largely reversible following a 1 wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced beta-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism. PMID:27368153

Circulating vitamin D correlates with serum antimüllerian hormone levels in late-reproductive-aged women: Women's Interagency HIV Study.

PubMed

Merhi, Zaher O; Seifer, David B; Weedon, Jeremy; Adeyemi, Oluwatoyin; Holman, Susan; Anastos, Kathryn; Golub, Elizabeth T; Young, Mary; Karim, Roksana; Greenblatt, Ruth; Minkoff, Howard

2012-07-01

To study the correlation between circulating 25-hydroxyvitamin D (25OH-D) levels and serum antimüllerian hormone (AMH) in women enrolled in the Women's Interagency HIV Study. Cross-sectional study. None. All premenopausal women (n = 388) with regular menstrual cycles were included and subdivided into three groups: group 1 with age <35 years (n = 128), group 2 with age 35-39 years (n = 119), and group 3 with age ≥40 years (n = 141). Serum for 25OH-D, AMH, fasting glucose and insulin, and creatinine levels. Correlation between 25OH-D and AMH before and after adjusting for HIV status, body mass index, race, smoking, illicit drug use, glucose and insulin levels, estimated glomerular filtration rate, and geographic site of participation. After adjusting for all covariates, the regression slope in all participants for total 25OH-D predicting log(10)AMH for 25-year-olds (youngest participant) was -0.001 (SE = 0.008); and for 45-year-olds (oldest participant) the corresponding slope was +0.011 (SE = 0.005). Fasting insulin level was negatively correlated with serum AMH. The regression slope for the correlation between 25OH-D and AMH in group 1 was +0.002 (SE = 0.006); in group 2 was +0.006 (SE = 0.005); and in group 3 was +0.011 (SE = 0.005). There was no association between HIV and AMH. A novel relationship is reported between circulating 25OH-D and AMH in women aged ≥40 years, suggesting that 25OH-D deficiency might be associated with lower ovarian reserve in late-reproductive-aged women. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Serum progranulin concentrations are not responsive during oral lipid tolerance test and oral glucose tolerance test.

PubMed

Schmid, A; Leszczak, S; Ober, I; Schäffler, A; Karrasch, T

2015-07-01

The postprandial regulation of progranulin by oral uptake of lipids and carbohydrates in healthy individuals has not yet been investigated. The regulation of progranulin in 2 large cohorts of healthy volunteers during oral lipid tolerance test (OLTT; n=100) and oral glucose tolerance test (OGTT; n=100) was analyzed. One hundred healthy volunteers underwent OLTT and OGTT in an outpatient setting. Venous blood was drawn at 0 hours (h) (fasting) and at 2, 4, and 6 h in OLTT or 1 and 2 h in OGTT. A novel OLTT solution completely free of carbohydrates and protein was applied. Subjects were characterized by anthropometric and laboratory parameters. Serum concentrations of progranulin were measured by enzyme-linked immunosorbent assay (ELISA). Circulating progranulin levels remained unchanged during OLTT and OGTT. Fasting progranulin levels ranged between 31.3±8.7 and 40.6±7.7 ng/ml and were not different in subgroups addressing BMI, gender, family history, smoking habits, and hormonal contraception. There was a reciprocal correlation of progranulin with HDL (negative) and LDL cholesterol levels (positive). In healthy adults, fasting and postprandial circulating progranulin levels are not different in BMI subgroups. Oral uptake of carbohydrates and lipids does not influence circulating progranulin levels in a short-term manner. A postprandial and short-term regulation of this adipokine is absent, at least in healthy subjects. There is a negative correlation of progranulin with HDL cholesterol, but a positive correlation with LDL cholesterol. This reciprocal association might be of physiological importance for an individual's atherosclerotic risk. © Georg Thieme Verlag KG Stuttgart · New York.

High-Density Lipoprotein Maintains Skeletal Muscle Function by Modulating Cellular Respiration in Mice

PubMed Central

Lehti, Maarit; Donelan, Elizabeth; Abplanalp, William; Al-Massadi, Omar; Habegger, Kirk; Weber, Jon; Ress, Chandler; Mansfeld, Johannes; Somvanshi, Sonal; Trivedi, Chitrang; Keuper, Michaela; Ograjsek, Teja; Striese, Cynthia; Cucuruz, Sebastian; Pfluger, Paul T.; Krishna, Radhakrishna; Gordon, Scott M.; Silva, R. A. Gangani D.; Luquet, Serge; Castel, Julien; Martinez, Sarah; D'Alessio, David; Davidson, W. Sean; Hofmann, Susanna M.

2014-01-01

Background Abnormal glucose metabolism is a central feature of disorders with increased rates of cardio-vascular disease (CVD). Low levels of high density lipoprotein (HDL) are a key predictor for CVD. We used genetic mouse models with increased HDL levels (apoA-I tg) and reduced HDL levels (apoA-I ko) to investigate whether HDL modulates mitochondrial bioenergetics in skeletal muscle. Methods and Results ApoA-I ko mice exhibited fasting hyperglycemia and impaired glucose tolerance test (GTT) compared to wild type (wt) mice. Mitochondria isolated from gastrocnemius muscle of apoA-I ko mice displayed markedly blunted ATP synthesis. Endurance capacity (EC) during exercise exhaustion test was impaired in apoA-I ko mice. HDL directly enhanced glucose oxidation by increasing glycolysis and mitochondrial respiration rate (OCR) in C2C12 muscle cells. ApoA-I tg mice exhibited lower fasting glucose levels, improved GTT, increased lactate levels, reduced fat mass, associated with protection against age-induced decline of EC compared to wt mice. Circulating levels of fibroblast growth factor 21 (FGF21), a novel biomarker for mitochondrial respiratory chain deficiencies and inhibitor of white adipose lipolysis, were significantly reduced in apoA-I tg mice. Consistent with an increase in glucose utilization of skeletal muscle, genetically increased HDL and apoA-I levels in mice prevented high fat diet-induced impairment of glucose homeostasis. Conclusions In view of impaired mitochondrial function and decreased HDL levels in T2D, our findings indicate that HDL-raising therapies may preserve muscle mitochondrial function and address key aspects of T2D beyond CVD. PMID:24170386

Circulating ApoJ is closely associated with insulin resistance in human subjects.

PubMed

Seo, Ji A; Kang, Min-Cheol; Ciaraldi, Theodore P; Kim, Sang Soo; Park, Kyong Soo; Choe, Charles; Hwang, Won Min; Lim, Dong Mee; Farr, Olivia; Mantzoros, Christos; Henry, Robert R; Kim, Young-Bum

2018-01-01

Insulin resistance is a major risk factor for type 2 diabetes. ApolipoproteinJ (ApoJ) has been implicated in altered pathophysiologic states including cardiovascular and Alzheimer's disease. However, the function of ApoJ in regulation of glucose homeostasis remains unclear. This study sought to determine whether serum ApoJ levels are associated with insulin resistance in human subjects and if they change after interventions that improve insulin sensitivity. Serum ApoJ levels and insulin resistance status were assessed in nondiabetic (ND) and type 2 diabetic (T2D) subjects. The impacts of rosiglitazone or metformin therapy on serum ApoJ levels and glucose disposal rate (GDR) during a hyperinsulinemic/euglycemic clamp were evaluated in a separate cohort of T2D subjects. Total ApoJ protein or that associated with the HDL and LDL fractions was measured by immunoblotting or ELISA. Fasting serum ApoJ levels were greatly elevated in T2D subjects (ND vs T2D; 100±8.3 vs. 150.6±8.5AU, P<0.0001). Circulating ApoJ levels strongly correlated with fasting glucose, fasting insulin, HOMA-IR, and BMI. ApoJ levels were significantly and independently associated with HOMA-IR, even after adjustment for age, sex, and BMI. Rosiglitazone treatment in T2D subjects resulted in a reduction in serum ApoJ levels (before vs. after treatment; 100±13.9 vs. 77±15.2AU, P=0.015), whereas metformin had no effect on ApoJ levels. The change in ApoJ levels during treatment was inversely associated with the change in GDR. Interestingly, ApoJ content in the LDL fraction was inversely associated with HOMA-IR. Serum ApoJ levels are closely correlated with the magnitude of insulin resistance regardless of obesity, and decrease along with improvement of insulin resistance in response only to rosiglitazone in type 2 diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

Abnormal oral glucose tolerance and glucose malabsorption after vagotomy and pyloroplasty. A tracer method for measuring glucose absorption rates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radziuk, J.; Bondy, D.C.

1982-11-01

The mechanisms underlying the abnormal glucose tolerance in patients who had undergone vagotomy and pyloroplasty were investigated by measuring the rates of absorption of ingested glucose and the clearance rate of glucose using tracer methods. These methods are based on labeling a 100-g oral glucose load with (1-/sup 14/C)glucose and measuring glucose clearance using plasma levels of infused (3-/sup 3/H)glucose. The rate of appearance of both ingested and total glucose is then calculated continuously using a two-compartment model of glucose kinetics. It was found that about 30% of the ingested glucose (100 g) failed to appear in the systemic circulation.more » That this was due to malabsorption was confirmed using breath-hydrogen analysis. The absorption period is short (101 +/- 11 min) compared with normal values but the clearance of glucose is identical to that in control subjects, and it peaks 132 +/- 7 min after glucose loading. The peak plasma insulin values were more than four times higher in patients than in normal subjects, and this may afford an explanation of rates of glucose clearance that are inappropriate for the short absorption period. The combination of glucose malabsorption and this clearance pattern could yield the hypoglycemia that may be observed in patients after gastric surgery.« less

A randomized controlled trial: branched-chain amino acid levels and glucose metabolism in patients with obesity and sleep apnea.

PubMed

Barceló, Antonia; Morell-Garcia, Daniel; Salord, Neus; Esquinas, Cristina; Pérez, Gerardo; Pérez, Antonio; Monasterio, Carmen; Gasa, Merce; Fortuna, Ana Maria; Montserrat, Josep Maria; Mayos, Mercedes

2017-12-01

There is evidence that changes in branched-chain amino acid (BCAA) levels may correlate with the efficacy of therapeutic interventions for affecting improvement in metabolic control. The objective of this study was to evaluate whether serum concentrations of BCAAs (leucine, isoleucine, valine) could mediate in insulin sensitivity and glucose tolerance after continuous positive airway pressure (CPAP) treatment in patients with obstructive sleep apnea (OSA). A prospective randomized controlled trial of OSA patients with morbid obesity was conducted. Eighty patients were randomized into two groups: 38 received conservative treatment and 42 received CPAP treatment for 12 weeks. Plasma levels of BCAA, glucose tolerance and insulin resistance were evaluated at baseline and after treatment. After treatment, significant decreases of leucine levels were observed in both groups when compared with baseline levels (P < 0.005). With respect to patients with normal glucose tolerance (NGT), patients with impaired glucose tolerance (IGT) had higher baseline levels of isoleucine (78 ± 16 versus 70 ± 13 μmol L -1 , P = 0.014) and valine (286 ± 36 versus 268 ± 41 μmol L -1 , P = 0.049), respectively. Changes in levels of leucine and isoleucine after treatment were related negatively to changes in fasting plasma glucose and glycosylated haemoglobin values only in the conservative group (P < 0.05). In summary, we found that the treatment with CPAP for 12 weeks caused similar changes in circulating BCAAs concentrations to conservative treatment and a differential metabolic response of CPAP and conservative treatment was observed between the relationship of BCAAs and glucose homeostasis. Additional studies are needed to determine the interplay between branched-chain amino acids and glucose metabolism in patients with sleep apnea. © 2017 European Sleep Research Society.

Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats.

PubMed

Oakes, Nicholas D; Thalén, Pia; Hultstrand, Therese; Jacinto, Severina; Camejo, Germán; Wallin, Boel; Ljung, Bengt

2005-10-01

Insulin resistance, impaired glucose tolerance, high circulating levels of free fatty acids (FFA), and postprandial hyperlipidemia are associated with the metabolic syndrome, which has been linked to increased risk of cardiovascular disease. We studied the metabolic responses to an oral glucose/triglyceride (TG) (1.7/2.0 g/kg lean body mass) load in three groups of conscious 7-h fasted Zucker rats: lean healthy controls, obese insulin-resistant/dyslipidemic controls, and obese rats treated with the dual peroxisome proliferator-activated receptor alpha/gamma agonist, tesaglitazar, 3 mumol.kg(-1).day(-1) for 4 wk. Untreated obese Zucker rats displayed marked insulin resistance, as well as glucose and lipid intolerance in response to the glucose/TG load. The 2-h postload area under the curve values were greater for glucose (+19%), insulin (+849%), FFA (+53%), and TG (+413%) compared with untreated lean controls. Treatment with tesaglitazar lowered fasting plasma glucose, improved glucose tolerance, substantially reduced fasting and postload insulin levels, and markedly lowered fasting TG and improved lipid tolerance. Fasting FFA were not affected, but postprandial FFA suppression was restored to levels seen in lean controls. Mechanisms of tesaglitazar-induced lowering of plasma TG were studied separately using the Triton WR1339 method. In anesthetized, 5-h fasted, obese Zucker rats, tesaglitazar reduced hepatic TG secretion by 47%, increased plasma TG clearance by 490%, and reduced very low-density lipoprotein (VLDL) apolipoprotein CIII content by 86%, compared with obese controls. In conclusion, the glucose/lipid tolerance test in obese Zucker rats appears to be a useful model of the metabolic syndrome that can be used to evaluate therapeutic effects on impaired postprandial glucose and lipid metabolism. The present work demonstrates that tesaglitazar ameliorates these abnormalities and enhances insulin sensitivity in this animal model.

Alterations of fasting glucose and fat metabolism in intrauterine growth-retarded newborn dogs.

PubMed

Kliegman, R M

1989-03-01

Maternal nutritional deprivation resulted in reduced fetal weight at term gestation (251 +/- 7 vs. 277 +/- 7 g, P less than 0.01) in newborn dogs. Growth-retarded pups developed lower blood glucose levels after 3, 6, and 9 h of neonatal fasting, reduced plasma levels of free fatty acids (FFA) at 9 and 24 h, and lower ketone bodies at 24 h compared with age-matched newborn control pups. Systemic rates of palmitate and alanine turnover were not affected, but systemic glucose turnover was reduced for 3-9 h after birth. The rate of alanine incorporation into glucose from 3 to 9 h was also reduced in growth-retarded pups compared with timed controls. Paradoxically, the rate of incorporation of palmitate into triglycerides was augmented in the smaller growth-retarded pups. Hepatic glycogen content was reduced at every time in the study among growth-retarded pups, whereas the rates of glycogenolysis between birth and 24 h were equivalent in the two pup groups. In contrast, hepatic triglyceride levels were augmented throughout the study in pups with growth retardation. Maternal starvation and lower glucose levels resulted in a lower hepatic energy charge, and augmented cytoplasmic and mitochondrial NAD-to-NADH ratios in intrauterine growth-retarded pups. These data suggest that intrauterine growth retardation in dogs results in fasting neonatal hypoglycemia that is due in part to reduced systemic glucose production. We speculate that reduced rates of gluconeogenesis from alanine and reduced oxidation of alternate fuels such as FFA contribute to hypoglycemia. FFA recycling to triglyceride synthesis rather than oxidative pathways may contribute to the observed reduction of circulating glucose levels.

Association between circulating fibroblast growth factor 21 and mortality in end-stage renal disease.

PubMed

Kohara, Marina; Masuda, Takahiro; Shiizaki, Kazuhiro; Akimoto, Tetsu; Watanabe, Yuko; Honma, Sumiko; Sekiguchi, Chuji; Miyazawa, Yasuharu; Kusano, Eiji; Kanda, Yoshinobu; Asano, Yasushi; Kuro-O, Makoto; Nagata, Daisuke

2017-01-01

Fibroblast growth factor 21 (FGF21) is an endocrine factor that regulates glucose and lipid metabolism. Circulating FGF21 predicts cardiovascular events and mortality in type 2 diabetes mellitus, including early-stage chronic kidney disease, but its impact on clinical outcomes in end-stage renal disease (ESRD) patients remains unclear. This study enrolled 90 ESRD patients receiving chronic hemodialysis who were categorized into low- and high-FGF21 groups by the median value. We investigated the association between circulating FGF21 levels and the cardiovascular event and mortality during a median follow-up period of 64 months. A Kaplan-Meier analysis showed that the mortality rate was significantly higher in the high-FGF21 group than in the low-FGF21 group (28.3% vs. 9.1%, log-rank, P = 0.034), while the rate of cardiovascular events did not significantly differ between the two groups (30.4% vs. 22.7%, log-rank, P = 0.312). In multivariable Cox models adjusted a high FGF21 level was an independent predictor of all-cause mortality (hazard ratio: 3.98; 95% confidence interval: 1.39-14.27, P = 0.009). Higher circulating FGF21 levels were associated with a high mortality rate, but not cardiovascular events in patient with ESRD, suggesting that circulating FGF21 levels serve as a predictive marker for mortality in these subjects.

Effect of supplemental protein source during the winter on pre- and postpartum glucose metabolism

USDA-ARS?s Scientific Manuscript database

Circulating serum glucose concentrations as well as glucose utilization have been shown to be affected by forage quality. Supplemental protein provided to grazing range cows while consuming low quality forage may improve glucose metabolism. The objective of our study was to determine the effects of ...

Chronic alcohol consumption, type 2 diabetes mellitus, insulin-like growth factor-I (IGF-I), and growth hormone (GH) in ethanol-treated diabetic rats.

PubMed

Kim, Soo-Jeong; Ju, Anes; Lim, Seul-Gi; Kim, Dai-Jin

2013-11-13

Alcohol has deleterious influences on glucose metabolism which may contribute to the development of type 2 diabetes mellitus (T2DM). Insulin-like growth factor I (IGF-I) and growth hormone (GH), which interact with insulin to modulate metabolic control, have been shown to be related to impaired glucose tolerance. This study was conducted to assess the possibility that altered circulating IGF-I and GH levels contribute to the exacerbation of T2DM by alcohol use in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. OLETF rats were pair-fed a Lieber-DeCarli Regular Ethanol diet and LETO rats were pair-fed a control diet for 6 weeks. At 6 weeks, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and IGF-I and GH levels were evaluated. Prior to an IP-GTT, OLETF-Ethanol (O-E) group had significantly a decrease in the mean glucose levels compared to OLETF-Control (O-C) group. At 120 min post IP-GTT, the O-E group had significantly an increase in the mean glucose levels compared to O-C group. The serum IGF-I levels were significantly lower and the serum GH levels were significantly higher in the O-E group than in L-C group. These results suggest that IGF-I and GH are prominent in defining the risk and development of T2DM, and may be adversely affected by heavy alcohol use, possibly mediating its diabetogenic effects. Thus, the overall glucose intolerance in the setting of alcoholism may be attributable to inappropriate alteration of IGF-I and GH levels. © 2013. Published by Elsevier Inc. All rights reserved.

Relationship between circulating visfatin/NAMPT, nutritional status and insulin resistance in an elderly population - results from the PolSenior substudy.

PubMed

Olszanecka-Glinianowicz, Magdalena; Owczarek, Aleksander; Bożentowicz-Wikarek, Maria; Brzozowska, Aniceta; Mossakowska, Małgorzata; Zdrojewski, Tomasz; Grodzicki, Tomasz; Więcek, Andrzej; Chudek, Jerzy

2014-11-01

Circulating visfatin/nicotinamide phosphoribosyltransferase (visfatin/NAMPT) levels according to some studies are related to nutritional status and insulin resistance. These associations have not been studied in large elderly populations. Therefore, the aim of our study was to assess the relationships between circulating visfatin/NAMPT levels, nutritional status, and insulin resistance in a large population of the elderly. Concentrations of glucose, albumin, creatinine, CRP, interleukin-6, insulin, and visfatin/NAMPT (by ELISA) were assessed, and HOMA-IR calculated in 3050 elderly participants of the PolSenior study. The highest plasma visfatin/NAMPT levels were observed in obese, as well as in non-diabetic insulin resistant subjects; however there were only significant differences found in women. The regression models showed that plasma visfatin/NAMPT levels decline with age and increased with waist circumference, BMI, and hs-CRP. Waist circumference was better correlated than BMI for visfatin/NAMPT levels in statistical models not adjusted by sex, and just the opposite in models which were. We demonstrated a 0.023ng/mL increase of Visfatin/NAMPT levels for 1mg/L increase of hs-CRP, and a 0.007ng/mL decline for each year of age. Our study revealed that in elderly subjects, circulating visfatin/NAMPT levels are related to age, nutritional status, especially visceral obesity, and inflammation. Copyright © 2014 Elsevier Inc. All rights reserved.

Immediate effect of passive static stretching versus resistance exercises on postprandial blood sugar levels in type 2 diabetes mellitus: a randomized clinical trial.

PubMed

Gurudut, Peeyoosha; Rajan, Abey P

2017-10-01

The prevalence of diabetes is rapidly rising all over the globe at an alarming rate. In India, more than 61.3 million people have been presently diagnosed with type 2 diabetes mellitus. It is possible to control the circulating blood glucose levels by reducing life style risk factors through physical activities comprising of muscle stretches, aerobic training, resistance exercises (REs), yoga, etc. The aim of this study is to identify and compare the immediate effect of passive static stretching (PSS) versus RE on blood glucose level in individuals with type 2 diabetes mellitus. The present study included 51 participants between the age of 40-65 years with type 2 diabetes mellitus, to study the immediate effect of 60-min PSS (n=25) and 60-min RE (n=26). The outcome measure was blood glucose level which was checked by glucometer (free-style neo). Blood sugar was assessed at 3 points of time that included fasting blood sugar level, 2 hr after the meal and immediately after the exercise regimen. Results of this study showed significant reduction in blood glucose level in subjects according to glucometer with PSS ( P =0.000) and RE ( P =0.00). However, both groups demonstrated equal effect in terms of lowering blood sugar level immediately after the exercise. The conclusion is both PSS and RE are effective in reducing postprandial blood glucose level in type 2 diabetes mellitus and must be prescribed for the patients who demonstrate difficulty in controlling post prandial spike.

Fetal and neonatal responses to maternal canine starvation: circulating fuels and neonatal glucose production.

PubMed

Kliegman, R M; Miettinen, E L; Adam, P A

1981-06-01

Pregnant dogs were starved for 72 hr while controls were fasted overnight. Maternal starvation significantly reduced fetal birth weight (269 +/- 7.2 versus 294 +/- 4.4 g). Total caloric deprivation had no effect on maternal or fetal blood glucose concentration at the time of delivery; however, fasting neonatal blood glucose levels were depressed during the first 9 hr of life. Starvation produced a large elevation of maternal free fatty acids (1.68 +/- 0.39 versus 0.74 +/- 0.2 mM) and ketone bodies (2.99 +/- 0.70 versus 1.04 +/- 0.48). Although fetal free fatty acids increased minimally (0.39 +/- 0.03 versus 0.22 +/- 0.07), ketone body levels were markedly elevated (2.53 +/- 0.35 versus 1.01 +/- 0.32). After birth, plasma-free fatty acid and beta-hydroxybutyrate levels were lower in pups of starved mothers at 3 hr, and acetoacetate was lower at 6 and 9 hr. Other alternate fuels such as amino acids demonstrated lower levels of glutamine in pups of starved mothers throughout the day (except 3 hr), whereas alanine levels declined significantly only at 24 hr (114.9 +/- 15 versus 187.6 +/- 26 microM. Glucose production was significantly depressed in pups of starved mothers at 3 (13.7 +/- 1.4 versus 22.7 +/- 3) and 9 hr (17.5 +/- 2.2 versus 26.0 +/- 2.8 mumoles/kg/min), whereas glucose clearance rates were elevated at 3, 6 and 9 hr of age. Lactate carbon incorporation into glucose increased throughout the day but was not significantly affected by prior maternal starvation.

Inhibition by Natural Dietary Substances of Gastrointestinal Absorption of Starch and Sucrose in Rats and Pigs: 1. Acute Studies

PubMed Central

Preuss, Harry G.; Echard, Bobby; Bagchi, Debasis; Stohs, Sidney

2007-01-01

Rapid gastrointestinal absorption of refined carbohydrates (CHO) is linked to perturbed glucose-insulin metabolism that is, in turn, associated with many chronic health disorders. We assessed the ability of various natural substances, commonly referred to as “CHO blockers,” to influence starch and sucrose absorption in vivo in ninety-six rats and two pigs. These natural enzyme inhibitors of amylase/sucrase reportedly lessen breakdown of starches and sucrose in the gastrointestinal tract, limiting their absorption. To estimate absorption, groups of nine SD rats were gavaged with water or water plus rice starch and/or sucrose; and circulating glucose was measured at timed intervals thereafter. For each variation in the protocol a total of at least nine different rats were studied with an equal number of internal controls on three different occasions. The pigs rapidly drank CHO and inhibitors in their drinking water. In rats, glucose elevations above baseline over four hours following rice starch challenge as estimated by area-under-curve (AUC) were 40%, 27%, and 85% of their internal control after ingesting bean extract, hibiscus extract, and l-arabinose respectively in addition to the rice starch. The former two were significantly different from control. L-Arabinose virtually eliminated the rising circulating glucose levels after sucrose challenge, whereas hibiscus and bean extracts were associated with lesser decreases than l-arabinose that were still significantly lower than control. The glucose elevations above baseline over four hours in rats receiving sucrose (AUC) were 51%, 43% and 2% of control for bean extract, hibiscus extract, and L-arabinose, respectively. Evidence for dose-response of bean and hibiscus extracts is reported. Giving the natural substances minus CHO challenge caused no significant changes in circulating glucose concentrations, indicating no major effects on overall metabolism. A formula combining these natural products significantly decreased both starch and sucrose absorption, even when the CHO were given simultaneously. These results support the hypothesis that the enzyme inhibitors examined here at reasonable doses can safely lower the glycemic loads starch and sucrose. PMID:17713600

Inhibition by natural dietary substances of gastrointestinal absorption of starch and sucrose in rats and pigs: 1. Acute studies.

PubMed

Preuss, Harry G; Echard, Bobby; Bagchi, Debasis; Stohs, Sidney

2007-08-06

Rapid gastrointestinal absorption of refined carbohydrates (CHO) is linked to perturbed glucose-insulin metabolism that is, in turn, associated with many chronic health disorders. We assessed the ability of various natural substances, commonly referred to as "CHO blockers," to influence starch and sucrose absorption in vivo in ninety-six rats and two pigs. These natural enzyme inhibitors of amylase/sucrase reportedly lessen breakdown of starches and sucrose in the gastrointestinal tract, limiting their absorption. To estimate absorption, groups of nine SD rats were gavaged with water or water plus rice starch and/or sucrose; and circulating glucose was measured at timed intervals thereafter. For each variation in the protocol a total of at least nine different rats were studied with an equal number of internal controls on three different occasions. The pigs rapidly drank CHO and inhibitors in their drinking water. In rats, glucose elevations above baseline over four hours following rice starch challenge as estimated by area-under-curve (AUC) were 40%, 27%, and 85% of their internal control after ingesting bean extract, hibiscus extract, and l-arabinose respectively in addition to the rice starch. The former two were significantly different from control. L-Arabinose virtually eliminated the rising circulating glucose levels after sucrose challenge, whereas hibiscus and bean extracts were associated with lesser decreases than l-arabinose that were still significantly lower than control. The glucose elevations above baseline over four hours in rats receiving sucrose (AUC) were 51%, 43% and 2% of control for bean extract, hibiscus extract, and L-arabinose, respectively. Evidence for dose-response of bean and hibiscus extracts is reported. Giving the natural substances minus CHO challenge caused no significant changes in circulating glucose concentrations, indicating no major effects on overall metabolism. A formula combining these natural products significantly decreased both starch and sucrose absorption, even when the CHO were given simultaneously. These results support the hypothesis that the enzyme inhibitors examined here at reasonable doses can safely lower the glycemic loads starch and sucrose.

Glucose-responsive neurons in the subfornical organ of the rat--a novel site for direct CNS monitoring of circulating glucose.

PubMed

Medeiros, N; Dai, L; Ferguson, A V

2012-01-10

Glucose-sensitive neurons have been identified in a number of CNS regions including metabolic control centers of the hypothalamus. The location of these regions behind the blood-brain barrier restricts them to sensing central, but not circulating glucose concentrations. In this study, we have used patch-clamp electrophysiology to examine whether neurons in a specialized region lacking the blood-brain barrier, the subfornical organ (SFO), are also glucose sensitive. In dissociated SFO neurons, altering the bath concentration of glucose (1 mM, 5 mM, 10 mM) influenced the excitability of 49% of neurons tested (n=67). Glucose-inhibited (GI) neurons depolarized in response to decreased glucose (n=10; mean, 4.6±1.0 mV) or hyperpolarized in response to increased glucose (n=8; mean,-4.4±0.8 mV). In contrast, glucose-excited (GE) neurons depolarized in response to increased glucose (n=9; mean, 6.4±0.4 mV) or hyperpolarized in response to decreased glucose (n=6; mean,-4.8±0.6 mV). Using voltage-clamp recordings, we also identified GI (outward current to increased glucose) and GE (inward current to increased glucose) SFO neurons. The mean glucose-induced inward current had a reversal potential of -24±12 mV (n=5), while GE responses were maintained during sodium-dependent glucose transporter inhibition, supporting the conclusion that GE properties result from the activation of a nonselective cation conductance (NSCC). The glucose-induced outward current had a mean reversal potential of -78±1.2 mV (n=5), while GI responses were not observed in the presence of glibenclamide, suggesting that these properties result from the modulation of K(ATP) channels. These data demonstrate that SFO neurons are glucose responsive, further emphasizing the potential roles of this circumventricular organ as an important sensor and integrator of circulating signals of energy status. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Factors affecting the supply of glucose to the heart of the rat, in vivo.

PubMed Central

Daniel, P M; Love, E R; Pratt, O E

1980-01-01

1. The influx of glucose into the heart of intact, living, anaesthetized rats was measured when the levels of insulin the blood were (a) low (as a result of fasting), (b) normal, and (c) high (as a result of injecting insulin). The findings showed that the transport of glucose into cardiac cells is carrier-mediated and is strongly insulin-independent. 2. The major barrier to the supply glucose to the heart from the circulating blood is at the surface membrane of the cardiac cells, rather than at the endothelium of the cardiac capillaries. 3. The extracellular space of the heart was measured and was found to be approximately 25% of the cardiac tissue. 4. During life, glucose, as well as its analogue, 3-O-methylglucose passes across the membranes of the cells of the heart by means of a transport system which is strongly dependent upon insulin and appears to be carried-mediated. A likely explanation for the effect of insulin is that it increases considerably the affinity of the transport carrier for glucose. Saturation of the carrier takes place when the levels of insulin and of glucose in the blood are high. However, when the concentration of insulin is low, e.g. during a fast, the affinity of the carrier for glucose is reduced so that saturation cannot be demonstrated. 5. It is suggested that the low level of insulin that is found in the blood in the early morning, which is due to the night fast, may lead to the cardiac dysfunction which often develops at that time. PMID:6788938

The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice

PubMed Central

Mitchell, Sharon E.; Delville, Camille; Konstantopedos, Penelope; Hurst, Jane; Derous, Davina; Green, Cara; Chen, Luonan; Han, Jackie J.D.; Wang, Yingchun; Promislow, Daniel E.L.; Lusseau, David; Douglas, Alex; Speakman, John R.

2015-01-01

Limiting food intake attenuates many of the deleterious effects of aging, impacting upon healthspan and leading to an increased lifespan. Whether it is the overall restriction of calories (calorie restriction: CR) or the incidental reduction in macronutrients such as protein (protein restriction: PR) that mediate these effects is unclear. The impact of 3 month CR or PR, (10 to 40%), on C57BL/6 mice was compared to controls fed ad libitum. Reductions in circulating leptin, tumor necrosis factor-α and insulin-like growth factor-1 (IGF-1) were relative to the level of CR and individually associated with morphological changes but remained unchanged following PR. Glucose tolerance and insulin sensitivity were improved following CR but not affected by PR. There was no indication that CR had an effect on oxidative damage, however CR lowered antioxidant activity. No biomarkers of oxidative stress were altered by PR. CR significantly reduced levels of major urinary proteins suggesting lowered investment in reproduction. Results here support the idea that reduced adipokine levels, improved insulin/IGF-1 signaling and reduced reproductive investment play important roles in the beneficial effects of CR while, in the short-term, attenuation of oxidative damage is not applicable. None of the positive effects were replicated with PR. PMID:26061745

Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice

PubMed Central

Ejaz, Asma; Martinez-Guino, Laura; Goldfine, Allison B.; Ribas-Aulinas, Francesc; De Nigris, Valeria; Ribó, Sílvia; Gonzalez-Franquesa, Alba; Garcia-Roves, Pablo M.; Li, Elizabeth; Dreyfuss, Jonathan M.; Gall, Walt; Kim, Jason K.; Bottiglieri, Teodoro; Villarroya, Francesc; Gerszten, Robert E.

2016-01-01

Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21−/− mice, demonstrating that Fgf21 is necessary for betaine’s beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans. PMID:26858359

Independent Circadian and Sleep/Wake Regulation of Adipokines and Glucose in Humans

PubMed Central

Shea, Steven A.; Hilton, Michael F.; Orlova, Christine; Ayers, R. Timothy; Mantzoros, Christos S.

2010-01-01

Leptin and adiponectin play important physiological roles in regulating appetite, food intake, and energy balance and have pathophysiological roles in obesity and anorexia nervosa. To assess the relative contributions of day/night patterns in behaviors (sleep/wake cycle and food intake) and of the endogenous circadian pacemaker on observed day/night patterns of adipokines, in six healthy subjects we measured circulating leptin, soluble leptin receptor, adiponectin, glucose, and insulin levels throughout a constant routine protocol (38 h of wakefulness with constant posture, temperature, and dim light, as well as identical snacks every 2 h) and throughout sleep and fasting periods before and after the constant routine. There were significant endogenous circadian rhythms in leptin, glucose, and insulin, with peaks around the usual time of awakening. Sleep/fasting resulted in additional systematic decreases in leptin, glucose, and insulin, whereas wakefulness/food intake resulted in a systematic increase in leptin. Thus, the day/night pattern in leptin is likely caused by combined effects from the endogenous circadian pacemaker and day/night patterns in behaviors. Our data imply that alterations in the sleep/wake schedule would lead to an increased daily range in circulating leptin, with lowest leptin upon awakening, which, by influencing food intake and energy balance, could be implicated in the increased prevalence of obesity in the shift work population. PMID:15687326

Oral Supplementation with Non-Absorbable Antibiotics or Curcumin Attenuates Western Diet-Induced Atherosclerosis and Glucose Intolerance in LDLR−/− Mice – Role of Intestinal Permeability and Macrophage Activation

PubMed Central

Ghosh, Siddhartha S.; Bie, Jinghua; Wang, Jing; Ghosh, Shobha

2014-01-01

Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as Type 2 Diabetes and atherosclerosis) has shifted the focus from Western diet-induced changes in gut microbiota per se to release of gut bacteria-derived products into circulation as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. Under physiological conditions, an intact intestinal barrier prevents this release of LPS underscoring the importance of examining and modulating the direct effects of Western diet on intestinal barrier function. In the present study we evaluated two strategies, namely selective gut decontamination and supplementation with oral curcumin, to modulate Western-diet (WD) induced changes in intestinal barrier function and subsequent development of glucose intolerance and atherosclerosis. LDLR−/− mice were fed WD for 16 weeks and either received non-absorbable antibiotics (Neomycin and polymyxin) in drinking water for selective gut decontamination or gavaged daily with curcumin. WD significantly increased intestinal permeability as assessed by in vivo translocation of FITC-dextran and plasma LPS levels. Selective gut decontamination and supplementation with curcumin significantly attenuated the WD-induced increase in plasma LPS levels (3.32 vs 1.90 or 1.51 EU/ml, respectively) and improved intestinal barrier function at multiple levels (restoring intestinal alkaline phosphatase activity and expression of tight junction proteins, ZO-1 and Claudin-1). Consequently, both these interventions significantly reduced WD-induced glucose intolerance and atherosclerosis in LDLR−/− mice. Activation of macrophages by low levels of LPS (50 ng/ml) and its exacerbation by fatty acids is likely the mechanism by which release of trace amounts of LPS into circulation due to disruption of intestinal barrier function induces the development of these diseases. These studies not only establish the important role of intestinal barrier function, but also identify oral supplementation with curcumin as a potential therapeutic strategy to improve intestinal barrier function and prevent the development of metabolic diseases. PMID:25251395

Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice.

PubMed

Aleksunes, Lauren M; Reisman, Scott A; Yeager, Ronnie L; Goedken, Michael J; Klaassen, Curtis D

2010-04-01

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) induces a battery of cytoprotective genes after oxidative stress. Nrf2 aids in liver regeneration by altering insulin signaling; however, whether Nrf2 participates in hepatic glucose homeostasis is unknown. Compared with wild-type mice, mice lacking Nrf2 (Nrf2-null) have lower basal serum insulin and prolonged hyperglycemia in response to an intraperitoneal glucose challenge. In the present study, blood glucose, serum insulin, urine flow rate, and hepatic expression of glucose-related genes were quantified in male diabetic wild-type and Nrf2-null mice. Type 1 diabetes was induced with a single intraperitoneal dose (200 mg/kg) of streptozotocin (STZ). Histopathology and serum insulin levels confirmed depleted pancreatic beta-cells in STZ-treated mice of both genotypes. Five days after STZ, Nrf2-null mice had higher blood glucose levels than wild-type mice. Nine days after STZ, polyuria occurred in both genotypes with more urine output from Nrf2-null mice (11-fold) than wild-type mice (7-fold). Moreover, STZ-treated Nrf2-null mice had higher levels of serum beta-hydroxybutyrate, triglycerides, and fatty acids 10 days after STZ compared with wild-type mice. STZ reduced hepatic glycogen in both genotypes, with less observed in Nrf2-null mice. Increased urine output and blood glucose in STZ-treated Nrf2-null mice corresponded with enhanced gluconeogenesis (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase)- and reduced glycolysis (pyruvate kinase)-related mRNA expression in their livers. Furthermore, the Nrf2 activator oltipraz lowered blood glucose in wild-type but not Nrf2-null mice administered STZ. Collectively, these data indicate that the absence of Nrf2 worsens hyperglycemia in type I diabetic mice and Nrf2 may represent a therapeutic target for reducing circulating glucose levels.

Long-term reversal of diabetes in non-obese diabetic mice by liver-directed gene therapy.

PubMed

Ren, Binhai; O'Brien, Bronwyn A; Byrne, Michelle R; Ch'ng, Edwin; Gatt, Prudence N; Swan, M Anne; Nassif, Najah T; Wei, Ming Q; Gijsbers, Rik; Debyser, Zeger; Simpson, Ann M

2013-01-01

Type 1 diabetes (T1D) results from an autoimmune attack against the insulin-producing β-cells of the pancreas. The present study aimed to reverse T1D by gene therapy. We used a novel surgical technique, which involves isolating the liver from the circulation before the delivery of a lentiviral vector carrying furin-cleavable human insulin (INS-FUR) or empty vector to the livers of diabetic non-obese diabetic mice (NOD). This was compared with the direct injection of the vector into the portal circulation. Mice were monitored for body weight and blood glucose. Intravenous glucose tolerance tests were performed. Expression of insulin and pancreatic transcription factors was determined by the reverse transcriptase-polymerase chain reaction and immunohistochemistry and immunoelectron microscopy was used to localise insulin. Using the novel surgical technique, we achieved long-term transduction (42% efficiency) of hepatocytes, restored normoglycaemia for 150 days (experimental endpoint) and re-established normal glucose tolerance. We showed the expression of β-cell transcription factors, murine insulin, glucagon and somatostatin, and hepatic storage of insulin in granules. The expression of hepatic markers, C/EBP-β, G6PC, AAT and GLUI was down-regulated in INS-FUR-treated livers. Liver function tests remained normal, with no evidence of intrahepatic inflammation or autoimmune destruction of the insulin-secreting liver tissue. By comparison, direct injection of INS-FUR reduced blood glucose levels, and no pancreatic transdifferentiation or normal glucose tolerance was observed. This gene therapy protocol has, for the first time, permanently reversed T1D with normal glucose tolerance in NOD mice and, as such, represents a novel therapeutic strategy for the treatment of T1D. Copyright © 2013 John Wiley & Sons, Ltd.

Can Glucose Be Monitored Accurately at the Site of Subcutaneous Insulin Delivery?

PubMed Central

Castle, Jessica R.; Jacobs, Peter G.; Cargill, Robert S.

2014-01-01

Because insulin promotes glucose uptake into adipocytes, it has been assumed that during measurement of glucose at the site of insulin delivery, the local glucose level would be much lower than systemic glucose. However, recent investigations challenge this notion. What explanations could account for a reduced local effect of insulin in the subcutaneous space? One explanation is that, in humans, the effect of insulin on adipocytes appears to be small. Another is that insulin monomers and dimers (from hexamer disassociation) might be absorbed into the circulation before they can increase glucose uptake locally. In addition, negative cooperativity of insulin action (a lower than expected effect of very high insulin concentrations)may play a contributing role. Other factors to be considered include dilution of interstitial fluid by the insulin vehicle and the possibility that some of the local decline in glucose might be due to the systemic effect of insulin. With regard to future research, redundant sensing units might be able to quantify the effects of proximity, leading to a compensatory algorithm. In summary, when measured at the site of insulin delivery, the decline in subcutaneous glucose level appears to be minimal, though the literature base is not large. Findings thus far support (1) the development of integrated devices that monitor glucose and deliver insulin and (2) the use of such devices to investigate the relationship between subcutaneous delivery of insulin and its local effects on glucose. A reduction in the number of percutaneous devices needed to manage diabetes would be welcome. PMID:24876621

Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents.

PubMed

Jastreboff, Ania M; Sinha, Rajita; Arora, Jagriti; Giannini, Cosimo; Kubat, Jessica; Malik, Saima; Van Name, Michelle A; Santoro, Nicola; Savoye, Mary; Duran, Elvira J; Pierpont, Bridget; Cline, Gary; Constable, R Todd; Sherwin, Robert S; Caprio, Sonia

2016-07-01

Increased sugar-sweetened beverage consumption has been linked to higher rates of obesity. Using functional MRI, we assessed brain perfusion responses to drinking two commonly consumed monosaccharides, glucose and fructose, in obese and lean adolescents. Marked differences were observed. In response to drinking glucose, obese adolescents exhibited decreased brain perfusion in brain regions involved in executive function (prefrontal cortex [PFC]) and increased perfusion in homeostatic appetite regions of the brain (hypothalamus). Conversely, in response to drinking glucose, lean adolescents demonstrated increased PFC brain perfusion and no change in perfusion in the hypothalamus. In addition, obese adolescents demonstrated attenuated suppression of serum acyl-ghrelin and increased circulating insulin level after glucose ingestion; furthermore, the change in acyl-ghrelin and insulin levels after both glucose and fructose ingestion was associated with increased hypothalamic, thalamic, and hippocampal blood flow in obese relative to lean adolescents. Additionally, in all subjects there was greater perfusion in the ventral striatum with fructose relative to glucose ingestion. Finally, reduced connectivity between executive, homeostatic, and hedonic brain regions was observed in obese adolescents. These data demonstrate that obese adolescents have impaired prefrontal executive control responses to drinking glucose and fructose, while their homeostatic and hedonic responses appear to be heightened. Thus, obesity-related brain adaptations to glucose and fructose consumption in obese adolescents may contribute to excessive consumption of glucose and fructose, thereby promoting further weight gain. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Effect of ghrelin on glucose regulation in mice

USDA-ARS?s Scientific Manuscript database

Improvement of glucose metabolism after bariatric surgery appears to be from the composite effect of the alterations in multiple circulating gut hormone concentrations. However, their individual effect on glucose metabolism during different conditions is not clear. The objective of this study was to...

Interleukin-20 circulating levels in obese women: effect of weight loss.

PubMed

Maiorino, M I; Schisano, B; Di Palo, C; Vietri, M T; Cioffi, M; Giugliano, G; Giugliano, D; Esposito, K

2010-03-01

Obesity is associated with an increased risk of developing atherosclerosis. Interleukin-20 (IL-20) is a pleiotropic cytokine thought to be involved in the onset and progression of atherosclerosis. The aim of this study was to determine whether circulating levels of IL-20 are elevated in obese women and whether they could be affected by a substantial decrease in body weight. Fifty obese and 50 age-matched, normal weight, premenopausal women participated in the study. Obese women entered into a medically supervised weight loss program aimed at reducing body weight to 90% of baseline. We measured anthropometric, glucose and lipid parameters, and IL-20, C-Reactive Protein (CRP) and interleukin-10 (IL-10) circulating levels. Circulating IL-20 and CRP levels were significantly higher in obese than control women (P=0.01), while IL-10 levels were significantly lower; IL-20 levels were positively associated with body weight (r=0.35; P=0.02) and visceral fat (waist-hip ratio; r=0.32; P=0.025). Caloric restriction-induced weight loss (>10% of original weight) over 6 months reduced IL-20 levels from 152 (112/184) to 134 (125/153)pg/ml (median and 25%/75%; P=0.03), and it was positively associated with changes in body mass index and waist-hip ratio. In premenopausal obese women, IL-20 levels are higher than matched normal weight control women, are associated with body weight and waist-hip ratio, and are reduced by weight loss. (c) 2009 Elsevier B.V. All rights reserved.

[Oxygen-transporting function of the blood circulation system in sevoflurane anesthesia during myocardial revascularization under extracorporeal circulation].

PubMed

Skopets, A A; Lomivorotov, V V; Karakhalis, N B; Makarov, A A; Duman'ian, E S; Lomivorotova, L V

2009-01-01

The purpose of the study was to evaluate the efficiency of oxygen-transporting function of the circulatory system under sevoflurane anesthesia during myocardial revascularization operations under extracorporeal circulation. Twenty-five patients with coronary heart disease were examined. Mean blood pressure, heart rate, cardiac index, total peripheral vascular resistance index, pulmonary pressure, pulmonary wedge pressure, and central venous pressure were measured. Arterial and mixed venous blood oxygen levels, oxygen delivery and consumption index, arteriovenous oxygen difference, and glucose and lactate concentrations were calculated. The study has demonstrated that sevoflurane is an effective and safe anesthetic for myocardial revascularization operations in patients with coronary heart disease. The use of sevoflurane contributes to steady-state oxygen-transporting function of the circulatory system at all surgical stages.

α1-Adrenergic receptor downregulates hepatic FGF21 production and circulating FGF21 levels in mice.

PubMed

Nonogaki, Katsunori; Kaji, Takao

2017-01-18

Fibroblast growth factor 21 (FGF21) is primarily secreted by the liver as an endocrine hormone and is suggested as a promising target for the treatment of metabolic diseases. FGF21 acts centrally to exert its effects on energy expenditure and body weight via the sympathetic nervous system in mice. Here we show that intraperitoneal injection of phentolamine (an α-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the saline controls in C57BL6J mice, whereas alprenolol (a β-adrenergic receptor antagonist, 6mg/kg) had no effect. In addition, intraperitoneal injection of prazosin (an α1-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the controls, whereas yohimbine (an α2-adrenergic receptor antagonist, 5mg/kg) had no effect. Moreover, the treatment with prazosin significantly increased the expression of hepatic FGF21, while having no effect on the expression of hepatic PPARα and PPARγ. After a 5-h fast, intraperitoneal injection of prazosin significantly increased plasma FGF21 levels and impaired glucose tolerance compared with controls. These findings suggest that α1-adrenergic receptor downregulates the expression of hepatic FGF21 and plasma FGF21 levels independently of feeding and hepatic PPARα and PPARγ expression in mice, and that the increases in circulating FGF21 levels might be related to impaired glucose tolerance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Relationship Between Serum Macrophage Migration Inhibitory Factor Level and Insulin Resistance, High-Sensitivity C-Reactive Protein and Visceral Fat Mass in Prediabetes.

PubMed

Bilgir, Oktay; Gökçen, Belma; Bilgir, Ferda; Guler, Aslı; Calan, Mehmet; Yuksel, Arif; Aslanıpour, Behnaz; Akşit, Murat; Bozkaya, Giray

2018-01-01

Growing evidence suggest that macrophage migration inhibitory factor (MIF) plays a vital role in glucose metabolism. We aimed to ascertain whether MIF levels are altered in subjects with prediabetes and also to determine the relationship between MIF and metabolic parameters as well as visceral fat mass. This cross-sectional study included 40 subjects with prediabetes and 40 age-, body mass index (BMI)- and sex-matched subjects with normal glucose tolerance. Circulating MIF levels were measured using enzyme-linked immunosorbent assay. Metabolic parameters of recruited subjects were evaluated. Visceral fat mass was measured using bioelectrical impedance method. Circulating MIF levels were found to be elevated in subjects with prediabetes compared to controls (26.46 ± 16.98 versus 17.44 ± 11.80 ng/mL, P = 0.007). MIF positively correlated with BMI, visceral fat mass and indirect indices of homeostasis model assessment of insulin resistance. In linear regression model, an independent association was found between MIF levels and metabolic parameters, including BMI, visceral fat mass and homeostasis model assessment of insulin resistance. Multivariate logistic regression analyses revealed that the odds ratio for prediabetes was higher in subjects in the highest quartile of MIF compared to those in the lowest quartile, after adjusting for potential confounders. Increased MIF levels are associated with the elevation of prediabetic risk. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies.

PubMed

Pisani, Paola

2008-02-01

A substantial body of evidence links sex hormones, diet, excess body weight and physical activity to the risk of developing cancer at several sites common in affluent countries. The hypothesis that high circulating levels of insulin could be the underlying factor increasing cancer risk has been proposed. Epidemiological studies on markers of hyper-insulinaemia and cancer are reviewed and summarized. Studies of cancers of the colon and rectum, pancreas, breast, and endometrium examining the association with blood levels of C-peptide, insulin, glucose, glycated haemoglobin (HbA1c) were searched in PubMed. Multivariate, adjusted relative risks (RR) and their 95% confidence intervals were abstracted and summarized by meta-analyses. Most of the studies identified were cohorts that relied on measurements obtained at baseline or assessed in blood stored at low temperature several years before the onset of cancer. The meta-analyses showed excess risks of colorectal and pancreatic cancers associated with higher levels of circulating C-peptide/insulin and with markers of glycaemia. Significant heterogeneity was found among four epidemiological studies of endometrial cancer and C-peptide giving a summary RR compatible with no association. Overall breast cancer risk was significantly higher in the upper categories of C-peptide/insulin, however, the excess derived entirely from retrospective studies. Current evidence suggests that subjects who develop colorectal and pancreatic cancers have increased pre-diagnostic blood levels of insulin and glucose.

Insulin resistance in porphyria cutanea tarda.

PubMed

Calcinaro, F; Basta, G; Lisi, P; Cruciani, C; Pietropaolo, M; Santeusanio, F; Falorni, A; Calafiore, R

1989-06-01

It has been reported that patients with porphyria cutanea tarda (PCT) develop carbohydrate (CHO) intolerance and manifest diabetes melitus (DM) more frequently than the normal population. In order to verify whether this is due to insulin resistance we studied 5 patients with PCT and 5 normal subjects matched for age, sex and weight. In all the patients an evaluation consisted of the glycemic curve and insulin response to an iv glucose tolerance test (IVGTT: 0.33 g/kg) as well as of an evaluation of the circulating monocyte insulin receptors. Blood samples were drawn in the basal state to measure plasma levels of NEFA, glycerol, and intermediate metabolites. The patients with PCT showed normal glucose tolerance which was obtained, however, at the expense of the elevated insulin levels: therefore a condition of insulin resistance was demonstrated in these subjects. An involvement of the lipid metabolism, observed by the raised levels of plasma NEFA and glycerol, was also evident. The insulin binding to circulating monocytes was reduced but not enough to justify the degree of insulin resistance observed. Therefore, it could be hypothesized, in agreement with similar studies, that a postreceptor defect is responsible for the insulin-resistance observed in patients with PCT and that the reduction of insulin receptors is determined by the down regulation in response to elevated insulinemic levels. An alteration of the porphyrin metabolism might be responsible for this disorder.

The Rise in Growth Hormone during Starvation Does Not Serve to Maintain Glucose Levels or Lean Mass but Is Required for Appropriate Adipose Tissue Response in Female Mice

PubMed Central

Gahete, Manuel D.; Córdoba-Chacón, José; Luque, Raúl M.

2013-01-01

In mice, GH levels rise in response to short-term fasting or starvation (food restriction to 40% of ad libitum intake), similar to that which occurs in humans in response to fasting or anorexia. Recent studies using acyl-ghrelin knockout mice have suggested that the rise in GH during food restriction is essential to support glucose levels. To directly test this hypothesis, adult-onset isolated GH deficient (AOiGHD) mice and their GH-replete littermate controls were provided 40% of ad libitum food intake for 11 d. As previously shown, food restriction increased GH levels in controls, and this response was not observed in AOiGHD mice. In both controls and AOiGHD, food restriction resulted in an initial decline in glucose, which stabilized to 82–85% of ad libitum-fed values by d 2. In addition, loss of lean mass in response to food restriction was not altered by GH status. However, the loss of fat mass and the associated rise in circulating free fatty acids and ketones was blunted in starved AOiGHD mice compared with controls. Taken together, these results suggest a rise of GH during starvation is not required to support glucose levels and muscle mass but may be important in supporting fat mobilization. PMID:23150490

Effect of Letrozole, a selective aromatase inhibitor, on testicular activities in adult mice: Both in vivo and in vitro study.

PubMed

Verma, Rachna; Krishna, Amitabh

2017-01-15

The aim of present study was to evaluate the significance of estradiol (E2) in testicular activities and to find out the mechanism by which E2 regulates spermatogenesis in mice. To achieve this, both in vivo and in vitro effect of Letrozole on testis of adult mice was investigated. Letrozole-induced changes in testicular histology, cell proliferation (proliferating cell nuclear antigen; PCNA), cell survival (B cell lymphoma factor-2; Bcl2), apoptotic (cysteine-aspartic proteases; caspase-3), steroidogenic (side chain cleavage; SCC, 3β-hydroxy steroid dehydrogenase enzyme; 3β HSD, steroidogenic acute regulatory protein; StAR, aromatase and luteinizing hormone receptor; LH-R) markers, glucose level, and rate of expression of glucose transporter (GLUT) 8 and insulin receptor (IR) proteins in the testis along with changes in serum E2 and testosterone (T) levels were evaluated. Letrozole acts on testis and caused significant decrease in E2 synthesis, but increase in testosterone level and showed regressive changes in the spermatogenesis. Letrozole-induced changes in various testicular markers were compared with the changes in serum E2 level. The correlation study showed that decreased circulating E2 level may be responsible for decreased insulin receptor (IR) level in the testis. The decreased effects of insulin inhibited the glucose transport in the testis by suppressing GLUT8. The decreased level of testicular glucose may produce less lactate as energy support to developing germ cells consequently resulting in decreased cell proliferation and cell survival, but increased apoptosis. Thus, Letrozole suppresses spermatogenesis by reducing insulin sensitivity and glucose transport in the testis, but significantly increased testosterone level by promoting gonadotrophin release by decreased E2. Copyright © 2016 Elsevier Inc. All rights reserved.

Exendin-4 increases blood glucose levels acutely in rats by activation of the sympathetic nervous system.

PubMed

Pérez-Tilve, Diego; González-Matías, Lucas; Aulinger, Benedikt A; Alvarez-Crespo, Mayte; Gil-Lozano, Manuel; Alvarez, Elias; Andrade-Olivie, Amalia M; Tschöp, Matthias H; D'Alessio, David A; Mallo, Federico

2010-05-01

Exendin-4 (Ex-4), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), shares many of the actions of GLP-1 on pancreatic islets, the central nervous system (CNS), and the gastrointestinal tract that mediates glucose homeostasis and food intake. Because Ex-4 has a much longer plasma half-life than GLP-1, it is an effective drug for reducing blood glucose levels in patients with type 2 diabetes mellitus (T2DM). Here, we report that acute administration of Ex-4, in relatively high doses, into either the peripheral circulation or the CNS, paradoxically increased blood glucose levels in rats. This effect was independent of the insulinotropic and hypothalamic-pituitary-adrenal activating actions of Ex-4 and could be blocked by a GLP-1R antagonist. Comparable doses of GLP-1 did not induce hyperglycemia, even when protected from rapid metabolism by a dipeptidyl peptidase IV inhibitor. Acute hyperglycemia induced by Ex-4 was blocked by hexamethonium, guanethidine, and adrenal medullectomy, indicating that this effect was mediated by sympathetic nervous system (SNS) activation. The potency of Ex-4 to elevate blood glucose waned with chronic administration such that after 6 days the familiar actions of Ex-4 to improve glucose tolerance were evident. These findings indicate that, in rats, high doses of Ex-4 activate a SNS response that can overcome the expected benefits of this peptide on glucose metabolism and actually raise blood glucose. These results have important implications for the design and interpretation of studies using Ex-4 in rats. Moreover, since there are many similarities in the response of the GLP-1R system across mammalian species, it is important to consider whether there is acute activation of the SNS by Ex-4 in humans.

Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes.

PubMed

Heise, T; Nosek, L; Bøttcher, S G; Hastrup, H; Haahr, H

2012-10-01

Insulin degludec (IDeg) is a new-generation, ultra-long-acting basal insulin that forms soluble multihexamers upon subcutaneous injection, resulting in a depot from which IDeg is absorbed slowly and continuously into circulation. This double-blind, two-period, incomplete block cross-over trial investigated the pharmacodynamic and pharmacokinetic properties of IDeg at steady state (SS) in people with type 2 diabetes. Forty-nine subjects treated with insulin without concomitant oral anti-diabetic drugs were given IDeg (0.4, 0.6 and/or 0.8 U/kg) once daily for two 6-day periods, separated by an interval of 13-21 days. Following dosing on Day 6, subjects underwent a 26-h euglycaemic glucose clamp (Biostator®; clamp blood glucose level: 90 mg/dl; 5.0 mmol/l). Pharmacokinetic samples were taken until 120 h after last dosing. For all dose levels, the mean glucose infusion rate (GIR) profiles were flat and stable. The glucose-lowering effect of IDeg was evenly distributed over the dosing interval τ, with area under the curve (AUC) for each of the four 6-h intervals being approximately 25% of the total AUC (AUC(GIR) (,τ,) (SS) ). Total glucose-lowering effect increased linearly with increasing dose. The blood glucose levels of all subjects stayed very close to the clamp target until end of clamp. The terminal half-life of IDeg was approximately 25 h at steady state. IDeg was well tolerated and no safety concerns were identified. No injection site reactions were reported. IDeg has a flat and consistent glucose-lowering effect in people with type 2 diabetes. © 2012 Blackwell Publishing Ltd.

CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress

PubMed Central

Petersen, Pia S.; Lei, Xia; Wolf, Risa M.; Rodriguez, Susana; Tan, Stefanie Y.; Little, Hannah C.; Schweitzer, Michael A.; Magnuson, Thomas H.; Steele, Kimberley E.

2017-01-01

Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes. PMID:28223291

Roux-en-Y gastric bypass surgery, but not calorie restriction, reduces plasma branched-chain amino acids in obese women independent of weight loss or the presence of type 2 diabetes.

PubMed

Lips, Mirjam A; Van Klinken, Jan B; van Harmelen, Vanessa; Dharuri, Harish K; 't Hoen, Peter A C; Laros, Jeroen F J; van Ommen, Gert-Jan; Janssen, Ignace M; Van Ramshorst, Bert; Van Wagensveld, Bart A; Swank, Dingeman J; Van Dielen, Francois; Dane, Adrie; Harms, Amy; Vreeken, Rob; Hankemeier, Thomas; Smit, Johannes W A; Pijl, Hanno; Willems van Dijk, Ko

2014-12-01

Obesity and type 2 diabetes mellitus (T2DM) have been associated with increased levels of circulating branched-chain amino acids (BCAAs) that may be involved in the pathogenesis of insulin resistance. However, weight loss has not been consistently associated with the reduction of BCAA levels. We included 30 obese normal glucose-tolerant (NGT) subjects, 32 obese subjects with T2DM, and 12 lean female subjects. Obese subjects underwent either a restrictive procedure (gastric banding [GB], a very low-calorie diet [VLCD]), or a restrictive/bypass procedure (Roux-en-Y gastric bypass [RYGB] surgery). Fasting blood samples were taken for the determination of amine group containing metabolites 4 weeks before, as well as 3 weeks and 3 months after the intervention. BCAA levels were higher in T2DM subjects, but not in NGT subjects, compared with lean subjects. Principal component (PC) analysis revealed a concise PC consisting of all BCAAs, which showed a correlation with measures of insulin sensitivity and glucose tolerance. Only after the RYGB procedure, and at both 3 weeks and 3 months, were circulating BCAA levels reduced. Our data confirm an association between deregulation of BCAA metabolism in plasma and insulin resistance and glucose intolerance. Three weeks after undergoing RYGB surgery, a significant decrease in BCAAs in both NGT as well as T2DM subjects was observed. After 3 months, despite inducing significant weight loss, neither GB nor VLCD induced a reduction in BCAA levels. Our results indicate that the bypass procedure of RYGB surgery, independent of weight loss or the presence of T2DM, reduces BCAA levels in obese subjects. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Odd Chain Fatty Acids; New Insights of the Relationship Between the Gut Microbiota, Dietary Intake, Biosynthesis and Glucose Intolerance.

PubMed

Jenkins, Benjamin J; Seyssel, Kevin; Chiu, Sally; Pan, Pin-Ho; Lin, Shih-Yi; Stanley, Elizabeth; Ament, Zsuzsanna; West, James A; Summerhill, Keith; Griffin, Julian L; Vetter, Walter; Autio, Kaija J; Hiltunen, Kalervo; Hazebrouck, Stéphane; Stepankova, Renata; Chen, Chun-Jung; Alligier, Maud; Laville, Martine; Moore, Mary; Kraft, Guillaume; Cherrington, Alan; King, Sarah; Krauss, Ronald M; de Schryver, Evelyn; Van Veldhoven, Paul P; Ronis, Martin; Koulman, Albert

2017-03-23

Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1 -/- mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1 -/- only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease.

The Effect of Ingested Glucose Dose on the Suppression of Endogenous Glucose Production in Humans.

PubMed

Kowalski, Greg M; Moore, Samantha M; Hamley, Steven; Selathurai, Ahrathy; Bruce, Clinton R

2017-09-01

Insulin clamp studies have shown that the suppressive actions of insulin on endogenous glucose production (EGP) are markedly more sensitive than for stimulating glucose disposal ( R d ). However, clamp conditions do not adequately mimic postprandial physiological responses. Here, using the variable infusion dual-tracer approach, we used a threefold range of ingested glucose doses (25, 50, and 75 g) to investigate how physiological changes in plasma insulin influence EGP in healthy subjects. Remarkably, the glucose responses were similar for all doses tested, yet there was a dose-dependent increase in insulin secretion and plasma insulin levels. Nonetheless, EGP was suppressed with the same rapidity and magnitude (∼55%) across all doses. The progressive hyperinsulinemia, however, caused a dose-dependent increase in the estimated rates of R d , which likely accounts for the lack of a dose effect on plasma glucose excursions. This suggests that after glucose ingestion, the body preferentially permits a transient and optimal degree of postprandial hyperglycemia to efficiently enhance insulin-induced changes in glucose fluxes, thereby minimizing the demand for insulin secretion. This may represent an evolutionarily conserved mechanism that not only reduces the secretory burden on β-cells but also avoids the potential negative consequences of excessive insulin release into the systemic arterial circulation. © 2017 by the American Diabetes Association.

Hypoglycaemia and hypoxic-ischaemic encephalopathy.

PubMed

Boardman, James P; Hawdon, Jane M

2015-04-01

The transition from fetal to neonatal life requires metabolic adaptation to ensure that energy supply to vital organs and systems is maintained after separation from the placental circulation. Under normal conditions, this is achieved through the mobilization and use of alternative cerebral fuels (fatty acids, ketone bodies, and lactate) when blood glucose concentration falls. Severe hypoxia-ischaemia is associated with impaired metabolic adaptation, and animal and human data suggest that levels of hypoglycaemia that are tolerated under normal conditions can be harmful in association with hypoxia-ischaemia. The optimal target blood glucose level for ensuring adequate energy provision in hypoxic-ischaemic encephalopathy (HIE) remains unknown. However, recent data support guidance to maintain a blood glucose concentration of 2.5 mmol/L or more in neonates with signs of acute neurological dysfunction, which includes those with HIE, and this is higher than the accepted threshold of 2 mmol/L in infants without signs of neurological dysfunction or hyperinsulinism. © The Authors. Journal compilation © 2015 Mac Keith Press.

Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus.

PubMed

Oh, Tae Jung; Ahn, Chang Ho; Kim, Bo-Rahm; Kim, Kyoung Min; Moon, Jae Hoon; Lim, Soo; Park, Kyong Soo; Lim, Cheong; Jang, HakChul; Choi, Sung Hee

2017-07-20

A previous genome-wide association study showed that a genetic variant of sortilin was associated with the risk of coronary artery disease (CAD). However, the role of circulating sortilin is still unknown. We investigated the potential role of plasma sortilin as a biomarker for CAD and diabetes mellitus. We enrolled statin-naïve subjects with CAD (n = 31) who underwent coronary artery bypass surgery and control subjects (n = 116) who were free from CAD as evaluated by coronary CT angiography. The presence of diabetes mellitus was evaluated and plasma sortilin levels were measured with a commercial ELISA kit. Plasma sortilin levels were higher in subjects with CAD and subjects with diabetes mellitus than in those without CAD or diabetes mellitus. Subjects in the highest sortilin tertile group were older and had higher glucose and HbA1c levels, but lipid profiles in the three tertile groups were comparable. Multivariable logistic regression analysis revealed that sortilin levels were independently associated with CAD. In addition, the receiver operating characteristic curve analysis showed that plasma sortilin levels could identify the presence of CAD or diabetes mellitus. Elevated circulating sortilin levels are associated with CAD and diabetes mellitus and can be used as a biomarker of both diseases in statin-naïve subjects.

Oral salmon calcitonin protects against impaired fasting glycemia, glucose intolerance, and obesity induced by high-fat diet and ovariectomy in rats.

PubMed

Feigh, Michael; Andreassen, Kim V; Hjuler, Sara T; Nielsen, Rasmus H; Christiansen, Claus; Henriksen, Kim; Karsdal, Morten A

2013-07-01

Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored. For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations. For prevention, oral sCT reduced body weight by ∼16% to 19% (P < 0.001), reduced plasma insulin and leptin by ∼50%, and improved impaired fasting glycemia (P < 0.05) concomitantly with amelioration of IR (HOMA-IR; P < 0.01) in HFD- and OVX-induced obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ∼40% and ∼70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P < 0.001). Finally, oral sCT alleviated glucose intolerance predominantly in the portal circulation. Oral sCT treatment displays weight-regulatory and glucoregulatory efficacy in HFD- and OVX-induced obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes.

Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-hour glucose and insulin excursions

USDA-ARS?s Scientific Manuscript database

It has been proposed that the adverse metabolic effects of chronic consumption of sugar-sweetened beverages which contain both glucose and fructose are a consequence of increased circulating glucose and insulin excursions, i.e dietary glycemic index (GI). Objective: We determined if the greater adv...

Single-cell codetection of metabolic activity, intracellular functional proteins, and genetic mutations from rare circulating tumor cells.

PubMed

Zhang, Yu; Tang, Yin; Sun, Shuai; Wang, Zhihua; Wu, Wenjun; Zhao, Xiaodong; Czajkowsky, Daniel M; Li, Yan; Tian, Jianhui; Xu, Ling; Wei, Wei; Deng, Yuliang; Shi, Qihui

2015-10-06

The high glucose uptake and activation of oncogenic signaling pathways in cancer cells has long made these features, together with the mutational spectrum, prime diagnostic targets of circulating tumor cells (CTCs). Further, an ability to characterize these properties at a single cell resolution is widely believed to be essential, as the known extensive heterogeneity in CTCs can obscure important correlations in data obtained from cell population-based methods. However, to date, it has not been possible to quantitatively measure metabolic, proteomic, and genetic data from a single CTC. Here we report a microchip-based approach that allows for the codetection of glucose uptake, intracellular functional proteins, and genetic mutations at the single-cell level from rare tumor cells. The microchip contains thousands of nanoliter grooves (nanowells) that isolate individual CTCs and allow for the assessment of their glucose uptake via imaging of a fluorescent glucose analog, quantification of a panel of intracellular signaling proteins using a miniaturized antibody barcode microarray, and retrieval of the individual cell nuclei for subsequent off-chip genome amplification and sequencing. This approach integrates molecular-scale information on the metabolic, proteomic, and genetic status of single cells and permits the inference of associations between genetic signatures, energy consumption, and phosphoproteins oncogenic signaling activities in CTCs isolated from blood samples of patients. Importantly, this microchip chip-based approach achieves this multidimensional molecular analysis with minimal cell loss (<20%), which is the bottleneck of the rare cell analysis.

Short-term secretory regulation of ghrelin during growth hormone provocative tests in prepubertal children with various growth hormone secretory capacities.

PubMed

Matsuoka, Hisafumi; Hosoda, Hiroshi; Sugawara, Hisae; Iwama, Saika; Kim, Hye Sook; Kangawa, Kenji; Sugihara, Shigetaka

2005-01-01

Ghrelin is a novel gastric peptide which stimulates GH secretion and has been demonstrated to have orexigenic and adipogenic properties. Insulin is a physiological and dynamic modulator of plasma ghrelin, and insulinemia possibly mediates the effect of the nutritional state on the plasma concentrations of ghrelin in adults. No data on the regulation of GH secretion by ghrelin have so far been reported, nor has the possible influence of hypoglycemia on the plasma ghrelin levels in children been reported. Provocative studies were performed using a variety of stimuli, including insulin-induced hypoglycemia, and glucagon, arginine and L-dopa loading. We studied a group of 27 children with short stature being investigated for GH deficiency (10 F, 17 M; age 4-14 years; height SDS -0.92 to -3.27); the subjects were instructed to fast overnight, and the following morning, the relationships among the plasma ghrelin, GH and glucose levels were investigated by determining the plasma ghrelin profiles during those provocative tests. Using a new method for determining the two types of ghrelin, samples were obtained for determination of the plasma ghrelin, serum glucose and serum GH levels after the administration of the aforementioned stimulating agents. All the four stimuli caused a significant decrease in the circulating C- and N-ghrelin levels with a nadir at +30 min, with the exception of the N-ghrelin level following the L-dopa loading. During the same period, the plasma GH level increased following insulin, arginine and L-dopa loading, and the plasma glucose level increased significantly following glucagon loading. In the arginine and L-dopa load connected, a significant correlation was observed between the 30-min change in the serum GH level and the 30-min change in the plasma C-ghrelin level. In the multiple regression analysis to explain the 30-min change in the plasma level of C-ghrelin, the baseline plasma level of C-ghrelin (basal), height and % overweight were the only three significant parameters, accounting for 85.2% of the variance. This study demonstrated that the inverse relation between the circulating GH and ghrelin levels may indicate the existence of a feedback loop, and also lends support to the assumption of a GH-independent relationship between plasma ghrelin and glucose levels. These observations constitute further evidence to suggest that peripheral ghrelin is a direct growth-promoting hormone. Copyright 2005 S. Karger AG, Basel

Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes.

PubMed

Goldfine, Allison B; Silver, Robert; Aldhahi, Waleed; Cai, Dongsheng; Tatro, Elizabeth; Lee, Jongsoon; Shoelson, Steven E

2008-05-01

Chronic subacute inflammation is implicated in the pathogenesis of insulin resistance and type 2 diabetes. Salicylates were shown years ago to lower glucose and more recently to inhibit NF-kappaB activity. Salsalate, a prodrug form of salicylate, has seen extensive clinical use and has a favorable safety profile. We studied the efficacy of salsalate in reducing glycemia and insulin resistance and potential mechanisms of action to validate NF-kappaB as a potential pharmacologic target in diabetes. In open label studies, both high (4.5 g/d) and standard (3.0 g/d) doses of salsalate reduced fasting and postchallenge glucose levels after 2 weeks of treatment. Salsalate increased glucose utilization during euglycemic hyperinsulinemic clamps, by approximately 50% and 15% at the high and standard doses, respectively, and insulin clearance was decreased. Dose-limiting tinnitus occurred only at the higher dose. In a third, double-masked, placebo-controlled trial, 1 month of salsalate at maximum tolerable dose (no tinnitus) improved fasting and postchallenge glucose levels. Circulating free fatty acids were reduced and adiponectin increased in all treated subjects. These data demonstrate that salsalate improves in vivo glucose and lipid homeostasis, and support targeting of inflammation and NF-kappaB as a therapeutic approach in type 2 diabetes.

Leptin Directly Promotes T Cell Glycolytic Metabolism to Drive Effector T cell Differentiation in Autoimmunity

PubMed Central

Gerriets, Valerie A.; Danzaki, Keiko; Kishton, Rigel J.; Eisner, William; Nichols, Amanda G.; Saucillo, Donte C.; Shinohara, Mari L.; MacIver, Nancie J.

2016-01-01

Upon activation, T cells require energy for growth, proliferation and function. Effector T cells (Teff), such as Th1 and Th17, utilize high levels of glucose uptake and glycolysis to fuel proliferation and function. In contrast, Treg instead require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg metabolism is altered in settings of malnutrition, when nutrients are limited and circulating leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg. We found that both malnutrition-associated hypoleptinemia and T cell-specific leptin receptor knockout suppressed Teff number, function, and glucose metabolism, but did not alter Treg metabolism or suppressive function. Using the autoimmune model EAE, we confirmed that fasting-induced hypoleptinemia altered Teff, but not Treg, glucose metabolism and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF-1α, a key regulator of Th17 differentiation and Teff glucose metabolism, and found HIF-1α expression was decreased in T cell-specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg. Altogether, these data demonstrate a selective, cell-intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg. PMID:27222115

Glucose-Responsive Implantable Polymeric Microdevices for "Smart" Insulin Therapy of Diabetes

NASA Astrophysics Data System (ADS)

Chu, Michael Kok Loon

Diabetes mellitus is a chronic illness manifested by improper blood glucose management, affecting over 350 million worldwide. As a result, all type 1 patients and roughly 20% of type 2 patients require exogenous insulin therapy to survive. Typically, daily multiple injections are taken to maintain normal glucose levels in response glucose spikes from meals. However, patient compliance and dosing accuracy can fluctuate with variation in meals, exercise, glucose metabolism or stress, leading to poor clinical outcomes. A 'smart', closed-loop insulin delivery system providing on-demand release kinetics responding to circulating glucose levels would be a boon for diabetes patients, replacing constant self monitoring and insulin. This thesis focuses on the development of a novel, 'smart' insulin microdevice that can provide on-demand insulin release in response to blood glucose levels. In the early stage, the feasibility of integrating a composite membrane with pH-responsive nanoparticles embedded in ethylcellulose membrane to provide pH-responsive in vitro release was examined and confirmed using a model drug, vitamin B12. In the second microdevice, glucose oxidase for generating pH signals from glucose oxidation, catalase and manganese dioxide nanoparticles, as peroxide scavengers, were used in a bioinorganic, albumin-based membrane cross-linked with a polydimethylsiloxane (PDMS) grid-microdevice system. This prototype device demonstrated insulin release in response to glucose levels in vitro and regulating plasma glucose in type 1 diabetic rats when implanted intraperitoneally. Advancement allowing for subcutaneous implantation and improved biocompatibility was achieved with surface modification of PDMS microdevices grafted with activated 20 kDa polyethylene glycol (PEG) chains, dramatically reducing immune response and local inflammation. When implanted subcutaneously in diabetic rats, glucose-responsive insulin delivery microdevices showed short and long-term efficacy up to an 18 day period. Finally, to improve insulin stability within microdevice reservoirs, an in situ gelling zinc-insulin formulation was designed. High concentration insulin gel complexed with zinc provided physical and chemical stability against thermal denaturation over a 30 day period. Long-term stability of the zinc-insulin gel formulation shows potential for sustained release application, providing low-level, basal insulin release. These combined technologies present significant progress towards the goal of an 'artificial pancreas' to combat diabetes through 'smart' insulin therapy.

Glucogenic treatment creates an optimal metabolic milieu for the conception period in ewes.

PubMed

Porcu, C; Pasciu, V; Succu, S; Baralla, E; Manca, M E; Serra, E; Leoni, G G; Dattena, M; Bomboi, G C; Molle, G; Naitana, S; Berlinguer, F

2017-04-01

This study determined the influence of a short-term glucogenic nutritional treatment on circulating concentrations of glucose, insulin, insulin-like growth factor 1 (IGF-1), nonesterified fatty acids (NEFA), and urea, and on their correspondent levels in follicular fluid (FF) collected 12 h after the end of the treatment. After estrous synchronization with intravaginal progestagen-impregnated sponges, 20 Sarda ewes were randomly allocated into two experimental groups (GLU and WAT) and, from day 7 to day 10 (day 0 = day of sponge removal), the GLU group was gavaged with a glycogenic mixture, whereas the WAT group was gavaged with water (control group). Follicular development was stimulated by FSH administration from day 8 to 10. At day 11, ovaries were collected and follicular fluid processed. Plasma changes were assessed from day 6 to 11. In GLU group, circulating concentration of glucose (P < 0.0001), insulin (P < 0.0001), and IGF-1 (P < 0.01) rose significantly, whereas NEFA and urea concentrations decreased (P < 0.0001), as compared with controls. In particular, in FF the higher glucose concentrations found in GLU ewes compared with controls (P < 0.0001) were not accompanied by any increase in insulin and IGF-1 concentrations. NEFA (P < 0.0001) and urea (P < 0.0001) were lower in FF of GLU than WAT group, although NEFA clearance in the ovary proved to be less efficient than at the systemic level. No significant difference between groups was found in FF concentrations of pregnancy-associated plasma protein A (a protease regulating the levels of free IGF-1 in follicles), glutathione, and in its total antioxidant capacity. These results suggest that glycogenic mixture administration creates a suitable follicular microenvironment for the conception period in dairy ewes. Copyright © 2016 Elsevier Inc. All rights reserved.

Circulating Betatrophin Levels and Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis.

PubMed

Kong, Fei-Juan; Ma, Lei-Lei; Li, Ge; Chen, Yi-Xin; Zhou, Jia-Qiang

2017-01-01

The association between circulating betatrophin levels and gestational diabetes mellitus (GDM) is controversial. The aim of our study was to systematically review available literature linking betatrophin to GDM for a comprehensive understanding of the relationship between circulating betatrophin levels and GDM in human. PubMed, The Cochrane Library, Medline and CNKI were searched for studies published up to August 2016. Manual searches of references of the relevant original studies were conducted. Pooled estimates were measured using the fixed or random effect model. Overall effect was reported in a standard mean difference (SMD). All data were analyzed with Review Manager 5.3 and Stata 12.0. Of 25 references reviewed, 8 studies met our inclusion criteria and contributed to meta-analysis. All the studies were used to evaluate the relationship between betatrophin levels in blood and GDM. Betatrophin levels were significantly elevated in women with GDM compared with those without GDM (SMD = 1.05; 95% CI: 0.41-1.68, P = 0.001). This evidence was more consistent among women with betatrophin blood draw during the third trimester (SMD = 1.3, 95% CI: 1-1.61, P < 0.001) and for women BMI ≥ 28 kg/m2 (SMD = 1.53, 95% CI: 1.30-1.75, P < 0.001). The evidences from this meta-analysis indicated that the levels of circulating betatrophin were significantly elevated among women with GDM compared with women with normal glucose tolerance, especially with BMI ≥ 28 kg/m2 and in the third trimester.

Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Desinia B.

Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25 ppm or 1.00 ppm ozone, 5 h/day, 3 consecutive days/week (wk) for 13 wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13 wk ormore » following a 1 wk recovery period (13 wk + 1 wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13 wk, however, these responses were largely reversible following a 1 wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced beta-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism. - Highlights: • Subchronic episodic ozone exposure caused pulmonary and metabolic effects. • These effects were largely reversible upon one week recovery. • Ozone exposure did not cause liver or muscle insulin resistance. • Subchronic ozone exposure led to decrease in serum insulin. • Ozone severely impaired beta cell insulin secretion in response to glucose.« less

Effects of routine handling and tagging procedures on physiological stress responses in juvenile chinook salmon

USGS Publications Warehouse

Sharpe, C.S.; Thompson, D.A.; Blankenship, H.L.; Schreck, C.B.

1998-01-01

Juvenile chinook salmon Oncorhynchus tshawytscha were subjected to handling and tagging protocols typical of normal hatchery operations and monitored for their physiological response to stress. Treatments included coded-wire-tagging, counting, ventral fin clipping, adipose fin clipping, and a procedure simulating a pond split. Treatment fish were also subjected to a standardized stress challenge (1 h confinement) to evaluate their ability to deal with disturbances subsequent to a handling or tagging procedure. Circulating levels of cortisol and glucose were used as indicators of stress. Each of the treatments elicited very similar responses among treatment groups. Cortisol increased from resting levels of about 20 ng/mL to about 90 ng/mL by 1 h poststress and returned to near resting levels by 8 h poststress. Glucose levels increased from 50 mg/dL to about 80 mg/dL by 1 h poststress and remained elevated for much of the experiment. The cortisol and glucose responses to the confinement stress did not differ over time or among treatments. However, the confinement stress results do suggest a small but significant cumulative response, indicating small residual effects of the original handling protocols. No deaths were noted among treatment groups.

Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a β-Cell Glucagon-Like Peptide 1 Receptor.

PubMed

Douros, Jonathan D; Lewis, Alfor G; Smith, Eric P; Niu, JingJing; Capozzi, Megan; Wittmann, April; Campbell, Jonathan; Tong, Jenny; Wagner, Constance; Mahbod, Parinaz; Seeley, Randy; D'Alessio, David A

2018-05-14

Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell specific Glp1r knockdown ( Glp1r β-cell-ko ). Mice with VSG lost ∼20% of body weight over 30 days compared to sham-operated controls and had a ∼60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in β-cells caused glucose intolerance in diet-induced obese mice compared to obese controls, but VSG improved glycemic profiles to similar levels during oral and intraperitoneal glucose challenges in Glp1r βcell-ko and Glp1r WT mice. Therefore, while the β-cell GLP-1R seems to be important for maintaining glucose tolerance in obese mice, in these experiments it is dispensable for the improvement in glucose tolerance after VSG. Moreover, the metabolic physiology activated by VSG can overcome the deficits in glucose regulation caused by lack of β-cell GLP-1 signaling in obesity. © 2018 by the American Diabetes Association.

Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

PubMed Central

Ingelsson, Erik; Langenberg, Claudia; Hivert, Marie-France; Prokopenko, Inga; Lyssenko, Valeriya; Dupuis, Josée; Mägi, Reedik; Sharp, Stephen; Jackson, Anne U.; Assimes, Themistocles L.; Shrader, Peter; Knowles, Joshua W.; Zethelius, Björn; Abbasi, Fahim A.; Bergman, Richard N.; Bergmann, Antje; Berne, Christian; Boehnke, Michael; Bonnycastle, Lori L.; Bornstein, Stefan R.; Buchanan, Thomas A.; Bumpstead, Suzannah J.; Böttcher, Yvonne; Chines, Peter; Collins, Francis S.; Cooper, Cyrus C.; Dennison, Elaine M.; Erdos, Michael R.; Ferrannini, Ele; Fox, Caroline S.; Graessler, Jürgen; Hao, Ke; Isomaa, Bo; Jameson, Karen A.; Kovacs, Peter; Kuusisto, Johanna; Laakso, Markku; Ladenvall, Claes; Mohlke, Karen L.; Morken, Mario A.; Narisu, Narisu; Nathan, David M.; Pascoe, Laura; Payne, Felicity; Petrie, John R.; Sayer, Avan A.; Schwarz, Peter E. H.; Scott, Laura J.; Stringham, Heather M.; Stumvoll, Michael; Swift, Amy J.; Syvänen, Ann-Christine; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Tönjes, Anke; Valle, Timo T.; Williams, Gordon H.; Lind, Lars; Barroso, Inês; Quertermous, Thomas; Walker, Mark; Wareham, Nicholas J.; Meigs, James B.; McCarthy, Mark I.; Groop, Leif; Watanabe, Richard M.; Florez, Jose C.

2010-01-01

OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. PMID:20185807

Ventromedial hypothalamic glucose sensing and glucose homeostasis vary throughout the estrous cycle

PubMed Central

Santiago, Ammy M.; Clegg, Deborah J.; Routh, Vanessa H.

2016-01-01

Objective 17β-Estradiol (17βE) regulates glucose homeostasis in part by centrally mediated mechanisms. In female rodents, the influence of the ovarian cycle on hypoglycemia counterregulation and glucose tolerance is unclear. We found previously that in prepubertal females, 17βE modulates glucose sensing in nonadapting glucose-inhibited (GI) and adapting GI (AdGI) neurons within the ventrolateral portion of the ventromedial nucleus (VL-VMN). Nonadapting GI neurons persistently decrease their activity as glucose increases while AdGI neurons transiently respond to a glucose increase. To begin to understand if endogenous fluctuations in estrogen levels across the estrous cycle impact hypothalamic glucose sensing and glucose homeostasis, we assessed whether hypoglycemia counterregulation and glucose tolerance differed across the phases of the estrous cycle. We hypothesized that the response to insulin-induced hypoglycemia (IIH) and/or glucose tolerance would vary throughout the estrous cycle according to changes in 17βE availability. Moreover, that these changes would correlate with estrous-dependent changes in the glucose sensitivity of VL-VMN glucose-sensing neurons (GSNs). Methods These hypotheses were tested in female mice by measuring the response to IIH, glucose tolerance and the glucose sensitivity of VL-VMN GSNs during each phase of the estrous cycle. Furthermore, a physiological brain concentration of 17βE seen during proestrus was acutely applied to brain slices isolated on the day of diestrous and the response to low glucose in VL-VMN GSNs was assayed. Results The response to IIH was strongest during diestrous. The response of nonadapting GI and AdGI neurons to a glucose decrease from 2.5 to 0.5mM also peaked during diestrous; an effect which was blunted by the addition of 17βE. In contrast, the glucose sensitivity of the subpopulation of GSNs which are excited by glucose (GE) was not affected by estrous phase or exogenous 17βE application. Conclusion These data suggest that physiological fluctuations in circulating 17βE levels across the estrous cycle lead to changes in hypothalamic glucose sensing and the response to IIH. PMID:27666162

Ventromedial hypothalamic glucose sensing and glucose homeostasis vary throughout the estrous cycle.

PubMed

Santiago, Ammy M; Clegg, Deborah J; Routh, Vanessa H

2016-12-01

17β-Estradiol (17βE) regulates glucose homeostasis in part by centrally mediated mechanisms. In female rodents, the influence of the ovarian cycle on hypoglycemia counterregulation and glucose tolerance is unclear. We found previously that in prepubertal females, 17βE modulates glucose sensing in nonadapting glucose-inhibited (GI) and adapting GI (AdGI) neurons within the ventrolateral portion of the ventromedial nucleus (VL-VMN). Nonadapting GI neurons persistently decrease their activity as glucose increases while AdGI neurons transiently respond to a glucose increase. To begin to understand if endogenous fluctuations in estrogen levels across the estrous cycle impact hypothalamic glucose sensing and glucose homeostasis, we assessed whether hypoglycemia counterregulation and glucose tolerance differed across the phases of the estrous cycle. We hypothesized that the response to insulin-induced hypoglycemia (IIH) and/or glucose tolerance would vary throughout the estrous cycle according to changes in 17βE availability. Moreover, that these changes would correlate with estrous-dependent changes in the glucose sensitivity of VL-VMN glucose-sensing neurons (GSNs). These hypotheses were tested in female mice by measuring the response to IIH, glucose tolerance and the glucose sensitivity of VL-VMN GSNs during each phase of the estrous cycle. Furthermore, a physiological brain concentration of 17βE seen during proestrus was acutely applied to brain slices isolated on the day of diestrous and the response to low glucose in VL-VMN GSNs was assayed. The response to IIH was strongest during diestrous. The response of nonadapting GI and AdGI neurons to a glucose decrease from 2.5 to 0.5mM also peaked during diestrous; an effect which was blunted by the addition of 17βE. In contrast, the glucose sensitivity of the subpopulation of GSNs which are excited by glucose (GE) was not affected by estrous phase or exogenous 17βE application. These data suggest that physiological fluctuations in circulating 17βE levels across the estrous cycle lead to changes in hypothalamic glucose sensing and the response to IIH. Copyright © 2016 Elsevier Inc. All rights reserved.

A role for glucose in hypothermic hamsters

NASA Technical Reports Server (NTRS)

Resch, G. E.; Musacchia, X. J.

1976-01-01

Hypothermic hamsters at a rectal temperature of 7 C showed a fivefold increase in survival times from 20 to 100.5 hr when infused with glucose which maintained a blood level at about 45 mg/100 ml. A potential role for osmotic effects of the infusion was tested and eliminated. There was no improvement in survival of 3-O-methylglucose or dextran 40-infused animals. The fact that death eventually occurs even in the glucose-infused animal after about 4 days and that oxygen consumption undergoes a slow decrement in that period suggests that hypothermic survival is not wholly substrate limited. Radioactive tracer showed that localization of the C-14 was greatest in brain tissue and diaphragm, intermediate in heart and kidney, and lowest in skeletal muscle and liver. The significance of the label at sites important to respiration and circulation was presented.

Acute Low-Dose Endotoxin Treatment Results in Improved Whole-Body Glucose Homeostasis in Mice

PubMed Central

Stevens, Joseph R.; McMillan, Ryan P.; Resendes, Justin T.; Lloyd, Shannon K.; Ali, Mostafa M.; Frisard, Madlyn I.; Hargett, Stefan; Keller, Susanna R.; Hulver, Matthew W.

2017-01-01

Background Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood. Purpose/Procedures The goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model. Main Findings Contrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P<.05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P<.01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production. Conclusions This research shows that low-magnitude, short-term changes in LPS can have significant effects on whole body glucose metabolism and this likely occurs through its direct actions on the liver. Additional studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels. PMID:28183447

Acute low-dose endotoxin treatment results in improved whole-body glucose homeostasis in mice.

PubMed

Stevens, Joseph R; McMillan, Ryan P; Resendes, Justin T; Lloyd, Shannon K; Ali, Mostafa M; Frisard, Madlyn I; Hargett, Stefan; Keller, Susanna R; Hulver, Matthew W

2017-03-01

Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood. The goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model. Contrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P<.05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P<.01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production. This research shows that low-magnitude, short-term changes in LPS can have significant effects on whole body glucose metabolism and this likely occurs through its direct actions on the liver. Additional studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels. Copyright © 2016 Elsevier Inc. All rights reserved.

Longitudinal Examination of Links Between Risk Factors for the Metabolic Syndrome and Both Age and Fasting Glucose Levels in Nondiabetic Subjects.

PubMed

Preuss, Harry G; Kaats, Gilbert R; Mrvichin, Nate; Bagchi, Debasis; Swaroop, Anand

2018-01-01

Previous evaluations in nondiabetic subjects revealed statistically significant correlations between fasting blood glucose (FBG) levels used as an estimate of insulin resistance and many components constituting the metabolic syndrome. Similar significant correlations were not found employing chronological age as the independent variable in the same nondiabetic individuals. The major purpose here was to replicate as well as corroborate the previous cross-sectional observations, emphasizing results obtained from data collected longitudinally. Material was assessed from 99 nondiabetic volunteers who had undergone 2 separate baseline measurements carried out over a minimum of 5 and up to a maximum of 20 years. Findings from the starting baseline measurements mimicked many observations perceived in the earlier published cross-sectional material. The following correlations with elements constituting the metabolic syndrome using FBG as an independent variable were once more statistically significantly positive: scale weight, fat mass, circulating levels of triglycerides and high-sensitivity C-reactive protein (hsCRP). High-density lipoprotein (HDL) cholesterol was once again appropriately significant in a negative direction. In contrast, the same correlations were generally nonsignificant when age replaced FBG as the independent variable. Examining the 2 data sets over the 5-20-year intervals, FBG increased statistically significantly over time. However, the average increase clinically was relatively minor: -92.1 mg/dL ± 1.1 (SEM) vs 95.1 mg/dL ± 1.1 (SEM), p < 0.007. When the actual changes (delta) in the dependent parameters were correlated with the individual passages of time (intervals in years), only downward changes in aspartate aminotransferase (AST) levels were statistically significant. Fat-free mass showed a trend downward, whereas fat mass, trunk fat, and triglycerides merely demonstrated trends upward. Current findings gathered over years are consistent with the original hypothesis that maintaining relatively low, stable circulating glucose levels during aging retards the development and intensity of many common manifestations of the metabolic syndrome.

Circulating Vitamin D Correlates with Serum Anti-Mullerian Hormone Levels in Late Reproductive-Aged Women: Women’s Interagency HIV Study

PubMed Central

Merhi, Zaher O.; Seifer, David B.; Weedon, Jeremy; Adeyemi, Oluwatoyin; Holman, Susan; Anastos, Kathryn; Golub, Elizabeth T.; Young, Mary; Karim, Roksana; Greenblatt, Ruth; Minkoff, Howard

2012-01-01

Objective To study the correlation between circulating 25 hydroxy-vitamin D (25OH-D) levels and serum AMH in women enrolled in the Women’s Interagency HIV Study (WIHS). Design A cross-sectional study. Setting WIHS, a multicenter prospective study. Patient(s) All premenopausal women (n=388) with regular menstrual cycles were included and subdivided into three groups: group 1 with age <35 (N=128), group 2 with age 35 to 39 (N=119), and group 3 with age ≥ 40 (N=141). Intervention(s) Serum for 25OH-D, AMH, fasting glucose and insulin, and creatinine levels. Main Outcome Measure(s) Correlation between 25OH-D and AMH before and after adjusting for HIV status, BMI, race, smoking, illicit drug use, glucose and insulin levels, estimated glomerular filtration rate and geographic site of participation. Result(s) After adjusting for all covariates, the regression slope in all participants for total 25OH-D predicting log10AMH for 25-year-olds (youngest participant) was −0.001 (SE=0.008, p=0.847); and for 45-year-olds (oldest participant), the corresponding slope was +0.011 (SE=0.005, p=0.021). Fasting insulin level was negatively correlated with serum AMH (p=0.016). The regression slope for the correlation between 25OH-D and AMH in group 1 was +0.002 (SE=0.006, p=0.764); in group 2 was +0.006 (SE=0.005, p=0.269); and in group 3 was +0.011 (SE=0.005, p=0.022). There was no association between HIV and AMH. Conclusion(s) A novel relationship is reported between circulating 25OH-D and AMH in women aged = 40 suggesting that 25OH-D deficiency might be associated with lower ovarian reserve in late reproductive-aged women. PMID:22494925

Decreased serum betatrophin levels correlate with improved fasting plasma glucose and insulin secretion capacity after Roux-en-Y gastric bypass in obese Chinese patients with type 2 diabetes: a 1-year follow-up.

PubMed

Guo, Kaifeng; Yu, Haoyong; Lu, Junxi; Bao, Yuqian; Chen, Haibing; Jia, Weiping

2016-08-01

There is increasing evidence that serum betatrophin levels, a hormone derived from adipose tissue and liver, are elevated in type 2 diabetes (T2D). To investigate the relationships among betatrophin and metabolic control, insulin resistance, and pancreatic β-cell function in obese Chinese patients with T2D who underwent Roux-en-Y gastric bypass (RYGB). University hospital, China. This 1-year follow-up study included 34 obese individuals with T2D (18 males, 16 females) who underwent RYGB in our hospital. Anthropometric results, glucose levels, lipid profiles, and serum betatrophin levels were determined before and 1 year after RYGB. The serum betatrophin level decreased significantly after RYGB (72.0 ng/mL [33.4-180.9] versus 35.7 ng/mL [14.8-103.3]); P<.001]. The change in betatrophin was significantly positively correlated with the changes in hemoglobin A1c and fasting plasma glucose and negatively correlated with the changes in the 2-hour C-peptide/fasting C-peptide and homeostasis model of assessment of β-cell function (P<.05). Multiple stepwise regression analysis indicated that the change in the serum betatrophin level was independently and significantly associated with the changes in fasting plasma glucose (β = .586, P<.001) and 2-hour C-peptide/fasting C-peptide (β = -.309, P = .021). Circulating betatrophin might be involved in the regulation of glucose control and insulin secretion in obese Chinese with T2D soon after RYGB. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Effect of khat, its constituents and restraint stress on free radical metabolism of rats.

PubMed

Al-Qirim, Tariq M; Shahwan, Moyad; Zaidi, Kashif R; Uddin, Qamar; Banu, Naheed

2002-12-01

The leaves of khat (Catha edulis) are found to have stimulating and pleasurable effect and are chewed habitually by people of East Africa and Arabian Peninsula. Due to various toxic and psychostimulative effect of khat the present study was undertaken to evaluate the effect of intragastric khat alone or its major constituents flavonoids/alkaloids administration and before and after 4 h of immobilization stress in terms of alteration of free radical scavenging/metabolizing enzymes, uric acid and glucose in rats. Oral khat, alkaloid administration or 4 h restraint stress resulted in the decrease of the circulating levels of superoxide dismutase, catalase, glutathione-S-transferase and glucose with enhanced uric acid concentrations as compared with control rats. Oral treatment with flavonoid fraction of khat was found to enhance the activities of GST and catalase but showed no effect on SOD while the level of glucose was decreased and uric acid increased. The levels of these biochemical parameters were more altered in post stress khat/alkaloid treated rats than pre stress khat/alkaloid treated rats. The alteration in the levels of SOD, GST, catalase and uric acid in the pre stress khat treated rats were comparable with that of khat alone, except the level of glucose which was further decreased in pre stress khat treated rats. The flavonoid fraction of khat reduced the stress induced oxidative stress in terms of above mentioned biochemical parameters. The present study suggests that khat alone or khat/alkaloid consumption preceding stress may significantly decrease the levels of free radical metabolizing/scavenging enzymes and glucose leading to enhanced free radical concentration and toxicity of khat, which could be due to its alkaloid fraction as flavonoids were found to show antioxidant properties for oxidative stress generated during restraint stress.

Circulating insulin-like peptide 5 levels and its association with metabolic and hormonal parameters in women with polycystic ovary syndrome.

PubMed

Bicer, M; Alan, M; Alarslan, P; Guler, A; Kocabas, G U; Imamoglu, C; Aksit, M; Bozkaya, G; Isil, A M; Baloglu, A; Aslanipoiur, B; Calan, Mehmet

2018-06-28

Insulin-like peptide 5 (INSL5) is a gut peptide hormone that is a member of relaxin/insulin superfamily. Growing evidence implicates the crucial role of the peptide in some metabolisms including food intake, glucose homeostasis and reproductive system. Polycystic ovary syndrome (PCOS) is involved in both reproductive and metabolic issues. The aim of the study was determination of circulating levels of INSL5 alteration in women with PCOS and evaluation of the relationship between INSL5 and hormonal-metabolic parameters as well as carotid intima media thickness (cIMT). A total of 164 subjects were recruited in this cross-sectional study (82 women with PCOS and 82 age- and BMI-matched controls). Circulating INSL5 levels were assessed via ELISA method. High-resolution B-mode ultrasound was used to measure cIMT. The hormonal and metabolic parameters of the recruited subjects were determined. Circulating INSL5 levels were significantly elevated in women with PCOS compared to controls (27.63 ± 7.74 vs. 19.90 ± 5.85 ng/ml, P < 0.001). The mean values of INSL5 were significantly higher in overweight subjects compared to lean weight subjects in both groups. The women with PCOS having insulin resistance have increased INSL5 compared to those of PCOS subjects without insulin resistance. INSL5 is associated with insulin resistance, BMI, luteinizing hormone and free androgen index. Multivariate logistic regression analyses revealed that the odds ratio for having PCOS in the highest tertile of INSL5 was higher than in the lowest tertile. PCOS subjects exhibited an elevation in circulating INSL5 levels along with a link between INSL5 level induction and metabolic-hormonal parameters.

Dynamics of Nampt/visfatin and high molecular weight adiponectin in response to oral glucose load in obese and lean women.

PubMed

Unlütürk, Uğur; Harmanci, Ayla; Yildiz, Bülent Okan; Bayraktar, Miyase

2010-04-01

High molecular weight adiponectin (HMWA) is the active circulating form of adiponectin. Nampt/visfatin is the enzyme secreted from adipocytes in an active form and is one of the putative regulators of insulin secretion. To investigate the dynamics of total adiponectin (TA), HMWA and Nampt/visfatin in obese and lean women during oral glucose tolerance test (OGTT). We studied normal glucose-tolerant (NGT), age-matched, 30 obese and 30 lean women. All subjects underwent a standard 75 g, 2-h OGTT, and area under the curve (AUC) during OGTT for glucose, insulin, Nampt/visfatin, TA and HMWA was calculated. Body fat mass was assessed by bioimpedance analysis. Results Obese women had significantly higher basal and AUC values for insulin and Nampt/visfatin, whereas basal and AUC-HMWA were significantly lower in this group. Alternatively, obese and lean groups had similar basal and AUC values for glucose and TA. Basal insulin levels were negatively correlated with HMWA levels, but not with basal Nampt/visfatin. AUC-insulin was correlated positively with AUC-visfatin, and negatively with AUC-HMWA. Total and truncal body fat mass showed positive correlation with basal and AUC-visfatin, and negative correlation with basal and AUC-HMWA. In the NGT state, obese women have higher Nampt/visfatin and lower HMWA levels, both basally and in response to oral glucose challenge. The dynamics of Nampt/visfatin and HMWA during OGTT appear to be linked with insulin and adiposity. Counter-regulatory adaptations in HMWA and Nampt/visfatin might have an impact on suggested adipoinsular axis, contributing to maintenance of normal glucose tolerance.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gross, P.M.; Kadekaro, M.; Andrews, D.W.

The subfornical organ is a major receptor area for one of the principal stimuli of thirst, the octapeptide, angiotensin II. In conscious water-sated rats, the authors examined the effects of intravenous infusion of angiotensin II on the rate of glucose utilization in the subfornical organ and in structures anatomically and functionally connected with it. Angiotensin II produced pressor and drinking responses and increased glucose utilization selectively in the subfornical organ and pituitary neural lobe and in no other brain structure. Treatment with the angiotensin II antagonist, sar1-leu8-angiotensin II, before intravenous administration of angiotensin II prevented metabolic stimulation of the subfornicalmore » organ and neural lobe. Captopril, an inhibitor of angiotensin-converting enzyme, reduced subfornical organ glucose metabolism to a level similar to that found in control animals. These results demonstrate that peripheral angiotensin II stimulates glucose metabolism in the subfornical organ under conditions in which it provokes drinking and pressor responses. The findings suggest that circulating angiotensin II is responsible for the high rate of glucose utilization observed in the subfornical organ of Brattleboro rats homozygous for diabetes insipidus.« less

Glucose improves object-location binding in visual-spatial working memory.

PubMed

Stollery, Brian; Christian, Leonie

2016-02-01

There is evidence that glucose temporarily enhances cognition and that processes dependent on the hippocampus may be particularly sensitive. As the hippocampus plays a key role in binding processes, we examined the influence of glucose on memory for object-location bindings. This study aims to study how glucose modifies performance on an object-location memory task, a task that draws heavily on hippocampal function. Thirty-one participants received 30 g glucose or placebo in a single 1-h session. After seeing between 3 and 10 objects (words or shapes) at different locations in a 9 × 9 matrix, participants attempted to immediately reproduce the display on a blank 9 × 9 matrix. Blood glucose was measured before drink ingestion, mid-way through the session, and at the end of the session. Glucose significantly improves object-location binding (d = 1.08) and location memory (d = 0.83), but not object memory (d = 0.51). Increasing working memory load impairs object memory and object-location binding, and word-location binding is more successful than shape-location binding, but the glucose improvement is robust across all difficulty manipulations. Within the glucose group, higher levels of circulating glucose are correlated with better binding memory and remembering the locations of successfully recalled objects. The glucose improvements identified are consistent with a facilitative impact on hippocampal function. The findings are discussed in the context of the relationship between cognitive processes, hippocampal function, and the implications for glucose's mode of action.

Decreases in circulating uncarboxylated osteocalcin are not associated with HOMA-IR changes in humans

USDA-ARS?s Scientific Manuscript database

Osteocalcin (OC) in its uncarboxylated form (ucOC) may improve glucose metabolism in mice. However, human data are equivocal. Vitamin K (VK) is the only known factor to reduce the proportion of circulating OC that is uncarboxylated. We hypothesized that a decrease in circulating ucOC through VK supp...

Postprandial dysmetabolism: Too early or too late?

PubMed

Pappas, Christos; Kandaraki, Eleni A; Tsirona, Sofia; Kountouras, Dimitrios; Kassi, Georgia; Diamanti-Kandarakis, Evanthia

2016-07-01

Postprandial dysmetabolism is a postprandial state characterized by abnormal metabolism of glucose and lipids and, more specifically, of elevated levels of glucose and triglyceride (TG) containing lipoproteins. Since there is evidence that postprandial dysmetabolism is associated with increased cardiovascular mortality and morbidity, due to macro- and microvascular complications, as well as with conditions such as polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD), it is recommended that clinicians be alert for early detection and management of this condition. Management consists of a holistic approach including dietary modification, exercise and use of hypoglycemic and hypolipidemic medication aiming to decrease the postprandial values of circulating glucose and triglycerides. This review aims to explain glucose and lipid homeostasis and the impact of postprandial dysmetabolism on the cardiovascular system as well as to offer suggestions with regard to the therapeutic approach for this entity. However, more trials are required to prevent or reverse early and not too late the actual tissue damage due to postprandial dysmetabolism.

Live imaging using a FRET glucose sensor reveals glucose delivery to all cell types in the Drosophila brain.

PubMed

Volkenhoff, Anne; Hirrlinger, Johannes; Kappel, Johannes M; Klämbt, Christian; Schirmeier, Stefanie

2018-04-01

All complex nervous systems are metabolically separated from circulation by a blood-brain barrier (BBB) that prevents uncontrolled leakage of solutes into the brain. Thus, all metabolites needed to sustain energy homeostasis must be transported across this BBB. In invertebrates, such as Drosophila, the major carbohydrate in circulation is the disaccharide trehalose and specific trehalose transporters are expressed by the glial BBB. Here we analyzed whether glucose is able to contribute to energy homeostasis in Drosophila. To study glucose influx into the brain we utilized a genetically encoded, FRET-based glucose sensor expressed in a cell type specific manner. When confronted with glucose all brain cells take up glucose within two minutes. In order to characterize the glucose transporter involved, we studied Drosophila Glut1, the homologue of which is primarily expressed by the BBB-forming endothelial cells and astrocytes in the mammalian nervous system. In Drosophila, however, Glut1 is expressed in neurons and is not found at the BBB. Thus, Glut1 cannot contribute to initial glucose uptake from the hemolymph. To test whether gap junctional coupling between the BBB forming cells and other neural cells contributes to glucose distribution we assayed these junctions using RNAi experiments and only found a minor contribution of gap junctions to glucose metabolism. Our results provide the entry point to further dissect the mechanisms underlying glucose distribution and offer new opportunities to understand brain metabolism. Copyright © 2017 Elsevier Ltd. All rights reserved.

Low-dose spironolactone ameliorates insulin resistance and suppresses elevated plasminogen activator inhibitor-1 during gestational testosterone exposure.

PubMed

Olatunji, Lawrence A; Usman, Taofeek O; Akinade, Aminat I; Adeyanju, Oluwaseun A; Kim, InKyeom; Soladoye, Ayodele O

2017-12-01

Elevated gestational circulating testosterone has been associated with pathological pregnancies that increase the risk of development of cardiometabolic disorder in later life. We hypothesised that gestational testosterone exposure, in late pregnancy, causes glucose deregulation and atherogenic dyslipidaemia that would be accompanied by high plasminogen activator inhibitor-1 (PAI-1). The study also hypothesise that low-dose spironolactone treatment would ameliorate these effects. Pregnant Wistar rats received vehicle, testosterone (0.5 mg/kg; sc), spironolactone (0.5 mg/kg, po) or testosterone and spironolactone daily between gestational days 15 and 19. Gestational testosterone exposure led to increased HOMA-IR, circulating insulin, testosterone, 1-h post-load glucose, atherogenic dyslipidaemia, PLR, PAI-1 and MDA. However, all these effects, except that of circulating testosterone, were ameliorated by spironolactone. These results demonstrate that low-dose spironolactone ameliorates glucose deregulation and atherogenic dyslipidaemia during elevated gestational testosterone exposure, at least in part, by suppressing elevated PAI-1.

The Role of Circulating Amino Acids in the Hypothalamic Regulation of Liver Glucose Metabolism123

PubMed Central

Arrieta-Cruz, Isabel; Gutiérrez-Juárez, Roger

2016-01-01

A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes. PMID:27422516

The Role of Circulating Amino Acids in the Hypothalamic Regulation of Liver Glucose Metabolism.

PubMed

Arrieta-Cruz, Isabel; Gutiérrez-Juárez, Roger

2016-07-01

A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes. © 2016 American Society for Nutrition.

CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress.

PubMed

Petersen, Pia S; Lei, Xia; Wolf, Risa M; Rodriguez, Susana; Tan, Stefanie Y; Little, Hannah C; Schweitzer, Michael A; Magnuson, Thomas H; Steele, Kimberley E; Wong, G William

2017-04-01

Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes. Copyright © 2017 the American Physiological Society.

Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling.

PubMed

Bakh, Naveed A; Bisker, Gili; Lee, Michael A; Gong, Xun; Strano, Michael S

2017-11-01

A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hepatic gluconeogenesis and the activity of PDH in individual tissues of GTG-obese mice following adrenalectomy.

PubMed

Blair, S C; Greenaway, T M; Bryson, J M; Phuyal, J L; Wensley, V R; Caterson, I D; Cooney, G J

1996-07-01

Adrenalectomy (ADX) lowers circulating glucose levels in animal models of non-insulin dependent diabetes (NIDDM) and obesity. To investigate the role of hepatic glucose production (HGP) and tissue glucose oxidation in the improvement in glucose tolerance, hepatocyte gluconeogenesis and the activity of pyruvate dehydrogenase (PDH) were examined in different tissues of gold thioglucose (GTG) obese mice 2 weeks after ADX or sham ADX. GTG-obese mice which had undergone ADX weighed significantly less than their adrenal intact counterparts (GTG ADX: 37.5 +/- 0.7 g; GTG: 44.1 +/- 0.4; p < 0.05), and demonstrated lower serum glucose (GTG ADX: 22.5 +/- 1.6 mmol/L; GTG: 29.4 +/- 1.9 mmol/L; p < 0.05) and serum insulin levels (GTG ADX: 76 +/- 10 microU/mL; GTG: 470 +/- 63 microU/mL; p < 0.05). Lactate conversion to glucose by hepatocytes isolated from ADX GTG mice was significantly reduced compared with that of hepatocytes from GTG mice (GTG ADX: 125 +/- 10 nmol glucose/10(6) cells; GTG: 403 +/- 65 nmol glucose/10(6) cells; p < 0.05). ADX also significantly reduced both the glycogen (GTG ADX: 165 +/- 27 mumol/liver; GTG: 614 +/- 60 mumol/liver; p < 0.05) and fatty acid content (GTG ADX: 101 +/- 9 mg fatty acid/g liver; GTG: 404 +/- 40 mg fatty acid/g liver; p < 0.05) of the liver of GTG-obese mice. ADX of GTG-obese mice reduced PDH activity by varying degrees in all tissues, except quadriceps muscle. These observations are consistent with an ADX induced decrease in hepatic lipid stores removing fatty acid-induced increases in gluconeogenesis and increased peripheral availability of fatty acids inhibiting PDH activity via the glucose/fatty acid cycle. It is also evident that the improvement in glucose tolerance which accompanies ADX of GTG-obese mice is not due to increased PDH activity resulting in enhanced peripheral glucose oxidation. Instead, it is more likely that reduced blood glucose levels after ADX of GTG-obese mice are the result of decreased gluconeogenesis in the liver.

Metabolic and histologic effects of sodium pyruvate treatment in the rat after cortical contusion injury.

PubMed

Fukushima, Masamichi; Lee, Stefan M; Moro, Nobuhiro; Hovda, David A; Sutton, Richard L

2009-07-01

This study determined the effects of intraperitoneal sodium pyruvate (SP) treatment on the levels of circulating fuels and on cerebral microdialysis levels of glucose (MD(glc)), lactate (MD(lac)), and pyruvate (MD(pyr)), and the effects of SP treatment on neuropathology after left cortical contusion injury (CCI) in rats. SP injection (1000 mg/kg) 5 min after sham injury (Sham-SP) or CCI (CCI-SP) significantly increased arterial pyruvate (p < 0.005) and lactate (p < 0.001) compared to that of saline-treated rats with CCI (CCI-Sal). Serum glucose also increased significantly in CCI-SP compared to that in CCI-Sal rats (p < 0.05), but not in Sham-SP rats. MD(pyr) was not altered after CCI-Sal, whereas MD(lac) levels within the cerebral cortex significantly increased bilaterally (p < 0.05) and those for MD(glc) decreased bilaterally (p < 0.05). MD(pyr) levels increased significantly in both Sham-SP and CCI-SP rats (p < 0.05 vs. CCI-Sal) and were higher in left/injured cortex of the CCI-SP group (p < 0.05 vs. sham-SP). In CCI-SP rats the contralateral MD(lac) decreased below CCI-Sal levels (p < 0.05) and the ipsilateral MD(glc) levels exceeded those of CCI-Sal rats (p < 0.05). Rats with a single low (500 mg/kg) or high dose (1000 mg/kg) SP treatment had fewer damaged cortical cells 6 h post-CCI than did saline-treated rats (p < 0.05), but three hourly injections of SP (1000 mg/kg) were needed to significantly reduce contusion volume 2 weeks after CCI. Thus, a single intraperitoneal SP treatment increases circulating levels of three potential brain fuels, attenuates a CCI-induced reduction in extracellular glucose while increasing extracellular levels of pyruvate, but not lactate, and can attenuate cortical cell damage occurring within 6 h of injury. Enduring (2 week) neuronal protection was achieved only with multiple SP treatments within the first 2 h post-CCI, perhaps reflecting the need for additional fuel throughout the acute period of increased metabolic demands induced by CCI.

Metabolic and Histologic Effects of Sodium Pyruvate Treatment in the Rat after Cortical Contusion Injury

PubMed Central

Fukushima, Masamichi; Lee, Stefan M.; Moro, Nobuhiro; Hovda, David A.

2009-01-01

Abstract This study determined the effects of intraperitoneal sodium pyruvate (SP) treatment on the levels of circulating fuels and on cerebral microdialysis levels of glucose (MDglc), lactate (MDlac), and pyruvate (MDpyr), and the effects of SP treatment on neuropathology after left cortical contusion injury (CCI) in rats. SP injection (1000 mg/kg) 5 min after sham injury (Sham-SP) or CCI (CCI-SP) significantly increased arterial pyruvate (p < 0.005) and lactate (p < 0.001) compared to that of saline-treated rats with CCI (CCI-Sal). Serum glucose also increased significantly in CCI-SP compared to that in CCI-Sal rats (p < 0.05), but not in Sham-SP rats. MDpyr was not altered after CCI-Sal, whereas MDlac levels within the cerebral cortex significantly increased bilaterally (p < 0.05) and those for MDglc decreased bilaterally (p < 0.05). MDpyr levels increased significantly in both Sham-SP and CCI-SP rats (p < 0.05 vs. CCI-Sal) and were higher in left/injured cortex of the CCI-SP group (p < 0.05 vs. sham-SP). In CCI-SP rats the contralateral MDlac decreased below CCI-Sal levels (p < 0.05) and the ipsilateral MDglc levels exceeded those of CCI-Sal rats (p < 0.05). Rats with a single low (500 mg/kg) or high dose (1000 mg/kg) SP treatment had fewer damaged cortical cells 6 h post-CCI than did saline-treated rats (p < 0.05), but three hourly injections of SP (1000 mg/kg) were needed to significantly reduce contusion volume 2 weeks after CCI. Thus, a single intraperitoneal SP treatment increases circulating levels of three potential brain fuels, attenuates a CCI-induced reduction in extracellular glucose while increasing extracellular levels of pyruvate, but not lactate, and can attenuate cortical cell damage occurring within 6 h of injury. Enduring (2 week) neuronal protection was achieved only with multiple SP treatments within the first 2 h post-CCI, perhaps reflecting the need for additional fuel throughout the acute period of increased metabolic demands induced by CCI. PMID:19594384

Circadian Rhythms of Heart Rate and Locomotion After Treatment With Low-Dose Acetylcholinesterase Inhibitors

DTIC Science & Technology

2006-01-01

with pyridostigmine bromide (PB), a carbamate AChE by air conditioned vans and air-freight to the Laboratory inhibitor that does not cross the blood ...15. SUBJECT TERMS Nerve agents, sarin, pyridostigmine bromide, cerebral glucose utilization, cerebrovascular circulation, low dose cholinesterase ...March 2006" Accepted 12 May 2006 ABSTRACT: This study tested the hypothesis that repeated exposure to low levels of sarin, pyridostigmine bromide (PB

RU486 did not exacerbate cytokine release in mice challenged with LPS nor in db/db mice

PubMed Central

Yang, Baichun; Trump, Ryan P; Shen, Ying; McNulty, Judi A; Clifton, Lisa G; Stimpson, Stephen A; Lin, Peiyuan; Pahel, Greg L

2008-01-01

Background Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. The glucocorticoid receptor (GR) antagonist RU486 may exacerbate the inflammatory response, and concerns over this exacerbation have limited the development and clinical use of GR antagonists in the treatment of diabetes and depression. We investigated the effects of RU486 on serum cytokines in db/db mice and on lipopolysaccharide (LPS)-induced circulating TNFα levels in both normal AKR mice and diet-induced obese (DIO) C57BL/6 mice. Results Chronic treatment of db/db mice with RU486 dose-dependently decreased blood glucose, increased serum corticosterone and ACTH, but did not affect serum MCP-1 and IL-6 levels. LPS dose-dependently increased serum TNFα in both AKR and C57BL/6 DIO mice, along with increased circulating corticosterone and ACTH. Pretreatment of the mice with RU486 dose-dependently suppressed the LPS induced increases in serum TNFα and further increased serum corticosterone. Conclusion RU486 at doses that were efficacious in lowering blood glucose did not exacerbate cytokine release in these three mouse models. RU486 actually suppressed the lower dose LPS-mediated TNFα release, possibly due to the increased release of glucocorticoids. PMID:18474108

Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates.

PubMed

Lundsgaard, Anne-Marie; Fritzen, Andreas M; Sjøberg, Kim A; Myrmel, Lene S; Madsen, Lise; Wojtaszewski, Jørgen F P; Richter, Erik A; Kiens, Bente

2017-01-01

Fibroblast-growth factor 21 (FGF21) is thought to be important in metabolic regulation. Recently, low protein diets have been shown to increase circulating FGF21 levels. However, when energy contribution from dietary protein is lowered, other macronutrients, such as carbohydrates, must be increased to meet eucaloric balance. This raises the possibility that intake of a diet rich in carbohydrates may induce an increase in plasma FGF21 levels per se. Here we studied the role of dietary carbohydrates on the levels of circulating FGF21 and concomitant physiologic effects by feeding healthy men a carbohydrate rich diet without reducing protein intake. A diet enriched in carbohydrates (80 E% carbohydrate; CHO) and a eucaloric control diet (CON) were provided to nine healthy men for three days. The energy intake during the CHO diet was increased (+75% energy) to ensure similar dietary protein intake in CHO and CON. To control for the effect of caloric surplus, we similarly overfed (+75% energy) the same subjects for three days with a fat-rich diet (78 E% fat; FAT), consisting of primarily unsaturated fatty acids. The three diets were provided in random order. After CHO, plasma FGF21 concentration increased 8-fold compared to CON (329 ± 99 vs. 39 ± 9 pg ml -1 , p < 0.05). In contrast, after FAT only a non-significant tendency (p = 0.073) to an increase in plasma FGF21 concentration was found. The increase in FGF21 concentration after CHO correlated closely (r = 0.88, p < 0.01) with increased leg glucose uptake (62%, p < 0.05) and increased hepatic glucose production (17%, p < 0.01), indicating increased glucose turnover. Plasma fatty acid (FA) concentration was decreased by 68% (p < 0.01), supported by reduced subcutaneous adipose tissue HSL Ser 660 phosphorylation (p < 0.01) and perilipin 1 protein content (p < 0.01), pointing to a suppression of adipose tissue lipolysis. Concomitantly, a 146% increase in the plasma marker of hepatic de novo lipogenesis C16:1 n-7 FA (p < 0.01) was observed together with 101% increased plasma TG concentration (p < 0.001) in association with CHO intake and increased plasma FGF21 concentration. Excess dietary carbohydrate, but not fat, led to markedly increased FGF21 secretion in humans, notably without protein restriction, and affected glucose and lipid homeostais.

Odd Chain Fatty Acids; New Insights of the Relationship Between the Gut Microbiota, Dietary Intake, Biosynthesis and Glucose Intolerance

PubMed Central

Jenkins, Benjamin J.; Seyssel, Kevin; Chiu, Sally; Pan, Pin-Ho; Lin, Shih-Yi; Stanley, Elizabeth; Ament, Zsuzsanna; West, James A.; Summerhill, Keith; Griffin, Julian L.; Vetter, Walter; Autio, Kaija J.; Hiltunen, Kalervo; Hazebrouck, Stéphane; Stepankova, Renata; Chen, Chun-Jung; Alligier, Maud; Laville, Martine; Moore, Mary; Kraft, Guillaume; Cherrington, Alan; King, Sarah; Krauss, Ronald M.; de Schryver, Evelyn; Van Veldhoven, Paul P.; Ronis, Martin; Koulman, Albert

2017-01-01

Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1−/− mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1−/− only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease. PMID:28332596

Low circulating levels of IGF-1 in healthy adults are associated with reduced β-cell function, increased intramyocellular lipid, and enhanced fat utilization during fasting.

PubMed

Thankamony, Ajay; Capalbo, Donatella; Marcovecchio, M Loredana; Sleigh, Alison; Jørgensen, Sine Wanda; Hill, Nathan R; Mooslehner, Katrin; Yeo, Giles S H; Bluck, Les; Juul, Anders; Vaag, Allan; Dunger, David B

2014-06-01

Low serum IGF-1 levels have been linked to increased risk for development of type 2 diabetes. However, the physiological role of IGF-1 in glucose metabolism is not well characterized. Our objective was to explore glucose and lipid metabolism associated with variations in serum IGF-1 levels. IGF-1 levels were measured in healthy, nonobese male volunteers aged 18 to 50 years from a biobank (n = 275) to select 24 subjects (age 34.8 ± 8.9 years), 12 each in the lowest (low-IGF) and highest (high-IGF) quartiles of age-specific IGF-1 SD scores. Evaluations were undertaken after a 24-hour fast and included glucose and glycerol turnover rates using tracers, iv glucose tolerance test to estimate peripheral insulin sensitivity (IS) and acute insulin and C-peptide responses (indices of insulin secretion), magnetic resonance spectroscopy to measure intramyocellular lipids (IMCLs), calorimetry, and gene expression studies in a muscle biopsy. Acute insulin and C-peptide responses, IS, and glucose and glycerol rate of appearance (Ra) were evaluated. Fasting insulin and C-peptide levels and glucose Ra were reduced (all P < .05) in low-IGF compared with high-IGF subjects, indicating increased hepatic IS. Acute insulin and C-peptide responses were lower (both P < .05), but similar peripheral IS resulted in reduced insulin secretion adjusted for IS in low-IGF subjects (P = 0.044). Low-IGF subjects had higher overnight levels of free fatty acids (P = .028) and β-hydroxybutyrate (P = .014), increased accumulation of IMCLs in tibialis anterior muscle (P = .008), and a tendency for elevated fat oxidation rates (P = .058); however, glycerol Ra values were similar. Gene expression of the fatty acid metabolism pathway (P = .0014) was upregulated, whereas the GLUT1 gene was downregulated (P = .005) in the skeletal muscle in low-IGF subjects. These data suggest that serum IGF-1 levels could be an important marker of β-cell function and glucose as well as lipid metabolic responses during fasting.

Synergistic association of elevated serum free fatty acid and glucose levels with large arterial stiffness in a general population: The Nagahama Study.

PubMed

Tabara, Yasuharu; Takahashi, Yoshimitsu; Setoh, Kazuya; Kawaguchi, Takahisa; Gotoh, Norimoto; Terao, Chikashi; Yamada, Ryo; Kosugi, Shinji; Sekine, Akihiro; Nakayama, Takeo; Matsuda, Fumihiko

2016-01-01

Previous studies have reported that artificial increases in circulating free fatty acid (FFA) levels might have adverse effects on the vasculature. However, whether or not this effect can be extrapolated to physiological variations in FFA levels has not been clarified. Given that FFAs exert a lipotoxic effect on pancreatic β-cells and might directly damage the arterial endothelium, we hypothesized that these adverse effects might synergize with hyperglycemia. A total of 9396 Japanese subjects were included in the study. Serum FFA levels were measured at baseline examination. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. As serum levels of FFA were markedly lower in subjects with higher insulin level, a significant association between FFA levels and baPWV was observed only in subjects with blood samples taken under fasting (≥12 h, P<0.001) or near-fasting (5-11 h, P<0.001) conditions, and not in those taken under non-fasting (<5 h, P=0.307) conditions. Although type 2 diabetes and HbA1c showed a strong association with baPWV, the association between FFA level and baPWV remained significant (β=0.052, P<0.001) after adjustment for glycemic levels. In addition to their direct relationship, FFA and glucose levels were synergistically associated with baPWV (FFA(⁎)glucose; β=0.036, P<0.001). Differences in baPWV between the lowest and highest subgroups divided by a combination of FFA and glucose reached approximately 300 cm/s. Physiological variations in FFA concentrations might be a risk factor for large arterial stiffness. FFA and hyperglycemia exert a synergistic adverse effect on the vasculature. Copyright © 2016 Elsevier Inc. All rights reserved.

[The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

PubMed

Escalada, Francisco Javier

2014-01-01

The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

Secretory response and immunochemical heterogeneity of glucagon in plasma and tumor extracts of a patient with glucagonoma.

PubMed

Torre, L; Vazquez, J A; Blázquez, E

1986-01-01

The secretory response and immunoreactive heterogeneity of glucagon was investigated in a patient with glucagonoma syndrome. After glucose administration, abnormal insulin release accompanied by glucose intolerance were observed, whereas the high glucagon circulating levels were only partially blocked after glucose or somatostatin infusion. Chromatographic fractionation of plasma samples, before and after arginine administration showed that most of the immunoreactivity eluted as true glucagon. Furthermore, when aliquots of the tumor extracts were fractionated by column chromatography or by polyacrylamide gel electrophoresis, most of the immunoreactivity eluted in the 3,500 molecular weight peak. In contrast with previous reports, our results indicate that neoplasia A cells can also manufacture and release into the bloodstream great amounts of genuine glucagon rather than larger glucagon immunoreactive forms. In spite of such findings, in this patient neither diabetes nor hyperglycemia were present.

Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance.

PubMed

Haselton, Aaron; Sharmin, Effat; Schrader, Janel; Sah, Megha; Poon, Peter; Fridell, Yih-Woei C

2010-08-01

In Drosophila melanogaster (D. melanogaster), neurosecretory insulin-like peptide-producing cells (IPCs), analogous to mammalian pancreatic beta cells are involved in glucose homeostasis. Extending those findings, we have developed in the adult fly an oral glucose tolerance test and demonstrated that IPCs indeed are responsible for executing an acute glucose clearance response. To further develop D. melanogaster as a relevant system for studying age-associated metabolic disorders, we set out to determine the impact of adult-specific partial ablation of IPCs (IPC knockdown) on insulin-like peptide (ILP) action, metabolic outcomes and longevity. Interestingly, while IPC knockdown flies are hyperglycemic and glucose intolerant, these flies remain insulin sensitive as measured by peripheral glucose disposal upon insulin injection and serine phosphorylation of a key insulin-signaling molecule, Akt. Significant increases in stored glycogen and triglyceride levels as well as an elevated level of circulating lipid measured in adult IPC knockdown flies suggest profound modulation in energy metabolism. Additional physiological outcomes measured in those flies include increased resistance to starvation and impaired female fecundity. Finally, increased life span and decreased mortality rates measured in IPC knockdown flies demonstrate that it is possible to modulate ILP action in adult flies to achieve life span extension without insulin resistance. Taken together, we have established and validated an invertebrate genetic system to further investigate insulin action, metabolic homeostasis and regulation of aging regulated by adult IPCs.

The impact of Roux-en-Y gastric bypass surgery on normal metabolism in a porcine model

PubMed Central

Lindqvist, Andreas; Ekelund, Mikael; Garcia-Vaz, Eliana; Ståhlman, Marcus; Pierzynowski, Stefan; Gomez, Maria F.; Rehfeld, Jens F.; Groop, Leif; Hedenbro, Jan

2017-01-01

Background A growing body of literature on Roux-en-Y gastric bypass surgery (RYGB) has generated inconclusive results on the mechanism underlying the beneficial effects on weight loss and glycaemia, partially due to the problems of designing clinical studies with the appropriate controls. Moreover, RYGB is only performed in obese individuals, in whom metabolism is perturbed and not completely understood. Methods In an attempt to isolate the effects of RYGB and its effects on normal metabolism, we investigated the effect of RYGB in lean pigs, using sham-operated pair-fed pigs as controls. Two weeks post-surgery, pigs were subjected to an intravenous glucose tolerance test (IVGTT) and circulating metabolites, hormones and lipids measured. Bile acid composition was profiled after extraction from blood, faeces and the gallbladder. Results A similar weight development in both groups of pigs validated our experimental model. Despite similar changes in fasting insulin, RYGB-pigs had lower fasting glucose levels. During an IVGTT RYGB-pigs had higher insulin and lower glucose levels. VLDL and IDL were lower in RYGB- than in sham-pigs. RYGB-pigs had increased levels of most amino acids, including branched-chain amino acids, but these were more efficiently suppressed by glucose. Levels of bile acids in the gallbladder were higher, whereas plasma and faecal bile acid levels were lower in RYGB- than in sham-pigs. Conclusion In a lean model RYGB caused lower plasma lipid and bile acid levels, which were compensated for by increased plasma amino acids, suggesting a switch from lipid to protein metabolism during fasting in the immediate postoperative period. PMID:28257455

Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency.

PubMed

Collantes, María; Serrano-Mendioroz, Irantzu; Benito, Marina; Molinet-Dronda, Francisco; Delgado, Mercedes; Vinaixa, María; Sampedro, Ana; Enríquez de Salamanca, Rafael; Prieto, Elena; Pozo, Miguel A; Peñuelas, Iván; Corrales, Fernando J; Barajas, Miguel; Fontanellas, Antonio

2016-04-01

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks when hepatic heme synthesis is activated by endogenous or environmental factors including fasting. While the molecular mechanisms underlying the nutritional regulation of hepatic heme synthesis have been described, glucose homeostasis during fasting is poorly understood in porphyria. Our study aimed to analyse glucose homeostasis and hepatic carbohydrate metabolism during fasting in PBGD-deficient mice. To determine the contribution of hepatic PBGD deficiency to carbohydrate metabolism, AIP mice injected with a PBGD-liver gene delivery vector were included. After a 14 h fasting period, serum and liver metabolomics analyses showed that wild-type mice stimulated hepatic glycogen degradation to maintain glucose homeostasis while AIP livers activated gluconeogenesis and ketogenesis due to their inability to use stored glycogen. The serum of fasted AIP mice showed increased concentrations of insulin and reduced glucagon levels. Specific over-expression of the PBGD protein in the liver tended to normalize circulating insulin and glucagon levels, stimulated hepatic glycogen catabolism and blocked ketone body production. Reduced glucose uptake was observed in the primary somatosensorial brain cortex of fasted AIP mice, which could be reversed by PBGD-liver gene delivery. In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Induction of hyperandrogenism in lean reproductive-age women stimulates proatherogenic inflammation.

PubMed

González, F; Sreekumaran Nair, K; Basal, E; Bearson, D M; Schimke, J M; Blair, H E

2015-06-01

We determined the effect of hyperandrogenemia as observed in polycystic ovary syndrome (PCOS) on fasting and glucose-stimulated proatherogenic inflammation markers in lean healthy reproductive-age women. Sixteen lean healthy ovulatory reproductive-age women were treated with 130 mg of DHEA or placebo (n=8 each) for 5 days. Interleukin-6 (IL-6) mRNA and IL-6 release from mononuclear cells (MNC), plasma IL-6 and C-reactive protein (CRP), and MNC-derived (matrix metalloproteinase-2) MMP-2 protein were quantified in the fasting state and 2 h after glucose ingestion, before and after treatment. Before treatment, subjects receiving dehydroepinadrosterone (DHEA) or placebo exhibited no differences in androgens, or any proatherogenic inflammation markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-sulfate (DHEA-S), and increased the percent change from baseline in fasting IL-6 mRNA, IL-6 release, plasma IL-6, and CRP and MMP-2 protein. However, there were no differences in any of the proatherogenic inflammation markers following glucose ingestion after DHEA administration. We conclude that in lean reproductive-age women, proatherogenic inflammation in the fasting state increases after raising circulating androgens to levels observed in PCOS. However, this hyperandrogenemia-induced MNC activation does not provoke a similar response to subsequent glucose ingestion. © Georg Thieme Verlag KG Stuttgart · New York.

Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma

PubMed Central

Strub, Graham M.; Kirsh, Andrew L.; Whipple, Mark E.; Kuo, Winston P.; Keller, Rachel B.; Kapur, Raj P.; Majesky, Mark W.; Perkins, Jonathan A.

2016-01-01

Infantile hemangioma (IH) is the most common vascular tumor of infancy, and it uniquely regresses in response to oral propranolol. MicroRNAs (miRNAs) have emerged as key regulators of vascular development and are dysregulated in many disease processes, but the role of miRNAs in IH growth has not been investigated. We report expression of C19MC, a primate-specific megacluster of miRNAs expressed in placenta with rare expression in postnatal tissues, in glucose transporter 1–expressing (GLUT-1–expressing) IH endothelial cells and in the plasma of children with IH. Tissue or circulating C19MC miRNAs were not detectable in patients having 9 other types of vascular anomalies or unaffected children, identifying C19MC miRNAs as the first circulating biomarkers of IH. Levels of circulating C19MC miRNAs correlated with IH tumor size and propranolol treatment response, and IH tissue from children treated with propranolol or from children with partially involuted tumors contained lower levels of C19MC miRNAs than untreated, proliferative tumors, implicating C19MC miRNAs as potential drivers of IH pathogenesis. Detection of C19MC miRNAs in the circulation of infants with IH may provide a specific and noninvasive means of IH diagnosis and identification of candidates for propranolol therapy as well as a means to monitor treatment response. PMID:27660822

The effect of PCSK1 variants on waist, waist-hip ratio and glucose metabolism is modified by sex and glucose tolerance status.

PubMed

Gjesing, Anette P; Vestmar, Marie A; Jørgensen, Torben; Heni, Martin; Holst, Jens J; Witte, Daniel R; Hansen, Torben; Pedersen, Oluf

2011-01-01

We aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans. Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2-1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005-0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1-1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (-0.7-9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test. PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance status.

The Effect of PCSK1 Variants on Waist, Waist-Hip Ratio and Glucose Metabolism Is Modified by Sex and Glucose Tolerance Status

PubMed Central

Gjesing, Anette P.; Vestmar, Marie A.; Jørgensen, Torben; Heni, Martin; Holst, Jens J.; Witte, Daniel R.; Hansen, Torben; Pedersen, Oluf

2011-01-01

Background We aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans. Methodology/Principal Findings Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2–1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005–0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1–1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (−0.7–9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test. Conclusions/Significance PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance status. PMID:21935364

Increased circulating heat shock protein 70 (HSPA1A) levels in gestational diabetes mellitus: a pilot study.

PubMed

Garamvölgyi, Zoltán; Prohászka, Zoltán; Rigó, János; Kecskeméti, András; Molvarec, Attila

2015-07-01

Recent data indicate that serum Hsp70 (HSPA1A) levels are increased in type 1 and 2 diabetes mellitus. However, there is no report in the literature on circulating Hsp70 levels in gestational diabetes mellitus. In this pilot study, we measured serum Hsp70 levels in 11 pregnant women with pregestational diabetes, 38 women with gestational diabetes, and 40 healthy pregnant women with ELISA. Plasma glucose levels, serum insulin concentrations, HbA1c values, and the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) index were also determined. According to our results, serum Hsp70 concentrations were significantly higher in women with pregestational and gestational diabetes mellitus than in healthy pregnant women. In addition, pregestational diabetic women had significantly higher Hsp70 levels than those with gestational diabetes. Furthermore, in the group of women with gestational diabetes mellitus, serum Hsp70 levels showed a significant positive correlation with HbA1c values. However, there was no other relationship between clinical features and metabolic parameters of the study subjects and their serum Hsp70 levels in either study group. In conclusion, we demonstrated for the first time in the literature that serum Hsp70 levels are increased and correlate with HbA1c values in women with gestational diabetes mellitus. Nevertheless, further studies are needed to determine whether circulating Hsp70 plays a causative role in the pathogenesis of gestational diabetes or elevated serum Hsp70 levels are only consequences of the disease.

Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.

PubMed

Ejaz, Asma; Martinez-Guino, Laura; Goldfine, Allison B; Ribas-Aulinas, Francesc; De Nigris, Valeria; Ribó, Sílvia; Gonzalez-Franquesa, Alba; Garcia-Roves, Pablo M; Li, Elizabeth; Dreyfuss, Jonathan M; Gall, Walt; Kim, Jason K; Bottiglieri, Teodoro; Villarroya, Francesc; Gerszten, Robert E; Patti, Mary-Elizabeth; Lerin, Carles

2016-04-01

Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Effects of the oral contraceptive pill cycle on physiological responses to hypoxic exercise

NASA Technical Reports Server (NTRS)

Sandoval, Darleen A.; Matt, Kathleen S.

2003-01-01

To test whether the oral contraceptive pill cycle affects endocrine and metabolic responses to hypoxic (fraction of inspired oxygen = 13%, P(IO2): 95 mmHg; H) versus normoxic (P(IO2):153 mmHg; N) exercise, we examined eight women (28 +/- 1.2 yr) during the third (PILL) and placebo (PLA) weeks of their monthly oral contraceptive pill cycle. Cardiopulmonary, metabolic, and neuroendocrine measurements were taken before, during, and after three 5-min consecutive workloads at 30%, 45%, and 60% of normoxic V(O2peak) in H and N trials. Heart rate response to exercise was greater in H versus N, but was not different between PILL and PLA. Lactate levels were significantly greater during exercise, and both lactate and glucose levels were significantly greater for 30 min after exercise in H versus N (p < 0.0001). When expressed relative to baseline, lactate levels were lower in PILL versus PLA, but glucose was greater in PILL versus PLA (p < 0.001). Cortisol levels were also significantly greater in PILL versus PLA (p < 0.001). Norepinephrine levels were significantly increased during exercise (p < 0.0001) and in H versus N (p < 0.0001). However, epinephrine levels were not different over time or with trial. Thus, the presence of circulating estradiol and progesterone during the PILL phase reduces glucose and lactate responses to hypoxic exercise.

Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study.

PubMed

Abdulnour, Joseph; Yasari, Siham; Rabasa-Lhoret, Rémi; Faraj, May; Petrosino, Stefania; Piscitelli, Fabiana; Prud' Homme, Denis; Di Marzo, Vincenzo

2014-01-01

To measure the circulating levels of endocannabinoids and related molecules at fasting, after acute hyperinsulinemia and after weight loss in insulin sensitive vs. insulin resistant obese postmenopausal women. The sample consisted of 30 obese postmenopausal women (age: 58.9 ± 5.2 yrs; BMI: 32.9 ± 3.6 kg/m(2) ). Subjects underwent a 3-hour hyperinsulinaemic-euglycaemic clamp (HEC) (glucose disposal rate (M-value): 10.7 ± 3.3 mg min(-1) kg(-1) FFM) and 6-month weight loss intervention. Participants were classified as insulin sensitive obese (ISO) or insulin resistant obese (IRO) based on a predefined cutoff. Plasma levels of the endocannabinoids, anandamide (AEA), 2-arachidonoylglycerol (2-AG), and of the AEA-related compounds, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), were measured by liquid chromatography-mass spectrometry. IRO presented higher levels of 2-AG (P < 0.05) independently of the HEC and weight loss, whereas the HEC had an independent inhibitory effect on AEA, PEA, and OEA levels (P < 0.05) in both groups. Furthermore, there was an independent stimulatory effect of weight loss only on PEA levels in both groups (P < 0.05). This study is the first to show that higher circulating levels of the endocannabinoid 2-AG are found in IRO compared to ISO postmenopausal women, and that weight loss is associated with an increase in PEA, a PPAR-α ligand. © 2013 The Obesity Society.

Excessive fuel availability amplifies the FTO-mediated obesity risk: results from the TUEF and Whitehall II studies.

PubMed

Wagner, Róbert; Tabák, Ádám G; Fehlert, Ellen; Fritsche, Louise; Jaghutriz, Benjamin A; Bánhegyi, Róbert J; Schmid, Sebastian M; Staiger, Harald; Machicao, Fausto; Peter, Andreas; Häring, Hans-Ulrich; Fritsche, Andreas; Heni, Martin

2017-11-14

Variation in FTO is the most important common genetic determinant of body weight. Altered energy metabolism could underlie this association. We hypothesized that higher circulating glucose or triglycerides can amplify the FTO impact on BMI. In 2671 subjects of the TUEF study, we investigated the interaction effect of fasting glucose and triglyceride levels with rs9939609 in FTO on BMI. We analysed the same interaction effect by longitudinally utilizing mixed effect models in the prospective Whitehall II study. In TUEF, we detected an interaction effect between fasting glucose and fasting triglycerides with rs9939609 on BMI (p = 0.0005 and p = 5 × 10 -7 , respectively). The effect size of one risk allele was 1.4 ± 0.3 vs. 2.2 ± 0.44 kg/m² in persons with fasting glucose levels below and above the median, respectively. Fasting triglycerides above the median increased the per-allele effect from 1.4 ± 0.3 to 1.7 ± 0.4 kg/m 2 . In the Whitehall II study, body weight increased by 2.96 ± 6.5 kg during a follow-up of 13.5 ± 4.6 yrs. Baseline fasting glucose and rs9939609 interacted on weight change (p = 0.009). Higher fasting glucose levels may amplify obesity-risk in FTO carriers and lead to an exaggerated weight gain over time. Since weight gain perpetuates metabolic alterations, this interplay may trigger a vicious circle that leads to obesity and diabetes.

N-Acetyl-Cysteine Alleviates Gut Dysbiosis and Glucose Metabolic Disorder in High-Fat Diet-Induced Mice.

PubMed

Zheng, Junping; Yuan, Xubing; Zhang, Chen; Jia, Peiyuan; Jiao, Siming; Zhao, Xiaoming; Yin, Heng; Du, Yuguang; Liu, Hongtao

2018-05-30

N-acetyl cysteine (NAC), an anti-oxidative reagent for clinical diseases, shows potential application to diabetes and other metabolic diseases. However, it is unknown how NAC modulates the gut microbiota of mice with metabolic syndrome. In present study, we aim to demonstrate the preventive effect of NAC on intestinal dysbiosis and glucose metabolic disorder. C57BL/6J mice were fed with normal chow diet (NCD), NCD plus NAC, high-fat diet (HFD) or HFD plus NAC for five months. After the treatment, the glucose level, circulating endotoxin and metabolism-related key proteins were determined. The fecal samples were analyzed by 16S rRNA sequencing. A novel analysis was carried out to predict the functional changes of gut microbiota. In addition, Spearman's correlation between metabolic biomarkers and bacterial abundance was also assayed. The results show that NAC treatment significantly reversed the glucose intolerance, fasting glucose level, body weight and plasma endotoxin in HFD-fed mice. Further, NAC upregulated the levels of Occludin protein and mucin glycoproteins in proximal colons of HFD-treated mice. Noticeably, NAC promoted the growth of beneficial bacteria such as Akkermansia, Bifidobacterium, Lactobacillus and Allobaculum, and hampered the population of diabetes-related genera including Desulfovibrio and Blautia. Also, NAC may influence the metabolic pathways of intestinal bacteria including lipopolysaccharide biosynthesis, oxidative stress and bacterial motility. Finally, the modified gut microbiota showed close association with the metabolic changes of the NAC treated HFD-fed mice. In summary, NAC may be a potential drug to prevent glucose metabolic disturbance by reshaping the structure of gut microbiota. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels.

PubMed

Mahendran, Yuvaraj; Jonsson, Anna; Have, Christian T; Allin, Kristine H; Witte, Daniel R; Jørgensen, Marit E; Grarup, Niels; Pedersen, Oluf; Kilpeläinen, Tuomas O; Hansen, Torben

2017-05-01

Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with circulating BCAA levels and insulin resistance as instrumental variables. We measured circulating BCAA levels in blood plasma by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort. We complemented our analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 46,186) and from a GWAS of serum BCAA levels (n = 24,925). We used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels. Fasting plasma BCAA levels were associated with higher HOMA-IR in ADDITION-PRO (β 0.137 [95% CI 0.08, 0.19] p = 6 × 10 -7 ). However, the GRS for circulating BCAA levels was not associated with fasting insulin levels or HOMA-IR in ADDITION-PRO (β -0.011 [95% CI -0.053, 0.032] p = 0.6 and β -0.011 [95% CI -0.054, 0.031] p = 0.6, respectively) or in GWAS results for HOMA-IR from MAGIC (β for valine-increasing GRS -0.012 [95% CI -0.069, 0.045] p = 0.7). By contrast, the insulin-resistance-increasing GRS was significantly associated with increased BCAA levels in ADDITION-PRO (β 0.027 [95% CI 0.005, 0.048] p = 0.01) and in GWAS results for serum BCAA levels (β 1.22 [95% CI 0.71, 1.73] p = 4 × 10 -6 , β 0.96 [95% CI 0.45, 1.47] p = 3 × 10 -4 , and β 0.67 [95% CI 0.16, 1.18] p = 0.01 for isoleucine, leucine and valine levels, respectively) and instrumental variable analyses in ADDITION-PRO indicated that HOMA-IR is causally related to higher circulating fasting BCAA levels (β 0.73 [95% CI 0.26, 1.19] p = 0.002). Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance while increased insulin resistance drives higher circulating fasting BCAA levels.

Long Noncoding RNA H19 Promotes Neuroinflammation in Ischemic Stroke by Driving Histone Deacetylase 1-Dependent M1 Microglial Polarization.

PubMed

Wang, Jue; Zhao, Haiping; Fan, Zhibin; Li, Guangwen; Ma, Qingfeng; Tao, Zhen; Wang, Rongliang; Feng, Juan; Luo, Yumin

2017-08-01

Long noncoding RNA H19 is repressed after birth, but can be induced by hypoxia. We aim to investigate the impact on and underlying mechanism of H19 induction after ischemic stroke. Circulating H19 levels in stroke patients and mice subjected to middle cerebral artery occlusion were assessed using real-time polymerase chain reaction. H19 siRNA and histone deacetylase 1 (HDAC1) plasmid were used to knock down H19 and overexpress HDAC1, respectively. Microglial polarization and ischemic outcomes were assessed in middle cerebral artery occlusion mice and BV2 microglial cells subjected to oxygen-glucose deprivation. Circulating H19 levels were significantly higher in stroke patients compared with healthy controls, indicating high diagnostic sensitivity and specificity. Moreover, plasma H19 levels showed a positive correlation with National Institute of Health Stroke Scale score and tumor necrosis factor-α levels. After middle cerebral artery occlusion in mice, H19 levels increased in plasma, white blood cells, and brain. Intracerebroventricular injection of H19 siRNA reduced infarct volume and brain edema, decreased tumor necrosis factor-α and interleukin-1β levels in brain tissue and plasma, and increased plasma interleukin-10 concentrations 24 hours poststroke. Additionally, H19 knockdown attenuated brain tissue loss and neurological deficits 14 days poststroke. BV2 cell-based experiments showed that H19 knockdown blocked oxygen-glucose deprivation-driven M1 microglial polarization, decreased production of tumor necrosis factor-α and CD11b, and increased the expression of Arg-1 and CD206. Furthermore, H19 knockdown reversed oxygen-glucose deprivation-induced upregulation of HDAC1 and downregulation of acetyl-histone H3 and acetyl-histone H4. In contrast, HDAC1 overexpression negated the effects of H19 knockdown. Our findings indicate that H19 promotes neuroinflammation by driving HDAC1-dependent M1 microglial polarization, suggesting a novel H19-based diagnosis and therapy for ischemic stroke. © 2017 American Heart Association, Inc.

Effects of Sugar-sweetened Beverages on plasma Acylation Stimulating Protein, Leptin & Adiponectin and Metabolic Parameters

PubMed Central

Rezvani, Reza; Cianflone, Katherine; McGahan, John P.; Berglund, Lars; Bremer, Andrew A.; Keim, Nancy L.; Griffen, Steven C.; Havel, Peter J.; Stanhope, Kimber L.

2013-01-01

Objective We determined the effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity. Design and Methods 32 overweight/obese adults consumed glucose- or fructose-sweetened beverages (25% energy requirement) with their ad libitum diets for 8 weeks, followed by sweetened beverage consumption for 2 weeks with a standardized, energy-balanced diet. Plasma variables were measured at baseline, 2, 8 and 10 weeks, and body adiposity and insulin sensitivity at baseline and 10 weeks. Results Fasting and postprandial ASP concentrations increased at 2 and/or 8 weeks. ASP increases correlated with changes in late-evening triglyceride concentrations. At 10 weeks, fasting adiponectin levels decreased in both groups, and decreases were inversely associated with baseline intra-abdominal fat volume. Sugar consumption increased fasting leptin concentrations; increases were associated with body weight changes. 24-h leptin profiles increased during glucose consumption and decreased during fructose consumption. These changes correlated with changes of 24-h insulin levels. Conclusions The consumption of fructose and glucose beverages induced changes in plasma concentrations of ASP, adiponectin and leptin. Further study is required to determine if these changes contribute to the metabolic dysfunction observed during fructose consumption. PMID:23512943

Loss of CTRP1 disrupts glucose and lipid homeostasis

PubMed Central

Rodriguez, Susana; Lei, Xia; Petersen, Pia S.; Tan, Stefanie Y.; Little, Hannah C.

2016-01-01

C1q/TNF-related protein 1 (CTRP1) is a conserved plasma protein of the C1q family with notable metabolic and cardiovascular functions. We have previously shown that CTRP1 infusion lowers blood glucose and that transgenic mice with elevated circulating CTRP1 are protected from diet-induced obesity and insulin resistance. Here, we used a genetic loss-of-function mouse model to address the requirement of CTRP1 for metabolic homeostasis. Despite similar body weight, food intake, and energy expenditure, Ctrp1 knockout (KO) mice fed a low-fat diet developed insulin resistance and hepatic steatosis. Impaired glucose metabolism in Ctrp1 KO mice was associated with increased hepatic gluconeogenic gene expression and decreased skeletal muscle glucose transporter glucose transporter 4 levels and AMP-activated protein kinase activation. Loss of CTRP1 enhanced the clearance of orally administered lipids but did not affect intestinal lipid absorption, hepatic VLDL-triglyceride export, or lipoprotein lipase activity. In contrast to triglycerides, hepatic cholesterol levels were reduced in Ctrp1 KO mice, paralleling the reduced expression of cholesterol synthesis genes. Contrary to expectations, when challenged with a high-fat diet to induce obesity, Ctrp1 KO mice had increased physical activity and reduced body weight, adiposity, and expression of lipid synthesis and fibrotic genes in adipose tissue; these phenotypes were linked to elevated FGF-21 levels. Due in part to increased hepatic AMP-activated protein kinase activation and reduced expression of lipid synthesis genes, Ctrp1 KO mice fed a high-fat diet also had reduced liver and serum triglyceride and cholesterol levels. Taken together, these results provide genetic evidence to establish the significance of CTRP1 to systemic energy metabolism in different metabolic and dietary contexts. PMID:27555298

Post-partum plasma C-peptide and ghrelin concentrations are predictive of type 2 diabetes in women with previous gestational diabetes mellitus.

PubMed

Lappas, Martha; Jinks, Debra; Ugoni, Antony; Louizos, Connie C J; Permezel, Michael; Georgiou, Harry M

2015-07-01

Women with previous gestational diabetes mellitus (pGDM) are at increased risk of developing type 2 diabetes later in life. The aim of this study was to determine if circulating levels of metabolic hormones 12 weeks following a GDM pregnancy are associated with an increased risk of type 2 diabetes 8-10 years later. Fasting plasma concentrations of glucose, insulin, C-peptide, ghrelin, GIP, GLP-1, glucagon, leptin, PAI-1, resistin and visfatin were measured in 98 normal glucose tolerant women, 12 weeks following an index GDM pregnancy. Women were assessed every 2 years for up to 10 years for development of overt type 2 diabetes. After a median follow-up period of 8.7 years, 22.5% of women with a pGDM pregnancy developed type 2 diabetes. Significant risk factors for the development of type 2 diabetes were fasting plasma glucose levels >5 mmol/L during pregnancy and at 12 weeks post-pregnancy. In addition, higher C-peptide levels and lower ghrelin levels at 12 weeks post-pregnancy were also significant risk factors for the development of type 2 diabetes. Fasting plasma glucose during pregnancy and post-partum, and post-partum C-peptide and ghrelin levels were significant risk factors for the development of type 2 diabetes in women with pGDM. This is the first report that identifies C-peptide and ghrelin as potential biomarkers for the prediction of type 2 diabetes in women with a history of GDM. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Prevention of diet-induced obesity by safflower oil: insights at the levels of PPARalpha, orexin, and ghrelin gene expression of adipocytes in mice.

PubMed

Zhang, Zhong; Li, Qiang; Liu, Fengchen; Sun, Yuqian; Zhang, Jinchao

2010-03-15

The aim of this study was to investigate the prevention of diet-induced obesity by a high safflower oil diet and adipocytic gene expression in mice. Forty 3-week-old C57BL/6 mice were randomly divided into three groups: control group (CON, 5% lard + 5% safflower oil), high lard group (LAR, 45% lard + 5% safflower oil), and high safflower oil group (SAF, 45% safflower oil + 5% lard). After 10 weeks, 10 mice of the LAR group were switched to high safflower oil diet (LAR-SAF). Ten weeks later, glucose tolerance tests were performed by intraperitoneal injection of glucose. Circulating levels of lipid and insulin were measured and white adipose tissues were taken for gene chip and reverse transcriptase-polymerase chain reaction analysis. The LAR group showed higher body weight, adiposity index, insulin, and lipids than the CON group (P<0.05). The body weight in the LAR-SAF group decreased after dietary reversal. The plasma biochemical profiles decreased in the LAR-SAF and SAF groups (P<0.05) compared with those of the LAR group. The blood glucose level of the LAR-SAF group was reduced during intraperitoneal glucose tolerance test compared with that of the LAR group. The LAR-SAF group had lower levels of Orexin and Ghrelin gene expression, whereas the level of PPARalpha gene expression was significantly enhanced compared with that of the LAR group. So, the SAF diet can alter adipocytic adiposity-related gene expression and result in effective amelioration of diet-induced obesity.

Diabetic Hyperglycemia: Link to Impaired Glucose Transport in Pancreatic β Cells

NASA Astrophysics Data System (ADS)

Unger, Roger H.

1991-03-01

Glucose uptake into pancreatic β cells by means of the glucose transporter GLUT-2, which has a high Michaelis constant, is essential for the normal insulin secretory response to hyperglycemia. In both autoimmune and nonautoimmune diabetes, this glucose transport is reduced as a consequence of down-regulation of the normal β-cell transporter. In autoimmune diabetes, circulating immunoglobulins can further impair this glucose transport by inhibiting functionally intact transporters. Insights into mechanisms of the unresponsiveness of β cells to hyperglycemia may improve the management and prevention of diabetes.

Glucose, insolin, and feed restriction challenges reveal altered glucose and insulin dynamics in temperamental steers

USDA-ARS?s Scientific Manuscript database

Temperamental cattle are behaviorally, physiologically, and immunologically different than Calm cattle. Recently the dramatic metabolic differences between Temperamental and Calm cattle have been elucidated; Temperamental cattle appear to maintain greater circulating concentrations of non-esterified...

Regulating Glucose and pH, and Monitoring Oxygen in a Bioreactor

NASA Technical Reports Server (NTRS)

Anderson, Melody M.; Pellis, Neat R.; Jeevarajan, Antony S.; Taylor, Thomas D.; Xu, Yuanhang; Gao, Frank

2006-01-01

A system that automatically regulates the concentration of glucose or pH in a liquid culture medium that is circulated through a rotating-wall perfused bioreactor is described. Another system monitors the concentration of oxygen in the culture medium.

Metformin and insulin receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vigneri, R.; Gullo, D.; Pezzino, V.

The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific /sup 125/I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific /sup 125/I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitromore » to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded.« less

Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

PubMed

Kazierad, D J; Bergman, A; Tan, B; Erion, D M; Somayaji, V; Lee, D S; Rolph, T

2016-08-01

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia. © 2016 John Wiley & Sons Ltd.

Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

NASA Astrophysics Data System (ADS)

Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

2015-06-01

Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

Change in circulating microRNA profile of obese children indicates future risk of adult diabetes.

PubMed

Cui, Xianwei; You, Lianghui; Zhu, Lijun; Wang, Xing; Zhou, Yahui; Li, Yun; Wen, Juan; Xia, Yankai; Wang, Xinru; Ji, Chenbo; Guo, Xirong

2018-01-01

Childhood obesity increases susceptibility to type 2 diabetes (T2D) in adults. Circulating microRNAs (miRNAs) in serum have been proposed as potential diagnostic biomarkers, and they may contribute to the progression toward T2D. Here, we investigated the possibility of predicting the future risk of adult T2D in obese children by using circulating miRNAs. We performed miRNA high-throughput sequencing to screen relevant circulating miRNAs in obese children. The expression patterns of targeted miRNAs were further explored in obese children and adults with T2D. To investigate the underlying contributions of these miRNAs to the development of T2D, we detected the impacts of the candidate miRNAs on preadipocyte proliferation, insulin secretion by pancreatic β-cell, and glucose uptake by skeletal muscle cells. Three miRNAs (miR-486, miR-146b and miR-15b), whose expression in the circulation was most dramatically augmented in obese children and adult T2D patients, were selected for further investigation. Of these 3 miRNAs, miR-486 was implicated in accelerating preadipocyte proliferation and myotube glucose intolerance, miR-146b and miR-15b were engaged in the suppression of high concentration glucose-induced pancreatic insulin secretion, and they all contributed to the pathological processes of obesity and T2D. Our results provide a better understanding of the role of circulating miRNAs, particularly miR-486, miR-146b and miR-15b, in predicting the future risk of T2D in obese children. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Systemic metabolic signaling in acute and chronic gastrointestinal inflammation of inflammatory bowel diseases.

PubMed

Karrasch, T; Obermeier, F; Straub, R H

2014-06-01

Acute and chronic intestinal inflammation stimulates innate and adaptive immune systems, thereby increasing energy demand of activated immune cells. Energy regulation by systemically released mediators is of critical importance for homeostasis. We wanted to find out how systemic metabolic mediators are affected during intestinal inflammation. A total of 123 patients suffering from Crohn's disease (CD), 76 patients with ulcerative colitis (UC), and 21 healthy controls were recruited. Patients receiving systemic steroids or therapy regimens including biologicals (anti-TNF) were excluded from the study. Serum levels of IL-6, CRP, insulin, glucose, free fatty acid, and RBP-4 were measured by ELISA and RIA. Intestinal inflammation was accompanied by elevated systemic inflammatory para-meters such as IL-6 and CRP in UC and CD and, concomitantly, with elevated insulin levels and increased insulin/glucose ratio in patients with UC. This indicates insulin resistance in liver, muscle, and fat. In addition, intestinal inflammation was associated with elevated levels of circulating free fatty acids in UC and CD, indicating an activation of the organism's appeal for energy-rich substrates (energy appeal reaction). RBP-4 serum levels were also high in acute and chronic intestinal inflammation in UC and CD, which can support insulin resistance. The organism's "energy appeal reaction" in response to acute and chronic inflammation provides free energy in the circulation, which is needed by inflammatory cells. A major mechanism of the redirection program is insulin resistance. New therapeutic strategies might be developed in the future, directly impacting on the storage and utilization of energy-rich fuels. © Georg Thieme Verlag KG Stuttgart · New York.

Association of serum orosomucoid with 30-min plasma glucose and glucose excursion during oral glucose tolerance tests in non-obese young Japanese women.

PubMed

Tsuboi, Ayaka; Minato, Satomi; Yano, Megumu; Takeuchi, Mika; Kitaoka, Kaori; Kurata, Miki; Yoshino, Gen; Wu, Bin; Kazumi, Tsutomu; Fukuo, Keisuke

2018-01-01

Inflammatory markers are elevated in insulin resistance (IR) and diabetes. We tested whether serum orosomucoid (ORM) is associated with postload glucose, β-cell dysfunction and IR inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT). 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period in 168 non-obese Japanese women (aged 18-24 years). OGTT responses, serum adiponectin and high-sensitivity C reactive protein (hsCRP) were cross-sectionally analyzed by analysis of variance and then Bonferroni's multiple comparison procedure. Stepwise multivariate linear regression analyses were used to identify most important determinants of ORM. Of 168 women, 161 had normal glucose tolerance. Postload glucose levels and the area under the glucose curve (AUCg) increased in a stepwise fashion from the first through the third ORM tertile. In contrast, there was no or modest, if any, association with fat mass index, trunk/leg fat ratio, adiponectin, hsCRP, postload insulinemia, the Matsuda index and homeostasis model assessment IR. In multivariable models, which incorporated the insulinogenic index, the Matsuda index and HOMA-IR, 30 min glucose (standardized β: 0.517) and AUCg (standardized β: 0.495) explained 92.8% of ORM variations. Elevated circulating orosomucoid was associated with elevated 30 min glucose and glucose excursion in non-obese young Japanese women independently of adiposity, IR, insulin secretion, adiponectin and other investigated markers of inflammation. Although further research is needed, these results may suggest a clue to identify novel pathways that may have utility in monitoring dysglycemia within normal glucose tolerance.

Fuels, Hormones, and Liver Metabolism at Term and during the Early Postnatal Period in the Rat

PubMed Central

Girard, J. R.; Cuendet, G. S.; Marliss, E. B.; Kervran, A.; Rieutort, M.; Assan, R.

1973-01-01

The metabolic response to the first fast experienced by all mammals has been studied in the newborn rat. Levels of fuels and hormones have been compared in the fetal and maternal circulations at term. Then, after cesarean section just before the normal time of birth, sequential changes in the same parameters were quantified during the first 16 h of the neonatal period. No caloric intake was permitted, and the newborns were maintained at 37°C. Activities of three key hepatic enzymes involved in glucose production were estimated. Marked differences in maternal and fetal hormones and fuels were observed. Lower levels of glucose, free fatty acids, and glycerol but higher levels of lactate, α-amino nitrogen, alanine, and glutamine were present in the fetus. Pyruvate, glutamate, and ketone bodies were not significantly different. The combination of a strikingly higher fetal immunoreactive insulin and a slightly lower immunoreactive glucagon (pancreatic) resulted in a profound elevation in the insulin-to-glucagon ratio, a finding consistent with an organism in an anabolic state. The rat at birth presents a body composition with respect to fuels available for mobilization and conversion which is dominated by carbohydrate and protein, since little fat is present. However, at birth a transient period of hypoglycemia occurred, associated with a rapid fall in insulin and rise in glucagon, causing reversal of the insulin-to-glucagon relationship toward ratios such as were observed in the mother. After a lag period, hepatic activities of phosphorylase, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased. Concurrent with these enzyme changes, the blood glucose returned to levels at or above those of the fetus. Interestingly, the fall observed in levels of the gluconeogenic precursors, lactate and amino acids, preceded the rise in enzyme activities and restoration of blood glucose. After 4 h, however, hypoglycemia recurred, during a period of decreasing hepatic glycogen content and blood lactate, pyruvate, and glycerol levels but of stable or increasing amino acid concentrations. Hepatic gluconeogenesis in this phase of depleted glycogen stores was insufficient to maintain euglycemia. Substrates derived from fat showed early changes of smaller magnitude. The rise in free fatty acids which occurred was less than twofold the value at birth, though this rise persisted up to 6 h. Whereas glycerol rose transiently, acetoacetate did not change and β-hydroxybutyrate concentration fell. Both ketone bodies showed a marked rise at 16 h. at a time of diminished free fatty acid levels. Plasma growth hormone, though higher in the fetal than the maternal circulation, showed no consistent change during the period of observation. The changes in levels of the endocrine pancreatic hormones at birth were appropriate in time, magnitude, and direction to be implicated as prime regulators of the metabolic response during the neonatal period in the rat. PMID:4750449

Metabolic response to high-carbohydrate and low-carbohydrate meals in a nonhuman primate model.

PubMed

Fabbrini, Elisa; Higgins, Paul B; Magkos, Faidon; Bastarrachea, Raul A; Voruganti, V Saroja; Comuzzie, Anthony G; Shade, Robert E; Gastaldelli, Amalia; Horton, Jay D; Omodei, Daniela; Patterson, Bruce W; Klein, Samuel

2013-02-15

We established a model of chronic portal vein catheterization in an awake nonhuman primate to provide a comprehensive evaluation of the metabolic response to low-carbohydrate/high-fat (LCHF; 20% carbohydrate and 65% fat) and high-carbohydrate/low-fat (HCLF; 65% carbohydrate and 20% fat) meal ingestion. Each meal was given 1 wk apart to five young adult (7.8 ± 1.3 yr old) male baboons. A [U-¹³C]glucose tracer was added to the meal, and a [6,6-²H₂]glucose tracer was infused systemically to assess glucose kinetics. Plasma areas under the curve (AUCs) of glucose, insulin, and C-peptide in the femoral artery and of glucose and insulin in the portal vein were higher (P ≤ 0.05) after ingestion of the HCLF compared with the LCHF meal. Compared with the LCHF meal, the rate of appearance of ingested glucose into the portal vein and the systemic circulation was greater after the HCLF meal (P < 0.05). Endogenous glucose production decreased by ∼40% after ingestion of the HCLF meal but was not affected by the LCHF meal (P < 0.05). Portal vein blood flow increased (P < 0.001) to a similar extent after consumption of either meal. In conclusion, a LCHF diet causes minimal changes in the rate of glucose appearance in both portal and systemic circulations, does not affect the rate of endogenous glucose production, and causes minimal stimulation of C-peptide and insulin. These observations demonstrate that LCHF diets cause minimal perturbations in glucose homeostasis and pancreatic β-cell activity.

Spexin peptide is expressed in human endocrine and epithelial tissues and reduced after glucose load in type 2 diabetes.

PubMed

Gu, Liping; Ma, Yuhang; Gu, Mingyu; Zhang, Ying; Yan, Shuai; Li, Na; Wang, Yufan; Ding, Xiaoying; Yin, Jiajing; Fan, Nengguang; Peng, Yongde

2015-09-01

Spexin mRNA and protein are widely expressed in rat tissues and associate with weight loss in rodents of diet-induced obesity. Its location in endocrine and epithelial cells has also been suggested. Spexin is a novel peptide that involves weight loss in rodents of diet-induced obesity. Therefore, we aimed to examine its expression in human tissues and test whether spexin could have a role in glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). The expression of the spexin gene and immunoreactivity in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney was higher than that in the muscle and connective tissue. Immunoreactive serum spexin levels were reduced in T2DM patients and correlated with fasting blood glucose (FBG, r=-0.686, P<0.001), hemoglobin A1c (HbA1c, r=-0.632, P<0.001), triglyceride (TG, r=-0.236, P<0.001) and low density lipoprotein-cholesterol (LDL-C, r=-0.382, P<0.001). A negative correlation of blood glucose with spexin was observed during oral glucose tolerance test (OGTT). Spexin is intensely expressed in normal human endocrine and epithelial tissues, indicating that spexin may be involved in physiological functions of endocrine and in several other tissues. Circulating spexin levels are low in T2DM patients and negatively related to blood glucose and lipids suggesting that the peptide may play a role in glucose and lipid metabolism in T2DM. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Circulating SFRP5 levels are elevated in drug-naïve recently diagnosed type 2 diabetic patients as compared with prediabetic subjects and controls.

PubMed

Canivell, Silvia; Rebuffat, Sandra; Ruano, Elena G; Kostov, Belchin; Sisó-Almirall, Antoni; Novials, Anna; Ceriello, Antonio; Gomis, Ramon

2015-02-01

Secreted frizzled-related protein 5 (SFRP5) has been linked to obesity. Results are conflicting regarding its association with type 2 diabetes (T2D) in humans. We aimed to investigate circulating SFRP5 in prediabetes and T2D and its potential association with parameters of insulin resistance and beta-cell function. We studied 70 drug-naïve T2D patients, 70 prediabetic subjects and 70 controls. All subjects were body mass index matched to the T2D patients and overweight or obese. SFRP5, hormones and cytokines levels were measured by ELISA. Serum SFRP5 levels were elevated in T2D patients as compared with prediabetic subjects (median 15.6, interquartile range [9-24.5] ng/mL vs 9.8 [5-14.2] ng/mL, p < 0.001, respectively) and controls (15.6 [9-24.5] ng/mL vs 10.4 [6.7-16.6] ng/mL, P < 0.001, respectively). No differences were found in serum SFRP5 levels between prediabetic subjects and controls (9.8 [5-14.2] ng/mL vs 10.4 [6.7-16.6] ng/mL, p = 0.472, respectively). After adjusting for potential confounders (age, gender, body mass index, triglycerides, high-density lipoprotein cholesterol and blood pressure), T2D was still associated with higher values of SFRP5 as compared with prediabetes in multinomial logistic regression analysis (fully adjusted odds ratio 3.50, 95% confidence interval 1.40-8.79, p = 0.008). The association was more subtle when comparing T2D with normal glucose tolerance state (fully adjusted odds ratio 2.18, 95% confidence interval 0.91-5.21, p = 0.078). Circulating SFRP5 levels were independently associated with T2D as compared with prediabetes and normal glucose tolerance state. Copyright © 2014 John Wiley & Sons, Ltd.

Down-Regulation of Renal Gluconeogenesis in Type II Diabetic Rats Following Roux-en-Y Gastric Bypass Surgery: A Potential Mechanism in Hypoglycemic Effect

PubMed Central

Wen, Yi; Lin, Ning; Yan, Hong-Tao; Luo, Hao; Chen, Guang-Yu; Cui, Jian-Feng; Shi, Li; Chen, Tao; Wang, Tao; Tang, Li-Jun

2015-01-01

Objective This study was initiated to evaluate the effects of Roux-en-Y gastric bypass surgery on renal gluconeogenesis in type 2 diabetic rats and its relationship with hormonal parameters. Methods Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ; 35 mg/kg) combined with a high-fat diet. They were then randomly divided into three groups: diabetes model group (DM group, n = 8), sham Roux-en-Y gastric bypass group (SRYGB group, n = 8), and Roux-en-Y gastric bypass group (RYGB group, n = 14). Another 8 normal rats comprised the normal control group (NC group, n = 8). Body weight, glucose, serum lipid, insulin, glucagon-like peptide-1 (GLP-1), leptin, and adiponectin were measured pre- and postoperatively. Glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor-α (IR-α), insulin receptor-β (IR-β), and glycogen synthase kinase 3 beta (Gsk3b) were measured in renal cortex by using RT-PCR and Western immune-blot analyses on the 4th week after operation. Results Following RYGB surgery, surgery-treated rats showed significantly improved oral glucose tolerance, dyslipidemia and insulin resistance as well as increased post-gavage insulin levels and serum circulating levels of GLP-1 and adiponectin. RT-PCR and Western immune-blot analyses showed PEPCK and G6Pase protein and mRNA to be significantly decreased in the renal cortex in the RYGB group (p < 0.05 vs. DM or SRYGB group); in addition, IR-α and Gsk3b phosphorylation levels increased in the RYGB group (p < 0.05 vs. DM or SRYGB group). Conclusion Down-regulation of renal gluconeogenic enzymes might be a potential mechanism in hypoglycemia. An improved insulin signal pathway in the renal cortex and increased circulating adiponectin concentrations may contribute to the decline of renal gluconeogenesis following RYGB surgery. PMID:25832593

Application of D-Crustacean Hyperglycemic Hormone Induces Peptidases Transcription and Suppresses Glycolysis-Related Transcripts in the Hepatopancreas of the Crayfish Pontastacus leptodactylus — Results of a Transcriptomic Study

PubMed Central

De Moro, Gianluca; Gerdol, Marco; Guarnaccia, Corrado; Mosco, Alessandro; Pallavicini, Alberto; Giulianini, Piero Giulio

2013-01-01

The crustacean Hyperglycemic Hormone (cHH) is a neuropeptide present in many decapods. Two different chiral isomers are simultaneously present in Astacid crayfish and their specific biological functions are still poorly understood. The present study is aimed at better understanding the potentially different effect of each of the isomers on the hepatopancreatic gene expression profile in the crayfish Pontastacus leptodactylus, in the context of short term hyperglycemia. Hence, two different chemically synthesized cHH enantiomers, containing either L- or D-Phe3, were injected to the circulation of intermolt females following removal of their X organ-Sinus gland complex. The effects triggered by the injection of the two alternate isomers were detected after one hour through measurement of circulating glucose levels. Triggered changes of the transcriptome expression profile in the hepatopancreas were analyzed by RNA-seq. A whole transcriptome shotgun sequence assembly provided the assumedly complete transcriptome of P. leptodactylus hepatopancreas, followed by RNA-seq analysis of changes in the expression level of many genes caused by the application of each of the hormone isomers. Circulating glucose levels were much higher in response to the D-isoform than to the L-isoform injection, one hour from injection. Similarly, the RNA-seq analysis confirmed a stronger effect on gene expression following the administration of D-cHH, while just limited alterations were caused by the L-isomer. These findings demonstrated a more prominent short term effect of the D-cHH on the transcription profile and shed light on the effect of the D-isomer on specific functional gene groups. Another contribution of the study is the construction of a de novo assembly of the hepatopancreas transcriptome, consisting of 39,935 contigs, that dramatically increases the molecular information available for this species and for crustaceans in general, providing an efficient tool for studying gene expression patterns in this organ. PMID:23840318

Plasma serpinB1 is related to insulin sensitivity but not pancreatic β-Cell function in non-diabetic adults.

PubMed

Glicksman, Michael; Asthana, Asha; Abel, Brent S; Walter, Mary F; Skarulis, Monica C; Muniyappa, Ranganath

2017-03-01

Pancreatic β -cell dysfunction because of reduced β -cell mass and function is a primary determinant in the progression of diabetes. Increase in β -cell mass and compensatory hyperinsulinaemia is frequently associated with insulin-resistant states. Although the humoral factors mediating this compensatory response are unknown, serpinB1, a protease inhibitor, has recently been proposed to be one such factor. In this study, we examine the relationships between plasma serpinB1, insulin sensitivity, and pancreatic β -cell function in non-diabetic individuals. 117 subjects (women, n  = 50, men, n  = 67; age= 37.6 ± 10.8; BMI=31.1 ± 7.7 kg/m 2 ) underwent an insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) at the NIH Clinical Research Center. Acute insulin response (AIR) and insulin sensitivity index (SI) were obtained from the FSIVGTT with MINMOD analysis. The Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated from fasting insulin and glucose values. Plasma serpinB1 levels were measured using an ELISA assay. Simple linear correlation analyses were performed to evaluate the relationship between serpinB1 and measures of insulin sensitivity and β -cell function. Circulating serpinB1 levels were unrelated to age, sex, race, BMI, or percent body fat. SI but not AIR significantly correlated with circulating serpinB1 levels ( r  = 0.23, P  < 0.05). QUICKI tended to positively correlate with serpinB1 ( r  = 0.16, P  = 0.09). Circulating serpinB1 is directly associated with insulin sensitivity but not β -cell function in non-diabetic adults. Whether this modest association plays a role in insulin sensitivity in humans remains to be clarified. Published [2017]. This article is a U.S. Government work and is in the public domain in the USA.

SUPPLY AND DEMAND IN CEREBRAL ENERGY METABOLISM: THE ROLE OF NUTRIENT TRANSPORTERS

PubMed Central

Simpson, Ian A.; Carruthers, Anthony; Vannucci, Susan J.

2007-01-01

Glucose is the obligate energetic fuel for the mammalian brain and most studies of cerebral energy metabolism assume that the vast majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state. Glucose transporter proteins (GLUTs) deliver glucose from the circulation to the brain: GLUT1 in the microvascular endothelial cells of the blood brain barrier (BBB) and glia; GLUT3 in neurons. Lactate, the glycolytic product of glucose metabolism, is transported into and out of neural cells by the monocarboxylate transporters: MCT1 in the BBB and astrocytes and MCT2 in neurons. The proposal of the astrocyte-neuron lactate shuttle hypothesis (Pellerin and Magistretti, 1994) suggested that astrocytes play the primary role in cerebral glucose utilization and generate lactate for neuronal energetics, especially during activation. Since the identification of the GLUTs and MCTs in brain, much has been learned about their transport properties, i.e. capacity and affinity for substrate, which must be considered in any model of cerebral glucose uptake and utilization. Using concentrations and kinetic parameters of GLUT1 and GLUT3 in BBB endothelial cells, astrocytes and neurons, along with the corresponding kinetic properties of the monocarboxylate transporters, we have successfully modeled brain glucose and lactate levels as well as lactate transients in response to neuronal stimulation. Simulations based on these parameters suggest that glucose readily diffuses through the basal lamina and interstitium to neurons, which are primarily responsible for glucose uptake, metabolism, and the generation of the lactate transients observed upon neuronal activation. PMID:17579656

Glucose Metabolism in High-Risk Subjects for Type 2 Diabetes Carrying the rs7903146 TCF7L2 Gene Variant.

PubMed

Daniele, Giuseppe; Gaggini, Melania; Comassi, Mario; Bianchi, Cristina; Basta, Giuseppina; Dardano, Angela; Miccoli, Roberto; Mari, Andrea; Gastaldelli, Amalia; Del Prato, Stefano

2015-08-01

The mechanisms responsible for contribution of variants in the gene TFC7L2 to the risk for type 2 diabetes (T2DM) remains far from being completely understood, and available studies have generated nonunivocal results. We investigated the postprandial glucose metabolism in subjects at risk for T2DM carrying the TCF7L2 risk allele. Twenty-three subjects carrying the risk-conferring TCF7L2 genotypes (11 TT and 12 CT at rs7901346) and 13 subjects with wild-type genotype (CC) underwent a standard mixed-meal test (MMT) in combination with stable isotope tracers. We evaluated endogenous and exogenous glucose fluxes and hormonal responses. Fasting plasma glucose, insulin, C-peptide, glycated hemoglobin, endogenous glucose production, and plasma glucose clearance were similar in the three groups, whereas plasma glucagon levels were lower in both CT and TT than in CC (64 ± 20, 63 ± 18 and 90 ± 29 pg/mL, respectively; both P = .01). In response to the MMT, TT subjects had lower plasma glucose levels than CC subjects [mean area under the time-concentration curve (AUC) 6.1 ± 3.9 vs 7.1 ± 12.0 mmol/L, P = .04] and lower insulin secretion rate (mean AUC 385 ± 95 vs 530 ± 159 pmol/m(2) · min, P = .02). Initial (0-60 min) rate of appearance (Ra) of oral glucose was lower in TT compared with CT/CC (AUC 2.7 ± 1.1 vs 3.8 ± 1.2 μmol/kg · min, P = .02) with no difference among the three groups in endogenous glucose production. The AUC0-60min for Ra of exogenous glucose (Raex) was positively correlated with the plasma glucose AUC0-60min. Total Raex AUC0-120min was correlated with total AUC0-120min of plasma glucose (r = 0.45, P < .01). Plasma glucagon-like peptide-1 and glucose-dependent insulinotropic peptide levels in response to the MMT were not affected by genotype. In subjects at risk for T2DM, the TCF7L2 polymorphisms were associated with reduced Raex into systemic circulation, causing reduced postprandial blood glucose increase and, in turn, lower insulin secretion rate with no impairment in β-cell function. The reduced Raex is likely due to greater glucose retention in the splanchnic area.

A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

PubMed Central

Naftalin, Richard J.

2016-01-01

A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP-1 agonist or glucagon antagonist usage. PMID:27347379

Novel cell-based assay reveals associations of circulating serum AhR-ligands with metabolic syndrome and mitochondrial dysfunction.

PubMed

Park, Wook-Ha; Jun, Dae Won; Kim, Jin Taek; Jeong, Jae Hoon; Park, Hyokeun; Chang, Yoon-Seok; Park, Kyong Soo; Lee, Hong Kyu; Pak, Youngmi Kim

2013-01-01

Serum concentrations of environmental pollutants have been positively correlated with diabetes and metabolic syndrome in epidemiologic studies. In turn, abnormal mitochondrial function has been associated with the diseases. The relationships between these variables, however, have not been studied. We developed novel cell-based aryl hydrocarbon receptor (AhR) agonist bioassay system without solvent extraction process and analyzed whether low-dose circulating AhR ligands in human serum are associated with parameters of metabolic syndrome and mitochondrial function. Serum AhR ligand activities were measured as serum 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent (sTCDDeq) in pM using 10 μL human sera from 97 Korean participants (47 with glucose intolerance and 50 matched controls, average age of 46.6 ± 9.9 years, 53 male and 45 female). sTCDDeq were higher in participants with glucose intolerance than normal controls and were positively associated (P < 0.01) with obesity, blood pressure, serum triglyceride, and fasting glucose, but not with HDL-cholesterol. Body mass index was in a positive linear relationship with serum AhR ligands in healthy participants. When myoblast cells were incubated with human sera, ATP generating power of mitochondria became impaired in an AhR ligand concentration-dependent manner. Our results support that circulating AhR ligands may directly reduce mitochondrial function in tissues, leading to weight gain, glucose intolerance, and metabolic syndrome. Our rapid cell-based assay using minute volume of human serum may provide one of the best monitoring systems for circulating AhR ligands, good clinical biomarkers for the progress of disease and therapeutic efficacy. Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.

Response to deep hypoglycemia does not involve glucoreceptors in carotid perfused tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cane, P.; Haun, C.K.; Evered, J.

1988-11-01

In the present study the authors examined whether the magnified hormonal counter-regulatory response seen during deep hypoglycemia (40 mg/dl) could be attenuated by supplying the forebrain with glucose furnished through carotid infusion. Two protocols were performed in conscious dogs. In the first protocol they infused glucose bilaterally into the carotid circulation to produce a forebrain glycemia of 55 {plus minus} 1 mg/dl whereas systemic glycemia declined to 39 {plus minus} 2 mg/dl. In the second protocol as a control they infused glucose into the systemic circulation at a rate matched to protocol 1 so that both systemic and jugular plasmamore » glucose concentrations were equivalent to the systemic glucose concentrations in protocol 1. In spite of a substantial difference in forebrain glycemia there were no differences in the counter-regulatory responses of catecholamines or glucagon. In addition, through the use of radiolabeled microspheres, they defined the precise regions of the forebrain irrigated during bilateral intracarotid glucose infusions. The concentration of microspheres was high in the forebrain but very low in the hindbrain. The results indicate that glucoreceptor cells in tissues perfused by carotid arteries may play a tautological role in the sympathetic response to hypoglycemia and imply that glucose-sensitive receptors must also be located elsewhere in the central nervous system or in the periphery.« less

Circulating C1q complement/TNF-related protein (CTRP) 1, CTRP9, CTRP12 and CTRP13 concentrations in Type 2 diabetes mellitus: In vivo regulation by glucose

PubMed Central

Zhang, Man Man; Tan, Bee Kang; Chen, Jing

2017-01-01

Objectives The C1q complement/TNF-related protein (CTRP) superfamily, which includes the adipokine adiponectin, has been shown in animal models to have positive metabolic and cardiovascular effects. We sought to investigate circulating CTRP1, CTRP9, CTRP12 and CTRP13 concentrations in persons with type 2 diabetes mellitus (T2DM), with age and BMI matched controls, and to examine the effects of a 2 hour 75g oral glucose tolerance test (OGTT) on serum CTRP1, CTRP9, CTRP12 and CTRP13 levels in persons with T2DM. Design Cross-sectional study [newly diagnosed T2DM (n = 124) and control (n = 139) participants]. Serum CTRP1, CTRP9, CTRP12 and CTRP13 were measured by ELISA. Results Systolic and diastolic blood pressure, total cholesterol (TCH), Low-density lipoprotein (LDL)-cholesterol, triglycerides, TCH/High-density lipoprotein (HDL) ratio, triglycerides/HDL ratio, glucose, insulin, homeostatic model assessment–insulin resistance (HOMA-IR), C-reactive protein and endothelial lipase were significantly higher, whereas leptin and adiponectin were significantly lower in T2DM participants. Serum CTRP1 were significantly higher and CTRP12 significantly lower in T2DM participants. Age, diastolic blood pressure, glucose and CTRP12 were predictive of serum CTRP1; leptin was predictive of serum CTRP9; glucose and CTRP1 were predictive of serum CTRP12; endothelial lipase was predictive of serum CTRP13. Finally, serum CTRP1 were significantly higher and CTRP12 significantly lower in T2DM participants after a 2 hour 75g OGTT. Conclusions Our data supports CTRP1 and CTRP12 as potential novel biomarkers for the prediction and early diagnosis of T2DM. Furthermore, pharmacological agents that target CTRP1 and CTRP12 could represent a new strategy in the treatment of T2DM. PMID:28207876

Closed-Loop Insulin Delivery for Adults with Type 1 Diabetes Undertaking High-Intensity Interval Exercise Versus Moderate-Intensity Exercise: A Randomized, Crossover Study.

PubMed

Jayawardene, Dilshani C; McAuley, Sybil A; Horsburgh, Jodie C; Gerche, André La; Jenkins, Alicia J; Ward, Glenn M; MacIsaac, Richard J; Roberts, Timothy J; Grosman, Benyamin; Kurtz, Natalie; Roy, Anirban; O'Neal, David N

2017-06-01

We aimed to compare closed-loop glucose control for people with type 1 diabetes undertaking high-intensity interval exercise (HIIE) versus moderate-intensity exercise (MIE). Adults with type 1 diabetes established on insulin pumps undertook HIIE and MIE stages in random order during automated insulin delivery via a closed-loop system (Medtronic). Frequent venous sampling for glucose, lactate, ketones, insulin, catecholamines, cortisol, growth hormone, and glucagon levels was performed. The primary outcome was plasma glucose <4.0 mmol/L for ≥15 min, from exercise commencement to 120 min postexercise. Secondary outcomes included continuous glucose monitoring and biochemical parameters. Twelve adults (age mean ± standard deviation 40 ± 13 years) were recruited; all completed the study. Plasma glucose of one participant fell to 3.4 mmol/L following MIE completion; no glucose levels were <4.0 mmol/L for HIIE (primary outcome). There were no glucose excursions >15.0 mmol/L for either stage. Mean (±standard error) plasma glucose did not differ between stages pre-exercise; was higher during exercise in HIIE than MIE (11.3 ± 0.5 mmol/L vs. 9.7 ± 0.6 mmol/L, respectively; P < 0.001); and remained higher until 60 min postexercise. There were no differences in circulating free insulin before, during, or postexercise. During HIIE compared with MIE, there were greater increases in lactate (P < 0.001), catecholamines (all P < 0.05), and cortisol (P < 0.001). Ketones increased more with HIIE than MIE postexercise (P = 0.031). Preliminary findings suggest that closed-loop glucose control is safe for people undertaking HIIE and MIE. However, the management of the postexercise rise in ketones secondary to counter-regulatory hormone-induced insulin resistance observed with HIIE may represent a challenge for closed-loop systems.

Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

PubMed Central

An, Zhibo; Johnson, Kathryn M. S.; Farmer, Tiffany; Farmer, Ben; Neal, Doss; Cherrington, Alan D.

2013-01-01

Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg−1·min−1, Ex-4-low; n = 5) or high (0.9 pmol·kg−1·min−1, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg−1·min−1 between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 μU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 μU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg−1·min−1), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver. PMID:23673158

Lasting monitoring of immune state in patients with coronary atherosclerosis

NASA Astrophysics Data System (ADS)

Malinova, Lidia I.; Denisova, Tatyana P.; Tuchin, Valery V.

2007-02-01

Immune state monitoring is an expensive, invasive and sometimes difficult necessity in patients with different disorders. Immune reaction dynamics study in patients with coronary atherosclerosis provides one of the leading components to complication development, clinical course prognosis and treatment and rehabilitation tactics. We've chosen intravenous glucose injection as metabolic irritant in the following four groups of patients: men with proved coronary atherosclerosis (CA), non insulin dependent diabetes mellitus (NIDDM), men hereditary burden by CA and NIDDM and practically healthy persons with longlivers in generation. Immune state parameters such as quantity of leukocytes and lymphocytes, circulating immune complexes levels, serum immunoglobulin levels, HLA antigen markers were studied at 0, 30 and 60 minutes during glucose loading. To obtain continues time function of studied parameters received data were approximated by polynomials of high degree with after going first derivatives. Time functions analyze elucidate principally different dynamics studied parameters in all chosen groups of patients, which couldn't be obtained from discontinuous data compare. Leukocyte and lymphocyte levels dynamics correlated HLA antigen markers in all studied groups. Analytical estimation of immune state in patients with coronary atherosclerosis shows the functional "margin of safety" of immune system state under glucose disturbance. Proposed method of analytical estimation also can be used in immune system monitoring in other groups of patients.

Control of hepatocyte metabolism by sympathetic and parasympathetic hepatic nerves.

PubMed

Püschel, Gerhard P

2004-09-01

More than any other organ, the liver contributes to maintaining metabolic equilibrium of the body, most importantly of glucose homeostasis. It can store or release large quantities of glucose according to changing demands. This homeostasis is controlled by circulating hormones and direct innervation of the liver by autonomous hepatic nerves. Sympathetic hepatic nerves can increase hepatic glucose output; they appear, however, to contribute little to the stimulation of hepatic glucose output under physiological conditions. Parasympathetic hepatic nerves potentiate the insulin-dependent hepatic glucose extraction when a portal glucose sensor detects prandial glucose delivery from the gut. In addition, they might coordinate the hepatic and extrahepatic glucose utilization to prevent hypoglycemia and, at the same time, warrant efficient disposal of excess glucose. Copyright 2004 Wiley-Liss, Inc.

Different effects of fenofibrate on metabolic and cardiovascular risk factors in mixed dyslipidemic women with normal thyroid function and subclinical hypothyroidism.

PubMed

Krysiak, Robert; Gilowski, Wojciech; Szkrobka, Witold; Okopien, Bogusław

2014-12-01

Subclinical hypothyroidism is suggested to increase cardiovascular risk. No previous study compared the effect of any fibrate on plasma levels of lipids and other cardiovascular risk factors in patients with different thyroid function status. The study included three age-, weight- and lipid-matched groups of women with mixed dyslipidemia in different thyroid function status: patients with untreated subclinical hypothyroidism (group 1, n = 18), women with treated hypothyroidism (group 2, n = 15), and subjects without thyroid disorders (group 3, n = 19). Plasma lipids, glucose homeostasis markers, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, and fibrinogen were determined before and after 12 weeks of fenofibrate therapy. Despite similar plasma lipid levels, mixed dyslipidemic patients with untreated hypothyroidism had decreased insulin sensitivity, as well as higher circulating levels of uric acid, hsCRP, homocysteine, and fibrinogen in comparison with the other groups. The effect of fenofibrate on plasma lipids and, with the exception of homocysteine, on circulating levels of all investigated risk factors was stronger in patients from groups 2 and 3 than in patients from group 1. The obtained results indicate that the effect of fenofibrate on plasma lipids and circulating levels of cardiovascular risk factors is partially related to thyroid function. They also suggest that to improve the strength of fibrate action in dyslipidemic patients with subclinical hypothyroidism, they should be administered together with L-thyroxine. © 2014 John Wiley & Sons Ltd.

Effects of Fructose vs Glucose on Regional Cerebral Blood Flow in Brain Regions Involved With Appetite and Reward Pathways

PubMed Central

Page, Kathleen A.; Chan, Owen; Arora, Jagriti; Belfort-DeAguiar, Renata; Dzuira, James; Roehmholdt, Brian; Cline, Gary W.; Naik, Sarita; Sinha, Rajita; Constable, R. Todd; Sherwin, Robert S.

2014-01-01

Importance Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Fructose ingestion produces smaller increases in circulating satiety hormones compared with glucose ingestion, and central administration of fructose provokes feeding in rodents, whereas centrally administered glucose promotes satiety. Objective To study neurophysiological factors that might underlie associations between fructose consumption and weight gain. Design, Setting, and Participants Twenty healthy adult volunteers underwent 2 magnetic resonance imaging sessions at Yale University in conjunction with fructose or glucose drink ingestion in a blinded, random-order, crossover design. Main Outcome Measures Relative changes in hypothalamic regional cerebral blood flow (CBF) after glucose or fructose ingestion. Secondary outcomes included whole-brain analyses to explore regional CBF changes, functional connectivity analysis to investigate correlations between the hypothalamus and other brain region responses, and hormone responses to fructose and glucose ingestion. Results There was a significantly greater reduction in hypothalamic CBF after glucose vs fructose ingestion (–5.45 vs 2.84 mL/g per minute, respectively; mean difference, 8.3 mL/g per minute [95% CI of mean difference, 1.87-14.70]; P=.01). Glucose ingestion (compared with baseline) increased functional connectivity between the hypothalamus and the thalamus and striatum. Fructose increased connectivity between the hypothalamus and thalamus but not the striatum. Regional CBF within the hypothalamus, thalamus, insula, anterior cingulate, and striatum (appetite and reward regions) was reduced after glucose ingestion compared with baseline (P<.05 significance threshold, family-wise error [FWE] whole-brain corrected). In contrast, fructose reduced regional CBF in the thalamus, hippocampus, posterior cingulate cortex, fusiform, and visual cortex (P<.05 significance threshold, FWE whole-brain corrected). In whole-brain voxel-level analyses, there were no significant differences between direct comparisons of fructose vs glucose sessions following correction for multiple comparisons. Fructose vs glucose ingestion resulted in lower peak levels of serum glucose (mean difference, 41.0 mg/dL [95% CI, 27.7-54.5]; P<.001), insulin (mean difference, 49.6 μU/mL [95% CI, 38.2-61.1]; P<.001), and glucagon-like polypep-tide 1 (mean difference, 2.1 pmol/L [95% CI, 0.9-3.2]; P=.01). Conclusion and Relevance In a series of exploratory analyses, consumption of fructose compared with glucose resulted in a distinct pattern of regional CBF and a smaller increase in systemic glucose, insulin, and glucagon-like polypeptide 1 levels. PMID:23280226

Plasma NOV/CCN3 Levels Are Closely Associated with Obesity in Patients with Metabolic Disorders

PubMed Central

Pakradouni, Jihane; Le Goff, Wilfried; Calmel, Claire; Antoine, Bénédicte; Villard, Elise; Frisdal, Eric; Abifadel, Marianne; Tordjman, Joan; Poitou, Christine; Bonnefont-Rousselot, Dominique; Bittar, Randa; Bruckert, Eric; Clément, Karine; Fève, Bruno; Martinerie, Cécile; Guérin, Maryse

2013-01-01

Objective Evidence points to a founder of the multifunctional CCN family, NOV/CCN3, as a circulating molecule involved in cardiac development, vascular homeostasis and inflammation. No data are available on the relationship between plasma NOV/CCN3 levels and cardiovascular risk factors in humans. This study investigated the possible relationship between plasma NOV levels and cardiovascular risk factors in humans. Methods NOV levels were measured in the plasma from 594 adults with a hyperlipidemia history and/or with lipid-lowering therapy and/or a body mass index (BMI) >30 kg/m2. Correlations were measured between NOV plasma levels and various parameters, including BMI, fat mass, and plasma triglycerides, cholesterol, glucose, and C-reactive protein. NOV expression was also evaluated in adipose tissue from obese patients and rodents and in primary cultures of adipocytes and macrophages. Results After full multivariate adjustment, we detected a strong positive correlation between plasma NOV and BMI (r = 0.36 p<0.0001) and fat mass (r = 0.33 p<0.0005). According to quintiles, this relationship appeared to be linear. NOV levels were also positively correlated with C-reactive protein but not with total cholesterol, LDL-C or blood glucose. In patients with drastic weight loss induced by Roux-en-Y bariatric surgery, circulating NOV levels decreased by 28% (p<0.02) and 48% (p<0.0001) after 3 and 6 months, respectively, following surgery. In adipose tissue from obese patients, and in human primary cultures NOV protein was detected in adipocytes and macrophages. In mice fed a high fat diet NOV plasma levels and its expression in adipose tissue were also significantly increased compared to controls fed a standard diet. Conclusion Our results strongly suggest that in obese humans and mice plasma NOV levels positively correlated with NOV expression in adipose tissue, and support a possible contribution of NOV to obesity-related inflammation. PMID:23785511

Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance.

PubMed

Du, Caiqi; Zhang, Cai; Wu, Wei; Liang, Yan; Wang, Anru; Wu, Shimin; Zhao, Yue; Hou, Ling; Ning, Qin; Luo, Xiaoping

2018-04-25

A novel bioactive peptide, mitochondrial-derived peptide (MOTS-c), has recently attracted attention as a potential prevention or therapeutic option for obesity and type 2 diabetes mellitus (T2DM). MOTS-c profiles have not yet been reported in human obesity and T2DM. We aimed to determine circulating MOTS-c levels in obesity and explore the association between MOTS-c levels and various metabolic parameters. In this case-control study, 40 obese children and adolescents (27 males) and 57 controls (40 males) were recruited in the Hubei Province of China in 2017. Circulating MOTS-c levels were measured, clinical data (e.g., glucose, insulin and lipid profile) were recorded, and anthropometric measurements were performed. Finally, we investigated correlations between MOTS-c levels and related variables. MOTS-c levels were significantly decreased in the obese group compared with the control group (472.61 ± 22.83 ng/mL vs. 561.64 ± 19.19 ng/mL, p < 0.01). After classification by sex, MOTS-c levels were significantly decreased in obese male children and adolescents compared to their counterparts (465.26 ± 24.53 ng/mL vs. 584.07 ± 21.18 ng/mL, p < 0.001), while they were comparable between the obese and healthy female subjects (487.89 ± 49.77 ng/mL vs. 508.85 ± 38.76 ng/mL, p > 0.05). Further, MOTS-c levels were negatively correlated with body mass index (BMI), BMI standard deviation score, waist circumference, waist-to-hip ratio, fasting insulin level, HOMA-IR, and HbA1c in the male cohort. Circulating MOTS-c levels were decreased in obese male children and adolescents and correlated with markers of insulin resistance and obesity. This article is protected by copyright. All rights reserved.

Relationship of Advanced Glycation End Products With Cardiovascular Disease in Menopausal Women

PubMed Central

Pertynska-Marczewska, Magdalena

2015-01-01

Cardiovascular disease (CVD) represents the most significant cause of death in postmenopausal women. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. This review focuses on the contribution of AGEs and their receptors to the development of CVD in menopause. Advanced glycation end products circulate and activate the proinflammatory endothelial cell surface receptor called RAGE, bind to the extracellular matrix of the cardiovascular system, or bind to the circulating anti-inflammatory soluble form of RAGE (sRAGE). Data emerging from human and animal studies suggest that AGEs and both receptors (RAGE and sRAGE) are implicated in the pathophysiology of CVD. Particular emphasis has been given to the role of AGE–RAGE axis in oxidative stress, inflammation, endothelial cell toxicity, and progression of atherosclerosis in menopause. Data accruing from human and animal studies suggest that RAGE expression level and circulating sRAGE level are associated with estradiol and are correlated with CVD risk factors, such as adiposity, dyslipidemia, insulin resistance, diabetes, and metabolic syndrome. By recognizing the impact of AGEs on atherosclerosis, pharmacological strategies targeting the AGE–RAGE pathway hold therapeutic potential for CVD in menopausal women. PMID:25228634

Relationship of Advanced Glycation End Products With Cardiovascular Disease in Menopausal Women.

PubMed

Pertynska-Marczewska, Magdalena; Merhi, Zaher

2015-07-01

Cardiovascular disease (CVD) represents the most significant cause of death in postmenopausal women. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. This review focuses on the contribution of AGEs and their receptors to the development of CVD in menopause. Advanced glycation end products circulate and activate the proinflammatory endothelial cell surface receptor called RAGE, bind to the extracellular matrix of the cardiovascular system, or bind to the circulating anti-inflammatory soluble form of RAGE (sRAGE). Data emerging from human and animal studies suggest that AGEs and both receptors (RAGE and sRAGE) are implicated in the pathophysiology of CVD. Particular emphasis has been given to the role of AGE-RAGE axis in oxidative stress, inflammation, endothelial cell toxicity, and progression of atherosclerosis in menopause. Data accruing from human and animal studies suggest that RAGE expression level and circulating sRAGE level are associated with estradiol and are correlated with CVD risk factors, such as adiposity, dyslipidemia, insulin resistance, diabetes, and metabolic syndrome. By recognizing the impact of AGEs on atherosclerosis, pharmacological strategies targeting the AGE-RAGE pathway hold therapeutic potential for CVD in menopausal women. © The Author(s) 2014.

[The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

PubMed

Escalada, Francisco Javier

2014-09-01

The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Role of Extracellular miR-122 in Breast Cancer Metastasis

DTIC Science & Technology

2016-02-01

expression by miR-122 reduced the level of the GLUT1 causing reduced glucose uptake; and 4) anti-miR-122 therapy suppressed metastasis in a xenograft mouse...metastatic niche selection by circulating tumor cells. 100% completed.  Major Task 3: Orthotopic xenograft tumors expressing high miR-122 and...aforementioned cell lines and used to treat NSG mice i.v (Fig. 5). Xenograft tumors were established in NSG mice for over-expression of miR-122 in

Signals from Fat After Injury: Plasma Adipokines and Ghrelin Concentrations in the Severely Burned

DTIC Science & Technology

2012-09-26

of insulin resis- tance was calculated with a modified version of homeostasis mod- el assessment of insulin resistance ( HOMA - IR ) formula by using...average glucose and average circulating insulin levels of subjects. In this study, HOMA - IR was used to assess severity of insulin resis- tance rather than...were 217% higher than controls (Table 2). Thus, based on the HOMA - IR , burned subjects were more insulin resistant than controls (Table 2). As all of the

Circulating levels of miR-7, miR-152 and miR-192 respond to vitamin D supplementation in adults with prediabetes and correlate with improvements in glycemic control.

PubMed

Nunez Lopez, Yury O; Pittas, Anastassios G; Pratley, Richard E; Seyhan, Attila A

2017-11-01

Vitamin D may play an important role in modifying the risk of type 2 diabetes. Supplementation with cholecalciferol has been shown to improve β cell function and to attenuate the rise in glycated hemoglobin in people at high risk of diabetes. We examined whether circulating microRNAs (miRNAs) reflect disease progression and/or respond to vitamin D supplementation. We measured plasma levels of select miRNAs implicated in diabetes in people with prediabetes treated either with placebo (n=21) or 2000 U of cholecalciferol daily (n=21) for 4 months in the Calcium and Vitamin D for Diabetes Mellitus trial and compared the baseline-adjusted changes after correcting for age, body mass index, race, time of study entry (season) and baseline disposition index. Circulating levels of miR-7 (sixfold reduction, P=.01), miR-152 (1.5-fold increase, P=.03), and miR-192 (1.7-fold reduction, P=.026) displayed significant treatment-by-time interactions between the placebo- and the vitamin-D-treated groups. Plasma levels of miR-7 were reduced in the vitamin D and increased in the placebo group. The change in miR-152 positively correlated with the change in levels of the circulating metabolite 25-hydroxyvitamin D (r=0.33, P=.046) and negatively correlated with the change in glycated hemoglobin (r=-0.37, P=.024). The change in miR-192 positively correlated with the change in fasting glucose (r=0.41, P<.011). In conclusion, reduction of circulating miR-7 and miR-192, accompanied by elevation of miR-152, reflects a beneficial metabolic response to vitamin D treatment in people with prediabetes. These miRNAs may be useful biomarkers in diabetes prevention trials and other studies of vitamin D. Copyright © 2017 Elsevier Inc. All rights reserved.

Estimating glucose requirements of an activated immune system in growing pigs.

PubMed

Kvidera, S K; Horst, E A; Mayorga, E J; Sanz-Fernandez, M V; Abuajamieh, M; Baumgard, L H

2017-11-01

Activated immune cells become obligate glucose utilizers, and a large i.v. lipopolysaccharide (LPS) dose causes insulin resistance and severe hypoglycemia. Therefore, study objectives were to quantify the amount of glucose needed to maintain euglycemia following an endotoxin challenge as a proxy of leukocyte glucose requirements. Fifteen fasted crossbred gilts (30.3 ± 1.7 kg) were bilaterally jugular catheterized and assigned 1 of 2 i.v. bolus treatments: control (CON; 10 mL sterile saline; = 7) or LPS challenge + euglycemic clamp (LPS-Eu; 055:B5; 5 μg/kg BW; 50% dextrose infusion to maintain euglycemia; = 8). Following administration, blood glucose was determined every 10 min and dextrose infusion rates were adjusted in LPS-Eu pigs to maintain euglycemia for 8 h. Pigs were fasted for 8 h prior to the bolus and remained fasted throughout the challenge. Rectal temperature was increased in LPS-Eu pigs relative to CON pigs (39.8 vs. 38.8°C; < 0.01). Relative to the baseline, CON pigs had 20% decreased blood glucose from 300 to 480 min postbolus ( = 0.01) whereas circulating glucose content in LPS-Eu pigs did not differ ( = 0.96) from prebolus levels. A total of 116 ± 8 g of infused glucose was required to maintain euglycemia in LPS-Eu pigs. Relative to CON pigs, overall plasma insulin, blood urea nitrogen, β-hydroxybutrate, lactate, and LPS-binding protein were increased in LPS-Eu pigs (295, 108, 29, 133, and 13%, respectively; ≤ 0.04) whereas NEFA was decreased (66%; < 0.01). Neutrophils in LPS-Eu pigs were decreased 84% at 120 min postbolus and returned to CON levels by 480 min ( < 0.01). Overall, lymphocytes, monocytes, eosinophils, and basophils were decreased in LPS-Eu pigs relative to CON pigs (75, 87, 70, and 50%, respectively; ≤ 0.05). These alterations in metabolism and the large amount of glucose needed to maintain euglycemia indicate nutrient repartitioning away from growth toward the immune system. Glucose is an important fuel for the immune system, and data from this study established that the glucose requirements of an intensely and acutely activated immune system in growing pigs are approximately 1.1 g/kg BW/h.

Cerebral metabolic intermediate response following severe canine intrauterine growth retardation.

PubMed

Kliegman, R M

1986-07-01

The effect of intrauterine growth retardation and neonatal hypoglycemia on cerebral metabolic intermediates were determined in newborn dogs subjected to 5 days of maternal canine starvation (MCS) before birth. Birth weight was reduced 23% (232 +/- 6 versus 300 +/- 10 g). Circulating blood glucose was reduced after 3 h of neonatal fasting in MCS pups (2.7 +/- 0.4 +/- versus 5.7 +/- 1.1 mM). Cerebral cortical levels of glucose were also reduced at this time. Cerebral glucose-6-phosphate was not altered; nonetheless fructose-6-phosphate was lower in MCS pups at 6 and 9 h, while fructose 1,6-diphosphate appeared elevated at 3 h. These data suggest that cerebral glycolytic activity may be increased by increased activity of phosphofructokinase. Cerebral glutamine appeared reduced in fasting MCS pups at 3, 6, and 8 h of age. A considerable disturbance of the adenine nucleotide pool was noted between 3-9 h in MCS pups; while the cerebral energy reserve was diminished in MCS pups between 3-24 h. The data of reduced cerebral energy status and reserve suggest that cerebral energy production was diminished. Although glucose levels were low at 3 h, subsequent recovery was not immediate as adenine-nucleotides remained low beyond the period of hypoglycemia. The combined effects of intrauterine growth retardation and transient neonatal hypoglycemia appear to result in reduced cerebral oxidative metabolism; this occurs despite an apparent enhanced utilization of alternate fuels.

Acute Ozone-Induced Pulmonary and Systemic Metabolic ...

EPA Pesticide Factsheets

Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1ppm), 4h/day for 1 or 2 days. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to air-exposed SHAM. Corticosterone levels tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (p=0.15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX>DMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not obser

Acute Ozone-Induced Pulmonary and Systemic Metabolic ...

EPA Pesticide Factsheets

Acute ozone exposure increases circulating stress hormones and induces peripheral metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for ozone-induced systemic metabolic effects and lung injury. Male Wistar-Kyoto rats (12 week-old) underwent total bilateral adrenalectomy (ADREX), adrenal demedullation (DEMED) or sham surgery (SHEM). After 4 day recovery, rats were exposed to air or ozone (1ppm), 4h/day for 1 or 2 days. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to air-exposed SHAM. Corticosterone levels tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids and branched-chain amino acids tended to increase after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX>DMED). Ozone-mediated decrease in circulating WBC in SHAM was not

Pancreas-enriched miRNAs are altered in the circulation of subjects with diabetes: a pilot cross-sectional study.

PubMed

Seyhan, Attila A; Nunez Lopez, Yury O; Xie, Hui; Yi, Fanchao; Mathews, Clayton; Pasarica, Magdalena; Pratley, Richard E

2016-08-25

The clinical presentation of diabetes sometimes overlaps, contributing to ambiguity in the diagnosis. Thus, circulating pancreatic islet-enriched microRNAs (miRNAs) might be useful biomarkers of β-cell injury/dysfunction that would allow more accurate subtyping of diabetes. We measured plasma levels of selected miRNAs in subjects with prediabetes (n = 12), type 2 diabetes (T2D, n = 31), latent autoimmune diabetes of adults (LADA, n = 6) and type 1 diabetes (T1D, n = 16) and compared them to levels in healthy control subjects (n = 27). The study was conducted at the Translational Research Institute for Metabolism and Diabetes (TRI-MD), Florida Hospital. MiRNAs including miR-375 (linked to β-cell injury), miR-21 (associated with islet inflammation), miR-24.1, miR-30d, miR-34a, miR-126, miR-146, and miR-148a were significantly elevated in subjects with various forms of diabetes compared to healthy controls. Levels of several miRNAs were significantly correlated with glucose responses during oral glucose tolerance testing, HbA1c, β-cell function, and insulin resistance in healthy controls, prediabetes, and T2D. These data suggest that miRNAs linked to β-cell injury and islet inflammation might be useful biomarkers to distinguish between subtypes of diabetes. This information could be used to predict progression of the disease, guide selection of optimal therapy and monitor responses to interventions, thus improving outcomes in patients with diabetes.

Glucose and hypothalamic astrocytes: More than a fueling role?

PubMed

Leloup, C; Allard, C; Carneiro, L; Fioramonti, X; Collins, S; Pénicaud, L

2016-05-26

Brain plays a central role in energy homeostasis continuously integrating numerous peripheral signals such as circulating nutrients, and in particular blood glucose level, a variable that must be highly regulated. Then, the brain orchestrates adaptive responses to modulate food intake and peripheral organs activity in order to achieve the fine tuning of glycemia. More than fifty years ago, the presence of glucose-sensitive neurons was discovered in the hypothalamus, but what makes them specific and identifiable still remains disconnected from their electrophysiological signature. On the other hand, astrocytes represent the major class of macroglial cells and are now recognized to support an increasing number of neuronal functions. One of these functions consists in the regulation of energy homeostasis through neuronal fueling and nutrient sensing. Twenty years ago, we discovered that the glucose transporter GLUT2, the canonical "glucosensor" of the pancreatic beta-cell together with the glucokinase, was also present in astrocytes and participated in hypothalamic glucose sensing. Since then, many studies have identified other actors and emphasized the astroglial participation in this mechanism. Growing evidence suggest that astrocytes form a complex network and have to be considered as spatially coordinated and regulated metabolic units. In this review we aim to provide an updated view of the molecular and respective cellular pathways involved in hypothalamic glucose sensing, and their relevance in physiological and pathological states. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Influence of high glucose and advanced glycation end-products (ages) levels in human osteoblast-like cells gene expression.

PubMed

Miranda, Cristina; Giner, Mercè; Montoya, M José; Vázquez, M Angeles; Miranda, M José; Pérez-Cano, Ramón

2016-08-31

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of osteoporotic fracture. Several factors have been identified as being potentially responsible for this risk, such as alterations in bone remodelling that may have been induced by changes in circulating glucose or/and by the presence of non-oxidative end products of glycosylation (AGEs). The aim of this study is to assess whether such variations generate a change in the gene expression related to the differentiation and osteoblast activity (OPG, RANKL, RUNX2, OSTERIX, and AGE receptor) in primary cultures of human osteoblast-like cells (hOB). We recruited 32 patients; 10 patients had osteoporotic hip fractures (OP group), 12 patients had osteoporotic hip fractures with T2DM (T2DM group), and 10 patients had hip osteoarthritis (OA group) with no osteoporotic fractures and no T2DM. The gene expression was analyzed in hOB cultures treated with physiological glucose concentration (4.5 mM) as control, high glucose (25 mM), and high glucose plus AGEs (2 μg/ml) for 24 h. The hOB cultures from patients with hip fractures presented slower proliferation. Additionally, the hOB cultures from the T2DM group were the most negatively affected with respect to RUNX2 and OSX gene expression when treated solely with high glucose or with high glucose plus AGEs. Moreover, high levels of glucose induced a major decrease in the RANKL/OPG ratio when comparing the OP and the T2DM groups to the OA group. Our data indicates an altered bone remodelling rate in the T2DM group, which may, at least partially, explain the reduced bone strength and increased incidence of non-traumatic fractures in diabetic patients.

Role of adiponectin in delayed embryonic development of the short-nosed fruit bat, Cynopterus sphinx.

PubMed

Anuradha; Krishna, Amitabh

2014-12-01

The aim of this study was to evaluate the role of adiponectin in the delayed embryonic development of Cynopterus sphinx. Adiponectin receptor (ADIPOR1) abundance was first observed to be lower during the delayed versus non-delayed periods of utero-embryonic unit development. The effects of adiponectin treatment on embryonic development were then evaluated during the period of delayed development. Exogenous treatment increased the in vivo rate of embryonic development, as indicated by an increase in weight, ADIPOR1 levels in the utero-embryonic unit, and histological changes in embryonic development. Treatment with adiponectin during embryonic diapause showed a significant increase in circulating progesterone and estradiol concentrations, and in production of their receptors in the utero-embryonic unit. The adiponectin-induced increase in estradiol synthesis was correlated with increased cell survival (BCL2 protein levels) and cell proliferation (PCNA protein levels) in the utero-embryonic unit, suggesting an indirect effect of adiponectin via estradiol synthesis by the ovary. An in vitro study further confirmed the in vivo findings that adiponectin treatment increases PCNA levels together with increased uptake of glucose by increasing the abundance of glucose transporter 8 (GLUT8) in the utero-embryonic unit. The in vitro study also revealed that adiponectin, together with estradiol but not alone, significantly increased ADIPOR1 protein levels. Thus, adiponectin works in concert with estradiol to increase glucose transport to the utero-embryonic unit and promote cell proliferation, which together accelerate embryonic development. © 2014 Wiley Periodicals, Inc.

Opuntia ficus-indica ingestion stimulates peripheral disposal of oral glucose before and after exercise in healthy men.

PubMed

Van Proeyen, Karen; Ramaekers, Monique; Pischel, Ivo; Hespel, Peter

2012-08-01

The purpose of this study was to investigate the effect of Opuntia ficus-indica (OFI) cladode and fruit-skin extract on blood glucose and plasma insulin increments due to high-dose carbohydrate ingestion, before and after exercise. Healthy, physically active men (n = 6; 21.0 ± 1.6 years, 78.1 ± 6.0 kg) participated in a double-blind placebo-controlled crossover study involving 2 experimental sessions. In each session, the subjects successively underwent an oral glucose tolerance test at rest (OGTT(R)), a 30-min cycling bout at ~75% VO(2max), and another OGTT after exercise (OGTT(EX)). They received capsules containing either 1,000 mg OFI or placebo (PL) 30 min before and immediately after the OGTT(R). Blood samples were collected before (t₀) and at 30-min intervals after ingestion of 75 g glucose for determination of blood glucose and serum insulin. In OGTT(EX) an additional 75-g oral glucose bolus was administered at t₆₀. In OGTT(R), OFI administration reduced the area under the glucose curve (AUC(GLUC)) by 26%, mainly due to lower blood glucose levels at t₃₀ and t₆₀ (p < .05). Furthermore, a higher serum insulin concentration was noted after OFI intake at baseline and at t₃₀ (p < .05). In OGTT(EX), blood glucose at t₆₀ was ~10% lower in OFI than in PL, which resulted in a decreased AUC(GLUC) (-37%, p < .05). However, insulin values and AUC(INS) were not different between OFI and PL. In conclusion, the current study shows that OFI extract can increase plasma insulin and thereby facilitate the clearance of an oral glucose load from the circulation at rest and after endurance exercise in healthy men.

Roux-en-Y Gastric Bypass Improves Hepatic Glucose Metabolism Involving Down-Regulation of Protein Tyrosine Phosphatase 1B in Obese Rats

PubMed Central

Mu, Song; Liu, Jiayu; Guo, Wei; Zhang, Shuping; Xiao, Xiaoqiu; Wang, Zhihong; Zhang, Jun

2017-01-01

Objective This study was initiated to investigate the effects of Roux-en-Y gastric bypass (RYGB) surgery on hepatic glucose metabolism and hepatic expression of protein tyrosine phosphatase 1B (PTP1B) in obese rats. Methods Body weight, glucose, intraperitoneal glucose, insulin, and pyruvate tolerance tests were performed pre- and postoperatively, and plasma lipid, insulin and glucagon-like peptide 1 (GLP-1) were measured. The mRNA levels of G6Pase, Pepck, Gsk-3β and Gys-2, and the expression levels of PTP1B mRNA, protein, and other components of the insulin signaling pathway were measured by using RT-PCR and western blotting. The intracellular localization of PTP1B and hepatic glycogen deposition was also observed. Results RYGB surgery-treated rats showed persistent weight loss, significantly improved glucose tolerance, pyruvate tolerance, and dyslipidemia, as well as increased insulin sensitivity, hepatic glycogen deposition and increased plasma GLP-1 in obese rats. RT-PCR analyses showed Pepck, G6Pase, and Gsk-3β mRNA to be significantly decreased, and Gys-2 mRNA to be significantly increased in liver tissue in the RYGB group (p < 0.05 vs. high-fat diet (HFD) or HFD + sham group); in addition, the expression of PTP1B were significantly decreased and insulin signaling were improved in the RYGB group (p < 0.05 vs. HFD or HFD + sham group). Conclusion RYGB can improve hepatic glucose metabolism and down-regulate PTP1B in obese rats. An increased circulating GLP-1 concentration may be correlated with the effects following RYGB in obese rats. PMID:28564652

Common genetic variants of surfactant protein-D (SP-D) are associated with type 2 diabetes.

PubMed

Pueyo, Neus; Ortega, Francisco J; Mercader, Josep M; Moreno-Navarrete, José M; Sabater, Monica; Bonàs, Sílvia; Botas, Patricia; Delgado, Elías; Ricart, Wifredo; Martinez-Larrad, María T; Serrano-Ríos, Manuel; Torrents, David; Fernández-Real, José M

2013-01-01

Surfactant protein-D (SP-D) is a primordial component of the innate immune system intrinsically linked to metabolic pathways. We aimed to study the association of single nucleotide polymorphisms (SNPs) affecting SP-D with insulin resistance and type 2 diabetes (T2D). We evaluated a common genetic variant located in the SP-D coding region (rs721917, Met(31)Thr) in a sample of T2D patients and non-diabetic controls (n = 2,711). In a subset of subjects (n = 1,062), this SNP was analyzed in association with circulating SP-D concentrations, insulin resistance, and T2D. This SNP and others were also screened in the publicly available Genome Wide Association (GWA) database of the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC). We found the significant association of rs721917 with circulating SP-D, parameters of insulin resistance and T2D. Indeed, G carriers showed decreased circulating SP-D (p = 0.004), decreased fasting glucose (p = 0.0002), glycated hemoglobin (p = 0.0005), and 33% (p = 0.002) lower prevalence of T2D, estimated under a dominant model, especially among women. Interestingly, these differences remained significant after controlling for origin, age, gender, and circulating SP-D. Moreover, this SNP and others within the SP-D genomic region (i.e. rs10887344) were significantly associated with quantitative measures of glucose homeostasis, insulin sensitivity, and T2D, according to GWAS datasets from MAGIC. SP-D gene polymorphisms are associated with insulin resistance and T2D. These associations are independent of circulating SP-D concentrations.

Enhanced serum cholesterol and triglyceride levels in bulimia nervosa: relationships to psychiatric comorbidity, psychopathology and hormonal variables.

PubMed

Monteleone, Palmiero; Santonastaso, Paolo; Pannuto, Marilena; Favaro, Angela; Caregaro, Lorenza; Castaldo, Eloisa; Zanetti, Tatiana; Maj, Mario

2005-04-30

Increased levels of cholesterol have been reported in patients with bulimia nervosa (BN), but all but one of the published studies were performed on non-fasting subjects, which limits the interpretation of this finding. Moreover, the relationships between serum lipids and comorbid psychiatric disorders or bulimic psychopathology have scarcely been investigated. We measured serum levels of total cholesterol, triglycerides, glucose, 17beta-estradiol and thyroid hormones in 75 bulimic women and 64 age-matched healthy females after an overnight fast. Compared with healthy women, bulimic patients exhibited significantly enhanced serum levels of cholesterol and triglycerides, but similar values of glucose, 17beta-estradiol, FT3 and FT4. No significant differences emerged in these variables between patients with or without comorbid depression, borderline personality disorder or lifetime anorexia nervosa. Circulating cholesterol was positively correlated to the patients' drive for thinness, ineffectiveness, enteroceptive awareness and impulse regulation sub-item scores of the Eating Disorder Inventory-2. These findings confirm that BN is associated with increased levels of serum lipids. This alteration may be involved in the pathophysiology of certain psychopathological characteristics of BN and cannot be explained by the co-occurrence of other psychiatric disorders.

Relationship between myostatin and irisin in type 2 diabetes mellitus: a compensatory mechanism to an unfavourable metabolic state?

PubMed

García-Fontana, Beatriz; Reyes-García, Rebeca; Morales-Santana, Sonia; Ávila-Rubio, Verónica; Muñoz-Garach, Araceli; Rozas-Moreno, Pedro; Muñoz-Torres, Manuel

2016-04-01

Myostatin and irisin are two myokines related to energy metabolism, acting on skeletal muscle and recently suggested on adipose tissue in mice. However, the exact role of these myokines in humans has not been fully established. Our aim was to evaluate the relationship between serum levels of myostatin and irisin in type 2 diabetes mellitus patients and non-diabetic controls and to explore its links with metabolic parameters. Case-control study including 73 type 2 diabetes mellitus patients and 55 non-diabetic subjects as control group. Circulating myostatin and irisin levels were measured by enzyme-linked immunosorbent assays. Type 2 diabetes mellitus patients showed significantly lower myostatin levels (p = 0.001) and higher irisin levels (p = 0.036) than controls. An inverse relationship was observed between myostatin and irisin levels (p = 0.002). Moreover, in type 2 diabetes mellitus patients, after adjusting by confounder factors, myostatin was negatively related to fasting plasma glucose (p = 0.005) and to triglyceride levels (p = 0.028) while irisin showed a positive association with these variables (p = 0.017 and p = 0.006 respectively). A linear regression analysis showed that irisin and fasting plasma glucose levels were independently associated to myostatin levels and that myostatin and triglyceride levels were independently associated to irisin concentrations in type 2 diabetes mellitus patients. Our results suggest that serum levels of myostatin and irisin are related in patients with type 2 diabetes. Triglyceride and glucose levels could modulate myostatin and irisin concentrations as a compensatory mechanism to improve the metabolic state in these patients although further studies are needed to elucidate whether the action of these myokines represents an adaptative response.

Hindbrain A2 noradrenergic neuron adenosine 5'-monophosphate-activated protein kinase activation, upstream kinase/phosphorylase protein expression, and receptivity to hormone and fuel reporters of short-term food deprivation are regulated by estradiol.

PubMed

Briski, Karen P; Alenazi, Fahaad S H; Shakya, Manita; Sylvester, Paul W

2017-07-01

Estradiol (E) mitigates acute and postacute adverse effects of 12 hr-food deprivation (FD) on energy balance. Hindbrain 5'-monophosphate-activated protein kinase (AMPK) regulates hyperphagic and hypothalamic metabolic neuropeptide and norepinephrine responses to FD in an E-dependent manner. Energy-state information from AMPK-expressing hindbrain A2 noradrenergic neurons shapes neural responses to metabolic imbalance. Here we investigate the hypothesis that FD causes divergent changes in A2 AMPK activity in E- vs. oil (O)-implanted ovariectomized female rats, alongside dissimilar adjustments in circulating metabolic fuel (glucose, free fatty acids [FFA]) and energy deficit-sensitive hormone (corticosterone, glucagon, leptin) levels. FD decreased blood glucose in oil (O)- but not E-implanted ovariectomized female rats and elevated and reduced glucagon levels in O and E, respectively. FD decreased circulating leptin in O and E, but increased corticosterone and FFA concentrations in E only. Western blot analysis of laser-microdissected A2 neurons showed that glucocorticoid receptor type II and very-long-chain acyl-CoA synthetase 3 protein profiles were amplified in FD/E vs. FD/O. A2 total AMPK protein was elevated without change in activity in FD/O, whereas FD/E exhibited increased AMPK activation along with decreased upstream phosphatase expression. The catecholamine biosynthetic enzyme dopamine-β-hydroxylase (DβH) was increased in FD/O but not FD/E A2 cells. The data show discordance between A2 AMPK activation and glycemic responses to FD; sensor activity was refractory to glucose decrements in FD/O but augmented in FD/E despite stabilized glucose and elevated FFA levels. E-dependent amplification of AMPK activity may reflect adaptive conversion to fatty acid oxidation and/or glucocorticoid stimulation. FD augmentation of A2 DβH protein profiles in FD/O but not FD/E animals suggests that FD may correspondingly regulate NE synthesis vs. metabolism/release in the absence vs. presence of E. Mechanisms underlying translation of E-contingent A2 neuron responses to FD into regulatory signaling remain to be determined. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

[Efficacy of complex therapy with metformin and ramipril combination for patients with metabolic syndrome].

PubMed

Kaĭdashev, I P; Savchenko, L H; Kaĭdasheva, E I; Kutsenko, N L; Kutsenko, L O; Solokhina, I L; Mamontova, T V

2010-01-01

We have studied efficiency of a complex therapy with metformin and ramipril combination (1000 mg and 5 mg per day) respectively in patients with metabolic syndrome (MS). The group of patients with MS which answered the basic criteria IDF (2005) was determined. Carbohydrate and Lipidic metabolism were studied. Patients were characterized with raised weight index (WI), arterial hypertension, increased concentration of triglycerides in blood serum, of glucose, of HbAlc level and S-peptide, and also high level of endotelin (1-38) and CD32+CD40+circulating particles of endothelium. Three months treatment lead to decrease in WI, arterial pressure, triglycerides concentration, HbAlc, glucose, except CD32+CD40+. Six months treatment lead to more expressed positive dynamics. Thus, metformin and ramipril combination in patients with MS leads to decrease in insulin resistancy, carbohydrate and lipid metabolism normalization, to restoration of endothelium functions that is possible to consider as prophylaxis of the development of type 2 diabetes melitus and its cardiovascular complications.

Conditional deletion of Hdac3 in osteoprogenitor cells attenuates diet-induced systemic metabolic dysfunction

PubMed Central

McGee-Lawrence, Meghan E.; White, Thomas A.; LeBrasseur, Nathan K.; Westendorf, Jennifer J.

2015-01-01

Obesity is a major health epidemic in the United States and a leading cause of preventable diseases including type 2 diabetes. A growing body of evidence indicates that the skeleton influences whole body metabolism and suggests a new avenue for developing novel therapeutic agents, but the underlying mechanisms are not well understood. Here, it is demonstrated that conditional deletion of an epigenetic regulator, Hdac3, in osteoblast progenitor cells abrogates high fat diet-induced insulin resistance and hepatic steatosis. These Hdac3-deficient mice have reduced bone formation and lower circulating levels of total and undercarboxylated osteocalcin, coupled with decreased bone resorption activity. They also maintain lower body fat and fasting glucose levels on normal and high fat chow diets. The mechanisms by which Hdac3 controls systemic energy homeostasis from within osteoblasts have not yet been fully realized, but the current study suggests that it does not involve elevated levels of circulating osteocalcin. Thus, Hdac3 is a new player in the emerging paradigm that the skeleton influences systemic energy metabolism. PMID:25666992

Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis.

PubMed

Felsted, Jennifer A; Chien, Cheng-Hao; Wang, Dongqing; Panessiti, Micaella; Ameroso, Dominique; Greenberg, Andrew; Feng, Guoping; Kong, Dong; Rios, Maribel

2017-12-05

The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus (VMH). These effects are body weight independent and involve regulation of SF1 + neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate α2δ-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

PubMed Central

Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga; Saxena, Richa; Soranzo, Nicole; Jackson, Anne U; Wheeler, Eleanor; Glazer, Nicole L; Bouatia-Naji, Nabila; Gloyn, Anna L; Lindgren, Cecilia M; Mägi, Reedik; Morris, Andrew P; Randall, Joshua; Johnson, Toby; Elliott, Paul; Rybin, Denis; Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Henneman, Peter; Grallert, Harald; Dehghan, Abbas; Hottenga, Jouke Jan; Franklin, Christopher S; Navarro, Pau; Song, Kijoung; Goel, Anuj; Perry, John R B; Egan, Josephine M; Lajunen, Taina; Grarup, Niels; Sparsø, Thomas; Doney, Alex; Voight, Benjamin F; Stringham, Heather M; Li, Man; Kanoni, Stavroula; Shrader, Peter; Cavalcanti-Proença, Christine; Kumari, Meena; Qi, Lu; Timpson, Nicholas J; Gieger, Christian; Zabena, Carina; Rocheleau, Ghislain; Ingelsson, Erik; An, Ping; O’Connell, Jeffrey; Luan, Jian'an; Elliott, Amanda; McCarroll, Steven A; Payne, Felicity; Roccasecca, Rosa Maria; Pattou, François; Sethupathy, Praveen; Ardlie, Kristin; Ariyurek, Yavuz; Balkau, Beverley; Barter, Philip; Beilby, John P; Ben-Shlomo, Yoav; Benediktsson, Rafn; Bennett, Amanda J; Bergmann, Sven; Bochud, Murielle; Boerwinkle, Eric; Bonnefond, Amélie; Bonnycastle, Lori L; Borch-Johnsen, Knut; Böttcher, Yvonne; Brunner, Eric; Bumpstead, Suzannah J; Charpentier, Guillaume; Chen, Yii-Der Ida; Chines, Peter; Clarke, Robert; Coin, Lachlan J M; Cooper, Matthew N; Cornelis, Marilyn; Crawford, Gabe; Crisponi, Laura; Day, Ian N M; de Geus, Eco; Delplanque, Jerome; Dina, Christian; Erdos, Michael R; Fedson, Annette C; Fischer-Rosinsky, Antje; Forouhi, Nita G; Fox, Caroline S; Frants, Rune; Franzosi, Maria Grazia; Galan, Pilar; Goodarzi, Mark O; Graessler, Jürgen; Groves, Christopher J; Grundy, Scott; Gwilliam, Rhian; Gyllensten, Ulf; Hadjadj, Samy; Hallmans, Göran; Hammond, Naomi; Han, Xijing; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hayward, Caroline; Heath, Simon C; Hercberg, Serge; Herder, Christian; Hicks, Andrew A; Hillman, David R; Hingorani, Aroon D; Hofman, Albert; Hui, Jennie; Hung, Joe; Isomaa, Bo; Johnson, Paul R V; Jørgensen, Torben; Jula, Antti; Kaakinen, Marika; Kaprio, Jaakko; Kesaniemi, Y Antero; Kivimaki, Mika; Knight, Beatrice; Koskinen, Seppo; Kovacs, Peter; Kyvik, Kirsten Ohm; Lathrop, G Mark; Lawlor, Debbie A; Le Bacquer, Olivier; Lecoeur, Cécile; Li, Yun; Lyssenko, Valeriya; Mahley, Robert; Mangino, Massimo; Manning, Alisa K; Martínez-Larrad, María Teresa; McAteer, Jarred B; McCulloch, Laura J; McPherson, Ruth; Meisinger, Christa; Melzer, David; Meyre, David; Mitchell, Braxton D; Morken, Mario A; Mukherjee, Sutapa; Naitza, Silvia; Narisu, Narisu; Neville, Matthew J; Oostra, Ben A; Orrù, Marco; Pakyz, Ruth; Palmer, Colin N A; Paolisso, Giuseppe; Pattaro, Cristian; Pearson, Daniel; Peden, John F; Pedersen, Nancy L.; Perola, Markus; Pfeiffer, Andreas F H; Pichler, Irene; Polasek, Ozren; Posthuma, Danielle; Potter, Simon C; Pouta, Anneli; Province, Michael A; Psaty, Bruce M; Rathmann, Wolfgang; Rayner, Nigel W; Rice, Kenneth; Ripatti, Samuli; Rivadeneira, Fernando; Roden, Michael; Rolandsson, Olov; Sandbaek, Annelli; Sandhu, Manjinder; Sanna, Serena; Sayer, Avan Aihie; Scheet, Paul; Scott, Laura J; Seedorf, Udo; Sharp, Stephen J; Shields, Beverley; Sigurðsson, Gunnar; Sijbrands, Erik J G; Silveira, Angela; Simpson, Laila; Singleton, Andrew; Smith, Nicholas L; Sovio, Ulla; Swift, Amy; Syddall, Holly; Syvänen, Ann-Christine; Tanaka, Toshiko; Thorand, Barbara; Tichet, Jean; Tönjes, Anke; Tuomi, Tiinamaija; Uitterlinden, André G; van Dijk, Ko Willems; van Hoek, Mandy; Varma, Dhiraj; Visvikis-Siest, Sophie; Vitart, Veronique; Vogelzangs, Nicole; Waeber, Gérard; Wagner, Peter J; Walley, Andrew; Walters, G Bragi; Ward, Kim L; Watkins, Hugh; Weedon, Michael N; Wild, Sarah H; Willemsen, Gonneke; Witteman, Jaqueline C M; Yarnell, John W G; Zeggini, Eleftheria; Zelenika, Diana; Zethelius, Björn; Zhai, Guangju; Zhao, Jing Hua; Zillikens, M Carola; Borecki, Ingrid B; Loos, Ruth J F; Meneton, Pierre; Magnusson, Patrik K E; Nathan, David M; Williams, Gordon H; Hattersley, Andrew T; Silander, Kaisa; Salomaa, Veikko; Smith, George Davey; Bornstein, Stefan R; Schwarz, Peter; Spranger, Joachim; Karpe, Fredrik; Shuldiner, Alan R; Cooper, Cyrus; Dedoussis, George V; Serrano-Ríos, Manuel; Morris, Andrew D; Lind, Lars; Palmer, Lyle J; Hu, Frank B.; Franks, Paul W; Ebrahim, Shah; Marmot, Michael; Kao, W H Linda; Pankow, James S; Sampson, Michael J; Kuusisto, Johanna; Laakso, Markku; Hansen, Torben; Pedersen, Oluf; Pramstaller, Peter Paul; Wichmann, H Erich; Illig, Thomas; Rudan, Igor; Wright, Alan F; Stumvoll, Michael; Campbell, Harry; Wilson, James F; Hamsten, Anders; Bergman, Richard N; Buchanan, Thomas A; Collins, Francis S; Mohlke, Karen L; Tuomilehto, Jaakko; Valle, Timo T; Altshuler, David; Rotter, Jerome I; Siscovick, David S; Penninx, Brenda W J H; Boomsma, Dorret; Deloukas, Panos; Spector, Timothy D; Frayling, Timothy M; Ferrucci, Luigi; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari; van Duijn, Cornelia M; Aulchenko, Yurii S; Cao, Antonio; Scuteri, Angelo; Schlessinger, David; Uda, Manuela; Ruokonen, Aimo; Jarvelin, Marjo-Riitta; Waterworth, Dawn M; Vollenweider, Peter; Peltonen, Leena; Mooser, Vincent; Abecasis, Goncalo R; Wareham, Nicholas J; Sladek, Robert; Froguel, Philippe; Watanabe, Richard M; Meigs, James B; Groop, Leif; Boehnke, Michael; McCarthy, Mark I; Florez, Jose C; Barroso, Inês

2010-01-01

Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes. PMID:20081858

Nitric oxide and superoxide dismutase modulate endothelial progenitor cell function in type 2 diabetes mellitus.

PubMed

Hamed, Saher; Brenner, Benjamin; Aharon, Anat; Daoud, Deeb; Roguin, Ariel

2009-10-30

The function of endothelial progenitor cells (EPCs), which are key cells in vascular repair, is impaired in diabetes mellitus. Nitric oxide (NO) and reactive oxygen species can regulate EPC functions. EPCs tolerate oxidative stress by upregulating superoxide dismutase (SOD), the enzyme that neutralizes superoxide anion (O2-). Therefore, we investigated the roles of NO and SOD in glucose-stressed EPCs. The functions of circulating EPCs from patients with type 2 diabetes were compared to those from healthy individuals. Healthy EPCs were glucose-stressed, and then treated with insulin and/or SOD. We assessed O2- generation, NO production, SOD activity, and their ability to form colonies. EPCs from diabetic patients generated more O2-, had higher NAD(P)H oxidase and SOD activity, but lower NO bioavailability, and expressed higher mRNA and protein levels of p22-phox, and manganese SOD and copper/zinc SOD than those from the healthy individuals. Plasma glucose and HbA1c levels in the diabetic patients were correlated negatively with the NO production from their EPCs. SOD treatment of glucose-stressed EPCs attenuated O2- generation, restored NO production, and partially restored their ability to form colonies. Insulin treatment of glucose-stressed EPCs increased NO production, but did not change O2- generation and their ability to form colonies. However, their ability to produce NO and to form colonies was fully restored after combined SOD and insulin treatment. Our data provide evidence that SOD may play an essential role in EPCs, and emphasize the important role of antioxidant therapy in type 2 diabetic patients.

Sub-chronic administration of the 11beta-HSD1 inhibitor, carbenoxolone, improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.

PubMed

Taylor, Ashley; Irwin, Nigel; McKillop, Aine M; Flatt, Peter R; Gault, Victor A

2008-04-01

We have examined the metabolic effects of daily administration of carbenoxolone (CBX), a naturally occurring 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) inhibitor, in mice with high fat diet-induced insulin resistance and obesity. Eight-week-old male Swiss TO mice placed on a synthetic high fat diet received daily intraperitoneal injections of either saline vehicle or CBX over a 16-day period. Daily administration of CBX had no effect on food intake, but significantly lowered body weight (1.1- to 1.2-fold) compared to saline-treated controls. Non-fasting plasma glucose levels were significantly decreased (1.6-fold) by CBX treatment on day 4 and remained lower throughout the treatment period. Circulating plasma corticosterone levels were not significantly altered by CBX treatment. Plasma glucose concentrations of CBX-treated mice were significantly reduced (1.4-fold) following an intraperitoneal glucose load compared with saline controls. Similarly, after 16-day treatment with CBX, exogenous insulin evoked a significantly greater reduction in glucose concentrations (1.4- to 1.8-fold). 11beta-HSD1 gene expression was significantly down-regulated in liver, whereas glucocorticoid receptor gene expression was increased in both liver and adipose tissue following CBX treatment. The reduced body weight and improved metabolic control in mice with high fat diet-induced obesity upon daily CBX administration highlights the potential value of selective 11beta-HSD1 inhibition as a new route for the treatment of type 2 diabetes and obesity.

Thyroid hormone modulates food intake and glycemia via ghrelin secretion in Zucker fatty rats.

PubMed

Patel, K; Joharapurkar, A; Dhanesha, N; Patel, V; Kshirsagar, S; Raval, P; Raval, S; Jain, M R

2014-10-01

Hyperthyroidism is known to increase food intake and central administration of thyroid hormone shows acute orexigenic effects in rodents. We investigated whether T3 influences appetite and glucose homeostasis by modulating circulating ghrelin, an important orexigenic hormone, in Zucker fatty rats. The acute anorectic effects of T3 and ghrelin mimetic MK-0677 were studied in rats trained for fasting induced food intake. The serum concentration of T3, ghrelin, glucose, triglycerides, and liver glycogen were estimated. The involvement of sympathetic nervous system was evaluated by conducting similar experiments in vagotomized rats. T3 increased food intake and glucose in rats over 4 h, with increase in serum T3 and decrease in liver glycogen. T3 treatment was associated with increase in serum ghrelin. An additive effect on appetite and glucose was observed when T3 (oral) was administered with central (intracerebroventricular) administration of a ghrelin mimetic, MK-0677. Ghrelin antagonist, compound 8a, antagonized the hyperglycemic and hyperphagic effects of T3. In vagotomized rats, T3 did not show increase in appetite as well as glucose. Serum ghrelin levels were unchanged in these animals after T3 treatment. However, T3 showed increase in serum triglyceride levels indicating its peripheral lipolytic effect, in vagotomized as well as sham treated animals. To conclude, acute orexigenic and hyperglycemic effects of T3 are associated with ghrelin secretion and activity. This effect seems to be mediated via vagus nerves, and is independent of glucoregulatory hormones. © Georg Thieme Verlag KG Stuttgart · New York.

Vitamin D supplementation reduces insulin resistance in Japanese adults: a secondary analysis of a double-blind, randomized, placebo-controlled trial.

PubMed

Sun, Xiaomin; Cao, Zhen-Bo; Tanisawa, Kumpei; Ito, Tomoko; Oshima, Satomi; Higuchi, Mitsuru

2016-10-01

Higher circulating 25-hydroxyvitamin D (25[OH]D) concentration has been linked to a lower prevalence of insulin resistance and type 2 diabetes mellitus. However, randomized controlled trials have not clarified the effect of vitamin D supplementation on insulin resistance in healthy adults. The objective of this study was to assess the effect of vitamin D supplementation for 1 year on insulin resistance; the study was a secondary analysis of a clinical trial. We hypothesized that increased 25(OH)D concentration after vitamin D supplementation for 1 year would significantly improve insulin resistance. Ninety-six healthy adults participated in this study, of whom 81 completed the study. The participants randomly received daily either 420 IU vitamin D 3 or placebo in a double-blind manner for 1 year. The levels of fasting insulin, glucose, and other parameters were assessed at baseline and after 1 year of intervention. Homeostasis model assessment of insulin resistance index was calculated from insulin and glucose levels. Visceral fat area and physical activity were also investigated. Serum 25(OH)D and 1,25-dihydroxyvitamin D concentrations were significantly increased by approximately 29.5 nmol/L and 7.0 pg/mL, respectively, after 1-year vitamin D supplementation. After vitamin D supplementation, fasting glucose levels and values of homeostasis model assessment of insulin resistance index significantly decreased from 88.3 to 85.3 mg/dL (P < .01) and 1.17 to 0.84 (P < .01), respectively, and the results were independent of physical activity and visceral fat accumulation. In conclusion, the present study showed that vitamin D supplementation for 1 year effectively improves fasting glucose level and insulin resistance in healthy Japanese adults. Copyright © 2016 Elsevier Inc. All rights reserved.

Carboxymethyl lysine, an advanced glycation end product, and incident diabetes: a case-cohort analysis of the ARIC Study.

PubMed

Luft, V C; Duncan, B B; Schmidt, M I; Chambless, L E; Pankow, J S; Hoogeveen, R C; Couper, D J; Heiss, G

2016-10-01

To verify whether elevated fasting levels of circulating carboxymethyl lysine (CML), an advanced glycation end product, predict the development of diabetes in middle-age adults. Using a stratified case-cohort design, we followed 543 middle-aged individuals who developed diabetes and 514 who did not over a median 9 years in the Atherosclerosis Risk in Communities Study. Weighted Cox proportional hazards analyses were used to account for the design. In weighted analyses, correlation between CML levels and anthropometric, inflammatory or metabolic variables was minimal (Pearson correlations usually < 0.10). CML, when modelled as a continuous variable and after adjustment for age, sex, race, centre, parental history of diabetes, BMI, waist-to-hip ratio, non-esterified fatty acids, oxidized LDL-cholesterol, GFR, smoking, an inflammation score, adiponectin, leptin, insulin and glucose levels, was associated with an increased risk of diabetes [Hazard ratio (HR) = 1.35; 95% confidence interval (CI) 1.09-1.67, for each 100 ng/ml CML increment]. Baseline glucose level and race each modified the association (P < 0.05 for interaction), which was present only among those with impaired fasting glucose (≥ 5.6 mmol/l, HR = 1.61, 95% CI 1.26-2.05) and among white participants (HR = 1.50, 95% CI 1.13-1.99). Elevated fasting CML, after adjustment for multiple risk factors for diabetes, predicts the development of incident diabetes, the association being present among those with impaired fasting glucose and in white participants. These prospective findings suggest that advanced glycation end products might play a role in the development of diabetes. © 2015 Diabetes UK.

Oxygen and energy availability interact to determine flight performance in the Glanville fritillary butterfly.

PubMed

Fountain, Toby; Melvin, Richard G; Ikonen, Suvi; Ruokolainen, Annukka; Woestmann, Luisa; Hietakangas, Ville; Hanski, Ilkka

2016-05-15

Flying insects have the highest known mass-specific demand for oxygen, which makes it likely that reduced availability of oxygen might limit sustained flight, either instead of or in addition to the limitation due to metabolite resources. The Glanville fritillary butterfly (Melitaea cinxia) occurs as a large metapopulation in which adult butterflies frequently disperse between small local populations. Here, we examine how the interaction between oxygen availability and fuel use affects flight performance in the Glanville fritillary. Individuals were flown under either normoxic (21 kPa O2) or hypoxic (10 kPa O2) conditions and their flight metabolism was measured. To determine resource use, levels of circulating glucose, trehalose and whole-body triglyceride were recorded after flight. Flight performance was significantly reduced in hypoxic conditions. When flown under normoxic conditions, we observed a positive correlation among individuals between post-flight circulating trehalose levels and flight metabolic rate, suggesting that low levels of circulating trehalose constrains flight metabolism. To test this hypothesis experimentally, we measured the flight metabolic rate of individuals injected with a trehalase inhibitor. In support of the hypothesis, experimental butterflies showed significantly reduced flight metabolic rate, but not resting metabolic rate, in comparison to control individuals. By contrast, under hypoxia there was no relationship between trehalose and flight metabolic rate. Additionally, in this case, flight metabolic rate was reduced in spite of circulating trehalose levels that were high enough to support high flight metabolic rate under normoxic conditions. These results demonstrate a significant interaction between oxygen and energy availability for the control of flight performance. © 2016. Published by The Company of Biologists Ltd.

Fasting leptin and glucose in normal weight, over weight and obese men and women diabetes patients with and without clinical depression.

PubMed

Haleem, Darakhshan Jabeen; Sheikh, Shehnaz; Fawad, Asher; Haleem, Muhammad A

2017-06-01

A large number of diabetes patients suffer from major depression and are at high risk of mortality. In view of a role of leptin in diabetes, depression and energy homeostasis, the present study concerns circulating levels of leptin in different BMI groups of un-depressed and depressed diabetes patients. Six hundred thirty male and female patients with a primary diagnosis of diabetes were grouped according to BMI and with or without clinical symptoms of depression. Age matched healthy, normal weight male and female volunteers without clinical symptoms of depression or diabetes were taken as controls. Blood samples were obtained after an overnight fast of 12 h. Serum was stored for the determination of leptin and glucose. We found that there were more female than male diabetes patients with comorbid depression. Fasting leptin was higher in normal weight non-diabetes women than men; but comparable in normal weight men and women diabetes patients. Fasting glucose levels were higher in diabetes than non diabetes groups; values were comparable in men and women. Depression was associated with a decrease and increase in leptin respectively in normal-overweight and obese men and women diabetes patients. Glucose levels were also higher in obese depressed than un-depressed diabetes patients. The results suggested that the female gender is at greater risk to comorbid diabetes with depression. Adipo-insular axis plays an important role in diabetes, associated depression and in the greater risk of the female gender to comorbid diabetes with depression.

Reduced circulating levels of sTWEAK are associated with NAFLD and may affect hepatocyte triglyceride accumulation.

PubMed

Lozano-Bartolomé, J; Llauradó, G; Rodriguez, M M; Fernandez-Real, J M; Garcia-Fontgivell, J F; Puig, J; Maymó-Masip, E; Vendrell, J; Chacón, M R

2016-09-01

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is strongly associated with obesity, dyslipidaemia and altered glucose regulation. Previous data demonstrated that low circulating levels of tumour necrosis factor weak inducer of apoptosis (sTWEAK) were associated with obesity, diabetes and insulin resistance, all traits associated with an increased risk of NALFD. Circulating sTWEAK levels are expected to be reduced in the presence of NAFLD. We aimed to explore the relationship between NAFLD and circulating sTWEAK levels in obese patients, and to evaluate the effect of sTWEAK on hepatocyte triglyceride accumulation.Design setting and patients:This is an observational case-control study performed in n=112 severely obese patients evaluated for NAFLD by abdominal ultrasound and n=32 non-obese patients without steatosis. Serum sTWEAK concentrations were measured by ELISA. Multivariable analyses were performed to determine the independent predictors of NAFLD. We analysed TWEAK and Fn14 protein expression in liver biopsies by western blotting and immunohistochemistry. An immortalized primary human hepatocyte cell line (HHL) was used to evaluate the effect of sTWEAK on triglyceride accumulation. We observed a reduction in serum circulating sTWEAK concentrations with the presence of liver steatosis. On multivariable analysis, lower sTWEAK concentrations were independently associated with the presence of NAFLD (odds ratio (OR)=0.023; 95% confidence interval: 0.001-0.579; P<0.022). In human hepatocytes, sTWEAK administration reduced fat accumulation as demonstrated by the reduction in palmitic acid-induced accumulation of triglyceride and the decreased expression of cluster of differentiation 36 (CD36) and perilipin 1 and 2 (PLIN1 and PLIN2) genes. Decreased sTWEAK concentrations are independently associated with the presence of NAFLD. This is concordant with the observation that TWEAK reduces lipid accumulation in human liver cells.

Metabolic and hormonal responses of growing modern meat type chickens to fasting

USDA-ARS?s Scientific Manuscript database

The present study compared the effects of fasting on circulating concentrations of glucose, insulin and glucagon in male and female modern meat-type chickens (Ross 708) at three ages (19 d, 33 d and 47 d). Plasma concentrations of glucose were reduced by fasting with reductions of 24.9% (19-d-old),...

An Overview of FGF19 and FGF21: The Therapeutic Role in the Treatment of the Metabolic Disorders and Obesity.

PubMed

Babaknejad, Nasim; Nayeri, Hashem; Hemmati, Roohullah; Bahrami, Somaye; Esmaillzadeh, Ahmad

2018-06-01

Fibroblast growth factors (FGFs) are responsible for the regulation of a wide range of biological functions, among which cellular proliferation, survival, migration, and differentiation could be pointed out. FGF19 controls the enterohepatic bile acid/cholesterol system, and FGF21 modulates fatty acid/glucose metabolism. Obesity, type 2 diabetes, coronary artery disease, and cancer, all can alter FGF21 circulating concentrations. In contrast to FGF21, metabolic diseases exhibit reduced serum FGF19 levels. Accordingly, FGF19 and FGF21 play important roles in regulating glucose and lipid metabolism. Hence, we present here a timely review on the relationship between FGF19/21 and metabolic diseases, especially obesity, and their probable role in development and treatment of obesity seems necessary. © Georg Thieme Verlag KG Stuttgart · New York.

Plasma levels of lysine, tyrosine, and valine during pregnancy are independent risk factors of insulin resistance and gestational diabetes.

PubMed

Park, Sunmin; Park, Jin Young; Lee, Ju Hong; Kim, Sung-Hoon

2015-03-01

This study compared plasma concentrations of amino acids in pregnant women with and without gestational diabetes mellitus (GDM) and identified the association between plasma amino acid levels and GDM, insulin resistance, and insulin secretion at 24-28 weeks of pregnancy. Circulating amino acid levels were evaluated using high-performance liquid chromatography at 24-28 weeks of pregnancy in 25 non-GDM and 64 GDM women after adjusting for covariates such as maternal age, body mass index (BMI) before pregnancy, BMI and gestational age at screening GDM, and daily caloric intake. Backward stepwise logistic regression analysis was used to identify the predictors of developing GDM, and homeostatic model assessments for insulin resistance (HOMA-IR) and β-cell function (HOMA-B). Circulating levels of amino acids except threonine and tyrosine were significantly higher in GDM women than non-GDM women. Along with the intakes of energy, protein, and fat from animal sources, the intakes of each amino acid were significantly higher in the GDM group without a direct correlation to plasma amino acid levels. The variation in GDM development was explained by maternal age, diastolic blood pressure, and plasma lysine levels (R(2)=0.691). Height, BMI before pregnancy, systolic blood pressure, and plasma tyrosine and valine levels accounted for the variation in HOMA-IR (R(2)=0.589). The 53.3% variation of HOMA-B was explained by maternal age, BMI at GDM screening, plasma insulin level at 1 h during the oral glucose tolerance test (OGTT), and plasma valine level. Circulating concentrations of lysine, tyrosine, and valine were independently and positively associated with GDM through modifying insulin resistance and secretion.

Circulating linoleic acid and alpha-linolenic acid and glucose metabolism: the Hoorn Study.

PubMed

Cabout, Mieke; Alssema, Marjan; Nijpels, Giel; Stehouwer, Coen D A; Zock, Peter L; Brouwer, Ingeborg A; Elshorbagy, Amany K; Refsum, Helga; Dekker, Jacqueline M

2017-09-01

Data on the relation between linoleic acid (LA) and alpha-linolenic acid (ALA) and type 2 diabetes mellitus (T2DM) risk are scarce and inconsistent. The aim of this study was to investigate the association of serum LA and ALA with fasting and 2 h post-load plasma glucose and glycated hemoglobin (HbA1c). This study included 667 participants from third examination (2000) of the population-based Hoorn study in which individuals with glucose intolerance were overrepresented. Fatty acid profiles in serum total lipids were measured at baseline, in 2000. Diabetes risk markers were measured at baseline and follow-up in 2008. Linear regression models were used in cross-sectional and prospective analyses. In cross-sectional analyses (n = 667), serum LA was inversely associated with plasma glucose, both in fasting conditions (B = -0.024 [-0.045, -0.002]) and 2 h after glucose tolerance test (B = -0.099 [-0.158, -0.039]), but not with HbA1c (B = 0.000 [-0.014, 0.013]), after adjustment for relevant factors. In prospective analyses (n = 257), serum LA was not associated with fasting (B = 0.003 [-0.019, 0.025]) or post-load glucose (B = -0.026 [-0.100, 0.049]). Furthermore, no significant associations were found between serum ALA and glucose metabolism in cross-sectional or prospective analyses. In this study, serum LA was inversely associated with fasting and post-load glucose in cross-sectional, but not in prospective analyses. Further studies are needed to elucidate the exact role of serum LA and ALA levels and dietary polyunsaturated fatty acids in glucose metabolism.

Family Planning for women unable to tolerate oral contraceptives.

PubMed

Spellacy, W N

1974-04-08

Should women with a family history of diabetes or myocardial infarcation, or women with abnormal blood glucose or cholesterol levels receive oral contraceptives? There is clear evidence that oral contraceptives can alter both carbohydrate and lipid metabolism in certain women. The lipid alteration is mainly an elevation of the circulating triglyceride levels, and only rarely is cholesterol content altered. It is also clear from extensive research during the past ten years that women who already have subclinical abnormalities, either in their triglyceride levels (family hyperlipoproteinemia) or glucose tolerance, are at great risk for the development of clinical disease while using oral contraceptives. Accordingly, all pharmaceutical firms are required by the Food and Drug Administration to instruct physicians about these problems through the package inserts and other means. Specifically, the physician should be alerted by the patient's history, and then he should use the laboratory to confirm any suspicion of abnormalities of carbohydrate or lipid metabolism. If there is any abnormal blood glucose or triglyceride value, the oral contraceptives should not be prescribed. There are other forms of contraception available for child spacing. Mechanical contraceptives will not aggravate a metabolic disorder. A useful substitute then would be an intrauterine device plus vaginal foam. When the woman has completed her family, she should be all means be offered surgical sterilization as a permanent family planning technique.

Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes

PubMed Central

Kanikarla-Marie, Preeti; Jain, Sushil K.

2016-01-01

Diets that boost ketone production are increasingly used for treating several neurological disorders. Elevation in ketones in most cases is considered favorable, as they provide energy and are efficient in fueling the body’s energy needs. Despite all the benefits from ketones, the above normal elevation in the concentration of ketones in the circulation tend to illicit various pathological complications by activating injurious pathways leading to cellular damage. Recent literature demonstrates a plausible link between elevated levels of circulating ketones and oxidative stress, linking hyperketonemia to innumerable morbid conditions. Ketone bodies are produced by the oxidation of fatty acids in the liver as a source of alternative energy that generally occurs in glucose limiting conditions. Regulation of ketogenesis and ketolysis plays an important role in dictating ketone concentrations in the blood. Hyperketonemia is a condition with elevated blood levels of acetoacetate (AA), 3-β-hydroxybutyrate (BHB), and acetone. Several physiological and pathological triggers, such as fasting, ketogenic diet, and diabetes cause an accumulation and elevation of circulating ketones. Complications of the brain, kidney, liver, and microvasculature were found to be elevated in diabetic patients who had elevated ketones compared to those diabetics with normal ketone levels. This review summarizes the mechanisms by which hyperketonemia and ketoacidosis cause an increase in redox imbalance and thereby increasing the risk of morbidity and mortality in patients. PMID:27036365

Hyperketonemia and ketosis increase the risk of complications in type 1 diabetes.

PubMed

Kanikarla-Marie, Preeti; Jain, Sushil K

2016-06-01

Diets that boost ketone production are increasingly used for treating several neurological disorders. Elevation in ketones in most cases is considered favorable, as they provide energy and are efficient in fueling the body's energy needs. Despite all the benefits from ketones, the above normal elevation in the concentration of ketones in the circulation tend to illicit various pathological complications by activating injurious pathways leading to cellular damage. Recent literature demonstrates a plausible link between elevated levels of circulating ketones and oxidative stress, linking hyperketonemia to innumerable morbid conditions. Ketone bodies are produced by the oxidation of fatty acids in the liver as a source of alternative energy that generally occurs in glucose limiting conditions. Regulation of ketogenesis and ketolysis plays an important role in dictating ketone concentrations in the blood. Hyperketonemia is a condition with elevated blood levels of acetoacetate, 3-β-hydroxybutyrate, and acetone. Several physiological and pathological triggers, such as fasting, ketogenic diet, and diabetes cause an accumulation and elevation of circulating ketones. Complications of the brain, kidney, liver, and microvasculature were found to be elevated in diabetic patients who had elevated ketones compared to those diabetics with normal ketone levels. This review summarizes the mechanisms by which hyperketonemia and ketoacidosis cause an increase in redox imbalance and thereby increase the risk of morbidity and mortality in patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Circulating IL-6 concentrations and associated anthropometric and metabolic parameters in South Asian men and women in comparison to European whites.

PubMed

Peters, Mike J L; Ghouri, Nazim; McKeigue, Paul; Forouhi, Nita G; Sattar, Naveed

2013-01-01

To determine any ethnic differences in circulating interleukin (IL)-6 concentrations among SAs and Europeans, and to assess their relationship with body composition and insulin resistance measures. Body composition was assessed among 80 SA and European men and women using anthropometry, dual-energy X-ray absorptiometry and abdominal CT scan. Oral glucose tolerance tests with insulin response were performed to assess insulin resistance measures. IL-6 levels were measured by high sensitivity ELISA. Median IL-6 values were higher in SA compared with European women: 1.94 mg/l versus 1.51 mg/l, p=0.041, but not so in men (1.56 mg/l versus 1.57 mg/l). Only measures of obesity, in particular percentage fat area (r=0.6, p=0.003), were positively correlated with IL-6 in SAs. Differences in body fat percentage (visceral and total) could explain up to 30% of the IL-6 difference between Asian and European women. SA women have elevated circulating IL-6 levels, in part due to greater visceral and percent fat levels compared with European women. This observation may in part explain why Asians are at elevated cardiovascular disease risk. Future studies should address the effects of lifestyle factors (physical activity, diet) on plasma IL-6 concentrations in SA women. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Circulating levels of MCP-1, VEGF-A, sICAM-1, sVCAM-1, sE-selectin and sVE-cadherin: Relationship with components of metabolic syndrome in young population].

PubMed

Guzmán-Guzmán, Iris Paola; Zaragoza-García, Oscar; Vences-Velázquez, Amalia; Castro-Alarcón, Natividad; Muñoz-Valle, José Francisco; Parra-Rojas, Isela

2016-11-18

Inflammation and endothelial dysfunction are considered the primary manifestations of the cardiovascular disease. Studies have established a relationship among components of metabolic syndrome (MetS) with inflammatory markers and the loss of permeability, vasoconstriction and vasodilatation endothelial. To determine the relationship among the concentrations of soluble endothelial dysfunction molecules and inflammation cytokines and components of the metabolic syndrome in young population. A study was performed in 240 young adult students ages 18-28 years. To define the presence of clinical and metabolic alterations and MetS the modified ATP-III criteria was considered. In all subjects were determined sociodemographic characteristics, anthropometric measures and the metabolic profile. Circulating levels of MCP-1, VEGF-A, sICAM-1, sVCAM-1, sE-selectin and sVE-cadherin were determined by ELISA immunoassay (Bioscience). Statistical analysis was performed using STATA statistical software v. 9.2. From all the participants, 44.6% had obesity, 59.9% had abdominal obesity, 49.6% low HDL-c and 16.7% high levels triglycerids. The 16.25% of the population showed 3 or more components of the MetS. Elevated MCP-1, sICAM-1 and sE-selectin levels were linked to the presence of obesity. In a model adjusted by age-gender, high soluble levels of MCP-1 and VEGF-A were linked with abdominal obesity (OR=1.83; 1.02-3.28 and OR=2.03; 1.15-3.56, respectively), as well as to the presence of the 2 components of MetS. sVCAM-1 levels were associated with impaired glucose (OR=4.74; 1.32-17.0); sE-selectin with low HDL-c (OR=1.99; 1.05-3.75), although sICAM-1 and sVE-cadherin were associated with impaired systolic blood pressure (OR=4.04; 1.24-13.1 and OR=6.28; 1.90-20.7, respectively). Levels of circulating MCP-1 and VEGF-A were associated with adiposity, levels of sVCAM-1 with the presence of impaired glucose, sE-selectin with low HDL-c, while the levels of sICAM-1 and sVE-cadherin were associated with impaired systolic blood pressure in young adults independently of other traditional risk factors. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Effect of dehydroepiandrosterone administration on recovery from mix-type exercise training-induced muscle damage.

PubMed

Liao, Yi-Hung; Liao, Kun-Fu; Kao, Chung-Lan; Chen, Chung-Yu; Huang, Chih-Yang; Chang, Wei-Hsiang; Ivy, John L; Bernard, Jeffrey R; Lee, Shin-Da; Kuo, Chia-Hua

2013-01-01

This study aimed to determine the role of DHEA-S in coping against the exercise training mixing aerobic and resistance components. During 5-day successive exercise training, 16 young male participants (19.2 ± 1.2 years) received either a placebo (flour capsule) or DHEA (100 mg/day) in a double-blinded and placebo-controlled design. Oral DHEA supplementation significantly increased circulating DHEA-S by 2.5-fold, but a protracted drop (~35 %) was observed from Day 3 during training. In the Placebo group, only a minimal DHEA-S reduction (~17 %) was observed. Changes in testosterone followed a similar pattern as DHEA-S. Muscle soreness was elevated significantly on Day 2 for both groups to a similar extent. Lower muscle soreness was observed in the DHEA-supplemented group on Day 3 and Day 6. In the Placebo group, training increased circulating creatine kinase (CK) levels by approximately ninefold, while only a threefold increase was observed in the DHEA-supplemented group. This mix-type exercise training improved glucose tolerance in both groups, while lowering the insulin response to the glucose challenge, but no difference between treatments was observed. Our results suggest that DHEA-S may play a role in protecting skeletal muscle from exercise training-induced muscle damage.

Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss

PubMed Central

Laferrère, Blandine; Reilly, David; Arias, Sara; Swerdlow, Nicholas; Gorroochurn, Prakash; Bawa, Baani; Bose, Mousumi; Teixeira, Julio; Stevens, Robert D.; Wenner, Brett R.; Bain, James R.; Muehlbauer, Michael J.; Haqq, Andrea; Lien, Lillian; Shah, Svati H.; Svetkey, Laura P.; Newgard, Christopher B.

2013-01-01

Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better metabolic response after GBP. Circulating amino acids (AAs) and acylcarnitines (ACs) were measured in plasma from fasted subjects by targeted tandem mass spectrometry before and after a matched 10-kilogram weight loss induced by GBP or diet. Total AAs and branched-chain AAs (BCAAs) decreased after GBP, but not after dietary intervention. Metabolites derived from BCAA oxidation also decreased only after GBP. Principal components (PC) analysis identified two major PCs, one composed almost exclusively of ACs (PC1) and another with BCAAs and their metabolites as major contributors (PC2). PC1 and PC2 were inversely correlated with pro-insulin concentrations, the C-peptide response to oral glucose, and the insulin sensitivity index after weight loss, whereas PC2 was uniquely correlated with levels of insulin resistance (HOMA-IR). These data suggest that the enhanced decrease in circulating AAs after GBP occurs by mechanisms other than weight loss and may contribute to the better improvement in glucose homeostasis observed with the surgical intervention. PMID:21525399

Heightened circulating levels of antimicrobial peptides in tuberculosis—Diabetes co-morbidity and reversal upon treatment

PubMed Central

Kumar, Nathella Pavan; Moideen, Kadar; Viswanathan, Vijay; Sivakumar, Shanmugam; Menon, Pradeep A.; Kornfeld, Hardy

2017-01-01

Background The association of antimicrobial peptides (AMPs) with tuberculosis—diabetes comorbidity (PTB-DM) is not well understood. Methods To study the association of AMPs with PTB-DM, we examined the systemic levels of cathelicidin (LL37), human beta defensin– 2 (HBD2), human neutrophil peptides 1–3, (HNP1-3) and granulysin in individuals with either PTB-DM, PTB, latent TB (LTB) or no TB infection (NTB). Results Circulating levels of cathelicidin and HBD2 were significantly higher and granulysin levels were significantly lower in PTB-DM compared to PTB, LTB or NTB, while the levels of HNP1-3 were significantly higher in PTB-DM compared to LTB or NTB individuals. Moreover, the levels of cathelicidin and/or HBD2 were significantly higher in PTB-DM or PTB individuals with bilateral and cavitary disease and also exhibited a significant positive relationship with bacterial burden. Cathelidin, HBD2 and HNP1-3 levels exhibited a positive relationship with HbA1c and/or fasting blood glucose levels. Finally, anti-tuberculosis therapy resulted in significantly diminished levels of cathelicidin, HBD2, granulysin and significantly enhanced levels of HNP1-3 and granulysin in PTB-DM and/or PTB individuals. Conclusion Therefore, our data demonstrate that PTB-DM is associated with markedly enhanced levels of AMPs and diminished levels of granulysin. PMID:28910369

Upregulation of growth signaling and nutrient transporters in cotyledons of early to mid-gestational nutrient restricted ewes

PubMed Central

Ma, Yan; Zhu, Mei J.; Uthlaut, Adam B.; Nijland, Mark J.; Nathanielsz, Peter W.; Hess, Bret W.; Ford, Stephen P.

2011-01-01

Multiparous ewes received 100% (control, C, n=13) or 50% (nutrient restricted, NR, n=14) of NRC dietary requirements from d28-d78 of gestation. On d78, 5 C and 6 NR ewes were necropsied. The remaining 8 C and 8 NR ewes were fed to 100% of NRC from d78-d135 and necropsied. Maternal blood was collected at both necropsies and at weekly intervals for assay of glucose, insulin and leptin. Fetal blood was collected at d78 and d135 necropsies for assay of glucose and lipids. Cotyledonary (COT) tissue was evaluated for protein and mRNA expression [fatty acid transporter (FATP)1, FATP4, CD36, glucose transporter (GLUT)1 and GLUT3], mRNA expression only [placenta fatty acid binding protein (FABPpm) and lipoprotein lipase (LPL)], or expression of phosphorylated and total protein forms [AMP kinase (AMPK)α, acetyl-CoA carboxylase (ACC), extracellular signal-regulated kinase (Erk)1/2, mammalian target of rapamycin (mTOR) and protein kinase B (Akt)]. On d78, but not d135, placental and fetal weights were reduced (P < 0.05) in NR vs. C ewes. Maternal circulating glucose, insulin and leptin levels were decreased in NR vs. C ewes on d78 (P < 0.05) but similar at d135. Fetal blood glucose and triglyceride levels were lower in NR vs. C ewes (P < 0.05) on d78, but similar on d135. On d78, GLUT1, FATP4, CD36 mRNA and protein expression levels, FABPpm mRNA level, and leptin protein level were all increased (P < 0.05) in COT of NR vs. C ewes. AMPK, ACC, and Erk1/2 activities were also increased (P < 0.05) in NR vs. C COT on d78. In contrast, only FATP4 was increased (P < 0.05) at both the mRNA and protein levels in COT of NR realimented vs. C ewes on d135. These data demonstrate placental adaptation to maternal NR through increasing nutrient transporter production and growth signaling activity. PMID:21292322

Regulatory peptides in the plasma of patients with chronic cardiac failure at rest and during exercise.

PubMed

Nicholls, D P; Riley, M; Elborn, J S; Stanford, C F; Shaw, C; McKillop, J M; Buchanan, K D

1992-10-01

The levels of several regulatory peptides were measured in peripheral plasma samples from individuals with chronic cardiac failure (CCF) and matched controls in both the resting state and during a short period of maximal exercise. Basal levels of noradrenaline (NA; 705 +/- 114 vs 195 +/- 54 ng.l-1; mean +/- SEM; P < 0.05), plasma renin activity (PRA; 12.9 +/- 2.9 vs 2.1 +/- 0.3 ng AI ml-1.h-1; P < 0.05) and aldosterone (ALDO; 325 +/- 49 vs 87 +/- 8 ng.l-1; P < 0.05) were all raised in the patients with CCF, and increased further with exercise. Basal circulating levels of atrial natriuretic peptide (ANP) were also significantly higher in the CCF group compared to controls (136 +/- 35 vs 27 +/- 5 ng.l-1; P < 0.01), but the response to exercise was attenuated, so that at peak exercise, no significant difference was observed. Basal circulating levels of gastrin-releasing peptide (GRP) (29 +/- 4 vs 40 +/- 4 ng.l-1; P < 0.05) and secretin (13 +/- 1 vs 32 +/- 4 ng.l-1; P < 0.05) were significantly lower in the CCF group when compared to controls and there was no significant change in the levels of either peptide with exercise. Levels of neurokinin A (NKA), neuropeptide Y (NPY) and neurotensin (NT) were somewhat higher in patients, but the differences were not significant, and there were no changes during exercise. There were also no significant differences in the levels of vasoactive intestinal peptide (VIP), glucose-dependent insulinotropic polypeptide (GIP), insulin or glucagon in either experimental group both before and during exercise. We have therefore identified different circulating levels of certain regulatory peptides in patients with CCF, but the significance of these remains unclear.

Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity

PubMed Central

Jacobsen, Mette J.; Mentzel, Caroline M. Junker; Olesen, Ann Sofie; Huby, Thierry; Jørgensen, Claus B.; Barrès, Romain; Fredholm, Merete

2016-01-01

Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity. PMID:26798656

Obesity-driven prepartal hepatic lipid accumulation in dairy cows is associated with increased CD36 and SREBP-1 expression.

PubMed

Prodanović, Radiša; Korićanac, Goran; Vujanac, Ivan; Djordjević, Ana; Pantelić, Marija; Romić, Snježana; Stanimirović, Zoran; Kirovski, Danijela

2016-08-01

We investigated the hypothesis that obesity in dairy cows enhanced expression of proteins involved in hepatic fatty acid uptake and metabolism. Sixteen Holstein-Friesian close-up cows were divided into 2 equal groups based on their body condition score (BCS) as optimal (3.25≤BCS≤3.5) and high (4.0≤BCS≤4.25). Intravenous glucose tolerance test (GTT) and liver biopsies were carried out at day 10 before calving. Blood samples were collected before (basal) and after glucose infusion, and glucose, insulin and non-esterified fatty acid (NEFA) levels were determined at each sample point. In addition, β-hydroxybutyrate and triglycerides levels were measured in the basal samples. The liver biopsies were analyzed for total lipid content and protein expression of insulin receptor beta (IRβ), fatty acid translocase (FAT/CD36) and sterol regulatory element-binding protein-1 (SREBP-1). Basal glucose and insulin were higher in high-BCS cows, which coincided with higher circulating triglycerides and hepatic lipid content. Clearance rate and AUC for NEFA during GTT were higher in optimal-BCS cows. The development of insulin resistance and fatty liver in obese cows was paralleled by increased hepatic expression of the IRβ, CD36 and SREBP-1. These results suggest that increased expression of hepatic CD36 and SREBP-1 is relevant in the obesity-driven lipid accumulation in the liver of dairy cows during late gestation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of Hypoglycemia on Circulating Stem and Progenitor Cells in Diabetic Patients.

PubMed

Fadini, Gian Paolo; Boscari, Federico; Cappellari, Roberta; Galasso, Silvia; Rigato, Mauro; Bonora, Benedetta Maria; D'Anna, Marianna; Bruttomesso, Daniela; Avogaro, Angelo

2018-03-01

Iatrogenic hypoglycemia is the most common acute diabetic complication, and it significantly increases morbidity. In people with diabetes, reduction in the levels of circulating stem and progenitor cells predicts adverse outcomes. To evaluate whether hypoglycemia in diabetes affects circulating stem cells and endothelial progenitor cells (EPCs). We performed an experimental hypoglycemia study (Study 1) and a case-control study (Study 2). Tertiary referral inpatient clinic. Type 1 diabetic patients (Study 1, n = 19); diabetic patients hospitalized for severe iatrogenic hypoglycemia, matched inpatient and outpatient controls (Study 2, n = 22/group). Type 1 diabetic patients underwent two in-hospital sessions of glucose monitoring during a breakfast meal with or without induction of hypoglycemia in random order. In Study 2, patients hospitalized for hypoglycemia and matched controls were compared. Circulating stem cells and EPCs were measured by flow cytometry based on the expression of CD34 and kinase insert domain receptor (KDR). In Study 1, the physiologic decline of CD34+KDR+ EPCs from 8 am to 2 pm was abolished by insulin-induced hypoglycemia in type 1 diabetic patients. In Study 2, diabetic patients hospitalized for severe iatrogenic hypoglycemia had significantly lower levels of CD34+ stem cells and CD34+KDR+ EPCs compared with diabetic inpatients or outpatient controls. In diabetic patients, a single mild hypoglycemic episode can compromise the physiologic EPC fluctuation, whereas severe hypoglycemia is associated with a marked reduction in stem cells and EPCs. These data provide a possible link between hypoglycemia and adverse outcomes of diabetes.

A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery

PubMed Central

Setchell, Kenneth DR; Kirby, Michelle; Myronovych, Andriy; Ryan, Karen K.; Ibrahim, Samar H.; Berger, Jose; Smith, Kathi; Toure, Mouhamadoul; Woods, Stephen C.; Seeley, Randy J.

2013-01-01

Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, whereas short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short circuiting the normal enterohepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the middistal jejunum for 4–5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis, and endoplasmic reticulum (ER) stress were measured. Rats post-BD lost significantly more weight than the SH rats. BD rats gained less fat mass after surgery. BD rats had improved glucose tolerance, increased higher postprandial glucagon-like peptide-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (C/EBP homologous protein mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/ursodeoxycholic acid [UDCA]) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (C/EBP homologous protein mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease. PMID:23592746

Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging.

PubMed

Bailey-Downs, Lora C; Sosnowska, Danuta; Toth, Peter; Mitschelen, Matthew; Gautam, Tripti; Henthorn, Jim C; Ballabh, Praveen; Koller, Akos; Farley, Julie A; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

2012-06-01

Previous studies suggest that the age-related decline in circulating growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels significantly contribute to vascular dysfunction in aging by impairing cellular oxidative stress resistance pathways. Obesity in elderly individuals is increasing at alarming rates, and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging, GH/IGF-1 deficiency, and obesity interact to promote the development of cardiovascular disease remain unclear. To test the hypothesis that low circulating GH/IGF-1 levels exacerbate the pro-oxidant and proinflammatory vascular effects of obesity, GH/IGF-1-deficient Lewis dwarf rats and heterozygous control rats were fed either a standard diet or a high-fat diet (HFD) for 7 months. Feeding an HFD resulted in similar relative weight gains and increases in body fat content in Lewis dwarf rats and control rats. HFD-fed Lewis dwarf rats exhibited a relative increase in blood glucose levels, lower insulin, and impaired glucose tolerance as compared with HFD-fed control rats. Analysis of serum cytokine expression signatures indicated that chronic GH/IGF-1 deficiency exacerbates HFD-induced inflammation. GH/IGF-1 deficiency also exacerbated HFD-induced endothelial dysfunction, oxidative stress, and expression of inflammatory markers (tumor necrosis factor-α, ICAM-1) in aortas of Lewis dwarf rats. Overall, our results are consistent with the available clinical and experimental evidence suggesting that GH/IGF-1 deficiency renders the cardiovascular system more vulnerable to the deleterious effects of obesity.

Growth Hormone and IGF-1 Deficiency Exacerbate High-Fat Diet–Induced Endothelial Impairment in Obese Lewis Dwarf Rats: Implications for Vascular Aging

PubMed Central

Bailey-Downs, Lora C.; Sosnowska, Danuta; Toth, Peter; Mitschelen, Matthew; Gautam, Tripti; Henthorn, Jim C.; Ballabh, Praveen; Koller, Akos; Farley, Julie A.; Sonntag, William E.; Csiszar, Anna

2012-01-01

Previous studies suggest that the age-related decline in circulating growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels significantly contribute to vascular dysfunction in aging by impairing cellular oxidative stress resistance pathways. Obesity in elderly individuals is increasing at alarming rates, and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging, GH/IGF-1 deficiency, and obesity interact to promote the development of cardiovascular disease remain unclear. To test the hypothesis that low circulating GH/IGF-1 levels exacerbate the pro-oxidant and proinflammatory vascular effects of obesity, GH/IGF-1–deficient Lewis dwarf rats and heterozygous control rats were fed either a standard diet or a high-fat diet (HFD) for 7 months. Feeding an HFD resulted in similar relative weight gains and increases in body fat content in Lewis dwarf rats and control rats. HFD-fed Lewis dwarf rats exhibited a relative increase in blood glucose levels, lower insulin, and impaired glucose tolerance as compared with HFD-fed control rats. Analysis of serum cytokine expression signatures indicated that chronic GH/IGF-1 deficiency exacerbates HFD-induced inflammation. GH/IGF-1 deficiency also exacerbated HFD-induced endothelial dysfunction, oxidative stress, and expression of inflammatory markers (tumor necrosis factor-α, ICAM-1) in aortas of Lewis dwarf rats. Overall, our results are consistent with the available clinical and experimental evidence suggesting that GH/IGF-1 deficiency renders the cardiovascular system more vulnerable to the deleterious effects of obesity. PMID:22080499

Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data.

PubMed

Kurosaki, Eiji; Ogasawara, Hideaki

2013-07-01

Sodium-glucose cotransporter-2 (SGLT2) is expressed in the proximal tubules of the kidneys and plays a key role in renal glucose reabsorption. A novel class of antidiabetic medications, SGLT2-selective inhibitors attempt to improve glycemic control in diabetics by preventing glucose from being reabsorbed through SGLT2 and re-entering circulation. Ipragliflozin is an SGLT2 inhibitor in Phase 3 clinical development for the treatment of type 2 diabetes mellitus (T2DM). In this review, we summarize recent animal and human studies on ipragliflozin and other SGLT2 inhibitors including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, and luseogliflozin. These agents all show potent and selective SGLT2 inhibition in vitro and reduce blood glucose levels and HbA1c in both diabetic animal models and patients with T2DM. SGLT2 inhibitors offer several advantages over other classes of hypoglycemic agents. Due to their insulin-independent mode of action, SGLT2 inhibitors provide steady glucose control without major risk for hypoglycemia and may also reverse β-cell dysfunction and insulin resistance. Other favorable effects of SGLT2 inhibitors include a reduction in both body weight and blood pressure. SGLT2 inhibitors are safe and well tolerated and can easily be combined with other classes of antidiabetic medications to achieve tighter glycemic control. The long-term safety and efficacy of these agents are under evaluation. Copyright © 2013 Elsevier Inc. All rights reserved.

Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice.

PubMed

Kooijman, Sander; Wang, Yanan; Parlevliet, Edwin T; Boon, Mariëtte R; Edelschaap, David; Snaterse, Gido; Pijl, Hanno; Romijn, Johannes A; Rensen, Patrick C N

2015-11-01

Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT. Lean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions. Central administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight. Collectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

Hyperandrogenism sensitizes mononuclear cells to promote glucose-induced inflammation in lean reproductive-age women

PubMed Central

Nair, K. Sreekumaran; Daniels, Janice K.; Basal, Eati; Schimke, Jill M.

2012-01-01

Hyperandrogenism and chronic low-grade inflammation are related in polycystic ovary syndrome (PCOS), but it is unknown whether hyperandrogenemia can activate inflammation. We determined the effect of oral androgen administration on fasting and glucose-stimulated nuclear factor-κB (NF-κB) activation and expression and related markers of inflammation in mononuclear cells (MNC) of lean reproductive-age women. Sixteen lean, ovulatory reproductive-age women were treated with 130 mg of DHEA or placebo (n = 8 each) for 5 days in a randomized, controlled, double-blind fashion. Nuclear activation of NF-κB, p65 and p105 NF-κB subunit RNA, TNFα and IL-1β mRNA, and NF-κB p65 and inhibitory-κB (IκB) protein were quantified from MNC obtained while fasting and 2 h after glucose ingestion, before and after DHEA or placebo administration. Before treatment, subjects receiving DHEA or placebo exhibited no differences in androgens or any inflammatory markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-S, increased the percent change in fasting and glucose-challenged activated NF-κB, p65, p105, TNFα, and IL-1β RNA and p65 protein, and decreased the percent change in fasting and glucose-challenged IκB protein. We conclude that elevation of circulating androgens to the range observed in PCOS upregulates the NF-κB inflammation pathway in lean reproductive-age women. Thus, hyperandrogenemia activates and sensitizes MNC to glucose in this population. PMID:22045316

Hyperandrogenism sensitizes mononuclear cells to promote glucose-induced inflammation in lean reproductive-age women.

PubMed

González, Frank; Nair, K Sreekumaran; Daniels, Janice K; Basal, Eati; Schimke, Jill M

2012-02-01

Hyperandrogenism and chronic low-grade inflammation are related in polycystic ovary syndrome (PCOS), but it is unknown whether hyperandrogenemia can activate inflammation. We determined the effect of oral androgen administration on fasting and glucose-stimulated nuclear factor-κB (NF-κB) activation and expression and related markers of inflammation in mononuclear cells (MNC) of lean reproductive-age women. Sixteen lean, ovulatory reproductive-age women were treated with 130 mg of DHEA or placebo (n = 8 each) for 5 days in a randomized, controlled, double-blind fashion. Nuclear activation of NF-κB, p65 and p105 NF-κB subunit RNA, TNFα and IL-1β mRNA, and NF-κB p65 and inhibitory-κB (IκB) protein were quantified from MNC obtained while fasting and 2 h after glucose ingestion, before and after DHEA or placebo administration. Before treatment, subjects receiving DHEA or placebo exhibited no differences in androgens or any inflammatory markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-S, increased the percent change in fasting and glucose-challenged activated NF-κB, p65, p105, TNFα, and IL-1β RNA and p65 protein, and decreased the percent change in fasting and glucose-challenged IκB protein. We conclude that elevation of circulating androgens to the range observed in PCOS upregulates the NF-κB inflammation pathway in lean reproductive-age women. Thus, hyperandrogenemia activates and sensitizes MNC to glucose in this population.

Circulating Adipocyte Fatty Acid Binding Protein (FABP4) Levels Are Associated with Irisin in the Middle-Aged General Chinese Population.

PubMed

Zhang, Shan; Yang, Lili; Chen, Peihong; Jin, Hua; Xie, Xinmiao; Yang, Meili; Gao, Ting; Hu, Cheng; Yu, Xuemei

2016-01-01

Adipocyte fatty acid binding protein (FABP4) has been recently characterized as an adipokine that is closely associated with obesity and metabolic syndrome. Irisin, a novel myokine, activates thermogenesis by increasing the transformation of white adipocytes to brown, and it has improved glucose homeostasis in animal models. In this study, we aimed to explore the relationship between serum FABP4 and irisin in middle-aged Chinese subjects. A total of 111 normal residents (56 men and 55 women) of Fengxian District who were 40 to 60 years of age were recruited. Circulating FABP4 and irisin were determined by enzyme-linked immunosorbent assay. Anthropometric parameters, oral glucose tolerance test results, hemoglobin A1C (HbA1C), blood lipids, homeostasis model assessment of insulin resistance, homeostasis model assessment-β and body fat composition were also determined. All participants were categorized by FABP4 tertiles. There were significant differences in blood pressure, body fat percentage, 2-h plasma glucose, and skeletal muscle mass among the three groups (P<0.05). Furthermore, FABP4 levels in the women were significantly higher than in the men (P<0.05). However, there was no sexual dimorphism in serum irisin (P>0.05). To exclude the effect of sex difference, partial correlations analysis showed that FABP4 was positively correlated with diastolic blood pressure (P<0.05) and body fat percentage (P<0.05) negatively correlated with skeletal muscle mass (P<0.05) and irisin (P<0.05), while irisin was positively correlated with HbA1c (P<0.05) and negatively correlated with creatinine (P<0.05). Multivariate regression analysis demonstrated that serum FABP4 was independently associated with skeletal muscle mass (P<0.001), diastolic blood pressure (P<0.05) and irisin (P<0.05) after adjustment for age, body mass index, body fat percentage, total cholesterol and HbA1C. Elevated FABP4 levels increase the risks of obesity-related metabolic disorders and hypertension. Serum irisin might exert antagonistic effects on FABP4 in the middle-aged Chinese population.

Metabolic phenotype in the mouse model of osteogenesis imperfecta.

PubMed

Boraschi-Diaz, Iris; Tauer, Josephine T; El-Rifai, Omar; Guillemette, Delphine; Lefebvre, Geneviève; Rauch, Frank; Ferron, Mathieu; Komarova, Svetlana V

2017-09-01

Osteogenesis imperfecta (OI) is the most common heritable bone fragility disorder, usually caused by dominant mutations in genes coding for collagen type I alpha chains, COL1A1 or COL1A2 Osteocalcin (OCN) is now recognized as a bone-derived regulator of insulin secretion and sensitivity and glucose homeostasis. Since OI is associated with increased rates of bone formation and resorption, we hypothesized that the levels of undercarboxylated OCN are increased in OI. The objective of this study was to determine changes in OCN and to elucidate the metabolic phenotype in the Col1a1 Jrt/+ mouse, a model of dominant OI caused by a Col1a1 mutation. Circulating levels of undercarboxylated OCN were higher in 4-week-old OI mice and normal by 8 weeks of age. Young OI animals exhibited a sex-dependent metabolic phenotype, including increased insulin levels in males, improved glucose tolerance in females, lower levels of random glucose and low adiposity in both sexes. The rates of O 2 consumption and CO 2 production, as well as energy expenditure assessed using indirect calorimetry were significantly increased in OI animals of both sexes, whereas respiratory exchange ratio was significantly higher in OI males only. Although OI mice have significant physical impairment that may contribute to metabolic differences, we specifically accounted for movement and compared OI and WT animals during the periods of similar activity levels. Taken together, our data strongly suggest that OI animals have alterations in whole body energy metabolism that are consistent with the action of undercarboxylated osteocalcin. © 2017 Society for Endocrinology.

Metabolic effects of soy supplementation in postmenopausal Caucasian and African American women: a randomized, placebo-controlled trial.

PubMed

Christie, Daniel R; Grant, Jan; Darnell, Betty E; Chapman, Victoria R; Gastaldelli, Amalia; Sites, Cynthia K

2010-08-01

We sought to determine the effect of daily soy supplementation on abdominal fat, glucose metabolism, and circulating inflammatory markers and adipokines in obese, postmenopausal Caucasian and African American women. In a double-blinded controlled trial, 39 postmenopausal women were randomized to soy supplementation or to a casein placebo without isoflavones. In all, 33 completed the study and were analyzed. At baseline and at 3 months, glucose disposal and insulin secretion were measured using hyperglycemic clamps, body composition and body fat distribution were measured by computed tomographic scan and dual energy x-ray absorptiometry, and serum levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, leptin, and adiponectin were measured by immunoassay. Soy supplementation reduced total and subcutaneous abdominal fat and interleukin-6. No difference between groups was noted for glucose metabolism, C-reactive protein, tumor necrosis factor-alpha, leptin, or adiponectin. Soy supplementation reduced abdominal fat in obese postmenopausal women. Caucasians primarily lost subcutaneous and total abdominal fat, and African Americans primarily lost total body fat. Copyright (c) 2010 Mosby, Inc. All rights reserved.

Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring.

PubMed

Abbott, David H; Bruns, Cristin R; Barnett, Deborah K; Dunaif, Andrea; Goodfriend, Theodore L; Dumesic, Daniel A; Tarantal, Alice F

2010-11-01

Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155-175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in pancreatic function in PA infants, suggesting in this nonhuman primate model that differential programming of insulin action and secretion may precede adult metabolic dysfunction.

Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring

PubMed Central

Bruns, Cristin R.; Barnett, Deborah K.; Dunaif, Andrea; Goodfriend, Theodore L.; Dumesic, Daniel A.; Tarantal, Alice F.

2010-01-01

Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155–175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in pancreatic function in PA infants, suggesting in this nonhuman primate model that differential programming of insulin action and secretion may precede adult metabolic dysfunction. PMID:20682841

Influence of Adiponectin Gene Polymorphisms on Adiponectin Level and Insulin Resistance Index in Response to Dietary Intervention in Overweight-Obese Patients With Impaired Fasting Glucose or Newly Diagnosed Type 2 Diabetes

PubMed Central

Chung, Hye Kyung; Chae, Jey Sook; Hyun, Yae Jung; Paik, Jean Kyung; Kim, Ji Young; Jang, Yangsoo; Kwon, Hyuck Moon; Song, Young Duk; Lee, Hyun Chul; Lee, Jong Ho

2009-01-01

OBJECTIVE The aim of this study was to determine the effect of common adiponectin gene polymorphisms on dietary intervention-mediated changes in adiponectin levels and homeostasis model assessment of insulin resistance (HOMA-IR) indexes. RESEARCH DESIGN AND METHODS A total of 363 subjects with impaired fasting glucose (IFG) or newly diagnosed type 2 diabetes followed a dietary intervention (replacement of cooked refined rice with whole grains and an increase in vegetable intake) and regular walking for 12 weeks without any medication. Adiponectin gene single nucleotide polymorphisms (SNPs) (45, 276, and −11377) were examined in these subjects. RESULTS After this dietary intervention, fasting glucose levels decreased in all three SNP 45T>G genotype groups. Subjects with the SNP 45TT genotype showed increased adiponectin levels and decreased HOMA-IR indexes. Haplotype analysis revealed that homozygous carriers of the TG haplotype (45TT and 276GG) and heterozygous carriers of the TG haplotype (TG/X) showed a reduction in the HOMA-IR index after adjustment for baseline levels. Significant differences were observed in changes in HOMA-IR indexes and adiponectin concentrations according to the 45-276 TG haplotype in overweight-obese, but not in normal-weight subjects: the greatest decrease in HOMA-IR indexes and the greatest increase in adiponectin levels were shown in overweight-obese subjects with the TG/TG haplotype. CONCLUSIONS ADIPOQ genetic variants can affect circulating adiponectin levels and insulin resistance indexes in subjects with IFG or newly diagnosed type 2 diabetes in response to dietary intervention. PMID:19131459

The dietary flavonoids naringenin and quercetin acutely impair glucose metabolism in rodents possibly via inhibition of hypothalamic insulin signalling.

PubMed

Koch, Christiane E; Ganjam, Goutham K; Steger, Juliane; Legler, Karen; Stöhr, Sigrid; Schumacher, Daniela; Hoggard, Nigel; Heldmaier, Gerhard; Tups, Alexander

2013-03-28

Secondary metabolites of herbs and spices are widely used as an alternative strategy in the therapy of various diseases. The polyphenols naringenin, quercetin and curcumin have been characterised as anti-diabetic agents. Conversely, in vitro, naringenin and quercetin are described to inhibit phosphoinositide-3-kinase (PI3K), an enzyme that is essential for the neuronal control of whole body glucose homoeostasis. Using both in vitro and in vivo experiments, we tested whether the inhibitory effect on PI3K occurs in neurons and if it might affect whole body glucose homoeostasis. Quercetin was found to inhibit basal and insulin-induced phosphorylation of Akt (Ser473), a downstream target of PI3K, in HT-22 cells, whereas naringenin and curcumin had no effect. In Djungarian hamsters (Phodopus sungorus) naringenin and quercetin (10 mg/kg administered orally) diminished insulin-induced phosphorylation of Akt (Ser473) in the arcuate nucleus, indicating a reduction in hypothalamic PI3K activity. In agreement with this finding, glucose tolerance in naringenin-treated hamsters (oral) and mice (oral and intracerebroventricular) was reduced compared with controls. Dietary quercetin also impaired glucose tolerance, whereas curcumin was ineffective. Circulating levels of insulin and insulin-like growth factor-binding protein were not affected by the polyphenols. Oral quercetin reduced the respiratory quotient, suggesting that glucose utilisation was impaired after treatment. These data demonstrate that low doses of naringenin and quercetin acutely and potently impair glucose homoeostasis. This effect may be mediated by inhibition of hypothalamic PI3K signalling. Whether chronic impairments in glucose homoeostasis occur after long-term application remains to be identified.

Lack of insulinotropic effect of endogenous and exogenous cholecystokinin in man.

PubMed

Reimers, J; Nauck, M; Creutzfeldt, W; Strietzel, J; Ebert, R; Cantor, P; Hoffmann, G

1988-05-01

Intraduodenal phenylalanine administration (333 mg/min over 60 min) released endogenous cholecystokinin in healthy young subjects as demonstrated radioimmunologically and by intraduodenal bilirubin and pancreatic enzyme output. Concomitantly, there was only a small increase over basal in circulating immunoreactive-insulin and immunoreactive-C-peptide concentrations. In healthy volunteers intraduodenal infusions of saline (10 ml/min), glucose (333 mg/min) or phenylalanine (333 mg/min) were performed for 60 min when plasma glucose was clamped at approximately 8 mmol/l. Phenylalanine enhanced immunoreactive-insulin and immunoreactive-C-peptide responses three-fold more than did the same amount of glucose. Immuno-reactive gastric inhibitory polypeptide responses were small and not different after glucose and phenylalanine administration. Immunoreactive cholecystokinin was significantly stimulated to 9.4 +/- 1.4 pmol/l only by intraduodenal phenylalanine. Plasma phenylalanine concentrations increased into the supraphysiological range (approximately 1.5 mmol/l). Intravenous infusions of phenylalanine achieving plasma concentrations of 1.2 mmol/l stimulated insulin secretion at elevated plasma glucose concentrations (approximately 8 mmol/l clamp experiments), but had no effect at basal plasma glucose concentrations. A small increase in cholecystokinin also was observed. Intravenous infusions of synthetic sulphated cholecystokinin-8 leading to plasma concentrations in the upper postprandial range (8-12 pmol/l) did not augment the immunoreactive-insulin or immunoreactive-C-peptide levels during hyperglycaemic clamp experiments, in the absence or presence of elevated plasma phenylalanine concentrations. It is concluded that the augmentation of the glucose-induced insulin release by intraduodenal administration of phenylalanine cannot be related to cholecystokinin release, but rather is explained by the combined effects of elevated glucose and phenylalanine concentrations. In man, cholecystokinin does not augment insulin secretion caused by moderate hyperglycaemia, elevations of phenylalanine concentrations, or combinations thereof.

Circulating leptin and adiponectin are associated with insulin resistance in healthy postmenopausal women with hot flashes.

PubMed

Huang, Wan-Yu; Chang, Chia-Chu; Chen, Dar-Ren; Kor, Chew-Teng; Chen, Ting-Yu; Wu, Hung-Ming

2017-01-01

Hot flashes have been postulated to be linked to the development of metabolic disorders. This study aimed to evaluate the relationship between hot flashes, adipocyte-derived hormones, and insulin resistance in healthy, non-obese postmenopausal women. In this cross-sectional study, a total of 151 women aged 45-60 years were stratified into one of three groups according to hot-flash status over the past three months: never experienced hot flashes (Group N), mild-to-moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, fasting levels of circulating glucose, lipid profiles, plasma insulin, and adipocyte-derived hormones. Multiple linear regression analysis was used to evaluate the associations of hot flashes with adipocyte-derived hormones, and with insulin resistance. The study was performed in a hospital medical center. The mean (standard deviation) of body-mass index was 22.8(2.7) for Group N, 22.6(2.6) for Group M, and 23.5(2.4) for Group S, respectively. Women in Group S displayed statistically significantly higher levels of leptin, fasting glucose, and insulin, and lower levels of adiponectin than those in Groups M and N. Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with higher leptin levels, lower adiponectin levels, and higher leptin-to-adiponectin ratio. Univariate linear regression analysis revealed that hot-flash severity was strongly associated with a higher HOMA-IR index (% difference, 58.03%; 95% confidence interval, 31.00-90.64; p < 0.001). The association between hot flashes and HOMA-IR index was attenuated after adjusting for leptin or adiponectin and was no longer significant after simultaneously adjusting for leptin and adiponectin. The present study provides evidence that hot flashes are associated with insulin resistance in postmenopausal women. It further suggests that hot flash association with insulin resistance is dependent on the combination of leptin and adiponectin variables.

Plasma Irisin Modestly Increases during Moderate and High-Intensity Afternoon Exercise in Obese Females

PubMed Central

Winn, Nathan C.; Grunewald, Zachary I.; Liu, Ying; Heden, Timothy D.; Nyhoff, Lauren M.; Kanaley, Jill A.

2017-01-01

Background and Purpose Irisin is an exercise-responsive myokine that has been proposed to exert anti-obesity benefits; yet its response during exercise in obese women is not described. This study characterized plasma irisin levels during a single bout of afternoon isocaloric-exercise of different intensities (moderate- vs high-intensity) in obese females. Methods Eleven obese females participated in 3 randomized study days beginning at 1600h: 1) no exercise (NoEx), 2) moderate exercise (ModEx; 55%VO2max) and 3) high intensity interval exercise (IntEx; 4 min (80%VO2max)/3 min (50% VO2max). Frequent blood samples were analyzed for glucose and lactate (whole-blood), and insulin, c-peptide, glucagon, and irisin (plasma) throughout 190 min of testing. Results Plasma irisin increased above baseline during ModEx and IntEx (P<0.05), but not NoEx (P>0.05). Peak irisin levels during ModEx and IntEx exercise were 11.9± 3.4% and 12.3 ± 4.1% relative to baseline (P<0.05), respectively, with no differences between exercise intensities (P>0.05). Irisin levels remained elevated above resting for 125 minutes post-exercise during ModEx, whereas levels returned to baseline within 15 minutes post-exercise during IntEx. Similarly, no associations were found between plasma irisin levels and circulating lactate, glucose, insulin, c-peptide, or glucagon among study days (P>0.05). However, there was an inverse association between basal irisin and lean mass (r = -0.70, P = 0.01). Conclusion A single bout of moderate and high intensity afternoon exercise induces modest increases in circulating irisin concentrations during exercise; however the regulation post-exercise appears to be dimorphic between exercise intensity in obese females. Future studies are needed to compare morning and afternoon exercise on irisin secretion. PMID:28125733

BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis.

PubMed

Sanderson, Michael P; Apgar, Joshua; Garin-Chesa, Pilar; Hofmann, Marco H; Kessler, Dirk; Quant, Jens; Savchenko, Alexander; Schaaf, Otmar; Treu, Matthias; Tye, Heather; Zahn, Stephan K; Zoephel, Andreas; Haaksma, Eric; Adolf, Günther R; Kraut, Norbert

2015-12-01

Inhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach of pharmacologic intervention in cancer, owing to the roles of the IGF1R and INSRA in promoting cell proliferation and survival. However, the central role of the INSRB isoform in glucose homeostasis suggests that prolonged inhibition of this kinase could result in metabolic toxicity. We describe here the profile of the novel compound BI 885578, a potent and selective ATP-competitive IGF1R/INSR tyrosine kinase inhibitor distinguished by rapid intestinal absorption and a short in vivo half-life as a result of rapid metabolic clearance. BI 885578, administered daily per os, displayed an acceptable tolerability profile in mice at doses that significantly reduced the growth of xenografted human GEO and CL-14 colon carcinoma tumors. We found that treatment with BI 885578 is accompanied by increases in circulating glucose and insulin levels, which in turn leads to compensatory hyperphosphorylation of muscle INSRs and subsequent normalization of blood glucose within a few hours. In contrast, the normalization of IGF1R and INSR phosphorylation in GEO tumors occurs at a much slower rate. In accordance with this, BI 885578 led to a prolonged inhibition of cell proliferation and induction of apoptosis in GEO tumors. We propose that the remarkable therapeutic window observed for BI 885578 is achieved by virtue of the distinctive pharmacokinetic properties of the compound, capitalizing on the physiologic mechanisms of glucose homeostasis and differential levels of IGF1R and INSR expression in tumors and normal tissues. ©2015 American Association for Cancer Research.

Nitric oxide and superoxide dismutase modulate endothelial progenitor cell function in type 2 diabetes mellitus

PubMed Central

Hamed, Saher; Brenner, Benjamin; Aharon, Anat; Daoud, Deeb; Roguin, Ariel

2009-01-01

Background The function of endothelial progenitor cells (EPCs), which are key cells in vascular repair, is impaired in diabetes mellitus. Nitric oxide (NO) and reactive oxygen species can regulate EPC functions. EPCs tolerate oxidative stress by upregulating superoxide dismutase (SOD), the enzyme that neutralizes superoxide anion (O2-). Therefore, we investigated the roles of NO and SOD in glucose-stressed EPCs. Methods The functions of circulating EPCs from patients with type 2 diabetes were compared to those from healthy individuals. Healthy EPCs were glucose-stressed, and then treated with insulin and/or SOD. We assessed O2- generation, NO production, SOD activity, and their ability to form colonies. Results EPCs from diabetic patients generated more O2-, had higher NAD(P)H oxidase and SOD activity, but lower NO bioavailability, and expressed higher mRNA and protein levels of p22-phox, and manganese SOD and copper/zinc SOD than those from the healthy individuals. Plasma glucose and HbA1c levels in the diabetic patients were correlated negatively with the NO production from their EPCs. SOD treatment of glucose-stressed EPCs attenuated O2- generation, restored NO production, and partially restored their ability to form colonies. Insulin treatment of glucose-stressed EPCs increased NO production, but did not change O2- generation and their ability to form colonies. However, their ability to produce NO and to form colonies was fully restored after combined SOD and insulin treatment. Conclusion Our data provide evidence that SOD may play an essential role in EPCs, and emphasize the important role of antioxidant therapy in type 2 diabetic patients. PMID:19878539

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline.

PubMed

Gault, V A; Lennox, R; Flatt, P R

2015-04-01

To examine whether prolonged dipeptidyl peptidase-4 (DPP-4) inhibition can reverse learning and memory impairment in high-fat-fed mice. High-fat-fed mice received oral sitagliptin (50 mg/kg body weight) once daily or saline vehicle over 21 days. An additional group of mice on standard chow received saline vehicle. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, novel object recognition, DPP-4 activity, hormone analysis, hippocampal gene expression and histology were performed. Sitagliptin decreased circulating DPP-4 activity and improved glucose tolerance, glucose-stimulated insulin secretion and insulin sensitivity, and reduced plasma triglycerides and cholesterol levels. DPP-4 inhibition improved recognition memory (1.2-fold increase) without affecting hypermoteric activity or anxiety levels. Improvement in memory and learning was linked to reduced immunostaining for 8-oxoguanine and increased doublecortin staining in the hippocampus, which were indicative of reduced brain oxidative stress and increased hippocampal neurogenesis, respectively. These effects were associated with significant upregulation of hippocampal gene expression of glucagon-like peptide-1 (GLP-1) receptor, glucose-dependent insulinotropic polypeptide receptor, synaptophysin, sirtuin 1, glycogen synthase kinase 3β, superdioxide mutase 2, nuclear factor (erythroid-derived 2)-like 2 and vascular endothelial growth factor. Total plasma and brain GLP-1 concentrations were significantly increased after sitagliptin therapy, whereas DPP-4 activity in brain tissue was not altered. These studies show that sitagliptin can reverse memory impairment in high-fat-fed mice and is also associated with improved insulin sensitivity, enhanced hippocampal neurogenesis and reduced oxidative stress. DPP-4 inhibitors may therefore exhibit dual benefits by improving metabolic control and reducing the decline in cognitive function. © 2015 John Wiley & Sons Ltd.

Circulating Concentrations of Advanced Glycation end Products, its Association With the Development of Diabetes Mellitus.

PubMed

Jiménez, Itzel Uribe; Díaz-Díaz, Eulises; Castro, Jorge Salmerón; Ramos, Julia Pérez; León, Mario Cárdenas; Alvarado Ríos, José Antonio; Auriostigue Bautista, Juan Carlos; Correa-Rotter, Ricardo; Aguilar Salinas, Carlos Alberto; Larrea, Fernando

2017-05-01

Diabetes Mellitus (DM) is characterized by the production and accumulation of advanced glycation end products (AGEs), which are one of the key mechanisms in the development of its chronic complications. To assess the serum AGEs concentration by a radioimmunoassay (RIA) developed in our laboratory, to establish reference values in healthy population and to evaluate the diagnostic potential of measuring longitudinal changes in circulating AGEs concentrations to predict the development of DM. Clinical and metabolic parameters were obtained from a cohort of 781 Mexican people, initially and then seven years later. AGEs were quantified by a specific RIA. Associations of the changes in circulating levels of AGEs with the appearance of impaired fasting glucose (IFG), and the development of DM were evaluated. Diabetic subjects had higher circulating levels of AGEs than normoglycemic subjects or individuals with IFG in both samples studied (471 vs. 246 and 342 μU/mL, p <0.001; and 912 vs. 428 and 519 μU/mL, p <0.001; respectively). A multinomial logistic regression analysis showed that subjects who had AGEs concentration ≥400 μU/mL in the baseline sample had a relative risk ratio of 1.98 to develop IFG seven years later (p = 0.003). While the subjects who had AGEs concentration ≥450 μU/mL in the baseline sample had a relative risk ratio of 10.7 to develop DM seven years later (p <0.001). Circulating AGEs concentration is a good early marker to predict risk of developing DM. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

Role of Substance P in the Regulation of Glucose Metabolism via Insulin Signaling-Associated Pathways

PubMed Central

Bakirtzi, Kyriaki; Kokkotou, Efi; Stavrakis, Dimitris; Margolis, Kara Gross; Thomou, Thomas; Giorgadze, Nino; Kirkland, James L.

2011-01-01

Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. Here we assessed the effects of SP on weight gain in response to HFD and determined glucose metabolism in Tac1-deficient (Tac1−/−) mice. The effect of SP on the expression of molecules that may predispose to reduced glucose uptake was also determined in isolated human mesenteric, omental, and sc preadipocytes. We show that although weight accumulation in response to HFD was similar between Tac1−/− mice and wild-type littermates, Tac1−/− mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase Cθ, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. Preincubation of human mesenteric preadipocytes with the protein kinase Cθ pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. Lastly, SP also induced insulin receptor substrate-1 phosphorylation in mature human sc adipocytes. Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes. PMID:22009727

Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways.

PubMed

Karagiannides, Iordanes; Bakirtzi, Kyriaki; Kokkotou, Efi; Stavrakis, Dimitris; Margolis, Kara Gross; Thomou, Thomas; Giorgadze, Nino; Kirkland, James L; Pothoulakis, Charalabos

2011-12-01

Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. Here we assessed the effects of SP on weight gain in response to HFD and determined glucose metabolism in Tac1-deficient (Tac1(-/-)) mice. The effect of SP on the expression of molecules that may predispose to reduced glucose uptake was also determined in isolated human mesenteric, omental, and sc preadipocytes. We show that although weight accumulation in response to HFD was similar between Tac1(-/-) mice and wild-type littermates, Tac1(-/-) mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase C, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. Preincubation of human mesenteric preadipocytes with the protein kinase C pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. Lastly, SP also induced insulin receptor substrate-1 phosphorylation in mature human sc adipocytes. Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.

Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults.

PubMed

Mukamal, Kenneth J; Wilk, Jemma B; Biggs, Mary L; Jensen, Majken K; Ix, Joachim H; Kizer, Jorge R; Tracy, Russell P; Zieman, Susan J; Mozaffarian, Dariush; Psaty, Bruce M; Siscovick, David S; Djoussé, Luc

2013-11-01

We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p ≤ 0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p = 0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency = 16 %; p = 0.001) and African Americans (frequency = 8 %; p = 0.04). The haplotype combined a SNP in the first intron with one in the 3'untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.

Association of Circulating C1q/TNF-Related Protein 1 Levels with Coronary Artery Disease in Men

PubMed Central

Yuasa, Daisuke; Ohashi, Koji; Shibata, Rei; Takeshita, Kyosuke; Kikuchi, Ryosuke; Takahashi, Ryotaro; Kataoka, Yoshiyuki; Miyabe, Megumi; Joki, Yusuke; Kambara, Takahiro; Uemura, Yusuke; Matsuo, Kazuhiro; Hayakawa, Satoko; Hiramatsu-Ito, Mizuho; Ito, Masanori; Ikeda, Nobuo; Murohara, Toyoaki; Ouchi, Noriyuki

2014-01-01

Objective Obesity is a major risk factor for cardiovascular disease. Recent evidence demonstrates that dysregulation of fat-derived hormones, also known as adipokines, is linked with the pathogenesis of obesity-related disorders including coronary artery disease (CAD). Here, we investigated whether circulating level of an adipokine C1q/TNF-related protein (CTRP) 1 is associated with the prevalence of CAD. Methods and Results Consecutive 76 male CAD patients were enrolled from inpatients that underwent coronary angiography. Sixty four healthy male subjects served as controls. Plasma CTRP1 concentration was determined by enzyme-linked immunosorbent assay. CTRP1 levels were correlated positively with systolic blood pressure (BP) and triglyceride levels, and negatively with HDL cholesterol levels in all subjects. Plasma levels of CTRP1 were significantly higher in CAD patients than in control subjects (CAD: 443.3±18.6 ng/ml, control: 307.8±21.5 ng/ml, p<0.001). Multiple logistic regression analysis with body mass index, systolic BP, glucose, total cholesterol, HDL cholesterol, triglyceride, adiponectin and CTRP1 revealed that CTRP1 levels, together with systolic BP and HDL cholesterol, correlated with CAD. Conclusions Our data indicate the close association of high CTRP1 levels with CAD prevalence, suggesting that CTRP1 represents a novel biomarker for CAD. PMID:24945145

Inhibition of Intestinal Bile Acid Transporter Slc10a2 Improves Triglyceride Metabolism and Normalizes Elevated Plasma Glucose Levels in Mice

PubMed Central

Snaith, Michael; Lindmark, Helena; Lundberg, Johanna; Östlund-Lindqvist, Ann-Margret; Angelin, Bo; Rudling, Mats

2012-01-01

Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2) and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c). Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF) 15 mRNA and normalized bile acid synthesis in Slc10a2−/− mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2 - Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes. PMID:22662222

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

PubMed

Strawbridge, Rona J; Dupuis, Josée; Prokopenko, Inga; Barker, Adam; Ahlqvist, Emma; Rybin, Denis; Petrie, John R; Travers, Mary E; Bouatia-Naji, Nabila; Dimas, Antigone S; Nica, Alexandra; Wheeler, Eleanor; Chen, Han; Voight, Benjamin F; Taneera, Jalal; Kanoni, Stavroula; Peden, John F; Turrini, Fabiola; Gustafsson, Stefan; Zabena, Carina; Almgren, Peter; Barker, David J P; Barnes, Daniel; Dennison, Elaine M; Eriksson, Johan G; Eriksson, Per; Eury, Elodie; Folkersen, Lasse; Fox, Caroline S; Frayling, Timothy M; Goel, Anuj; Gu, Harvest F; Horikoshi, Momoko; Isomaa, Bo; Jackson, Anne U; Jameson, Karen A; Kajantie, Eero; Kerr-Conte, Julie; Kuulasmaa, Teemu; Kuusisto, Johanna; Loos, Ruth J F; Luan, Jian'an; Makrilakis, Konstantinos; Manning, Alisa K; Martínez-Larrad, María Teresa; Narisu, Narisu; Nastase Mannila, Maria; Ohrvik, John; Osmond, Clive; Pascoe, Laura; Payne, Felicity; Sayer, Avan A; Sennblad, Bengt; Silveira, Angela; Stancáková, Alena; Stirrups, Kathy; Swift, Amy J; Syvänen, Ann-Christine; Tuomi, Tiinamaija; van 't Hooft, Ferdinand M; Walker, Mark; Weedon, Michael N; Xie, Weijia; Zethelius, Björn; Ongen, Halit; Mälarstig, Anders; Hopewell, Jemma C; Saleheen, Danish; Chambers, John; Parish, Sarah; Danesh, John; Kooner, Jaspal; Ostenson, Claes-Göran; Lind, Lars; Cooper, Cyrus C; Serrano-Ríos, Manuel; Ferrannini, Ele; Forsen, Tom J; Clarke, Robert; Franzosi, Maria Grazia; Seedorf, Udo; Watkins, Hugh; Froguel, Philippe; Johnson, Paul; Deloukas, Panos; Collins, Francis S; Laakso, Markku; Dermitzakis, Emmanouil T; Boehnke, Michael; McCarthy, Mark I; Wareham, Nicholas J; Groop, Leif; Pattou, François; Gloyn, Anna L; Dedoussis, George V; Lyssenko, Valeriya; Meigs, James B; Barroso, Inês; Watanabe, Richard M; Ingelsson, Erik; Langenberg, Claudia; Hamsten, Anders; Florez, Jose C

2011-10-01

Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency☆ab

PubMed Central

Mokadem, Mohamad; Zechner, Juliet F.; Margolskee, Robert F.; Drucker, Daniel J.; Aguirre, Vincent

2013-01-01

Glucagon-like peptide-1 (GLP-1) secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB). While intact GLP-1exerts its metabolic effects via the classical GLP-1 receptor (GLP-1R), proteolytic processing of circulating GLP-1 yields metabolites such as GLP-1(9–36)amide/GLP-1(28–36)amide, that exert similar effects independent of the classical GLP-1R. We investigated the hypothesis that GLP-1, acting via these metabolites or through its known receptor, is required for the beneficial effects of RYGB using two models of functional GLP-1 deficiency – α-gustducin-deficient (α-Gust−/−) mice, which exhibit attenuated nutrient-stimulated GLP-1 secretion, and GLP-1R-deficient mice. We show that the effect of RYGB to enhance glucose-stimulated GLP-1 secretion was greatly attenuated in α-Gust−/− mice. In both genetic models, RYGB reduced body weight and improved glucose homeostasis to levels observed in lean control mice. Therefore, GLP-1, acting through its classical GLP-1R or its bioactive metabolites, does not seem to be involved in the effects of RYGB on body weight and glucose homeostasis. PMID:24634822

Normal postprandial nonesterified fatty acid uptake in muscles despite increased circulating fatty acids in type 2 diabetes.

PubMed

Labbé, Sébastien M; Croteau, Etienne; Grenier-Larouche, Thomas; Frisch, Frédérique; Ouellet, René; Langlois, Réjean; Guérin, Brigitte; Turcotte, Eric E; Carpentier, André C

2011-02-01

Postprandial plasma nonesterified fatty acid (NEFA) appearance is increased in type 2 diabetes. Our objective was to determine whether skeletal muscle uptake of plasma NEFA is abnormal during the postprandial state in type 2 diabetes. Thigh muscle blood flow and oxidative metabolism indexes and NEFA uptake were determined using positron emission tomography coupled with computed tomography (PET/CT) with [(11)C]acetate and 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)FTHA) in seven healthy control subjects (CON) and seven subjects with type 2 diabetes during continuous oral intake of a liquid meal to achieve steady postprandial NEFA levels with insulin infusion to maintain similar plasma glucose levels in both groups. In the postprandial state, plasma NEFA level was higher in type 2 diabetic subjects versus CON (P < 0.01), whereas plasma glucose was at the same level in both groups. Muscle NEFA fractional extraction and blood flow index levels were 56% (P < 0.05) and 24% (P = 0.27) lower in type 2 diabetes, respectively. However, muscle NEFA uptake was similar to that of CON (quadriceps femoris [QF] 1.47 ± 0.23 vs. 1.37 ± 0.24 nmol·g(-1)·min(-1), P = 0.77; biceps femoris [BF] 1.54 ± 0.26 vs. 1.46 ± 0.28 nmol·g(-1)·min(-1), P = 0.85). Muscle oxidative metabolism was similar in both groups. Muscle NEFA fractional extraction and blood flow index were strongly and positively correlated (r = 0.79, P < 0.005). Postprandial muscle NEFA uptake is normal despite elevated systemic NEFA levels and acute normalization of plasma glucose in type 2 diabetes. Lower postprandial muscle blood flow with resulting reduction in muscle NEFA fractional extraction may explain this phenomenon.

Abnormal Glucose Metabolism and High-Energy Expenditure in Idiopathic Pulmonary Arterial Hypertension

PubMed Central

Malin, Steven K.; Barnes, Jarrod W.; Tian, Liping; Kirwan, John P.; Dweik, Raed A.

2017-01-01

Rationale: Insulin resistance has emerged as a potential mechanism related to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). However, direct measurements of insulin and glucose metabolism have not been performed in patients with IPAH to date. Objectives: To perform comprehensive metabolic phenotyping of humans with IPAH. Methods: We assessed plasma insulin and glucose, using an oral glucose tolerance test and estimated insulin resistance, and β-cell function in 14 patients with IPAH and 14 control subjects matched for age, sex, blood pressure, and body mass index. Body composition (dual-energy X-ray absorptiometry), inflammation (CXC chemokine ligand 10, endothelin-1), physical fitness (6-min walk test), and energy expenditure (indirect calorimetry) were also assessed. Measurements and Main Results: Patients with IPAH had a higher rate of impaired glucose tolerance (57 vs. 14%; P < 0.05) and reduced glucose-stimulated insulin secretion compared with matched control subjects (IPAH: 1.31 ± 0.76 μU/ml⋅mg/dl vs. control subjects: 2.21 ± 1.27 μU/ml⋅mg/dl; P < 0.05). Pancreatic β-cell function was associated with circulating endothelin-1 (r = –0.71, P < 0.01) and CXC chemokine ligand 10 (r = –0.56, P < 0.05). Resting energy expenditure was elevated in IPAH (IPAH: 32 ± 3.4 vs. control subjects: 28.8 ± 2.9 kcal/d/kg fat-free mass; P < 0.05) and correlated with the plasma glucose response (r = 0.51, P < 0.01). Greater insulin resistance was associated with reduced 6-minute walk distance (r = 0.55, P < 0.05). Conclusions: Independent of age, sex, blood pressure, and body mass index, patients with IPAH have glucose intolerance, decreased insulin secretion in response to glucose, and elevated resting energy expenditure. These abnormalities are associated with circulating markers of inflammation and vascular dysfunction. PMID:27922752

Associations of circulating calcium and 25-hydroxyvitamin D with glucose metabolism in pregnancy: a cross-sectional study in European and South Asian women.

PubMed

Whitelaw, Donald C; Scally, Andrew J; Tuffnell, Derek J; Davies, T Jeffrey; Fraser, William D; Bhopal, Raj S; Wright, John; Lawlor, Debbie A

2014-03-01

Vitamin D deficiency is thought to impair insulin action and glucose metabolism; however, previous studies have not examined ethnic differences or the influence of calcium and parathyroid hormone. We investigated this in a cohort of predominantly white European and south Asian women during pregnancy. In this cross-sectional study from an urban population in northern England (53.8°N), 1467 women were recruited when undergoing glucose tolerance testing (75 g oral glucose tolerance test) at 26 weeks' gestation. Gestational diabetes mellitus (GDM) was diagnosed in 137 women (9.3%). Median 25-hydroxyvitamin D concentration for the study population was 9.3 ng/mL (interquartile range 5.2, 16.9) and was higher in European [15.2 ng/mL (10.7, 23.5)] than in south Asian women [5.9 ng/mL (3.9, 9.4), P < .001]. After appropriate adjustment for confounders, 25-hydroxyvitamin D showed a weak inverse association with fasting plasma glucose (FPG; mean difference 1.0% per 1 SD; the ratio of geometric means (RGM) 0.99, 95% confidence interval (CI) 0.98, 1.00), and PTH was weakly associated with FPG (RGM 1.01, 95% CI 1.00, 1.02), but neither was associated with fasting insulin, postchallenge glucose, or GDM. Serum calcium (albumin adjusted) was strongly associated with fasting insulin (RGM 1.06; 95% CI 1.03, 1.08), postchallenge glucose (RGM 1.03, 95% CI 1.01, 1.04), and GDM (odds ratio 1.33, 95% CI 1.06, 1.66) but not with FPG. Associations were similar in European and south Asian women. These findings do not indicate any important association between vitamin D status and glucose tolerance in pregnancy. Relationships between circulating calcium and glucose metabolism warrant further investigation.

Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis

PubMed Central

Aryal, Binod; Singh, Abhishek K.; Zhang, Xinbo; Varela, Luis; Goedeke, Leigh; Chaube, Balkrishna; Camporez, Joao-Paulo; Vatner, Daniel F.; Horvath, Tamas L.; Suárez, Yajaira; Fernández-Hernando, Carlos

2018-01-01

Alterations in ectopic lipid deposition and circulating lipids are major risk factors for developing cardiometabolic diseases. Angiopoietin-like protein 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL), controls fatty acid (FA) uptake in adipose and oxidative tissues and regulates circulating triacylglycerol-rich (TAG-rich) lipoproteins. Unfortunately, global depletion of ANGPTL4 results in severe metabolic abnormalities, inflammation, and fibrosis when mice are fed a high-fat diet (HFD), limiting our understanding of the contribution of ANGPTL4 in metabolic disorders. Here, we demonstrate that genetic ablation of ANGPTL4 in adipose tissue (AT) results in enhanced LPL activity, rapid clearance of circulating TAGs, increased AT lipolysis and FA oxidation, and decreased FA synthesis in AT. Most importantly, we found that absence of ANGPTL4 in AT prevents excessive ectopic lipid deposition in the liver and muscle, reducing novel PKC (nPKC) membrane translocation and enhancing insulin signaling. As a result, we observed a remarkable improvement in glucose tolerance in short-term HFD-fed AT-specific Angptl4-KO mice. Finally, lack of ANGPTL4 in AT enhances the clearance of proatherogenic lipoproteins, attenuates inflammation, and reduces atherosclerosis. Together, these findings uncovered an essential role of AT ANGPTL4 in regulating peripheral lipid deposition, influencing whole-body lipid and glucose metabolism and the progression of atherosclerosis. PMID:29563332

Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study.

PubMed

Ahmed, Fahad W; Rider, Rachel; Glanville, Michael; Narayanan, Kilimangalam; Razvi, Salman; Weaver, Jolanta U

2016-08-26

Type 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control. This study was an open label and parallel standard treatment study. Twenty-three type 1 diabetes patients without overt CVD were treated with metformin for 8 weeks (treatment group-TG). They were matched with nine type 1 diabetes patients on standard treatment (SG) and 23 age- and sex-matched healthy volunteers (HC). Insulin dose was adjusted to keep unchanged glycaemic control. cEPCs and cECs counts were determined by flow cytometry using surface markers CD45(dim)CD34(+)VEGFR-2(+) and CD45(dim)CD133(-)CD34(+)CD144(+) respectively. Peripheral blood mononuclear cells were cultured to assess changes in PACs number, function and colony forming units (CFU-Hill's colonies). At baseline TG had lower cEPCs, PACs, CFU-Hills' colonies and PACs adhesion versus HC (p < 0.001-all variables) and higher cECs versus HC (p = 0.03). Metformin improved cEPCs, PACs, CFU-Hill's colonies number, cECs and PACs adhesion (p < 0.05-all variables) to levels seen in HC whilst HbA1c (one-way ANOVA p = 0.78) and glucose variability (average glucose, blood glucose standard deviation, mean amplitude of glycaemic excursion, continuous overall net glycaemic action and area under curve) remained unchanged. No changes were seen in any variables in SG. There was an inverse correlation between CFU-Hill's colonies with cECs. Metformin has potential cardio-protective effect through improving cEPCs, CFU-Hill's colonies, cECs, PACs count and function independently of hypoglycaemic effect. This finding needs to be confirmed by long term cardiovascular outcome studies in type 1 diabetes. Trial registration ISRCTN26092132.

Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

PubMed

Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

2016-05-01

GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1.

Differential effects of somatostatin on circulating tissue factor procoagulant activity and protein.

PubMed

Boden, Guenther; Vaidyula, Vijender; Homko, Carol; Mozzoli, Maria; Rao, A Koneti

2007-05-01

The tissue factor (TF) pathway is the primary mechanism for initiation of blood coagulation. Circulating blood contains TF, which originates mainly from monocytes and is thrombogenic. The presence of somatostatin (SMS) receptors on monocytes suggests the possibility that SMS may regulate TF synthesis and/or release. Circulating TF procoagulant activity (TF-PCA), factor VIIa activity (FVIIa; clotting assays), TF antigen (TF-Ag; ELISA), prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complexes (ELISAs), CD40 ligand expression on platelets, and monocyte-platelet aggregates (flow cytometry) were determined in blood from normal volunteers undergoing 24 h of basal glucose/basal insulin (BG/BI) clamps and high-glucose/high-insulin (HG/HI) clamps with and without SMS. Infusions of SMS under basal conditions (BG/BI) raised TF-PCA 1.8-fold (P < 0.03), TF-Ag 2.3-fold (P < 0.001), and TF expression on monocytes by 36% (P < 0.001) and decreased plasma levels of FVIIa by 30% (P < 0.001). Infusion of SMS reduced the 8.6-fold HG/HI-induced increase in TF-Ag by 26% and the 8.6-fold increase in TF-PCA by 100%. SMS also prevented the 60% increase in TF expression on monocytes, the 2.2-fold increase in F1.2, the 40% increase in CD40L expression on platelets, and the 17% increase in monocyte-platelet aggregates seen during HG/HI. We conclude that SMS completely prevented HG/HI-induced TF activation in normal volunteers and may be of use to reduce the procoagulant state and acute vascular events in hyperinsulinemic insulin-resistant patients with type 2 diabetes.

The role of vascular endothelial growth factor-B in metabolic homoeostasis: current evidence.

PubMed

Zafar, Mohammad Ishraq; Zheng, Juan; Kong, Wen; Ye, Xiaofeng; Gou, Luoning; Regmi, Anita; Chen, Lu-Lu

2017-08-31

It has been shown that adipose tissue and skeletal muscles in lean individuals respond to meal-induced hyperinsulinemia by increase in perfusion, the effect not observed in patients with metabolic syndrome. In conditions of hyperglycaemia and hypertriglyceridemia, this insufficient vascularization leads to the liberation of reactive oxygen species (ROS), and disruption of nitric oxide (NO) synthesis and endothelial signalling responsible for the uptake of circulating fatty acids (FAs), whose accumulation in skeletal muscles and adipose tissue is widely associated with the impairment of insulin signalling. While the angiogenic role of VEGF-A and its increased circulating concentrations in obesity have been widely confirmed, the data related to the metabolic role of VEGF-B are diverse. However, recent discoveries indicate that this growth factor may be a promising therapeutic agent in patients with metabolic syndrome. Preclinical studies agree over two crucial metabolic effects of VEGF-B: (i) regulation of FAs uptake and (ii) regulation of tissue perfusion via activation of VEGF-A/vascular endothelial growth factor receptor (VEGFR) 2 (VEGFR2) pathway. While in some preclinical high-fat diet studies, VEGF-B overexpression reverted glucose intolerance and stimulated fat burning, in others it further promoted accumulation of lipids and lipotoxicity. Data from clinical studies point out the changes in circulating or tissue expression levels of VEGF-B in obese compared with lean patients. Potentially beneficial effects of VEGF-B, achieved through enhanced blood flow (increased availability of insulin and glucose uptake in target organs) and decreased FAs uptake (prevention of lipotoxicity and improved insulin signalling), and its safety for clinical use, remain to be clarified through future translational research. © 2017 The Author(s).

The metabolites in peripheral blood mononuclear cells showed greater differences between patients with impaired fasting glucose or type 2 diabetes and healthy controls than those in plasma.

PubMed

Kim, Minjoo; Kim, Minkyung; Han, Ji Yun; Lee, Sang-Hyun; Jee, Sun Ha; Lee, Jong Ho

2017-03-01

To determine differences between peripheral blood mononuclear cells and the plasma metabolites in patients with impaired fasting glucose or type 2 diabetes and healthy controls. In all, 65 nononobese patients (aged 30-70 years) with impaired fasting glucose or type 2 diabetes and 65 nonobese sex-matched healthy controls were included, and fasting peripheral blood mononuclear cell and plasma metabolomes were profiled. The diabetic or impaired fasting glucose patients showed higher circulating and peripheral blood mononuclear cell lipoprotein phospholipase A 2 activities, high-sensitivity C-reactive protein and tumour necrosis factor-α than controls. Compared with controls, impaired fasting glucose or diabetic subjects showed increases in 11 peripheral blood mononuclear cell metabolites: six amino acids (valine, leucine, methionine, phenylalanine, tyrosine and tryptophan), l-pyroglutamic acid, two fatty acid amides containing palmitic amide and oleamide and two lysophosphatidylcholines. In impaired fasting glucose or diabetic patients, peripheral blood mononuclear cell lipoprotein phospholipase A 2 positively associated with peripheral blood mononuclear cell lysophosphatidylcholines and circulating inflammatory markers, including tumour necrosis factor-α, high-sensitivity C-reactive protein and lipoprotein phospholipase A 2 activities. In plasma metabolites between patients and healthy controls, we observed significant increases in only three amino acids (proline, valine and leucine) and decreases in only five lysophosphatidylcholines. This study demonstrates significant differences in the peripheral blood mononuclear cell metabolome in patients with impaired fasting glucose or diabetes compared with healthy controls. These differences were greater than those observed in the plasma metabolome. These data suggest peripheral blood mononuclear cells as a useful tool to better understand the inflammatory pathophysiology of diabetes.

Ursolic Acid Increases Glucose Uptake through the PI3K Signaling Pathway in Adipocytes

PubMed Central

He, Yonghan; Li, Wen; Li, Ying; Zhang, Shuocheng; Wang, Yanwen; Sun, Changhao

2014-01-01

Background Ursolic acid (UA), a triterpenoid compound, is reported to have a glucose-lowering effect. However, the mechanisms are not fully understood. Adipose tissue is one of peripheral tissues that collectively control the circulating glucose levels. Objective The objective of the present study was to determine the effect and further the mechanism of action of UA in adipocytes. Methods and Results The 3T3-L1 preadipocytes were induced to differentiate and treated with different concentrations of UA. NBD-fluorescent glucose was used as the tracer to measure glucose uptake and Western blotting used to determine the expression and activity of proteins involved in glucose transport. It was found that 2.5, 5 and 10 µM of UA promoted glucose uptake in a dose-dependent manner (17%, 29% and 35%, respectively). 10 µM UA-induced glucose uptake with insulin stimulation was completely blocked by the phosphatidylinositol (PI) 3-kinase (PI3K) inhibitor wortmannin (1 µM), but not by SB203580 (10 µM), the inhibitor of mitogen-activated protein kinase (MAPK), or compound C (2.5 µM), the inhibitor of AMP-activated kinase (AMPK) inhibitor. Furthmore, the downstream protein activities of the PI3K pathway, phosphoinositide-dependent kinase (PDK) and phosphoinositide-dependent serine/threoninekinase (AKT) were increased by 10 µM of UA in the presence of insulin. Interestingly, the activity of AS160 and protein kinase C (PKC) and the expression of glucose transporter 4 (GLUT4) were stimulated by 10 µM of UA under either the basal or insulin-stimulated status. Moreover, the translocation of GLUT4 from cytoplasm to cell membrane was increased by UA but decreased when the PI3K inhibitor was applied. Conclusions Our results suggest that UA stimulates glucose uptake in 3T3-L1 adipocytes through the PI3K pathway, providing important information regarding the mechanism of action of UA for its anti-diabetic effect. PMID:25329874

Artemisia Extract Improves Insulin Sensitivity in Women With Gestational Diabetes Mellitus by Up-Regulating Adiponectin.

PubMed

Sun, Xia; Sun, Hong; Zhang, Jing; Ji, Xianghong

2016-12-01

Gestational diabetes mellitus (GDM) has affected a great number of pregnant women worldwide. Artemisia extracts have been found to exhibit a potent antidiabetic effect in the treatment of type 2 diabetes mellitus. We aimed to examine the effects of Artemisia extract on insulin resistance and lipid profiles in pregnant GDM patients. Patients in their second trimester were randomly assigned to the Artemisia extract group (AE) or to a placebo group (PO). They were instructed to consume either AE or PO daily for a period of 10 weeks. Glucose and insulin profiles and adiponectin level were assessed at baseline (week 0) and after the treatment (week 10). Compared to the PO group, fasting plasma glucose, serum insulin levels, homeostasis model of assessment of insulin resistance (HOMA-IR), and β-cell function (HOMA-B) were significantly reduced in the AE group participants. Moreover, levels of circulating adiponectin were also significantly up-regulated in the AE group, which also positively contributed to improved insulin sensitivity. Daily administration of Artemisia extract improves insulin sensitivity by up-regulating adiponectin in women with gestational diabetes mellitus. © 2016, The American College of Clinical Pharmacology.

Implication of Progranulin and C1q/TNF-Related Protein-3 (CTRP3) on Inflammation and Atherosclerosis in Subjects with or without Metabolic Syndrome

PubMed Central

Yoo, Hye Jin; Hwang, Soon Young; Hong, Ho Cheol; Choi, Hae Yoon; Yang, Sae Jeong; Choi, Dong Seop; Baik, Sei Hyun; Blüher, Matthias

2013-01-01

Objective Progranulin and C1q/TNF-related protein-3 (CTRP3) were recently discovered as novel adipokines which may link obesity with altered regulation of glucose metabolism, chronic inflammation and insulin resistance. Research Design and Methods We examined circulating progranulin and CTRP3 concentrations in 127 subjects with (n = 44) or without metabolic syndrome (n = 83). Furthermore, we evaluated the relationship of progranulin and CTRP3 levels with inflammatory markers and cardiometabolic risk factors, including high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), estimated glomerular filtration rate (eGFR), and adiponectin serum concentrations, as well as carotid intima-media thickness (CIMT). Results Circulating progranulin levels are significantly related with inflammatory markers, hsCRP (r = 0.30, P = 0.001) and IL-6 (r = 0.30, P = 0.001), whereas CTRP3 concentrations exhibit a significant association with cardiometabolic risk factors, including waist circumference (r = −0.21), diastolic blood pressure (r = −0.21), fasting glucose (r = −0.20), triglyceride (r = −0.34), total cholesterol (r = −0.25), eGFR (r = 0.39) and adiponectin (r = 0.26) levels. Serum progranulin concentrations were higher in patients with metabolic syndrome than those of the control group (199.55 [179.33, 215.53] vs. 185.10 [160.30, 204.90], P = 0.051) and the number of metabolic syndrome components had a significant positive correlation with progranulin levels (r = 0.227, P = 0.010). In multiple regression analysis, IL-6 and triglyceride levels were significant predictors of serum progranulin levels (R 2 = 0.251). Furthermore, serum progranulin level was an independent predictor for increased CIMT in subjects without metabolic syndrome after adjusting for other cardiovascular risk factors (R 2 = 0.365). Conclusions Serum progranulin levels are significantly associated with systemic inflammatory markers and were an independent predictor for atherosclerosis in subjects without metabolic syndrome. Trial Registration ClinicalTrials.gov NCT01668888 PMID:23409033

Implication of progranulin and C1q/TNF-related protein-3 (CTRP3) on inflammation and atherosclerosis in subjects with or without metabolic syndrome.

PubMed

Yoo, Hye Jin; Hwang, Soon Young; Hong, Ho Cheol; Choi, Hae Yoon; Yang, Sae Jeong; Choi, Dong Seop; Baik, Sei Hyun; Blüher, Matthias; Youn, Byung-Soo; Choi, Kyung Mook

2013-01-01

Progranulin and C1q/TNF-related protein-3 (CTRP3) were recently discovered as novel adipokines which may link obesity with altered regulation of glucose metabolism, chronic inflammation and insulin resistance. We examined circulating progranulin and CTRP3 concentrations in 127 subjects with (n = 44) or without metabolic syndrome (n = 83). Furthermore, we evaluated the relationship of progranulin and CTRP3 levels with inflammatory markers and cardiometabolic risk factors, including high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), estimated glomerular filtration rate (eGFR), and adiponectin serum concentrations, as well as carotid intima-media thickness (CIMT). Circulating progranulin levels are significantly related with inflammatory markers, hsCRP (r = 0.30, P = 0.001) and IL-6 (r = 0.30, P = 0.001), whereas CTRP3 concentrations exhibit a significant association with cardiometabolic risk factors, including waist circumference (r = -0.21), diastolic blood pressure (r = -0.21), fasting glucose (r = -0.20), triglyceride (r = -0.34), total cholesterol (r = -0.25), eGFR (r = 0.39) and adiponectin (r = 0.26) levels. Serum progranulin concentrations were higher in patients with metabolic syndrome than those of the control group (199.55 [179.33, 215.53] vs. 185.10 [160.30, 204.90], P = 0.051) and the number of metabolic syndrome components had a significant positive correlation with progranulin levels (r = 0.227, P = 0.010). In multiple regression analysis, IL-6 and triglyceride levels were significant predictors of serum progranulin levels (R(2) = 0.251). Furthermore, serum progranulin level was an independent predictor for increased CIMT in subjects without metabolic syndrome after adjusting for other cardiovascular risk factors (R(2) = 0.365). Serum progranulin levels are significantly associated with systemic inflammatory markers and were an independent predictor for atherosclerosis in subjects without metabolic syndrome. ClinicalTrials.gov NCT01668888.

The important role of sleep in metabolism.

PubMed

Copinschi, Georges; Leproult, Rachel; Spiegel, Karine

2014-01-01

Both reduction in total sleep duration with slow-wave sleep (SWS) largely preserved and alterations of sleep quality (especially marked reduction of SWS) with preservation of total sleep duration are associated with insulin resistance without compensatory increase in insulin secretion, resulting in impaired glucose tolerance and increased risk of type 2 diabetes. When performed under rigorously controlled conditions of energy intake and physical activity, sleep restriction is also associated with a decrease in circulating levels of leptin (an anorexigenic hormone) and an increase in circulating levels of ghrelin (an orexigenic hormone), hunger and appetite. Furthermore, sleep restriction is also associated with a stimulation of brain regions sensitive to food stimuli, indicating that sleep loss may lead to obesity through the selection of high-calorie food. There is also evidence that sleep restriction could provide a permissive environment for the activation of genes that promote obesity. Indeed, the heritability of body mass index is increased in short sleepers. Thus, chronic sleep curtailment, which is on the rise in modern society, including in children, is likely to contribute to the current epidemics of type 2 diabetes and obesity. © 2014 S. Karger AG, Basel.

The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation.

PubMed Central

Stein, D T; Stevenson, B E; Chester, M W; Basit, M; Daniels, M B; Turley, S D; McGarry, J D

1997-01-01

Lowering of the elevated plasma FFA concentration in 18- 24-h fasted rats with nicotinic acid (NA) caused complete ablation of subsequent glucose-stimulated insulin secretion (GSIS). Although the effect of NA was reversed when the fasting level of total FFA was maintained by coinfusion of soybean oil or lard oil (plus heparin), the more saturated animal fat proved to be far more potent in enhancing GSIS. We therefore examined the influence of individual fatty acids on insulin secretion in the perfused rat pancreas. When present in the perfusion fluid at 0.5 mM (in the context of 1% albumin), the fold stimulation of insulin release from the fasted pancreas in response to 12.5 mM glucose was as follows: octanoate (C8:0), 3.4; linoleate (C18:2 cis/cis), 5.3; oleate (C18:1 cis), 9.4; palmitate (C16:0), 16. 2; and stearate (C18:0), 21.0. The equivalent value for palmitoleate (C16:1 cis) was 3.1. A cis--> trans switch of the double bond in the C16:1 and C18:1 fatty acids had only a modest, if any, impact on their potency. A similar profile emerged with regard to basal insulin secretion (3 mM glucose). When a subset of these fatty acids was tested in pancreases from fed animals, the same rank order of effectiveness at both basal and stimulatory levels of glucose was seen. The findings reaffirm the essentiality of an elevated plasma FFA concentration for GSIS in the fasted rat. They also show, however, that the insulinotropic effect of individual fatty acids spans a remarkably broad range, increasing and decreasing dramatically with chain length and degree of unsaturation, respectively. Thus, for any given level of glucose, insulin secretion will be influenced greatly not only by the combined concentration of all circulating (unbound) FFA, but also by the makeup of this FFA pool. Both factors will likely be important considerations in understanding the complex interplay between the nature of dietary fat and whole body insulin, glucose, and lipid dynamics. PMID:9218517

Short-term high-fat diet alters postprandial glucose metabolism and circulating vascular cell adhesion molecule-1 in healthy males.

PubMed

Numao, Shigeharu; Kawano, Hiroshi; Endo, Naoya; Yamada, Yuka; Takahashi, Masaki; Konishi, Masayuki; Sakamoto, Shizuo

2016-08-01

Short-term intake of a high-fat diet aggravates postprandial glucose metabolism; however, the dose-response relationship has not been investigated. We hypothesized that short-term intake of a eucaloric low-carbohydrate/high-fat diet (LCHF) would aggravate postprandial glucose metabolism and circulating adhesion molecules in healthy males. Seven healthy young males (mean ± SE; age: 26 ± 1 years) consumed either a eucaloric control diet (C, approximately 25% fats), a eucaloric intermediate-carbohydrate/intermediate-fat diet (ICIF, approximately 50% fats), or an LCHF (approximately 70% fats) for 3 days. An oral meal tolerance test (MTT) was performed after the 3-day dietary intervention. The concentrations of plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 (VCAM-1) were determined at rest and during MTT. The incremental area under the curve (iAUC) of plasma glucose concentration during MTT was significantly higher in LCHF than in C (P = 0.009). The first-phase insulin secretion indexes were significantly lower in LCHF than in C (P = 0.04). Moreover, the iAUC of GLP-1 and VCAM-1 concentrations was significantly higher in LCHF than in C (P = 0.014 and P = 0.04, respectively). The metabolites from ICIF and C were not significantly different. In conclusion, short-term intake of eucaloric diet containing a high percentage of fats in healthy males excessively increased postprandial glucose and VCAM-1 concentrations and attenuated first-phase insulin release.

Green tea extract with polyethylene glycol-3350 reduces body weight and improves glucose tolerance in db/db and high-fat diet mice.

PubMed

Park, Jae-Hyung; Choi, Yoon Jung; Kim, Yong Woon; Kim, Sang Pyo; Cho, Ho-Chan; Ahn, Shinbyoung; Bae, Ki-Cheor; Im, Seung-Soon; Bae, Jae-Hoon; Song, Dae-Kyu

2013-08-01

Green tea extract (GTE) is regarded to be effective against obesity and type 2 diabetes, but definitive evidences have not been proven. Based on the assumption that the gallated catechins (GCs) in GTE attenuate intestinal glucose and lipid absorption, while enhancing insulin resistance when GCs are present in the circulation through inhibiting cellular glucose uptake in various tissues, this study attempted to block the intestinal absorption of GCs and prolong their residence time in the lumen. We then observed whether GTE containing the nonabsorbable GCs could ameliorate body weight (BW) gain and glucose intolerance in db/db and high-fat diet mice. Inhibition of the intestinal absorption of GCs was accomplished by co-administering the nontoxic polymer polyethylene glycol-3350 (PEG). C57BLKS/J db/db and high-fat diet C57BL/6 mice were treated for 4 weeks with drugs as follows: GTE, PEG, GTE+PEG, voglibose, or pioglitazone. GTE mixed with meals did not have any ameliorating effects on BW gain and glucose intolerance. However, the administration of GTE plus PEG significantly reduced BW gain, insulin resistance, and glucose intolerance, without affecting food intake and appetite. The effect was comparable to the effects of an α-glucosidase inhibitor and a peroxisome proliferator-activated receptor-γ/α agonist. These results indicate that prolonging the action of GCs of GTE in the intestinal lumen and blocking their entry into the circulation may allow GTE to be used as a prevention and treatment for both obesity and obesity-induced type 2 diabetes.

Molecular aspects of glucose homeostasis in skeletal muscle--A focus on the molecular mechanisms of insulin resistance.

PubMed

Carnagarin, Revathy; Dharmarajan, Arun M; Dass, Crispin R

2015-12-05

Among all the varied actions of insulin, regulation of glucose homeostasis is the most critical and intensively studied. With the availability of glucose from nutrient metabolism, insulin action in muscle results in increased glucose disposal via uptake from the circulation and storage of excess, thereby maintaining euglycemia. This major action of insulin is executed by redistribution of the glucose transporter protein, GLUT4 from intracellular storage sites to the plasma membrane and storage of glucose in the form of glycogen which also involves modulation of actin dynamics that govern trafficking of all the signal proteins of insulin signal transduction. The cellular mechanisms responsible for these trafficking events and the defects associated with insulin resistance are largely enigmatic, and this review provides a consolidated overview of the various molecular mechanisms involved in insulin-dependent glucose homeostasis in skeletal muscle, as insulin resistance at this major peripheral site impacts whole body glucose homeostasis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Carbohydrates and insulin resistance in clinical nutrition: Recommendations from the ESPEN expert group.

PubMed

Barazzoni, R; Deutz, N E P; Biolo, G; Bischoff, S; Boirie, Y; Cederholm, T; Cuerda, C; Delzenne, N; Leon Sanz, M; Ljungqvist, O; Muscaritoli, M; Pichard, C; Preiser, J C; Sbraccia, P; Singer, P; Tappy, L; Thorens, B; Van Gossum, A; Vettor, R; Calder, P C

2017-04-01

Growing evidence underscores the important role of glycemic control in health and recovery from illness. Carbohydrate ingestion in the diet or administration in nutritional support is mandatory, but carbohydrate intake can adversely affect major body organs and tissues if resulting plasma glucose becomes too high, too low, or highly variable. Plasma glucose control is especially important for patients with conditions such as diabetes or metabolic stress resulting from critical illness or surgery. These patients are particularly in need of glycemic management to help lessen glycemic variability and its negative health consequences when nutritional support is administered. Here we report on recent findings and emerging trends in the field based on an ESPEN workshop held in Venice, Italy, 8-9 November 2015. Evidence was discussed on pathophysiology, clinical impact, and nutritional recommendations for carbohydrate utilization and management in nutritional support. The main conclusions were: a) excess glucose and fructose availability may exacerbate metabolic complications in skeletal muscle, adipose tissue, and liver and can result in negative clinical impact; b) low-glycemic index and high-fiber diets, including specialty products for nutritional support, may provide metabolic and clinical benefits in individuals with obesity, insulin resistance, and diabetes; c) in acute conditions such as surgery and critical illness, insulin resistance and elevated circulating glucose levels have a negative impact on patient outcomes and should be prevented through nutritional and/or pharmacological intervention. In such acute settings, efforts should be implemented towards defining optimal plasma glucose targets, avoiding excessive plasma glucose variability, and optimizing glucose control relative to nutritional support. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Leuprolide acetate-stimulated androgen response during female puberty.

PubMed

Hernandez, María Isabel; Martinez-Aguayo, Alejandro; Cavada, Gabriel; Avila, Alejandra; Iñiguez, German; Mericq, Veronica

2015-08-01

A physiological increase in androgen levels occurs during adolescence. Measuring androgen concentrations is the best method to distinguish normal evolution processes from hyperandrogenic disorders. The increase in circulating androgens during puberty is inversely associated with insulin sensitivity in normal weight girls. To assess circulating levels of ovarian androgens and anti-Müllerian hormone (AMH) at baseline and after GnRH analogue (GnRH-a) stimulation in normal pubertal girls across different Tanner stages. We also studied the association between this response and insulin sensitivity. Prospective study of healthy girls (6-12 years) from the local community (n = 63). Tanner I (n = 23) subjects were assessed cross-sectionally, and Tanner II girls (n = 40) were evaluated every 6 months until they reached Tanner V. Early morning dehydroepiandrosterone sulphate (DHEA-S), AMH, sex hormone-binding globulin (SHBG), androstenedione, glucose and insulin levels were measured. A GnRH-a test (500 μg/m(2) ; sc) and oral glucose intolerance test (OGTT) were performed. Differences throughout puberty were evaluated. Basal and/or stimulated Testosterone DHEA-S and 17-hydroxyprogesterone (17OHP) were inversely associated with insulin sensitivity (WIBSI) from the beginning of puberty, whereas androstenedione was directly associated with gonadotrophins. AMH was inversely associated with basal and stimulated gonadotrophins and directly with insulin area under the curve (AUC) only in the early stages of puberty. 17OHP and testosterone responsiveness increased significantly during puberty in all subjects, whereas testosterone levels changed less consistently. This pattern of ovarian-steroidogenic response was most evident during mid- and late puberty. Moreover, during late puberty only, basal 17OHP, testosterone and DHEA-S were positively associated with gonadotrophins. In normal nonobese girls born appropriate for gestational age, androgen synthesis was associated with insulin sensitivity in early puberty and with LH only in late puberty. © 2014 John Wiley & Sons Ltd.

Nuclear factor kappa B in patients with a history of unstable angina: case re-opened.

PubMed

Mozzini, Chiara; Garbin, Ulisse; Stranieri, Chiara; Salandini, Giulia; Pesce, Giancarlo; Fratta Pasini, Anna Maria; Cominacini, Luciano

2018-06-01

This study aims at assessing NF-kB activity in unstable angina (UA) patients free of symptoms after a 1 year follow-up (1YFU). Plasma oxidized low-density lipoproteins (oxLDL), circulating NF-kB, Interleukin 6 (IL-6) and Interleukin 1β (IL-1β), high-sensitivity C-reactive protein (hs-CRP), as markers of oxidative stress and inflammation and plasma double-stranded DNA (ds-DNA), as marker of Neutrophil Extracellular Traps (NETs), were measured in 23 of the previously enrolled 27 UA patients. These measurements were compared to the UA data at baseline, and then compared to the data derived from the stable angina (SA) and controls (C) enrolled in our previous study (we demonstrated that UA had higher levels of NF-kB compared to SA and C). After a 1YFU, UA patients show a significant decrease in NF-kB, IL-6, hs-CRP, oxLDL, and ds-DNA plasma levels (p < 0.001) and in IL-1β and White Blood Cells (WBC) (p < 0.005), without differences in lipid and glucose assessment. If compared to SA and C, UA after a 1YFU have higher levels of NF-kB, IL-6, ds-DNA, WBC, and oxLDL compared to C (p < 0.001), but only IL-6 is higher than SA (p < 0.001). No differences are found in lipid and glucose assessment. After a 1YFU, patients with a history of UA improve their oxidative and inflammatory status, such as the levels of circulating ds-DNA, without achieving the status of C. They become comparable to SA subjects. This study provides new insight on the multiple and apparently contradictory facets of NF-kB in UA and on its possible role as mediator in NETs' formation.

Combined Treatment with Amlodipine and Atorvastatin Calcium Reduces Circulating Levels of Intercellular Adhesion Molecule-1 and Tumor Necrosis Factor-α in Hypertensive Patients with Prediabetes.

PubMed

Huang, Zhouqing; Chen, Chen; Li, Sheng; Kong, Fanqi; Shan, Peiren; Huang, Weijian

2016-01-01

To assess the effect of amlodipine and atorvastatin on intercellular adhesion molecule (ICAM)-1 and tumor necrosis factor (TNF)-α expression, as endothelial function and inflammation indicators, respectively, in hypertensive patients with and without prediabetes. Forty-five consecutive patients with hypertension, diagnosed according to JNC7, were divided into two groups based on the presence (HD group, n = 23) or absence (H group, n = 22) of prediabetes, diagnosed according to 2010 ADA criteria, including impaired glucose tolerance (IGT) and fasting glucose tests. All patients simultaneously underwent 12-week treatment with daily single-pill amlodipine besylate/atorvastatin calcium combination (5/10 mg; Hisun-Pfizer Pharmaceuticals Co. Ltd). Serum isolated before and after treatment from overnight fasting blood samples was analyzed by ELISA. In the HD and H groups after vs. before 12-week amlodipine/atorvastatin treatment, there were significantly (all P < 0.01) lower levels of ICAM-1 (3.06 ± 0.34 vs. 4.07 ± 0.70 pg/ml; 3.26 ± 0.32 vs. 3.81 ± 0.60 pg/ml, respectively) and TNF-α (78.71 ± 9.19 vs. 110.94 ± 10.71 pg/ml; 80.95 ± 9.33 vs. 101.79 ± 11.72 pg/ml, respectively), with more pronounced reductions in HD vs. H group (ICAM-1Δ: 1.01 ± 0.80 vs. 0.55 ± 0.64 pg/ml, respectively, P = 0.037; TNF-αΔ: 32.23 ± 14.33 vs. 20.84 ± 14.89 pg/ml, respectively, P = 0.011), independent of the blood pressure (BP) and cholesterol level reduction. Amlodipine/atorvastatin improved endothelial function and inflammation, as reflected by lower circulating levels of ICAM-1 and TNF-α, more prominently in hypertensives with than without prediabetes. Starting statin treatment before overt diabetes in hypertensives might thus improve cardiovascular outcomes.

The effect of insulin upon the influx of tryptophan into the brain of the rabbit.

PubMed

Daniel, P M; Love, E R; Moorhouse, S R; Pratt, O E

1981-03-01

1. The effect of hyperinsulinaemia upon the influx of tryptophan into the brain was determined. A raised level of insulin was maintained in the circulation of rabbits for periods of up to 120 min by means of a continuous, programmed intravenous injection of the hormone, given by an electronically controlled variable-drive syringe. A similar, appropriately programmed, intravenous injection of glucose, given simultaneously with the insulin, maintained the concentration of the blood glucose within normal limits throughout each experiment, so that the results were not vitiated by the development of hypoglycaemia. 2. Raised levels of insulin in the blood affect the supply of tryptophan to the brain in two opposing ways: (a) by increasing the binding of tryptophan to the albumin in the blood, thereby reducing the level of the free tryptophan in the circulation by about a half, which would decrease the influx of tryptophan into the brain; (b) by simultaneously reducing the levels in the blood of six or more of the amino acids which compete with tryptophan for transport carriers into the brain, which would increase the influx of tryptophan. The net result of these two opposing effects is that insulin causes only a slight increase in the influx of tryptophan into the brain. 3. To account in quantitative terms for the effect of insulin upon the influx of tryptophan into the brain it proved necessary to make one assumption. This assumption was that a predictable proportion of the tryptophan which is loosely bound to blood albumin is being stripped off this protein by the transport carrier located on the luminal surface membranes of the endothelial cells during the passage of the blood through the cerebral capillaries. If this assumption is accepted the work reported here explains adequately the effect of insulin on the influx of tryptophan into the brain.

Serum Levels of the Adipokine Progranulin Depend on Renal Function

PubMed Central

Richter, Judit; Focke, Denise; Ebert, Thomas; Kovacs, Peter; Bachmann, Anette; Lössner, Ulrike; Kralisch, Susan; Kratzsch, Jürgen; Beige, Joachim; Anders, Matthias; Bast, Ingolf; Blüher, Matthias; Stumvoll, Michael; Fasshauer, Mathias

2013-01-01

OBJECTIVE Progranulin has recently been introduced as a novel adipokine inducing insulin resistance and obesity. In the current study, we investigated renal elimination, as well as association of the adipokine with markers of the metabolic syndrome. RESEARCH DESIGN AND METHODS Progranulin serum levels were quantified by enzyme-linked immunosorbent assay and correlated to anthropometric and biochemical parameters of renal function and glucose and lipid metabolism, as well as inflammation, in 532 patients with stages 1–5 of chronic kidney disease (CKD). RESULTS Median serum progranulin levels adjusted for age, sex, and BMI were significantly different between CKD stages with highest values detectable in stage 5 (stage 1, 58.3 µg/L; stage 2, 63.0 µg/L; stage 3, 65.4 µg/L; stage 4, 68.8 µg/L; and stage 5, 90.6 µg/L). Furthermore, CKD stage was the strongest independent predictor of circulating progranulin in our cohort. In addition, high-sensitivity interleukin-6 and adiponectin remained significantly and independently correlated with the adipokine. CONCLUSIONS We demonstrate that progranulin serum levels increase with deteriorating renal function. These findings are in accordance with the hypothesis that renal clearance is a major elimination route for circulating progranulin. Furthermore, the adipokine is positively and independently associated with markers of inflammation and adiponectin. PMID:23033238

Effect of seabuckthorn leaf extracts on circulating energy fuels, lipid peroxidation and antioxidant parameters in rats during exposure to cold, hypoxia and restraint (C-H-R) stress and post stress recovery.

PubMed

Saggu, Shalini; Kumar, Ratan

2008-06-01

The present study was carried out to study mechanism of adaptogenic activity of seabuckthorn leaf extract, administered orally in rats both in single and five doses at a dose of 100mg/kg body weight 30min prior to C-H-R exposure. The efficacy of the extract was studied on circulating energy fuels, lipid peroxidation and anti-oxidant parameters in rats on attaining the T(rec) 23 degrees C during C-H-R exposure and after recovery (T(rec) 37 degrees C) from C-H-R induced hypothermia. Single dose treatment in rats restricted rise in blood malondialdehyde (MDA) levels and decrease in glutathione (GSH) and catalase (CAT) levels. Both single and five doses also restricted the rise in serum free fatty acids (FFA) and lactate dehydrogenase (LDH) levels on attaining T(rec) 23 degrees C during C-H-R exposure, suggesting more efficient utilization of FFA for energy production and better maintained cell membrane permeability. This suggested that the adaptogenic activity of the extract might be due to its anti-oxidative activity, maintained blood glucose levels, better utilization of FFA and improved cell membrane permeability.

SNPs in FNDC5 (irisin) are associated with obesity and modulation of glucose and lipid metabolism in Saudi subjects.

PubMed

Al-Daghri, Nasser M; Mohammed, Abdul Khader; Al-Attas, Omar S; Amer, Osama E; Clerici, Mario; Alenad, Amal; Alokail, Majed S

2016-03-11

Irisin is a recently identified myokine that plays an important role in preventing obesity and insulin resistance. We investigated whether the common FNDC5 (irisin precursor) gene variants influence susceptibility to obesity and type 2 diabetes (T2D) and verified the impact of FNDC5 gene variants on serum irisin levels, glucose and lipid metabolism in a Saudi population. Genomic DNA from 814 (394 T2DM and 414 controls) subjects were genotyped for the five common SNPs (rs3480A/G, rs1746661G/T, rs1298190A/G, rs726344A/G and rs1570569G/T) of the FNDC5 gene using the TaqMan genotyping assay. Biochemical parameters and hematic concentrations of irisin and insulin as well as anthropometric indices were collected. Serum irisin levels were higher in T2DM patients compared to controls (p < 0.0001). Analyses of FNDC5 SNPs showed that: 1) The rs3480 GG associates with decreased risk of obesity (p = 0.005; odds ratio: 0.48) and lower body mass index (BMI) values (p = 0.03). In addition, GGAAG was identified as the protective haplotype against risk of obesity (p = 0.001; odds ratio: 0.23). 2) The rs1746661 G allele associates with higher triglyceride (TG) levels (p = 0.019). 3) The rs157069 TT genotype associates with higher fasting insulin (p = 0.029) and HOMA-IR (p = 0.002) as well as with lower circulating irisin levels (p = 0.016). SNPs in FNDC5 gene correlates with obesity and glucose-lipid metabolism possibly because they modulate the serum levels of irisin.

Resveratrol supplementation decreases blood glucose without changing the circulating CD14+CD16+ monocytes and inflammatory cytokines in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study.

PubMed

Khodabandehloo, Hadi; Seyyedebrahimi, ShadiSadat; Esfahani, Ensieh Nasli; Razi, Farideh; Meshkani, Reza

2018-06-01

Chronic low-grade inflammation is the hallmark of type 2 diabetes (T2D). Although in vitro and animal studies have shown that resveratrol exerts anti-inflammatory effects, clinical trials addressing these effects in patients with T2D are limited. Therefore, in the present study, we hypothesized that supplementation of resveratrol might improve inflammatory markers in patients with T2D in a randomized, double-blind, placebo-controlled clinical trial. A total of 45 T2D patients were supplemented with either of 800 mg/d resveratrol or placebo capsules for 8 weeks. Percentage of CD14 + CD16 + monocytes, plasma levels of inflammatory cytokines (tumor necrosis factor α, interleukin [IL] 1β, IL-6, and monocyte chemoattractant protein-1), the expression levels of genes involved in the inflammatory responses (toll-like receptor 2, toll-like receptor 4, and nuclear factor κB), lipopolysaccharide-stimulated cytokine (tumor necrosis factor α, IL-1β, and IL-6) secretion from peripheral blood mononuclear cells, and metabolic and anthropometric parameters were assessed at both the baseline level and the end of the study. Compared with the placebo group, we could not detect any significant difference in the percentage of CD14 + CD16 + monocytes, lipopolysaccharide-induced cytokine secretion, plasma levels of inflammatory cytokines, and the expression of inflammatory genes in resveratrol group. Moreover, we did not find any significant change in the metabolic and anthropometric parameters except for a significant reduction in fasting blood glucose and blood pressure. In conclusion, 8-week supplementation of resveratrol reduces blood glucose level in patients with T2D without improving their inflammatory markers. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of Rapid Weight Loss on Systemic and Adipose Tissue Inflammation and Metabolism in Obese Postmenopausal Women.

PubMed

Alemán, José O; Iyengar, Neil M; Walker, Jeanne M; Milne, Ginger L; Da Rosa, Joel Correa; Liang, Yupu; Giri, Dilip D; Zhou, Xi Kathy; Pollak, Michael N; Hudis, Clifford A; Breslow, Jan L; Holt, Peter R; Dannenberg, Andrew J

2017-06-01

Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear. To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women. Prospective cohort study. Rockefeller University Hospital, New York, NY. Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, ±3.6 years). Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured. Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, β -hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined. Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites ( i.e. , lactate, β -hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti-inflammatory effect of rapid weight loss.

Effects of Rapid Weight Loss on Systemic and Adipose Tissue Inflammation and Metabolism in Obese Postmenopausal Women

PubMed Central

Iyengar, Neil M.; Walker, Jeanne M.; Milne, Ginger L.; Da Rosa, Joel Correa; Liang, Yupu; Giri, Dilip D.; Zhou, Xi Kathy; Pollak, Michael N.; Hudis, Clifford A.; Breslow, Jan L.; Holt, Peter R.; Dannenberg, Andrew J.

2017-01-01

Context: Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear. Objective: To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women. Design: Prospective cohort study. Setting: Rockefeller University Hospital, New York, NY. Participants: Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, ±3.6 years). Main Outcome Measures: Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured. Results: Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, β-hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined. Conclusion: Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites (i.e., lactate, β-hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti-inflammatory effect of rapid weight loss. PMID:29264516

Glomerular hemodynamic alterations during acute hyperinsulinemia in normal and diabetic rats

NASA Technical Reports Server (NTRS)

Tucker, B. J.; Anderson, C. M.; Thies, R. S.; Collins, R. C.; Blantz, R. C.

1992-01-01

Treatment of insulin dependent diabetes invariably requires exogenous insulin to control blood glucose. Insulin treatment, independent of other factors associated with insulin dependent diabetes, may induce changes that affect glomerular function. Due to exogenous delivery of insulin in insulin dependent diabetes entering systemic circulation prior to the portal vein, plasma levels of insulin are often in excess of that observed in non-diabetics. The specific effects of hyperinsulinemia on glomerular hemodynamics have not been previously examined. Micropuncture studies were performed in control (non-diabetic), untreated diabetic and insulin-treated diabetic rats 7 to 10 days after administration of 65 mg/kg body weight streptozotocin. After the first period micropuncture measurements were obtained, 5 U of regular insulin (Humulin-R) was infused i.v., and glucose clamped at euglycemic values (80 to 120 mg/dl). Blood glucose concentration in non-diabetic controls was 99 +/- 6 mg/dl. In control rats, insulin infusion and glucose clamp increased nephron filtration rate due to decreases in both afferent and efferent arteriolar resistance (afferent greater than efferent) resulting in increased plasma flow and increased glomerular hydrostatic pressure gradient. However, insulin infusion and glucose clamp produced the opposite effect in both untreated and insulin-treated diabetic rats with afferent arteriolar vasoconstriction resulting in decreases in plasma flow, glomerular hydrostatic pressure gradient and nephron filtration rate. Thromboxane A2 (TX) synthetase inhibition partially decreased the vasoconstrictive response due to acute insulin infusion in diabetic rats preventing the decrease in nephron filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS).

Nutrient-intake-level-dependent regulation of intestinal development in newborn intrauterine growth-restricted piglets via glucagon-like peptide-2.

PubMed

Liu, J; Liu, Z; Gao, L; Chen, L; Zhang, H

2016-10-01

The objective of the present study was to investigate the intestinal development of newborn intrauterine growth-restricted (IUGR) piglets subjected to normal nutrient intake (NNI) or restricted nutrient intake (RNI). Newborn normal birth weight (NBW) and IUGR piglets were allotted to NNI or RNI levels for 4 weeks from day 8 postnatal. IUGR piglets receiving NNI had similar growth performance compared with that of NBW piglets. Small intestine length and villous height were greater in IUGR piglets fed the NNI than that of piglets fed the RNI. Lactase activity was increased in piglets fed the NNI compared with piglets fed the RNI. Absorptive function, represented by active glucose transport by the Ussing chamber method and messenger RNA (mRNA) expressions of two main intestinal glucose transporters, Na+-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), were greater in IUGR piglets fed the NNI compared with piglets fed the RNI regimen. The apoptotic process, characterized by caspase-3 activity (a sign of activated apoptotic cells) and mRNA expressions of p53 (pro-apoptotic), bcl-2-like protein 4 (Bax) (pro-apoptotic) and B-cell lymphoma-2 (Bcl-2) (anti-apoptotic), were improved in IUGR piglets fed the NNI regimen. To test the hypothesis that improvements in intestinal development of IUGR piglets fed NNI might be mediated through circulating glucagon-like peptide-2 (GLP-2), GLP-2 was injected subcutaneously to IUGR piglets fed the RNI from day 8 to day 15 postnatal. Although the intestinal development of IUGR piglets fed the RNI regimen was suppressed compared with those fed the NNI regimen, an exogenous injection of GLP-2 was able to bring intestinal development to similar levels as NNI-fed IUGR piglets. Collectively, our results demonstrate that IUGR neonates that have NNI levels could improve intestinal function via the regulation of GLP-2.

Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo.

PubMed

Amengual, Jaume; García-Carrizo, Francisco J; Arreguín, Andrea; Mušinović, Hana; Granados, Nuria; Palou, Andreu; Bonet, M Luisa; Ribot, Joan

2018-01-01

All-trans retinoic acid (ATRA) has protective effects against obesity and metabolic syndrome. We here aimed to gain further insight into the interaction of ATRA with skeletal muscle metabolism and secretory activity as important players in metabolic health. Cultured murine C2C12 myocytes were used to study direct effects of ATRA on cellular fatty acid oxidation (FAO) rate (using radioactively-labelled palmitate), glucose uptake (using radioactively-labelled 2-deoxy-D-glucose), triacylglycerol levels (by an enzymatic method), and the expression of genes related to FAO and glucose utilization (by RT-real time PCR). We also studied selected myokine production (using ELISA and immunohistochemistry) in ATRA-treated myocytes and intact mice. Exposure of C2C12 myocytes to ATRA led to increased fatty acid consumption and decreased cellular triacylglycerol levels without affecting glucose uptake, and induced the expression of the myokine irisin at the mRNA and secreted protein level in a dose-response manner. ATRA stimulatory effects on FAO-related genes and the Fndc5 gene (encoding irisin) were reproduced by agonists of peroxisome proliferator-activated receptor β/δ and retinoid X receptors, but not of retinoic acid receptors, and were partially blocked by an AMP-dependent protein kinase inhibitor. Circulating irisin levels were increased by 5-fold in ATRA-treated mice, linked to increased Fndc5 transcription in liver and adipose tissues, rather than skeletal muscle. Immunohistochemistry analysis of FNDC5 suggested that ATRA treatment enhances the release of FNDC5/irisin from skeletal muscle and the liver and its accumulation in interscapular brown and inguinal white adipose depots. These results provide new mechanistic insights on how ATRA globally stimulates FAO and enhances irisin secretion, thereby contributing to leaning effects and improved metabolic status. © 2018 The Author(s). Published by S. Karger AG, Basel.

Postprandial plasma incretin hormones in exercise-trained versus untrained subjects.

PubMed

Weiss, Edward P; Royer, Nathaniel K; Fisher, Jonathan S; Holloszy, John O; Fontana, Luigi

2014-06-01

After food ingestion, the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are secreted by the intestines into circulation where they act on the pancreas to promote insulin secretion. We evaluated the hypothesis that low postprandial plasma insulin levels in lean exercise-trained individuals are associated with low concentrations of incretin hormones. A cross-sectional study was performed to compare postprandial incretin hormone levels in lean endurance exercise-trained individuals (EX; n = 14, ≥40 yr) and age- and sex-matched, nonobese, sedentary control subjects (CON, n = 14). The main outcome measures were GLP-1, GIP, insulin, and glucose incremental areas under the curve (AUC) as measured in plasma samples collected during a 2-h,75-g oral glucose tolerance test (OGTT). The EX group had lower body fat percentage (14.6% ± 1.1% vs 23.3% ± 1.7%, P = 0.0002) and higher maximal oxygen uptake (53 ± 2 vs 34 ± 2, P < 0.0001) than CON. Glucose AUC did not differ between groups (P = 0.20). Insulin AUC was lower in EX (2.5 ± 0.5 vs 4.2 ± 1.2 μU·mL·1000 min, P = 0.02). No differences were observed between groups (EX and CON, respectively) for GLP-1 AUC (3.5 ± 0.7 vs 4.1 ± 1.1 pmol·min·100 L, P = 0.61) or GIP AUC (19.2 ± 1.4 vs 18.0 ± 1.4 pg·min·1000 mL; P = 0.56). In CON, insulin AUC was correlated with AUC for GLP-1 (r = 0.53, P = 0.05) and GIP (r = 0.71, P = 0.004), but no such correlations were observed in EX (both P ≥ 0.67). Low postprandial insulin levels in lean exercise-trained individuals are not attributable to lower incretin hormone concentrations. However, exercise may decrease the dependency of postprandial insulin levels on incretin hormones.

Facilitative glucose transporter gene expression in human lymphocytes, monocytes, and macrophages: a role for GLUT isoforms 1, 3, and 5 in the immune response and foam cell formation.

PubMed

Fu, Yuchang; Maianu, Lidia; Melbert, Barry R; Garvey, W Timothy

2004-01-01

Cellular glucose uptake is mediated by a family of facilitative glucose transporters (GLUT) exhibiting differences in kinetics, substrate specificity, and tissue-specific expression. GLUT isoform expression has not been comprehensively studied in human leukocytes, which participate in immune and inflammatory responses and are critical for host defense. Therefore, we studied the regulated expression of GLUT 1-5 mRNA and protein in isolated human lymphocytes and monocytes and in human THP-1 macrophages and foam cells. Lymphocytes expressed GLUT 1 and GLUT 3 proteins, and cellular levels of both isoforms were augmented 3.5- to 6-fold following activation by phytohemagglutinin (PHA). Monocytes expressed 8.4-fold more GLUT 3 protein and 88% less GLUT 1 than lymphocytes, and activation by lipopolysaccharide (LPS) led to a 1.9-fold increase in GLUT 1. At the level of mRNA expression, GLUT 3 mRNA was the most prevalent GLUT mRNA species in monocytes, while lymphocytes expressed equal numbers of GLUT 1 and GLUT 3 transcripts. Differentiation of THP-1 monocytes into macrophages was associated with marked induction of GLUT 3 and GLUT 5 protein expression, and high levels of GLUT 1, GLUT 3, and GLUT 5 were maintained after transformation to foam cells. GLUT 5 mRNA was expressed in 2-fold greater abundance in macrophages and foam cells than that observed for GLUT 1 mRNA, while the level of GLUT 3 mRNA was intermediate. This facilitative glucose transporters are differentially expressed and regulated in human leukocytes in a pattern that could facilitate cellular functions. Speculatively, high GLUT 1 and GLUT 3 expression could provide cellular fuel for the immune response, and high levels of high-affinity GLUT 3 in macrophages might allow the cell to compete with pathogens for hexoses, even in the presence of low interstitial glucose concentrations. Ample expression of GLUT 1 and GLUT 3 in foam cells could also provide hexose substrates and promote lipid loading. The role for high levels of the fructose transporter GLUT 5 in macrophages and foam cells is unknown since interstitial and circulating fructose concentrations are low in these cells.

Fasting plasma levels of nesfatin-1 in patients with type 1 and type 2 diabetes mellitus and the nutrient-related fluctuation of nesfatin-1 level in normal humans.

PubMed

Li, Qing-Chun; Wang, Hai-Yan; Chen, Xi; Guan, Hong-Zai; Jiang, Zheng-Yao

2010-01-08

The novel satiety factor nesfatin-1 has been shown to decrease food intake and body weight in rodents after i.c.v. injection. However, no further developments regarding the true patho-physiological relevance of nesfatin-1 in obesity and type 1 diabetes mellitus (T1 DM) and type 2 diabetes mellitus (T2 DM) have been reported. A recent study by Stengel et al. demonstrated that a down-regulation of NUCB2 mRNA in gastric endocrine cells was observed after 24-h fasting. They raised the possibility that nesfatin/NUCB2 gene expression may be regulated by nutritional status, suggesting that nesfatin-1 in the stomach might play a role in satiety. In the present study, fasting levels in plasma nesfatin-1, insulin and glucose were measured and analyzed in healthy subjects and in patients with T1 DM and T2 DM. Plasma nesfatin-1 levels were measured 6 times before and after oral glucose ingestion in healthy subjects. No sex differences in plasma nesfatin-1 were found. The mean fasting plasma nesfatin-1 levels were slightly but not significantly higher in T1 DM patients compared to healthy subjects. However, fasting plasma nesfatin-1 levels were significantly lower in T2 DM patients compared to healthy subjects and T1 DM patients. Plasma nesfatin-1 did not change acutely, although a small rise in circulating nesfatin-1 occurred within 30 min after the beginning of an oral glucose ingestion (from a mean basal value of 0.99+/-0.23 ng/ml to a maximum of 1.08+/-0.24 ng/ml). No significant difference in plasma nesfatin-1 before and after an oral glucose was observed. In conclusion, we showed that fasting nesfatin-1 was significantly lower in T2 DM patients compared to healthy subjects and T1 DM patients. The significance of this result is unclear but the reduction in fasting nesfatin-1 may be one of the appetite-related hormones involved in diabetic hyperphagia. In addition, neither glucose nor saline ingestions affected plasma nesfatin-1, suggesting that gastric chemosensation is not sufficient for the nesfatin-1 response under the present conditions.

Fetal in vivo continuous cardiovascular function during chronic hypoxia

PubMed Central

Allison, B. J.; Brain, K. L.; Niu, Y.; Kane, A. D.; Herrera, E. A.; Thakor, A. S.; Botting, K. J.; Cross, C. M.; Itani, N.; Skeffington, K. L.; Beck, C.

2016-01-01

Key points The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing.We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth‐restricted fetus.This technology permits wireless recording in free‐moving animals of longitudinal maternal and fetal cardiovascular function, including beat‐to‐beat alterations in pressure and blood flow signals in regional circulations.The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism. Abstract Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2) hypoxia, yielding fetal mean PaO2 levels (11.5 ± 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7 ± 0.2 to 3.8 ± 0.8; P < 0.05) and of glucose (from 2.3 ± 0.1 to 3.3 ± 0.6; P < 0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (Δ: 4.8 ± 1.6 vs. 0.5 ± 1.4 μmol l−1, P<0.05). The data support the hypotheses tested and show persisting redistribution of substrate delivery away from peripheral and towards essential circulations in the chronically hypoxic fetus, associated with increases in xanthine oxidase‐derived reactive oxygen species. PMID:26926316

Photoperiodic responses of depression-like behavior, the brain serotonergic system, and peripheral metabolism in laboratory mice.

PubMed

Otsuka, Tsuyoshi; Kawai, Misato; Togo, Yuki; Goda, Ryosei; Kawase, Takahiro; Matsuo, Haruka; Iwamoto, Ayaka; Nagasawa, Mao; Furuse, Mitsuhiro; Yasuo, Shinobu

2014-02-01

Seasonal affective disorder (SAD) is characterized by depression during specific seasons, generally winter. The pathophysiological mechanisms underlying SAD remain elusive due to a limited number of animal models with high availability and validity. Here we show that laboratory C57BL/6J mice display photoperiodic changes in depression-like behavior and brain serotonin content. C57BL/6J mice maintained under short-day conditions, as compared to those under long-day conditions, demonstrated prolonged immobility times in the forced swimming test with lower brain levels of serotonin and its precursor l-tryptophan. Furthermore, photoperiod altered multiple parameters reflective of peripheral metabolism, including the ratio of plasma l-tryptophan to the sum of other large neutral amino acids that compete for transport across the blood-brain barrier, responses of circulating glucose and insulin to glucose load, sucrose intake under restricted feeding condition, and sensitivity of the brain serotonergic system to peripherally administered glucose. These data suggest that the mechanisms underlying SAD involve the brain-peripheral tissue network, and C57BL/6J mice can serve as a powerful tool for investigating the link between seasons and mood. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dietary composition of carbohydrates contributes to the development of experimental type 2 diabetes.

PubMed

Hodgson, K; Govan, B; Ketheesan, N; Morris, J

2013-04-01

Evidence has emerged supporting a link between high glycaemic index (GI) diets and type 2 diabetes (T2D). The aim of this study was to determine if dietary GI influences the development of hyperglycaemia in C57BL/6 mice to more closely reflect T2D. Male C57BL/6 mice (n=30) were randomly divided into 3 dietary groups consisting of either standard rodent chow (4.8 % fat, 20 % protein), or a high fat (HF) diet (21-23 % fat, 19 % protein) with low GI (15.4 % starch; HF-LG) or high GI (50.5 % dextrose; HF-HG) ad libitum for 10 weeks. Body weight, blood glucose, glucose tolerance, and circulating cholesterol and triglyceride levels were measured for the duration of the study. We found that increasing the GI of a moderately HF diet induces severe hyperglycaemia and insulin resistance in C57BL/6 mice, reflective of criteria for diagnosis of T2D, whilst littermates consuming an equivalent low GI diet maintain glucose homeostasis. This study demonstrates the significant contribution of both dietary carbohydrate and fat composition in the aetiopathogenesis of T2D.

NRG1-Fc improves metabolic health via dual hepatic and central action.

PubMed

Zhang, Peng; Kuang, Henry; He, Yanlin; Idiga, Sharon O; Li, Siming; Chen, Zhimin; Yang, Zhao; Cai, Xing; Zhang, Kezhong; Potthoff, Matthew J; Xu, Yong; Lin, Jiandie D

2018-03-08

Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat-enriched secreted factor NRG4 protects mice from high-fat diet-induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake.

NRG1-Fc improves metabolic health via dual hepatic and central action

PubMed Central

Kuang, Henry; Idiga, Sharon O.; Li, Siming; Chen, Zhimin; Cai, Xing; Zhang, Kezhong; Potthoff, Matthew J.; Xu, Yong; Lin, Jiandie D.

2018-01-01

Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat–enriched secreted factor NRG4 protects mice from high-fat diet–induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake. PMID:29515030

Metabolism of 13C-enriched D-fructose in hepatocytes from Goto-Kakizaki rats.

PubMed

Malaisse, Willy J; Ladriere, Laurence; Verbruggen, Ingrid; Willem, Rudolph

2004-05-01

This study aims at assessing the conversion of exogenous D-[1-13C]fructose, D-[2-13C]fructose or D-[6-13C]-fructose (10 mM) to 13C-enriched and either hydrogenated or deuterated D-glucose, L-lactate and L-alanine released by rat liver cells prepared from Goto-Kakizaki rats and incubated for 120 min in the presence of unlabelled D-glucose (also 10 mM) and D2O. The results of this study are relevant to the relative contribution of fructokinase and hexokinase isoenzyme to the phosphorylation of D-fructose, the capacity of D-glucose to confer to glucokinase positive cooperativity towards D-fructose, the circulation of D-fructose 6-phosphate in the pentose phosphate pathway, the regulation of the cytosolic NADD/NADH ratio, the respective fate of D-fructose-derived D-glyceraldehyde and dihydroxyacetone phosphate, the deuteration of fructose-derived glycolytic intermediates at the phosphoglucoisomerase, phosphomannoisomerase, enolase, pyruvate kinase and glutamate-alanine transaminase levels, and the unequal generation of L-[1-13C]lactate by cells exposed to D-[1-13C]fructose or D-[6-13C]fructose versus D-[2-13C]-fructose.

Current Advances in the Biochemical and Physiological Aspects of the Treatment of Type 2 Diabetes Mellitus with Thiazolidinediones.

PubMed

Alemán-González-Duhart, D; Tamay-Cach, F; Álvarez-Almazán, S; Mendieta-Wejebe, J E

2016-01-01

The present review summarizes the current advances in the biochemical and physiological aspects in the treatment of type 2 diabetes mellitus (DM2) with thiazolidinediones (TZDs). DM2 is a metabolic disorder characterized by hyperglycemia, triggering the abnormal activation of physiological pathways such as glucose autooxidation, polyol's pathway, formation of advance glycation end (AGE) products, and glycolysis, leading to the overproduction of reactive oxygen species (ROS) and proinflammatory cytokines, which are responsible for the micro- and macrovascular complications of the disease. The treatment of DM2 has been directed toward the reduction of hyperglycemia using different drugs such as insulin sensitizers, as the case of TZDs, which are able to lower blood glucose levels and circulating triglycerides by binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) as full agonists. When TZDs interact with PPARγ, the receptor regulates the transcription of different genes involved in glucose homeostasis, insulin resistance, and adipogenesis. However, TZDs exhibit some adverse effects such as fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures, and congestive heart failure, which limits their use in DM2 patients.

A leptin-regulated circuit controls glucose mobilization during noxious stimuli.

PubMed

Flak, Jonathan N; Arble, Deanna; Pan, Warren; Patterson, Christa; Lanigan, Thomas; Goforth, Paulette B; Sacksner, Jamie; Joosten, Maja; Morgan, Donald A; Allison, Margaret B; Hayes, John; Feldman, Eva; Seeley, Randy J; Olson, David P; Rahmouni, Kamal; Myers, Martin G

2017-08-01

Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor-expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores.

Plasma YKL-40 during pregnancy and gestational diabetes mellitus.

PubMed

Rinnov, Anders R; Rathcke, Camilla N; Bonde, Lisbeth; Vilsbøll, Tina; Knop, Filip K

2015-11-01

Gestational diabetes mellitus (GDM) is characterised by hyperglycaemia during pregnancy. The clinical circumstances involved in the development of GDM leaves the patient at a high risk of the subsequent development of type 2 diabetes. Plasma levels of the inflammation marker YKL-40 are elevated in type 2 diabetes and correlate with fasting plasma glucose levels and insulin resistance in patients with type 2 diabetes. With the present study we aimed to determine if pregnancy (and associated insulin resistance) with or without GDM affects plasma YKL-40 levels. Plasma from women diagnosed with GDM and healthy normal glucose-tolerant pregnant women (non-GDM) was obtained at the third trimester of pregnancy and again 3-4 months following delivery, and levels of YKL-40 and interleukin 6 (IL-6; known to regulate YKL-40) were measured. Plasma YKL-40 levels were similarly low during pregnancy in both groups and increased significantly after delivery, but remained lower in the GDM group compared with the non-GDM group postpartum. In contrast, plasma IL-6 levels were not affected by pregnancy or diagnosis of GDM, Nevertheless, YKL-40 levels were associated with IL-6 levels in the non-GDM group (but not in the GDM group). Pregnancy seems to be associated with a temporary reduction in circulating YKL-40, which increases after delivery, but to a much lesser extent in women with GDM than in non-GDM women. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Circulating early biomarkers of atherogenesis in participants of the Longitudinal Study of Adult Health (ELSA-Brasil) without diabetes or cardiovascular disease.

PubMed

Almeida-Pititto, Bianca de; Ribeiro-Filho, Fernando Flexa; Barreto, Sandhi; Duncan, Bruce B; Schmidt, Maria Inês; Lotufo, Paulo A; Bensenor, Isabela M; Ferreira, Sandra R G

2016-01-01

Our aim was to describe the distribution of selected biomarkers according to age and sex, adjusted for HOMA-IR and adiposity, in a subset of middle-aged individuals of Brazilian Longitudinal Study of Adult Health-ELSA without diabetes mellitus or CVD. This cross-sectional study was conducted in 998 participants of the ELSA-Brasil without diabetes and/or cardiovascular disease. In addition to the traditional risk factors, several biomarkers concentrations were compared according to sex, age groups (35-44; 45-54 yrs) and HOMA-IR tertiles. Linear regression was used to examine independent associations of sex and age with selected novel biomarkers, adjusted for body adiposity and HOMA-IR. Fifty-five percent were women. Men had higher mean values of body mass index, waist circumference, blood pressure, plasma glucose, HOMA-IR, worse lipid profile and higher E-selectin and lower leptin concentrations than women; while women had higher levels of HDL-cholesterol and leptin than men. Mean values of waist circumference, systolic BP, plasma glucose and apolipoprotein B (Apo B) increased with age in both sexes. Leptin and E-selectin concentrations increased across HOMA-IR tertiles. Independent associations of Apo B with age were found only in male sex, while of leptin with body mass index and HOMA-IR, and of E-selectin with HOMA-IR in both sexes. In conclusion, our data indicate age, sex, adiposity and, consequently, insulin resistance, influence circulating levels of Apo B, leptin and E-selectin, suggesting that those aspects should be taken into consideration when assessing these parameters for research or clinical purposes in individuals at relatively low cardiometabolic risk.

Glucocorticoids, stress, and fertility.

PubMed

Whirledge, S; Cidlowski, J A

2010-06-01

Modifications of the hypothalamo-pituitary-adrenal axis and associated changes in circulating levels of glucocorticoids form a key component of the response of an organism to stressful challenges. Increased levels of glucocorticoids promote gluconeogenesis, mobilization of amino acids, and stimulation of fat breakdown to maintain circulating levels of glucose necessary to mount a stress response. In addition to profound changes in the physiology and function of multiple tissues, stress and elevated glucocorticoids can also inhibit reproduction, a logical effect for the survival of self. Precise levels of glucocorticoids are required for proper gonadal function; where the balance is disrupted, so is fertility. Glucocorticoids affect gonadal function at multiple levels in hypothalamo-pituitary-gonadal axis: 1) the hypothalamus (to decrease the synthesis and release of gonadotropin-releasing hormone [GnRH]); 2) the pituitary gland (to inhibit the synthesis and release of luteinizing hormone [LH] and follicle stimulating hormone [FSH]); 3) the testis/ovary (to modulate steroidogenesis and/or gametogenesis directly). Furthermore, maternal exposure to prenatal stress or exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal function and stress-related behaviors in offspring. Glucocorticoids are vital to many aspects of normal brain development, but fetal exposure to superabundant glucocorticoids can result in life-long effects on neuroendocrine function. This review focuses on the molecular mechanisms believed to mediate glucocorticoid inhibition of reproductive functions and the anatomical sites at which these effects take place.

Association between circulating irisin and insulin resistance in non-diabetic adults: A meta-analysis.

PubMed

Qiu, Shanhu; Cai, Xue; Yin, Han; Zügel, Martina; Sun, Zilin; Steinacker, Jürgen Michael; Schumann, Uwe

2016-06-01

Exogenous administration of recombinant irisin improves glucose metabolism. However, the association of endogenous circulating (plasma/serum) irisin with insulin resistance remains poorly delineated. This study was aimed to examine this association by meta-analyzing the current evidence without study design restriction in non-diabetic adults. Peer-reviewed studies written in English from 3 databases were searched to December 2015. Studies that reported the association between circulating irisin and insulin resistance (or its reverse, insulin sensitivity) in non-diabetic non-pregnant adults (mean ages ≥18years) were included. The pooled correlation coefficient (r) and 95% confidence intervals (CIs) were calculated using a random-effects model. Subgroup analyses and meta-regression were performed to explore potential sources of heterogeneity. Of the 195 identified publications, 17 studies from 15 articles enrolling 1912 participants reported the association between circulating irisin and insulin resistance. The pooled effect size was 0.15 (95% CI: 0.07 to 0.22) with a substantial heterogeneity (I(2)=55.5%). This association seemed to be modified by glycemic status (fasting blood glucose ≥6.1mmol/L versus <6.1mmol/L) and racial-ethnic difference (Asians versus Europeans versus Americans), but not by sex difference, sampling time-point, blood sample type, ELISA kits used, baseline age, or body mass index. Circulating irisin was inversely associated with insulin sensitivity (6 studies; r=-0.17, 95% CI: -0.25 to -0.09). Circulating irisin is directly and positively associated with insulin resistance in non-diabetic adults. However, this association is rather small and requires further clarification, in particular by well-designed large epidemiological studies with overall, race-, and sex-specific analyses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Calibration Experiments Conducted for Noninvasive Blood Glucose Sensing Through the Eye

NASA Technical Reports Server (NTRS)

Ansari, Rafat R.; Bockle, Stefan; Suh, Kwang I.; Rovati, Luigi L.

2004-01-01

There are more than 16 million diabetics in the United States and more than 100 million worldwide. Diabetes can lead to severe complications over time such as blindness, renal and cardiovascular diseases, and peripheral neuropathy in the limbs. Poor blood circulation in diabetics can lead to gangrene and the subsequent amputation of extremities. In addition, this pathology is the fourth leading cause of death in the United States. The most effective way to manage diabetes is frequent blood glucose monitoring performed by the patients themselves. However, because of pain, inconvenience, and the fear of developing infections from finger-prick blood tests or implants, many patients monitor their blood glucose levels less frequently than is recommended by their physicians. Therefore, a noninvasive, painless, and convenient method to monitor blood glucose would greatly benefit diabetics. Likewise, detecting, preventing, and treating the untoward effects of prolonged space travel (e.g., a human mission to Mars) in real-time requires the development of noninvasive diagnostic technologies that are compact and powerful. As a "window to the body," the eye offers the opportunity to use light in various forms to detect ocular and systemic abnormalities long before clinical symptoms appear and to help develop preventative and therapeutic countermeasures early. The noninvasive feature of these technologies permits frequent repetition of tests, enabling an evaluation of the response to therapy.

Partial deficiency of CTRP12 alters hepatic lipid metabolism

PubMed Central

Tan, Stefanie Y.; Little, Hannah C.; Lei, Xia; Li, Shuoyang; Rodriguez, Susana

2016-01-01

Secreted hormones play pivotal roles in tissue cross talk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted protein involved in regulating glucose metabolism whose circulating levels are reduced in obese and insulin-resistant mouse models. Its role in lipid metabolism, however, is unknown. Using a novel heterozygous mouse model, we show that the loss of a single copy of the Ctrp12 gene (also known as Fam132a and adipolin) affects whole body lipid metabolism. In Ctrp12 (+/−) male mice fed a control low-fat diet, hepatic fat oxidation was upregulated while hepatic VLDL-triglyceride secretion was reduced relative to wild-type (WT) littermates. When challenged with a high-fat diet, Ctrp12 (+/−) male mice had impaired lipid clearance in response to acute lipid gavage, reduced hepatic triglyceride secretion, and greater steatosis with higher liver triglyceride and cholesterol levels. Unlike male mice, Ctrp12 (+/−) female mice fed a control low-fat diet were indistinguishable from WT littermates. When obesity was induced by high-fat feeding, Ctrp12 (+/−) female mice developed mild insulin resistance with impaired insulin tolerance. In contrast to male mice, hepatic triglyceride secretion was increased in Ctrp12 (+/−) female mice fed a high-fat diet. Thus, in different dietary and metabolic contexts, loss of a single Ctrp12 allele affects glucose and lipid metabolism in a sex-dependent manner, highlighting the importance of genetic and environmental determinants of metabolic phenotypes. PMID:27815536

Partial deficiency of CTRP12 alters hepatic lipid metabolism.

PubMed

Tan, Stefanie Y; Little, Hannah C; Lei, Xia; Li, Shuoyang; Rodriguez, Susana; Wong, G William

2016-12-01

Secreted hormones play pivotal roles in tissue cross talk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted protein involved in regulating glucose metabolism whose circulating levels are reduced in obese and insulin-resistant mouse models. Its role in lipid metabolism, however, is unknown. Using a novel heterozygous mouse model, we show that the loss of a single copy of the Ctrp12 gene (also known as Fam132a and adipolin) affects whole body lipid metabolism. In Ctrp12 (+/-) male mice fed a control low-fat diet, hepatic fat oxidation was upregulated while hepatic VLDL-triglyceride secretion was reduced relative to wild-type (WT) littermates. When challenged with a high-fat diet, Ctrp12 (+/-) male mice had impaired lipid clearance in response to acute lipid gavage, reduced hepatic triglyceride secretion, and greater steatosis with higher liver triglyceride and cholesterol levels. Unlike male mice, Ctrp12 (+/-) female mice fed a control low-fat diet were indistinguishable from WT littermates. When obesity was induced by high-fat feeding, Ctrp12 (+/-) female mice developed mild insulin resistance with impaired insulin tolerance. In contrast to male mice, hepatic triglyceride secretion was increased in Ctrp12 (+/-) female mice fed a high-fat diet. Thus, in different dietary and metabolic contexts, loss of a single Ctrp12 allele affects glucose and lipid metabolism in a sex-dependent manner, highlighting the importance of genetic and environmental determinants of metabolic phenotypes. Copyright © 2016 the American Physiological Society.

Expression Patterns and Correlations with Metabolic Markers of Zinc Transporters ZIP14 and ZNT1 in Obesity and Polycystic Ovary Syndrome

PubMed Central

Maxel, Trine; Svendsen, Pernille Fog; Smidt, Kamille; Lauridsen, Jesper Krogh; Brock, Birgitte; Pedersen, Steen Bønlykke; Rungby, Jørgen; Larsen, Agnete

2017-01-01

Polycystic ovary syndrome (PCOS) is associated with infertility, increased androgen levels, and insulin resistance. In adipose tissue, zinc facilitates insulin signaling. Circulating zinc levels are altered in obesity, diabetes, and PCOS; and zinc supplementation can ameliorate metabolic disturbances in PCOS. In adipose tissue, expression of zinc influx transporter ZIP14 varies with body mass index (BMI), clinical markers of metabolic syndrome, and peroxisome proliferator-activated receptor gamma (PPARG). In this study, we investigated expression levels of ZIP14 and PPARG in subcutaneous adipose tissue of 36 PCOS women (17 lean and 19 obese women) compared with 23 healthy controls (7 lean and 16 obese women). Further, expression levels of zinc transporter ZIP9, a recently identified androgen receptor, and zinc efflux transporter ZNT1 were investigated, alongside lipid profile and markers of glucose metabolism [insulin degrading enzyme, retinol-binding protein 4 (RBP4), and glucose transporter 4 (GLUT4)]. We find that ZIP14 expression is reduced in obesity and positively correlates with PPARG expression, which is downregulated with increasing BMI. ZNT1 is upregulated in obesity, and both ZIP14 and ZNT1 expression significantly correlates with clinical markers of altered glucose metabolism. In addition, RBP4 and GLUT4 associate with obesity, but an association with PCOS as such was present only for PPARG and RBP4. ZIP14 and ZNT1 does not relate to clinical androgen status and ZIP9 is unaffected by all parameters investigated. In conclusion, our findings support the existence of a zinc dyshomeostasis in adipose tissue in metabolic disturbances including PCOS-related obesity. PMID:28303117

Hyperphagia induced by sucrose: relation to circulating and CSF glucose and corticosterone and orexigenic peptides in the arcuate nucleus.

PubMed

Gaysinskaya, V A; Karatayev, O; Shuluk, J; Leibowitz, S F

2011-01-01

Sucrose-rich diets compared to starch-rich diets are known to stimulate overeating under chronic conditions. The present study in normal-weight rats established an acute "preload-to-test meal" paradigm for demonstrating sucrose-induced hyperphagia and investigating possible mechanisms that mediate this behavioral phenomenon. In this acute paradigm, the rats were first given a small (15 kcal) sucrose preload (30% sucrose) for 30 min compared to an equicaloric, starch preload (25% starch with 5% sucrose) and then allowed to freely consume a subsequent test meal of lab chow. The sucrose preload, when compared to a starch preload equal in energy density and palatability, consistently increased food intake in the subsequent test meal occurring between 60 and 120 min after the end of the preload. Measurements of hormones, metabolites and hypothalamic peptides immediately preceding this hyperphagia revealed marked differences between the sucrose vs starch groups that could contribute to the increase in food intake. Whereas the sucrose group compared to the starch group immediately after the preload (at 10 min) had elevated levels of glucose in serum and cerebrospinal fluid (CSF) along with reduced expressions of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus (ARC), the subsequent effects (at 30-60 min) just preceding the test meal hyperphagia were the reverse. Along with lower levels of glucose, they included markedly elevated serum and CSF levels of corticosterone and mRNA levels of NPY and AgRP in the ARC. In addition to establishing an animal model for sucrose-induced hyperphagia, these results demonstrate peripheral and central mechanisms that may mediate this behavioral phenomenon. Copyright © 2010 Elsevier Inc. All rights reserved.

HYPERPHAGIA INDUCED BY SUCROSE: RELATION TO CIRCULATING AND CSF GLUCOSE AND CORTICOSTERONE AND OREXIGENIC PEPTIDES IN THE ARCUATE NUCLEUS

PubMed Central

Gaysinskaya, V. A.; Karatayev, O.; Shuluk, J.; Leibowitz, S. F.

2010-01-01

Sucrose-rich diets compared to starch-rich diets are known to stimulate overeating under chronic conditions. The present study in normal-weight rats established an acute “preload-to-test meal” paradigm for demonstrating sucrose-induced hyperphagia and investigating possible mechanisms that mediate this behavioral phenomenon. In this acute paradigm, the rats were first given a small (15 kcals) sucrose preload (30% sucrose) for 30 min compared to an equicaloric, starch preload (25% starch with 5% sucrose) and then allowed to freely consume a subsequent test meal of lab chow. The sucrose preload, when compared to a starch preload equal in energy density and palatability, consistently increased food intake in the subsequent test meal occurring between 60–120 min after the end of the preload. Measurements of hormones, metabolites and hypothalamic peptides immediately preceding this hyperphagia revealed marked differences between the sucrose vs starch groups that could contribute to the increase in food intake. Whereas the sucrose group compared to starch group immediately after the preload (at 10 min) had elevated levels of glucose in serum and cerebrospinal fluid (CSF) along with reduced expression of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus (ARC), the subsequent effects (at 30–60 min) just preceding the test meal hyperphagia were the reverse. Along with lower levels of glucose, they included markedly elevated serum and CSF levels of corticosterone and mRNA levels of NPY and AgRP in the ARC. In addition to establishing an animal model for sucrose-induced hyperphagia, these results demonstrate peripheral and central mechanisms that may mediate this behavioral phenomenon. PMID:21036188

Postpartum IGF-I and IGFBP-2 levels are prospectively associated with the development of type 2 diabetes in women with previous gestational diabetes mellitus.

PubMed

Lappas, M; Jinks, D; Shub, A; Willcox, J C; Georgiou, H M; Permezel, M

2016-12-01

Women with previous gestational diabetes mellitus (GDM) are at greater risk of developing type 2 diabetes. In the general population, the insulin-like growth factor (IGF) system has been implicated in the development of type 2 diabetes. The aim of this study was to determine if circulating IGF-I, IGF-II, IGFBP-1 and IGFBP-2 levels 12weeks following a GDM pregnancy are associated with an increased risk of developing type 2 diabetes. IGF-I, IGF-II, IGFBP-1 and IGFBP-2 levels were measured in 98 normal glucose tolerant women, 12weeks following an index GDM pregnancy using enzyme immunoassay. Women were assessed for up to 10years for the development of overt type 2 diabetes. Among the 98 women with previous GDM, 21 (21%) developed diabetes during the median follow-up period of 8.5years. After adjusting for age and BMI, IGF-I and IGFBP-2 were significantly associated with the development of type 2 diabetes. In a clinical model of prediction of type 2 diabetes that included age, BMI, pregnancy fasting glucose and postnatal fasting glucose, the addition of IGF-I and IGFBP-2 resulted in an improvement in the net reclassification index of 17.8%. High postpartum IGF-I and low postpartum IGFBP-2 levels are a significant risk factor for the development of type 2 diabetes in women with a previous history of GDM. This is the first report that identifies IGF-I and IGFBP-2 as a potential biomarker for the prediction of type 2 diabetes in women with a history of GDM. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes.

PubMed

Gómez-Ambrosi, Javier; Pascual, Eider; Catalán, Victoria; Rodríguez, Amaia; Ramírez, Beatriz; Silva, Camilo; Gil, María J; Salvador, Javier; Frühbeck, Gema

2014-10-01

Betatrophin is a secreted protein recently involved in β-cell replication with a potential role in type 2 diabetes mellitus (T2D). The aim of the present study was to compare the circulating concentrations of betatrophin in human obesity and T2D. Serum concentrations of betatrophin were measured by ELISA in 153 subjects: 75 obese normoglycemic subjects (OB-NG), 30 obese subjects with impaired glucose tolerance (OB-IGT), and 15 obese subjects with T2D (OB-T2D) matched by sex, age, and body adiposity, in comparison with 33 lean normoglycemic individuals (LN-NG). Circulating levels of betatrophin were significantly decreased in obese individuals and further diminished in IGT and T2D participants (LN-NG, 45.1 ± 24.4 ng/mL; OB-NG, 26.9 ± 15.4 ng/mL; OB-IGT, 18.3 ± 10.7 ng/mL; OB-T2D, 13.5 ± 8.8 ng/mL; P < .001). A marked sexual dimorphism was found, with betatrophin levels being significantly higher in women than in men (males, 21.1 ± 16.0 ng/mL; females, 34.1 ± 20.1 ng/mL; P < .001). Interestingly, betatrophin levels were positively correlated with the quantitative insulin sensitivity check index (r = 0.46; P < .001) and with high-density lipoprotein-cholesterol concentrations (r = 0.51; P < .001). We conclude that serum betatrophin is decreased in human obesity, being further reduced in obesity-associated insulin resistance. Betatrophin levels are closely related to obesity-associated cardiometabolic risk factors, emerging as a potential biomarker of insulin resistance and T2D.

Natural Killer Cell Activity and Interleukin-12 in Metabolically Healthy versus Metabolically Unhealthy Overweight Individuals

PubMed Central

Kim, Minjoo; Kim, Minkyung; Yoo, Hye Jin; Lee, Jong Ho

2017-01-01

The purpose of this study was to determine whether the immune system is involved in the different metabolic circumstances in healthy and unhealthy overweight individuals. We examined the metabolic and immune characteristics of 117 overweight individuals. Subjects were classified as metabolically healthy overweight (MHO, n = 72) or metabolically unhealthy overweight (MUO, n = 45). The immune response was measured by circulating levels of natural killer (NK) cell activity and cytokines. Both groups were comparable with regards to age, sex distribution, smoking and drinking status, and body mass index. When compared to the MHO group, the MUO group showed higher systolic and diastolic blood pressure, serum levels of triglyceride, glucose, glucose-related markers, and lower levels of HDL cholesterol. Compared to the MHO group, the MUO group showed 39% lower interferon-γ levels (not significant) and 41% lower interleukin (IL)-12 levels (significant). The MUO group also showed lower NK cell activity at E:T ratios of 10:1, 5:1, 2.5:1, and 1.25:1 (all Ps < 0.05) than the MHO group. This study indicates that individuals displaying the MUO phenotype present an unfavorable immune system with lower NK cell activities under all assay conditions and lower serum levels of IL-12 than the activities and levels in similarly overweight MHO individuals. This result suggests that the immune system may be altered in overweight individuals who are at risk for overweight/obesity-related comorbidities. PMID:29238351

Metabolic factors, adipose tissue, and plasminogen activator inhibitor-1 levels in type 2 diabetes: findings from the look AHEAD study.

PubMed

Belalcazar, L Maria; Ballantyne, Christie M; Lang, Wei; Haffner, Steven M; Rushing, Julia; Schwenke, Dawn C; Pi-Sunyer, F Xavier; Tracy, Russell P

2011-07-01

Plasminogen activator inhibitor-1 (PAI-1) production by adipose tissue is increased in obesity, and its circulating levels are high in type 2 diabetes. PAI-1 increases cardiovascular risk by favoring clot stability, interfering with vascular remodeling, or both. We investigated in obese diabetic persons whether an intensive lifestyle intervention for weight loss (ILI) would decrease PAI-1 levels independently of weight loss and whether PAI-1 reduction would be associated with changes in fibrinogen, an acute phase reactant, or fibrin fragment D-dimer (D-dimer), a marker of ambient coagulation balance. We examined 1-year changes in PAI-1, D-dimer, and fibrinogen levels; adiposity; fitness; glucose; and lipid control with ILI in 1817 participants from Look AHEAD, a randomized trial investigating the effects of ILI, compared with usual care, on cardiovascular events in overweight or obese diabetic persons. Median PAI-1 levels decreased 29% with ILI and 2.5% with usual care (P < 0.0001). Improvements in fitness, glucose control, and high-density lipoprotein cholesterol were associated with decreased PAI-1, independently of weight loss (P = 0.03 for fitness, P < 0.0001 for others). Fibrinogen and D-dimer remained unchanged. Reductions in PAI-1 levels with ILI in obese diabetic individuals may reflect an improvement in adipose tissue health that could affect cardiovascular risk without changing fibrinogen or d-dimer levels. Clinical Trial Registration- URL: http://clinicaltrials.gov/ct2/show/NCT00017953. Unique identifier: NCT00017953.

Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp

PubMed Central

Farmer, Tiffany D.; Jenkins, Erin C.; O'Brien, Tracy P.; McCoy, Gregory A.; Havlik, Allison E.; Nass, Erik R.; Nicholson, Wendell E.; Printz, Richard L.

2014-01-01

To understand the underlying pathology of metabolic diseases, such as diabetes, an accurate determination of whole body glucose flux needs to be made by a method that maintains key physiological features. One such feature is a positive differential in insulin concentration between the portal venous and systemic arterial circulation (P/S-IG). P/S-IG during the determination of the relative contribution of liver and extra-liver tissues/organs to whole body glucose flux during an insulin clamp with either systemic (SID) or portal (PID) insulin delivery was examined with insulin infusion rates of 1, 2, and 5 mU·kg−1·min−1 under either euglycemic or hyperglycemic conditions in 6-h-fasted conscious normal rats. A P/S-IG was initially determined with endogenous insulin secretion to exist with a value of 2.07. During an insulin clamp, while inhibiting endogenous insulin secretion by somatostatin, P/S-IG remained at 2.2 with PID, whereas, P/S-IG disappeared completely with SID, which exhibited higher arterial and lower portal insulin levels compared with PID. Consequently, glucose disappearance rates and muscle glycogen synthetic rates were higher, but suppression of endogenous glucose production and liver glycogen synthetic rates were lower with SID compared with PID. When the insulin clamp was performed with SID at 2 and 5 mU·kg−1·min−1 without managing endogenous insulin secretion under euglycemic but not hyperglycemic conditions, endogenous insulin secretion was completely suppressed with SID, and the P/S-IG disappeared. Thus, compared with PID, an insulin clamp with SID underestimates the contribution of liver in response to insulin to whole body glucose flux. PMID:25516552

Effect of Peripheral 5-HT on Glucose and Lipid Metabolism in Wether Sheep

PubMed Central

Watanabe, Hitoshi; Saito, Ryo; Nakano, Tatsuya; Takahashi, Hideyuki; Takahashi, Yu; Sumiyoshi, Keisuke; Sato, Katsuyoshi; Chen, Xiangning; Okada, Natsumi; Iwasaki, Shunsuke; Harjanti, Dian W.; Sekiguchi, Natsumi; Sano, Hiroaki; Kitazawa, Haruki; Rose, Michael T.; Ohwada, Shyuichi; Watanabe, Kouichi; Aso, Hisashi

2014-01-01

In mice, peripheral 5-HT induces an increase in the plasma concentrations of glucose, insulin and bile acids, and a decrease in plasma triglyceride, NEFA and cholesterol concentrations. However, given the unique characteristics of the metabolism of ruminants relative to monogastric animals, the physiological role of peripheral 5-HT on glucose and lipid metabolism in sheep remains to be established. Therefore, in this study, we investigated the effect of 5-HT on the circulating concentrations of metabolites and insulin using five 5-HT receptor (5HTR) antagonists in sheep. After fasting for 24 h, sheep were intravenously injected with 5-HT, following which-, plasma glucose, insulin, triglyceride and NEFA concentrations were significantly elevated. In contrast, 5-HT did not affect the plasma cholesterol concentration, and it induced a decrease in bile acid concentrations. Increases in plasma glucose and insulin concentrations induced by 5-HT were attenuated by pre-treatment with Methysergide, a 5HTR 1, 2 and 7 antagonist. Additionally, decreased plasma bile acid concentrations induced by 5-HT were blocked by pre-treatment with Ketanserin, a 5HTR 2A antagonist. However, none of the 5HTR antagonists inhibited the increase in plasma triglyceride and NEFA levels induced by 5-HT. On the other hand, mRNA expressions of 5HTR1D and 1E were observed in the liver, pancreas and skeletal muscle. These results suggest that there are a number of differences in the physiological functions of peripheral 5-HT with respect to lipid metabolism between mice and sheep, though its effect on glucose metabolism appears to be similar between these species. PMID:24505376

The l-α-Lysophosphatidylinositol/GPR55 System and Its Potential Role in Human Obesity

PubMed Central

Moreno-Navarrete, José María; Catalán, Victoria; Whyte, Lauren; Díaz-Arteaga, Adenis; Vázquez-Martínez, Rafael; Rotellar, Fernando; Guzmán, Rocío; Gómez-Ambrosi, Javier; Pulido, Marina R.; Russell, Wendy R.; Imbernón, Mónica; Ross, Ruth A.; Malagón, María M.; Dieguez, Carlos; Fernández-Real, José Manuel; Frühbeck, Gema; Nogueiras, Ruben

2012-01-01

GPR55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. We investigated 1) whether GPR55 is expressed in fat and liver; 2) the correlation of both GPR55 and LPI with several metabolic parameters; and 3) the actions of LPI on human adipocytes. We analyzed CB1, CB2, and GPR55 gene expression and circulating LPI levels in two independent cohorts of obese and lean subjects, with both normal or impaired glucose tolerance and type 2 diabetes. Ex vivo experiments were used to measure intracellular calcium and lipid accumulation. GPR55 levels were augmented in the adipose tissue of obese subjects and further so in obese patients with type 2 diabetes when compared with nonobese subjects. Visceral adipose tissue GPR55 correlated positively with weight, BMI, and percent fat mass, particularly in women. Hepatic GPR55 gene expression was similar in obese and type 2 diabetic subjects. Circulating LPI levels were increased in obese patients and correlated with fat percentage and BMI in women. LPI increased the expression of lipogenic genes in visceral adipose tissue explants and intracellular calcium in differentiated visceral adipocytes. These findings indicate that the LPI/GPR55 system is positively associated with obesity in humans. PMID:22179809

TNFα dynamics during the oral glucose tolerance test vary according to the level of insulin resistance in pregnant women.

PubMed

Guillemette, Laetitia; Lacroix, Marilyn; Battista, Marie-Claude; Doyon, Myriam; Moreau, Julie; Ménard, Julie; Ardilouze, Jean-Luc; Perron, Patrice; Hivert, Marie-France

2014-05-01

TNFα is suspected to play a role in inflammation and insulin resistance leading to higher risk of metabolic impairment. Controversies exist concerning the role of TNFα in gestational insulin resistance. We investigated the interrelations between TNFα and insulin resistance in a large population-based cohort of pregnant women. Women (n = 756) were followed prospectively at 5-16 weeks and 24-28 weeks of pregnancy. Anthropometric measures and blood samples were collected at both visits. A 75-g oral glucose tolerance test (OGTT) was conducted at the second trimester to assess insulin sensitivity status (homeostasis model of assessment of insulin resistance and Matsuda index). TNFα was measured at the first trimester (nonfasting) and at each time point of the OGTT. Participants were 28.4 ± 4.4 years old and had a mean body mass index of 25.5 ± 5.5 kg/m(2) at first trimester. Median TNFα levels were 1.56 (interquartile range, 1.18-2.06) pg/mL at first trimester and 1.61 (interquartile range, 1.12-2.13) pg/mL at second trimester (1 h after glucose load). At second trimester, higher TNFα levels were associated with higher insulin resistance index levels (r = 0.37 and -0.30 for homeostasis model of assessment of insulin resistance and Matsuda index, respectively; P < .0001), even after adjustment for age, body mass index, triglycerides, and adiponectin. Women with higher insulin resistance showed a continuing decrease in TNFα levels during the OGTT, whereas women who were more insulin sensitive showed an increase in TNFα at hour 1 and a decrease at hour 2 of the test. Higher insulin resistance is associated with higher levels of circulating TNFα at first and second trimesters of pregnancy. TNFα level dynamics during an OGTT at second trimester vary according to insulin-resistance state.

Proteomic profiling of non-obese type 2 diabetic skeletal muscle.

PubMed

Mullen, Edel; Ohlendieck, Kay

2010-03-01

Abnormal glucose handling has emerged as a major clinical problem in millions of diabetic patients worldwide. Insulin resistance affects especially one of the main target organs of this hormone, the skeletal musculature, making impaired glucose metabolism in contractile fibres a major feature of type 2 diabetes. High levels of circulating free fatty acids, an increased intramyocellular lipid content, impaired insulin-mediated glucose uptake, diminished mitochondrial functioning and an overall weakened metabolic flexibility are pathobiochemical hallmarks of diabetic skeletal muscles. In order to increase our cellular understanding of the molecular mechanisms that underlie this complex diabetes-associated skeletal muscle pathology, we initiated herein a mass spectrometry-based proteomic analysis of skeletal muscle preparations from the non-obese Goto-Kakizaki rat model of type 2 diabetes. Following staining of high-resolution two-dimensional gels with colloidal Coomassie Blue, 929 protein spots were detected, whereby 21 proteins showed a moderate differential expression pattern. Decreased proteins included carbonic anhydrase, 3-hydroxyisobutyrate dehydrogenase and enolase. Increased proteins were identified as monoglyceride lipase, adenylate kinase, Cu/Zn superoxide dismutase, phosphoglucomutase, aldolase, isocitrate dehydrogenase, cytochrome c oxidase, small heat shock Hsp27/B1, actin and 3-mercaptopyruvate sulfurtransferase. These proteomic findings suggest that the diabetic phenotype is associated with a generally perturbed protein expression pattern, affecting especially glucose, fatty acid, nucleotide and amino acid metabolism, as well as the contractile apparatus, the cellular stress response, the anti-oxidant defense system and detoxification mechanisms. The altered expression levels of distinct skeletal muscle proteins, as documented in this study, might be helpful for the future establishment of a comprehensive biomarker signature of type 2 diabetes. Reliable markers could be used for improving diagnostics, monitoring of disease progression and therapeutic evaluations.

Effects of chronic sugar consumption on lipid accumulation and autophagy in the skeletal muscle.

PubMed

De Stefanis, Daniela; Mastrocola, Raffaella; Nigro, Debora; Costelli, Paola; Aragno, Manuela

2017-02-01

In recent years, the increasing consumption of soft drinks containing high-fructose corn syrup or sucrose has caused a rise in fructose intake, which has been related to the epidemic of metabolic diseases. As fructose and glucose intake varies in parallel, it is still unclear what the effects of the increased consumption of the two single sugars are. In the present study, the impact of chronic consumption of glucose or fructose on skeletal muscle of healthy mice was investigated. C57BL/6J male mice received water (C), 15 % fructose (ChF) or 15 % glucose (ChG) to drink for up to 7 months. Lipid metabolism and markers of inflammation and autophagy were assessed in gastrocnemius muscle. Increased body weight and gastrocnemius muscle mass, as well as circulating glucose, insulin, and lipid plasma levels were observed in sugar-drinking mice. Although triglycerides increased in the gastrocnemius muscle of both ChF and ChG mice (+32 and +26 %, vs C, respectively), intramyocellular lipids accumulated to a significantly greater extent in ChF than in ChG animals (ChF +10 % vs ChG). Such perturbations were associated with increased muscle interleukin-6 levels (threefold of C) and with the activation of autophagy, as demonstrated by the overexpression of LC3B-II (ChF, threefold and ChG, twofold of C) and beclin-1 (ChF, sevenfold and ChG, tenfold of C). The present results suggest that intramyocellular lipids and the pro-inflammatory signaling could contribute to the onset of insulin resistance and lead to the induction of autophagy, which could be an adaptive response to lipotoxicity.

Associations among circulating branched-chain amino acids and tyrosine with muscle volume and glucose metabolism in individuals without diabetes.

PubMed

Honda, Tatsuro; Kobayashi, Yoshinao; Togashi, Kenji; Hasegawa, Hiroshi; Iwasa, Motoh; Taguchi, Osamu; Takei, Yoshiyuki; Sumida, Yasuhiro

2016-05-01

Amino acid metabolites, including branched-chain amino acids (BCAA) and tyrosine (Tyr), affect glucose metabolism. The effects of BCAA on insulin resistance in patients with diabetes seem to conflict with mechanisms determined in animal models and cultured cells. The aim of this study was to clarify the controversy surrounding the effects of BCAA by investigating the physiological effects of BCAA and Tyr on glucose metabolism in healthy community dwellers. We investigated associations among BCAA and Tyr and metabolic parameters in 78 residents (median age, 52 y) of Mie, Japan, who did not have prediabetes, diabetes, or a body mass index >30 kg/m(2). Muscle volume, serum BCAA, and Tyr levels were higher in men than in women (n = 32 and 46, respectively; all P < 0.0001). Stepwise multiple regression analysis associated BCAA positively with muscle volume (regression coefficient/t/p/95% confidence interval, 281.8/3.7/0.0004/129.7-433.8), fasting blood glucose (FBG; 12699.4/3.22/0.0020/4830.9-20567.8), fasting immunoreactive insulin (IRI; 8505.1/2.75/0.0078/2322.5-14687.6), and homeostasis model assessment of β-cell function (HOMA-β; 893.6/2.58/0.0122/201.8-1585.5), and negatively with the HOMA-insulin resistance (HOMA-IR; -9294.1/-2.89/0.0052/-15711.0 to -2877.1). Tyr positively correlated with fasting IRI (26/2.77/0.0072/7.3-44.7). Insulin sensitivity and muscle volume are positively associated with BCAA in individuals without diabetes. In turn, BCAA correlate with increased FBG and fasting IRI levels. Tyr correlated with fasting IRI, but not with insulin sensitivity. Copyright © 2016 Elsevier Inc. All rights reserved.

The postprandial state and risk of cardiovascular disease.

PubMed

Lefèbvre, P J; Scheen, A J

1998-01-01

Metabolism in man is regulated by complex hormonal signals and substrate interactions, and for many years the clinical focus has centred on the metabolic and hormonal picture after an overnight fast. More recently, the postprandial state, i.e. 'the period that comprises and follows a meal', has received more attention. The oral glucose tolerance test (OGTT), although highly non-physiological, has been used largely as a model of the postprandial state. Epidemiological studies have shown that, when 'impaired', oral glucose tolerance is associated with an increased risk of cardiovascular disease. Postprandial hyperlipidaemia has been investigated more recently in epidemiological, mechanistical and intervention studies, most of which indicate that high postprandial triglyceride levels, and particularly postprandial rich triglyceride remnants, constitute an increased risk for cardiovascular disease. Recent studies have shown that excessive postprandial glucose excursions are accompanied by oxidative stress and, less well known, activation of blood coagulation (increase in circulating D-dimers and prothrombin fragments). The mechanisms through which increased postprandial glucose levels and lipid concentrations may damage endothelial cells on blood vessel walls appear to be complex. These mechanisms include the activation of protein kinase C, increased expression of adhesion molecules, increased adhesion and uptake of leucocytes, increased production of proliferative substances such as endothelin, increased proliferation of endothelial cells, increased synthesis of collagen IV and fibronectin, and decreased production of nitric oxide (NO). In conclusion, the 'postprandial state' cumulatively covers almost half of the nycthemeral period, and its physiology involves numerous finely regulated motor, secretory, hormonal and metabolic events. Epidemiological and mechanistical studies have suggested that perturbations of the postprandial state are involved in cardiovascular disease. Correcting the abnormalities of the postprandial state must form part of the strategy for the prevention and management of cardiovascular diseases, particularly those that are associated with diabetes mellitus.

Common genetic variation in the SERPINF1 locus determines overall adiposity, obesity-related insulin resistance, and circulating leptin levels.

PubMed

Böhm, Anja; Ordelheide, Anna-Maria; Machann, Jürgen; Heni, Martin; Ketterer, Caroline; Machicao, Fausto; Schick, Fritz; Stefan, Norbert; Fritsche, Andreas; Häring, Hans-Ulrich; Staiger, Harald

2012-01-01

Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥ 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.

Circulating Adipokines and Vascular Function: Cross-Sectional Associations in a Community-Based Cohort.

PubMed

Zachariah, Justin P; Hwang, Susan; Hamburg, Naomi M; Benjamin, Emelia J; Larson, Martin G; Levy, Daniel; Vita, Joseph A; Sullivan, Lisa M; Mitchell, Gary F; Vasan, Ramachandran S

2016-02-01

Adipokines may be potential mediators of the association between excess adiposity and vascular dysfunction. We assessed the cross-sectional associations of circulating adipokines with vascular stiffness in a community-based cohort of younger adults. We related circulating concentrations of leptin and leptin receptor, adiponectin, retinol-binding protein 4, and fatty acid-binding protein 4 to vascular stiffness measured by arterial tonometry in 3505 Framingham Third Generation cohort participants free of cardiovascular disease (mean age 40 years, 53% women). Separate regression models estimated the relations of each adipokine to mean arterial pressure and aortic stiffness, as carotid femoral pulse wave velocity, adjusting for age, sex, smoking, heart rate, height, antihypertensive treatment, total and high-density lipoprotein cholesterol, diabetes mellitus, alcohol consumption, estimated glomerular filtration rate, glucose, and C-reactive protein. Models evaluating aortic stiffness also were adjusted for mean arterial pressure. Mean arterial pressure was positively associated with blood retinol-binding protein 4, fatty acid-binding protein 4, and leptin concentrations (all P<0.001) and inversely with adiponectin (P=0.002). In fully adjusted models, mean arterial pressure was positively associated with retinol-binding protein 4 and leptin receptor levels (P<0.002 both). In fully adjusted models, aortic stiffness was positively associated with fatty acid-binding protein 4 concentrations (P=0.02), but inversely with leptin and leptin receptor levels (P≤0.03 both). In our large community-based sample, circulating concentrations of select adipokines were associated with vascular stiffness measures, consistent with the hypothesis that adipokines may influence vascular function and may contribute to the relation between obesity and hypertension. © 2015 American Heart Association, Inc.

Increased gluconeogenesis in hyper-G stressed rats

NASA Technical Reports Server (NTRS)

Daligcon, B. C.; Oyama, J.

1982-01-01

The role of gluconeogenesis in the altered carbohydrate metabolism in rats exposed to hyper-G stress is investigated. The blood levels of the substrates and hormones involved in gluconeogenesis were determined in rats exposed to 3.1 G for various time periods (0.25 to 24 hr). It is found that hyper-G stressed rats showed an immediate increase in plasma glucose at the onset of centrifugation which persisted throughout all the exposure periods. A substantial part of the initial rise in blood glucose is attributed to an increased rate of gluconeogenesis. An increase in liver glycogen deposition was observed in centrifuged rats as early as 0.50 hr exposure time, with progressively larger amounts accumulated as the exposure time was extended to 24 hr. It is concluded that the increase in gluconeogenic activity of hyper-G stressed rats is due to an increase in the mobilization of gluconeogenic substrates from perpheral tissues to the liver as a result of increases in circulating catecholamines and glucagon.

Circulating leptin and adiponectin are associated with insulin resistance in healthy postmenopausal women with hot flashes

PubMed Central

Huang, Wan-Yu; Chang, Chia-Chu; Chen, Dar-Ren; Kor, Chew-Teng; Chen, Ting-Yu; Wu, Hung-Ming

2017-01-01

Introduction Hot flashes have been postulated to be linked to the development of metabolic disorders. This study aimed to evaluate the relationship between hot flashes, adipocyte-derived hormones, and insulin resistance in healthy, non-obese postmenopausal women. Participants and design In this cross-sectional study, a total of 151 women aged 45–60 years were stratified into one of three groups according to hot-flash status over the past three months: never experienced hot flashes (Group N), mild-to-moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, fasting levels of circulating glucose, lipid profiles, plasma insulin, and adipocyte-derived hormones. Multiple linear regression analysis was used to evaluate the associations of hot flashes with adipocyte-derived hormones, and with insulin resistance. Settings The study was performed in a hospital medical center. Results The mean (standard deviation) of body-mass index was 22.8(2.7) for Group N, 22.6(2.6) for Group M, and 23.5(2.4) for Group S, respectively. Women in Group S displayed statistically significantly higher levels of leptin, fasting glucose, and insulin, and lower levels of adiponectin than those in Groups M and N. Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with higher leptin levels, lower adiponectin levels, and higher leptin-to-adiponectin ratio. Univariate linear regression analysis revealed that hot-flash severity was strongly associated with a higher HOMA-IR index (% difference, 58.03%; 95% confidence interval, 31.00–90.64; p < 0.001). The association between hot flashes and HOMA-IR index was attenuated after adjusting for leptin or adiponectin and was no longer significant after simultaneously adjusting for leptin and adiponectin. Conclusion The present study provides evidence that hot flashes are associated with insulin resistance in postmenopausal women. It further suggests that hot flash association with insulin resistance is dependent on the combination of leptin and adiponectin variables. PMID:28448547

Glucose-stimulated insulin response in pregnant sheep following acute suppression of plasma non-esterified fatty acid concentrations

PubMed Central

Regnault, Timothy RH; Oddy, Hutton V; Nancarrow, Colin; Sriskandarajah, Nadarajah; Scaramuzzi, Rex J

2004-01-01

Background Elevated non-esterified fatty acids (NEFA) concentrations in non-pregnant animals have been reported to decrease pancreatic responsiveness. As ovine gestation advances, maternal insulin concentrations fall and NEFA concentrations increase. Experiments were designed to examine if the pregnancy-associated rise in NEFA concentration is associated with a reduced pancreatic sensitivity to glucose in vivo. We investigated the possible relationship of NEFA concentrations in regulating maternal insulin concentrations during ovine pregnancy at three physiological states, non-pregnant, non-lactating (NPNL), 105 and 135 days gestational age (dGA, term 147+/- 3 days). Methods The plasma concentrations of insulin, growth hormone (GH) and ovine placental lactogen (oPL) were determined by double antibody radioimmunoassay. Insulin responsiveness to glucose was measured using bolus injection and hyperglycaemic clamp techniques in 15 non-pregnant, non-lactating ewes and in nine pregnant ewes at 105 dGA and near term at 135 dGA. Plasma samples were also collected for hormone determination. In addition to bolus injection glucose and insulin Area Under Curve calculations, the Mean Plasma Glucose Increment, Glucose Infusion Rate and Mean Plasma Insulin Increment and Area Under Curve were determined for the hyperglycaemic clamp procedures. Statistical analysis of data was conducted with Students t-tests, repeated measures ANOVA and 2-way ANOVA. Results Maternal growth hormone, placental lactogen and NEFA concentrations increased, while basal glucose and insulin concentrations declined with advancing gestation. At 135 dGA following bolus glucose injections, peak insulin concentrations and insulin area under curve (AUC) profiles were significantly reduced in pregnant ewes compared with NPNL control ewes (p < 0.001 and P < 0.001, respectively). In hyperglycaemic clamp studies, while maintaining glucose levels not different from NPNL ewes, pregnant ewes displayed significantly reduced insulin responses and a maintained depressed insulin secretion. In NPNL ewes, 105 and 135 dGA ewes, the Glucose Infusion Rate (GIR) was constant at approximately 5.8 mg glucose/kg/min during the last 40 minutes of the hyperglycaemic clamp and the Mean Plasma Insulin Increment (MPII) was only significantly (p < 0.001) greater in NPNL ewes. Following the clamp, NEFA concentrations were reduced by approximately 60% of pre-clamp levels in all groups, though a blunted and suppressed insulin response was maintained in 105 and 135 dGA ewes. Conclusions Results suggest that despite an acute suppression of circulating NEFA concentrations during pregnancy, the associated steroids and hormones of pregnancy and possibly NEFA metabolism, may act to maintain a reduced insulin output, thereby sparing glucose for non-insulin dependent placental uptake and ultimately, fetal requirements. PMID:15352999

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

PubMed Central

Strawbridge, Rona J.; Dupuis, Josée; Prokopenko, Inga; Barker, Adam; Ahlqvist, Emma; Rybin, Denis; Petrie, John R.; Travers, Mary E.; Bouatia-Naji, Nabila; Dimas, Antigone S.; Nica, Alexandra; Wheeler, Eleanor; Chen, Han; Voight, Benjamin F.; Taneera, Jalal; Kanoni, Stavroula; Peden, John F.; Turrini, Fabiola; Gustafsson, Stefan; Zabena, Carina; Almgren, Peter; Barker, David J.P.; Barnes, Daniel; Dennison, Elaine M.; Eriksson, Johan G.; Eriksson, Per; Eury, Elodie; Folkersen, Lasse; Fox, Caroline S.; Frayling, Timothy M.; Goel, Anuj; Gu, Harvest F.; Horikoshi, Momoko; Isomaa, Bo; Jackson, Anne U.; Jameson, Karen A.; Kajantie, Eero; Kerr-Conte, Julie; Kuulasmaa, Teemu; Kuusisto, Johanna; Loos, Ruth J.F.; Luan, Jian'an; Makrilakis, Konstantinos; Manning, Alisa K.; Martínez-Larrad, María Teresa; Narisu, Narisu; Nastase Mannila, Maria; Öhrvik, John; Osmond, Clive; Pascoe, Laura; Payne, Felicity; Sayer, Avan A.; Sennblad, Bengt; Silveira, Angela; Stančáková, Alena; Stirrups, Kathy; Swift, Amy J.; Syvänen, Ann-Christine; Tuomi, Tiinamaija; van 't Hooft, Ferdinand M.; Walker, Mark; Weedon, Michael N.; Xie, Weijia; Zethelius, Björn; Ongen, Halit; Mälarstig, Anders; Hopewell, Jemma C.; Saleheen, Danish; Chambers, John; Parish, Sarah; Danesh, John; Kooner, Jaspal; Östenson, Claes-Göran; Lind, Lars; Cooper, Cyrus C.; Serrano-Ríos, Manuel; Ferrannini, Ele; Forsen, Tom J.; Clarke, Robert; Franzosi, Maria Grazia; Seedorf, Udo; Watkins, Hugh; Froguel, Philippe; Johnson, Paul; Deloukas, Panos; Collins, Francis S.; Laakso, Markku; Dermitzakis, Emmanouil T.; Boehnke, Michael; McCarthy, Mark I.; Wareham, Nicholas J.; Groop, Leif; Pattou, François; Gloyn, Anna L.; Dedoussis, George V.; Lyssenko, Valeriya; Meigs, James B.; Barroso, Inês; Watanabe, Richard M.; Ingelsson, Erik; Langenberg, Claudia; Hamsten, Anders; Florez, Jose C.

2011-01-01

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. PMID:21873549

Circulatory changes of the novel adipokine adipolin/CTRP12 in response to metformin treatment and an oral glucose challenge in humans.

PubMed

Tan, Bee K; Chen, Jing; Hu, Jiamiao; Amar, Omar; Mattu, Harman S; Ramanjaneya, Manjunath; Patel, Vanlata; Lehnert, Hendrik; Randeva, Harpal S

2014-12-01

Adipolin/CTRP12 is a novel adipokine with anti-inflammatory and glucose-lowering properties in rodents. We sought to investigate the effects of metformin treatment (850 mg twice daily for 6 months) and a 2 h 75 g oral glucose tolerance test (OGTT) on serum adipolin concentrations in humans. Cross-sectional study [PCOS (n = 83) and control (n = 39) subjects]. Serum adipolin was measured by ELISA. Metformin treatment (850 mg twice daily for 6 months) was offered to all women with PCOS, 34 women participated but 21 women completed 6 months of metformin therapy. Reasons for subjects not completing the study were nausea and gastrointestinal side effects (n = 4), pregnancies (n = 5), noncompliance (n = 2) and loss of contact (n = 2). Metformin treatment (850 mg twice daily for 6 months) substantially increased serum adipolin concentrations (P < 0·05) in women with polycystic ovary syndrome (PCOS), a pro-inflammatory state associated with obesity, diabetes, dyslipidaemia and atherosclerosis. Furthermore, changes in waist-hip ratio, glucose, triglycerides, CRP and carotid intima media thickness showed significant negative associations with changes in adipolin levels (P < 0·05, P < 0·01); in multiple regression analyses, only changes in glucose were predictive of changes in adipolin levels (β = -0·570, P = 0·009). Serum adipolin decreased significantly in response to the OGTT in PCOS and control subjects at 90 min (P < 0·05) and 120 min (P < 0·01). Adipolin and/or novel pharmacologic agents that increase adipolin's circulating concentrations might constitute a novel approach in the treatment of insulin resistant states. © 2014 John Wiley & Sons Ltd.

Effect of Urtica dioica on memory dysfunction and hypoalgesia in an experimental model of diabetic neuropathy.

PubMed

Patel, Sita Sharan; Udayabanu, M

2013-09-27

Diabetic neuropathy is considered as a disease of the peripheral nervous system, but recent evidences suggest the involvement of central nervous system as well. In this study we evaluated the effect of Urtica dioica (UD) extract against memory dysfunction and hypoalgesia on a mouse model of streptozotocin (STZ) induced diabetic neuropathy. STZ (50 mg/kg, i.p. consecutively for 5 days) was used to induce diabetes, followed by treatment with the UD extract (50 mg/kg, oral) and rosiglitazone (5 mg/kg, oral) for 8 weeks. Cognitive functions were evaluated using Morris water maze and passive avoidance step through task. Pain thresholds were measured using thermal, mechanical and chemical induced hyperalgesia. We observed that chronic diabetes resulted in a decline in circulating insulin level, elevated blood glucose, reduced body weight, increased water intake, cognitive impairment and hypoalgesia. UD significantly reduced the blood glucose and polydypsia, as well as improved the body weight, insulin level, cognition and insensate neuropathy. In conclusion, UD showed results comparable to rosiglitazone in reversing the long standing diabetes induced complications such as central and peripheral neuronal dysfunction. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Nutritional effects on T-cell immunometabolism

PubMed Central

Cohen, Sivan; Danzaki, Keiko; MacIver, Nancie J.

2017-01-01

T cells are highly influenced by nutrient uptake from their environment, and changes in overall nutritional status, such as malnutrition or obesity, can result in altered T-cell metabolism and behavior. In states of severe malnutrition or starvation, T-cell survival, proliferation, and inflammatory cytokine production are all decreased, as is T-cell glucose uptake and metabolism. The altered T-cell function and metabolism seen in malnutrition is associated with altered adipokine levels, most particularly decreased leptin. Circulating leptin levels are low in malnutrition, and leptin has been shown to be a key link between nutrition and immunity. The current view is that leptin signaling is required to upregulate activated T-cell glucose metabolism and thereby fuel T-cell activation. In the setting of obesity, T cells have been found to have a key role in promoting the recruitment of inflammatory macrophages to adipose depots along with the production of inflammatory cytokines that promote the development of insulin resistance leading to diabetes. Deletion of T cells, key T-cell transcription factors, or pro-inflammatory T-cell cytokines prevents insulin resistance in obesity and underscores the importance of T cells in obesity-associated inflammation and metabolic disease. Altogether, T cells have a critical role in nutritional immunometabolism. PMID:28054344

Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort.

PubMed

Org, Elin; Blum, Yuna; Kasela, Silva; Mehrabian, Margarete; Kuusisto, Johanna; Kangas, Antti J; Soininen, Pasi; Wang, Zeneng; Ala-Korpela, Mika; Hazen, Stanley L; Laakso, Markku; Lusis, Aldons J

2017-04-13

The gut microbiome is a complex and metabolically active community that directly influences host phenotypes. In this study, we profile gut microbiota using 16S rRNA gene sequencing in 531 well-phenotyped Finnish men from the Metabolic Syndrome In Men (METSIM) study. We investigate gut microbiota relationships with a variety of factors that have an impact on the development of metabolic and cardiovascular traits. We identify novel associations between gut microbiota and fasting serum levels of a number of metabolites, including fatty acids, amino acids, lipids, and glucose. In particular, we detect associations with fasting plasma trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite associated with coronary artery disease and stroke. We further investigate the gut microbiota composition and microbiota-metabolite relationships in subjects with different body mass index and individuals with normal or altered oral glucose tolerance. Finally, we perform microbiota co-occurrence network analysis, which shows that certain metabolites strongly correlate with microbial community structure and that some of these correlations are specific for the pre-diabetic state. Our study identifies novel relationships between the composition of the gut microbiota and circulating metabolites and provides a resource for future studies to understand host-gut microbiota relationships.

Gender Differences in Skeletal Muscle Substrate Metabolism – Molecular Mechanisms and Insulin Sensitivity

PubMed Central

Lundsgaard, Anne-Marie; Kiens, Bente

2014-01-01

It has become increasingly apparent that substrate metabolism is subject to gender-specific regulation, and the aim of this review is to outline the available evidence of molecular gender differences in glucose and lipid metabolism of skeletal muscle. Female sex has been suggested to have a favorable effect on glucose homeostasis, and the available evidence from hyperinsulinemic–euglycemic clamp studies is summarized to delineate whether there is a gender difference in whole-body insulin sensitivity and in particular insulin-stimulated glucose uptake of skeletal muscle. Whether an eventual higher insulin sensitivity of female skeletal muscle can be related to gender-specific regulation of molecular metabolism will be topic for discussion. Gender differences in muscle fiber type distribution and substrate availability to and in skeletal muscle are highly relevant for substrate metabolism in men and women. In particular, the molecular machinery for glucose and fatty acid oxidative and storage capacities in skeletal muscle and its implications for substrate utilization during metabolic situations of daily living are discussed, emphasizing their relevance for substrate choice in the fed and fasted state, and during periods of physical activity and recovery. Together, handling of carbohydrate and lipids and regulation of their utilization in skeletal muscle have implications for whole-body glucose homeostasis in men and women. 17-β estradiol is the most important female sex hormone, and the identification of estradiol receptors in skeletal muscle has opened for a role in regulation of substrate metabolism. Also, higher levels of circulating adipokines as adiponectin and leptin in women and their implications for muscle metabolism will be considered. PMID:25431568

Berries and anthocyanins: promising functional food ingredients with postprandial glycaemia-lowering effects.

PubMed

Castro-Acosta, Monica L; Lenihan-Geels, Georgia N; Corpe, Christopher P; Hall, Wendy L

2016-08-01

The prevalence of type 2 diabetes (T2D) is predicted to reach unprecedented levels in the next few decades. In addition to excess body weight, there may be other overlapping dietary drivers of impaired glucose homeostasis that are associated with an obesogenic diet, such as regular exposure to postprandial spikes in blood glucose arising from diets dominated by highly refined starches and added sugars. Strategies to reduce postprandial hyperglycaemia by optimising the functionality of foods would strengthen efforts to reduce the risk of T2D. Berry bioactives, including anthocyanins, are recognised for their inhibitory effects on carbohydrate digestion and glucose absorption. Regular consumption of berries has been associated with a reduction in the risk of T2D. This review aims to examine the evidence from in vitro, animal and human studies, showing that berries and berry anthocyanins may act in the gut to modulate postprandial glycaemia. Specifically, berry extracts and anthocyanins inhibit the activities of pancreatic α-amylase and α-glucosidase in the gut lumen, and interact with intestinal sugar transporters, sodium-dependent glucose transporter 1 and GLUT2, to reduce the rate of glucose uptake into the circulation. Growing evidence from randomised controlled trials suggests that berry extracts, purées and nectars acutely inhibit postprandial glycaemia and insulinaemia following oral carbohydrate loads. Evidence to date presents a sound basis for exploring the potential for using berries/berry extracts as an additional stratagem to weight loss, adherence to dietary guidelines and increasing physical exercise, for the prevention of T2D.

Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes.

PubMed

Chorell, Elin; Hall, Ulrika Andersson; Gustavsson, Carolina; Berntorp, Kerstin; Puhkala, Jatta; Luoto, Riitta; Olsson, Tommy; Holmäng, Agneta

2017-07-01

Gestational diabetes is commonly linked to development of type 2 diabetes mellitus (T2DM). There is a need to characterize metabolic changes associated with gestational diabetes in order to find novel biomarkers for T2DM. To find potential pathophysiological mechanisms and markers for progression from gestational diabetes mellitus to T2DM by studying the metabolic transition from pregnancy to postpartum. The metabolic transition profile from pregnancy to postpartum was characterized in 56 women by mass spectrometry-based metabolomics; 11 women had gestational diabetes mellitus, 24 had normal glucose tolerance, and 21 were normoglycaemic but at increased risk for gestational diabetes mellitus. Fasting serum samples collected during trimester 3 (gestational week 32±0.6) and postpartum (10.5±0.4months) were compared in diagnosis-specific multivariate models (orthogonal partial least squares analysis). Clinical measurements (e.g., insulin, glucose, lipid levels) were compared and models of insulin sensitivity and resistance were calculated for the same time period. Women with gestational diabetes had significantly increased postpartum levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and their circulating lipids did not return to normal levels after pregnancy. The increase in BCAAs occurred postpartum since the BCAAs did not differ during pregnancy, as compared to normoglycemic women. Postpartum levels of specific BCAAs, notably valine, are related to gestational diabetes during pregnancy. Copyright © 2017 Elsevier Inc. All rights reserved.

Naturally high plasma glucose levels in mourning doves (Zenaida macroura) do not lead to high levels of reactive oxygen species in the vasculature.

PubMed

Smith, Christina L; Toomey, Matthew; Walker, Benjimen R; Braun, Eldon J; Wolf, Blair O; McGraw, Kevin; Sweazea, Karen L

2011-06-01

Plasma glucose (P(Glu)) concentrations in birds are 1.5-2 times higher than those of mammals of similar body mass. In mammals, sustained elevations of P(Glu) lead to oxidative stress and free radical-mediated scavenging of endogenous vasodilators (e.g., nitric oxide), contributing to elevated blood pressure. Despite the relatively high P(Glu) levels in birds, they appear resistant to the development of oxidative stress in tissues such as the heart, brain and kidneys. To our knowledge no information exists on oxidative stress susceptibility in the resistance vasculature of birds. Therefore, we compared endogenous antioxidant mechanisms in the resistance vasculature of mourning doves (MODO; Zenaida macroura) and rats (Rattus norvegicus). Reactive oxygen species (ROS) were assessed with the fluorescent indicator 7'-dichlorodihydrofluorescein diacetate, acetyl ester in mesenteric arteries from rats and wild-caught MODO. Despite having significantly higher P(Glu) than rats, there were no significant differences in ROS levels between mesenteric arteries from rats or doves. Although superoxide dismutase and catalase activities were lower in the plasma, total antioxidant capacity, uric acid, vitamin E (α-tocopherol), and carotenoids (lutein and zeaxanthin) were significantly higher in MODO than in rats. Thus, compared to rats, MODO have multiple circulating antioxidants that may prevent the development of oxidative stress in the vasculature. Copyright © 2011 Elsevier GmbH. All rights reserved.

Increased densities of monocarboxylate transporter MCT1 after chronic hyperglycemia in rat brain.

PubMed

Canis, Martin; Maurer, Martin H; Kuschinsky, Wolfgang; Duembgen, Lutz; Duelli, Roman

2009-02-27

The brain is capable of taking up monocarboxylates as energy substrates. Under physiological conditions, plasma levels of monocarboxylates are very low and glucose is the primary energy substrate in brain metabolism. However, given conditions such as hyperglycemia and ketosis, levels of circulating monocarboxylates such as lactate and pyruvate are elevated. Previous studies reported an increased expression of monocarboxylate transporter MCT1 in brain following ketotic diet. The major aim of the present study was to answer the question whether chronic hyperglycemia is likewise sufficient to change local densities of MCT1 in the brain. Moreover, chronic hyperglycemia increases local cerebral glucose utilization (LCGU) in particular brain areas. Glucose hereby enters the brain parenchyma via glucose transporters and is partially metabolised by astrocytes, which then release lactate to meet the energetic demands of surrounding neurons. Streptozotocin was given intravenously to induce chronic hyperglycemia and local densities of MCT1 were measured by immunoautoradiographic methods in cryosections of rat brains. The density of monocarboxylate transporter MCT1 was significantly increased in 10 of 24 brain structures investigated (median increase 11.7+/-3.4 %). Immunocytochemical stainings of these substructures revealed an expression of MCT1 within endothelial cells and astrocytes. A comparison of MCT1 densities with LCGU measured in a previous study under normo- and hyperglycemic conditions revealed a partial correlation between both parameters and under both conditions. Four out of 10 brain areas, which showed a significant increase in MCT1 density due to hyperglycemia, also showed a significant increase in LCGU. In summary, our data show that chronic hyperglycemia induces a moderate increase of local and global density of MCT1 in several brain structures. However, in terms of brain topologies and substructures this phenomenon did only partially match with increased LCGU. It is concluded that MCT1 transporters were up-regulated during chronic hyperglycemia at the level of brain substructures and independently of LCGU.

Glucose-dependent insulinotropic polypeptide directly induces glucose transport in rat skeletal muscle

PubMed Central

Snook, Laelie A.; Nelson, Emery M.; Dyck, David J.; Wright, David C.

2015-01-01

Several gastrointestinal proteins have been identified to have insulinotropic effects, including glucose-dependent insulinotropic polypeptide (GIP); however, the direct effects of incretins on skeletal muscle glucose transport remain largely unknown. Therefore, the purpose of the current study was to examine the role of GIP on skeletal muscle glucose transport and insulin signaling in rats. Relative to a glucose challenge, a mixed glucose+lipid oral challenge increased circulating GIP concentrations, skeletal muscle Akt phosphorylation, and improved glucose clearance by ∼35% (P < 0.05). These responses occurred without alterations in serum insulin concentrations. In an incubated soleus muscle preparation, GIP directly stimulated glucose transport and increased GLUT4 accumulation on the plasma membrane in the absence of insulin. Moreover, the ability of GIP to stimulate glucose transport was mitigated by the addition of the PI 3-kinase (PI3K) inhibitor wortmannin, suggesting that signaling through PI3K is required for these responses. We also provide evidence that the combined stimulatory effects of GIP and insulin on soleus muscle glucose transport are additive. However, the specific GIP receptor antagonist (Pro3)GIP did not attenuate GIP-stimulated glucose transport, suggesting that GIP is not signaling through its classical receptor. Together, the current data provide evidence that GIP regulates skeletal muscle glucose transport; however, the exact signaling mechanism(s) remain unknown. PMID:26041107

Normal Postprandial Nonesterified Fatty Acid Uptake in Muscles Despite Increased Circulating Fatty Acids in Type 2 Diabetes

PubMed Central

Labbé, Sébastien M.; Croteau, Etienne; Grenier-Larouche, Thomas; Frisch, Frédérique; Ouellet, René; Langlois, Réjean; Guérin, Brigitte; Turcotte, Eric E.; Carpentier, André C.

2011-01-01

OBJECTIVE Postprandial plasma nonesterified fatty acid (NEFA) appearance is increased in type 2 diabetes. Our objective was to determine whether skeletal muscle uptake of plasma NEFA is abnormal during the postprandial state in type 2 diabetes. RESEARCH DESIGN AND METHODS Thigh muscle blood flow and oxidative metabolism indexes and NEFA uptake were determined using positron emission tomography coupled with computed tomography (PET/CT) with [11C]acetate and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (18FTHA) in seven healthy control subjects (CON) and seven subjects with type 2 diabetes during continuous oral intake of a liquid meal to achieve steady postprandial NEFA levels with insulin infusion to maintain similar plasma glucose levels in both groups. RESULTS In the postprandial state, plasma NEFA level was higher in type 2 diabetic subjects versus CON (P < 0.01), whereas plasma glucose was at the same level in both groups. Muscle NEFA fractional extraction and blood flow index levels were 56% (P < 0.05) and 24% (P = 0.27) lower in type 2 diabetes, respectively. However, muscle NEFA uptake was similar to that of CON (quadriceps femoris [QF] 1.47 ± 0.23 vs. 1.37 ± 0.24 nmol ⋅ g−1 ⋅ min−1, P = 0.77; biceps femoris [BF] 1.54 ± 0.26 vs. 1.46 ± 0.28 nmol ⋅ g−1 ⋅ min−1, P = 0.85). Muscle oxidative metabolism was similar in both groups. Muscle NEFA fractional extraction and blood flow index were strongly and positively correlated (r = 0.79, P < 0.005). CONCLUSIONS Postprandial muscle NEFA uptake is normal despite elevated systemic NEFA levels and acute normalization of plasma glucose in type 2 diabetes. Lower postprandial muscle blood flow with resulting reduction in muscle NEFA fractional extraction may explain this phenomenon. PMID:21228312

Short and long-term impact of lipectomy on expression profile of hepatic anabolic genes in rats: a high fat and high cholesterol diet-induced obese model.

PubMed

Ling, Bey-Leei; Chiu, Chun-Tang; Lu, Hsiu-Chin; Lin, Jin-Jin; Kuo, Chiung-Yin; Chou, Fen-Pi

2014-01-01

To understand the molecular basis of the short and long-term effects of an immediate shortage of energy storage caused by lipectomy on expression profile of genes involved in lipid and carbohydrate metabolism in high fat and high cholesterol diet-induced obese rats. The hepatic mRNA levels of enzymes, regulator and transcription factors involved in glucose and lipid metabolism were analyzed by quantitative real time polymerase chain reaction (RT-qPCR) ten days and eight weeks after lipectomy in obese rats. Body and liver weights and serum biochemical parameters, adiponectin, leptin and insulin were determined. No significant difference was observed on the food intake between the lipectomized and sham-operated groups during the experimental period. Ten days after the operation, the lipectomized animals showed significant higher triacylglycerol, glucose and insulin levels, a lower adiponectin concentration than the sham-operated rats, along with significant higher hepatic mRNA levels of hepatocyte nuclear factor 4α (HNF4α) and the enzymes involved in lipogenesis, sterol biosynthesis and gluconeogenesis. The results of immunohistochemical (IHC) analysis also confirmed increased levels of lipogenic enzymes in the liver of lipectomized versus sham-operated animals. The lipectomized group had a significantly lower adiponectin/leptin ratio that was positively correlated to the level of LDL (r = 0.823, P<0.05) and negatively to glucose and insulin (r = -0.821 and -0.892 respectively, P<0.05). Eight weeks after the operation, the lipectomized animals revealed significant higher body and liver weights, weight gain, liver to body weight ratio, hepatic triacylglycerol and serum insulin level. In response to lipectomy a short term enhancement of the expression of hepatic anabolic genes involved in lipid and carbohydrate metabolism was triggered that might eventually lead to the final extra weight gain. These metabolic changes could be the results of reduced circulating adiponectin that further influences the functions of insulin and hepatic HNF4α.

Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity.

PubMed

Shi, Hao; Munk, Alexander; Nielsen, Thomas S; Daughtry, Morgan R; Larsson, Louise; Li, Shize; Høyer, Kasper F; Geisler, Hannah W; Sulek, Karolina; Kjøbsted, Rasmus; Fisher, Taylor; Andersen, Marianne M; Shen, Zhengxing; Hansen, Ulrik K; England, Eric M; Cheng, Zhiyong; Højlund, Kurt; Wojtaszewski, Jørgen F P; Yang, Xiaoyong; Hulver, Matthew W; Helm, Richard F; Treebak, Jonas T; Gerrard, David E

2018-05-01

Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Palmitic acid feeding increases ceramide supply in association with increased milk yield, circulating nonesterified fatty acids, and adipose tissue responsiveness to a glucose challenge.

PubMed

Rico, J E; Mathews, A T; Lovett, J; Haughey, N J; McFadden, J W

2016-11-01

Reduced insulin action is a key adaptation that facilitates glucose partitioning to the mammary gland for milk synthesis and enhances adipose tissue lipolysis during early lactation. The progressive recovery of insulin sensitivity as cows advance toward late lactation is accompanied by reductions in circulating nonesterified fatty acids (NEFA) and milk yield. Because palmitic acid can promote insulin resistance in monogastrics through sphingolipid ceramide-dependent mechanisms, palmitic acid (C16:0) feeding may enhance milk production by restoring homeorhetic responses. We hypothesized that feeding C16:0 to mid-lactation cows would enhance ceramide supply and ceramide would be positively associated with milk yield. Twenty multiparous mid-lactation Holstein cows were enrolled in a study consisting of a 5-d covariate, 49-d treatment, and 14-d posttreatment period. All cows were randomly assigned to a sorghum silage-based diet containing no supplemental fat (control; n=10; 138±45 d in milk) or C16:0 at 4% of ration dry matter (PALM; 98% C16:0; n=10; 136±44 d in milk). Blood and milk were collected at routine intervals. Liver and skeletal muscle tissue were biopsied at d 47 of treatment. Intravenous glucose tolerance tests (300mg/kg of body weight) were performed at d -1, 24, and 49 relative to start of treatment. The plasma and tissue concentrations of ceramide and glycosylated ceramide were determined using liquid chromatography coupled with tandem mass spectrometry. Data were analyzed as repeated measures using a mixed model with fixed effects of treatment and time, and milk yield served as a covariate. The PALM treatment increased milk yield, energy-corrected milk, and milk fat yield. The most abundant plasma and tissue sphingolipids detected were C24:0-ceramide, C24:0-monohexosylceramide (GlcCer), and C16:0-lactosylceramide. Plasma concentrations of total ceramide and GlcCer decreased as lactation advanced, and ceramide and GlcCer were elevated in cows fed PALM. Palmitic acid feeding increased hepatic ceramide levels, a response not observed in skeletal muscle tissue. Plasma ceramides (e.g., C24:0-ceramide) were positively correlated with plasma NEFA and milk yield, and positively correlated with NEFA levels following a glucose challenge. Our data demonstrate a remodeled plasma and hepatic sphingolipidome in mid-lactation dairy cows fed PALM. The potential involvement in ceramide in homeorhetic nutrient partitioning to support lactation requires further consideration. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A novel selective VPAC2 agonist peptide-conjugated chitosan modified selenium nanoparticles with enhanced anti-type 2 diabetes synergy effects.

PubMed

Zhao, Shao-Jun; Wang, De-Hua; Li, Yan-Wei; Han, Lei; Xiao, Xing; Ma, Min; Wan, David Chi-Cheong; Hong, An; Ma, Yi

2017-01-01

A novel neuroendocrine peptide, pituitary adenylate cyclase activating peptide (PACAP), was found to have an important role in carbohydrate or lipid metabolism and was susceptible to dipeptidyl peptidase IV degradation. It can not only mediate glucose-dependent insulin secretion and lower blood glucose by activating VPAC2 receptor, but also raise blood glucose by promoting glucagon production by VPAC1 receptor activation. Therefore, its therapeutic application is restricted by the exceedingly short-acting half-life and the stimulatory function for glycogenolysis. Herein, we generated novel peptide-conjugated selenium nanoparticles (SeNPs; named as SCD), comprising a 32-amino acid PACAP-derived peptide DBAYL that selectively binds to VPAC2, and chitosan-modified SeNPs (SeNPs-CTS, SC) as slow-release carrier. The circulating half-life of SCD is 14.12 h in mice, which is 168.4-and 7.1-fold longer than wild PACAP (~5 min) and DBAYL (~1.98 h), respectively. SCD (10 nmol/L) significantly promotes INS-1 cell proliferation, glucose uptake, insulin secretion, insulin receptor expression and also obviously reduces intracellular reactive oxygen species levels in H 2 O 2 -injured INS-1 cells. Furthermore, the biological effects of SCD are stronger than Exendin-4 (a clinically approved drug through its insulinotropic effect), DBAYL, SeNPs or SC. A single injection of SCD (20 nmol/kg) into db/db mice with type 2 diabetes leads to enhanced insulin secretion and sustained hypoglycemic effect, and the effectiveness and duration of SCD in enhancing insulin secretion and reducing blood glucose levels are much stronger than Exendin-4, SeNPs or SC. In db/db mice, chronic administration of SCD by daily injection for 12 weeks markedly improved glucose and lipid profiles, insulin sensitivity and the structures of pancreatic and adipose tissue. The results indicate that SC can play a role as a carrier for the slow release of bioactive peptides and SCD could be a hopeful therapeutic against type 2 diabetes through the synergy effects of DBAYL and SeNPs.

Comparative Effects of Fructose and Glucose on Lipogenic Gene Expression and Intermediary Metabolism in HepG2 Liver Cells

PubMed Central

Fiehn, Oliver; Adams, Sean H.

2011-01-01

Consumption of large amounts of fructose or sucrose increases lipogenesis and circulating triglycerides in humans. Although the underlying molecular mechanisms responsible for this effect are not completely understood, it is possible that as reported for rodents, high fructose exposure increases expression of the lipogenic enzymes fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC-1) in human liver. Since activation of the hexosamine biosynthesis pathway (HBP) is associated with increases in the expression of FAS and ACC-1, it raises the possibility that HBP-related metabolites would contribute to any increase in hepatic expression of these enzymes following fructose exposure. Thus, we compared lipogenic gene expression in human-derived HepG2 cells after incubation in culture medium containing glucose alone or glucose plus 5 mM fructose, using the HBP precursor 10 mM glucosamine (GlcN) as a positive control. Cellular metabolite profiling was conducted to analyze differences between glucose and fructose metabolism. Despite evidence for the active uptake and metabolism of fructose by HepG2 cells, expression of FAS or ACC-1 did not increase in these cells compared with those incubated with glucose alone. Levels of UDP-N-acetylglucosamine (UDP-GlcNAc), the end-product of the HBP, did not differ significantly between the glucose and fructose conditions. Exposure to 10 mM GlcN for 10 minutes to 24 hours resulted in 8-fold elevated levels of intracellular UDP-GlcNAc (P<0.001), as well as a 74–126% increase in FAS (P<0.05) and 49–95% increase in ACC-1 (P<0.01) expression above controls. It is concluded that in HepG2 liver cells cultured under standard conditions, sustained exposure to fructose does not result in an activation of the HBP or increased lipogenic gene expression. Should this scenario manifest in human liver in vivo, it would suggest that high fructose consumption promotes triglyceride synthesis primarily through its action to provide lipid precursor carbon and not by activating lipogenic gene expression. PMID:22096489

A novel selective VPAC2 agonist peptide-conjugated chitosan modified selenium nanoparticles with enhanced anti-type 2 diabetes synergy effects

PubMed Central

Zhao, Shao-Jun; Wang, De-Hua; Li, Yan-Wei; Han, Lei; Xiao, Xing; Ma, Min; Wan, David Chi-Cheong; Hong, An; Ma, Yi

2017-01-01

A novel neuroendocrine peptide, pituitary adenylate cyclase activating peptide (PACAP), was found to have an important role in carbohydrate or lipid metabolism and was susceptible to dipeptidyl peptidase IV degradation. It can not only mediate glucose-dependent insulin secretion and lower blood glucose by activating VPAC2 receptor, but also raise blood glucose by promoting glucagon production by VPAC1 receptor activation. Therefore, its therapeutic application is restricted by the exceedingly short-acting half-life and the stimulatory function for glycogenolysis. Herein, we generated novel peptide-conjugated selenium nanoparticles (SeNPs; named as SCD), comprising a 32-amino acid PACAP-derived peptide DBAYL that selectively binds to VPAC2, and chitosan-modified SeNPs (SeNPs-CTS, SC) as slow-release carrier. The circulating half-life of SCD is 14.12 h in mice, which is 168.4-and 7.1-fold longer than wild PACAP (~5 min) and DBAYL (~1.98 h), respectively. SCD (10 nmol/L) significantly promotes INS-1 cell proliferation, glucose uptake, insulin secretion, insulin receptor expression and also obviously reduces intracellular reactive oxygen species levels in H2O2-injured INS-1 cells. Furthermore, the biological effects of SCD are stronger than Exendin-4 (a clinically approved drug through its insulinotropic effect), DBAYL, SeNPs or SC. A single injection of SCD (20 nmol/kg) into db/db mice with type 2 diabetes leads to enhanced insulin secretion and sustained hypoglycemic effect, and the effectiveness and duration of SCD in enhancing insulin secretion and reducing blood glucose levels are much stronger than Exendin-4, SeNPs or SC. In db/db mice, chronic administration of SCD by daily injection for 12 weeks markedly improved glucose and lipid profiles, insulin sensitivity and the structures of pancreatic and adipose tissue. The results indicate that SC can play a role as a carrier for the slow release of bioactive peptides and SCD could be a hopeful therapeutic against type 2 diabetes through the synergy effects of DBAYL and SeNPs. PMID:28356733

Reducing dietary fat from a meal increases the bioavailability of exogenous carbohydrate without altering plasma glucose concentration.

PubMed

Knuth, Nicolas D; Shrivastava, Cara R; Horowitz, Jeffrey F

2009-01-01

The primary goal of this study was to determine the acute glycemic and endocrine responses to the reduction of fat content from a meal. On three separate occasions, nine overweight subjects (body mass index = 30 +/- 1 kg/m(2); 5 men, 4 women) consumed 1) a control meal ( approximately 800 kcal; 100 g of carbohydrate, 31 g of fat, and 30 g of protein), 2) a low-fat meal ( approximately 530 kcal; 100 g of carbohydrate, 1 g of fat, and 30 g of protein), or 3) a low-fat meal plus lipid infusion [same meal as low-fat meal, but the total energy provided was the same as control (800 kcal), with the "missing" fat ( approximately 30 g) provided via an intravenous lipid infusion]. All three meals contained [(13)C]glucose (3 mg/kg body wt) to assess the bioavailability of ingested glucose. During the 5-h period after each meal, we measured the recovery of [(13)C]glucose in plasma, plasma glucose, and insulin concentrations. We also measured plasma concentration of the gastrointestinal peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY(3-36) (PYY(3-36)). The recovery of the ingested [(13)C]glucose in the hour after ingestion was greater (P < 0.05) after the low-fat than after the control meal [area under the curve (AUC): 1,206 +/- 252 and 687 +/- 161 microM.h, respectively]. However, removing dietary fat from the meal did not affect the plasma concentration of glucose or insulin. Importantly, [(13)C]glucose recovery was not different during the low-fat and lipid infusion trials (AUC: 1,206 +/- 252 and 1,134 +/- 247 microM.h, respectively), indicating that the accelerated delivery of exogenous glucose found after removing fat from the meal is due exclusively to the reduction of fat in the gastrointestinal tract. In parallel with these findings, the reduction in fat calories from the meal reduced plasma concentration of GIP, GLP-1, and PYY(3-36). In summary, these data suggest that removing fat from the diet expedited exogenous glucose delivery into the systemic circulation and reduced the concentration of key gastrointestinal peptides, yet maintained plasma glucose concentration at control levels.

Blood glucose level reconstruction as a function of transcapillary glucose transport.

PubMed

Koutny, Tomas

2014-10-01

A diabetic patient occasionally undergoes a detailed monitoring of their glucose levels. Over the course of a few days, a monitoring system provides a detailed track of their interstitial fluid glucose levels measured in their subcutaneous tissue. A discrepancy in the blood and interstitial fluid glucose levels is unimportant because the blood glucose levels are not measured continuously. Approximately five blood glucose level samples are taken per day, and the interstitial fluid glucose level is usually measured every 5min. An increased frequency of blood glucose level sampling would cause discomfort for the patient; thus, there is a need for methods to estimate blood glucose levels from the glucose levels measured in subcutaneous tissue. The Steil-Rebrin model is widely used to describe the relationship between blood and interstitial fluid glucose dynamics. However, we measured glucose level patterns for which the Steil-Rebrin model does not hold. Therefore, we based our research on a different model that relates present blood and interstitial fluid glucose levels to future interstitial fluid glucose levels. Using this model, we derived an improved model for calculating blood glucose levels. In the experiments conducted, this model outperformed the Steil-Rebrin model while introducing no additional requirements for glucose sample collection. In subcutaneous tissue, 26.71% of the calculated blood glucose levels had absolute values of relative differences from smoothed measured blood glucose levels less than or equal to 5% using the Steil-Rebrin model. However, the same difference interval was encountered in 63.01% of the calculated blood glucose levels using the proposed model. In addition, 79.45% of the levels calculated with the Steil-Rebrin model compared with 95.21% of the levels calculated with the proposed model had 20% difference intervals. Copyright © 2014 Elsevier Ltd. All rights reserved.

ANGPTL8/Betatrophin R59W variant is associated with higher glucose level in non-diabetic Arabs living in Kuwaits.

PubMed

Abu-Farha, Mohamed; Melhem, Motasem; Abubaker, Jehad; Behbehani, Kazem; Alsmadi, Osama; Elkum, Naser

2016-02-11

ANGPTL8 (betatrophin) has been recently identified as a regulator of lipid metabolism through its interaction with ANGPTL3. A sequence variant in ANGPTL8 has been shown to associate with lower level of Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL). The objective of this study is to identify sequence variants in ANGPTL8 gene in Arabs and investigate their association with ANGPTL8 plasma level and clinical parameters. A cross sectional study was designed to examine the level of ANGPTL8 in 283 non-diabetic Arabs, and to identify its sequence variants using Sanger sequencing and their association with various clinical parameters. Using Sanger sequencing, we sequenced the full ANGPTL8 gene in 283 Arabs identifying two single nucleotide polymorphisms (SNPs) Rs.892066 and Rs.2278426 in the coding region. Our data shows for the first time that Arabs with the heterozygote form of (c.194C > T Rs.2278426) had higher level of Fasting Blood Glucose (FBG) compared to the CC homozygotes. LDL and HDL level in these subjects did not show significant difference between the two subgroups. Circulation level of ANGPTL8 did not vary between the two forms. No significant changes were observed between the various forms of Rs.892066 variant and FBG, LDL or HDL. Our data shows for the first time that heterozygote form of ANGPTL8 Rs.2278426 variant was associated with higher FBG level in Arabs highlighting the importance of these variants in controlling the function of betatrophin.

Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution.

PubMed

Maida, Adriano; Chan, Jessica S K; Sjøberg, Kim A; Zota, Annika; Schmoll, Dieter; Kiens, Bente; Herzig, Stephan; Rose, Adam J

2017-08-01

Dietary protein dilution (PD) has been associated with metabolic advantages such as improved glucose homeostasis and increased energy expenditure. This phenotype involves liver-induced release of FGF21 in response to amino acid insufficiency; however, it has remained unclear whether dietary dilution of specific amino acids (AAs) is also required. Circulating branched chain amino acids (BCAAs) are sensitive to protein intake, elevated in the serum of obese humans and mice and thought to promote insulin resistance. We tested whether replenishment of dietary BCAAs to an AA-diluted (AAD) diet is sufficient to reverse the glucoregulatory benefits of dietary PD. We conducted AA profiling of serum from healthy humans and lean and high fat-fed or New Zealand obese (NZO) mice following dietary PD. We fed wildtype and NZO mice one of three amino acid defined diets: control, total AAD, or the same diet with complete levels of BCAAs (AAD + BCAA). We quantified serum AAs and characterized mice in terms of metabolic efficiency, body composition, glucose homeostasis, serum FGF21, and tissue markers of the integrated stress response (ISR) and mTORC1 signaling. Serum BCAAs, while elevated in serum from hyperphagic NZO, were consistently reduced by dietary PD in humans and murine models. Repletion of dietary BCAAs modestly attenuated insulin sensitivity and metabolic efficiency in wildtype mice but did not restore hyperglycemia in NZO mice. While hepatic markers of the ISR such as P-eIF2α and FGF21 were unabated by dietary BCAA repletion, hepatic and peripheral mTORC1 signaling were fully or partially restored, independent of changes in circulating glucose or insulin. Repletion of BCAAs in dietary PD is sufficient to oppose changes in somatic mTORC1 signaling but does not reverse the hepatic ISR nor induce insulin resistance in type 2 diabetes during dietary PD.

Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells.

PubMed

Lavrentyev, Eduard N; Estes, Anne M; Malik, Kafait U

2007-08-31

Angiotensin II (Ang II), a circulating hormone that can be synthesized locally in the vasculature, has been implicated in diabetes-associated vascular complications. This study was conducted to determine whether high glucose (HG) (approximately 23.1 mmol/L), a diabetic-like condition, stimulates Ang II generation and the underlying mechanism of its production in rat vascular smooth muscle cells. The contribution of various enzymes involved in Ang II generation was investigated by silencing their expression with small interfering RNA in cells exposed to normal glucose (approximately 4.1 mmol/L) and HG. Angiotensin I (Ang I) was generated from angiotensinogen by cathepsin D in the presence of normal glucose or HG. Although HG did not affect the rate of angiotensinogen conversion, it decreased expression of angiotensin-converting enzyme (ACE), downregulated ACE-dependent Ang II generation, and upregulated rat vascular chymase-dependent Ang II generation. The ACE inhibitor captopril reduced Ang II levels in the media by 90% in the presence of normal glucose and 19% in HG, whereas rat vascular chymase silencing reduced Ang II production in cells exposed to HG but not normal glucose. The glucose transporter inhibitor cytochalasin B, the aldose reductase inhibitor alrestatin, and the advanced glycation end product formation inhibitor aminoguanidine attenuated HG-induced Ang II generation. HG caused a transient increase in extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and ERK1/2 inhibitors reduced Ang II accumulation by HG. These data suggest that polyol pathway metabolites and AGE can stimulate rat vascular chymase activity via ERK1/2 activation and increase Ang II production. In addition, decreased Ang II degradation, which, in part, could be attributable to a decrease in angiotensin-converting enzyme 2 expression observed in HG, contributes to increased accumulation of Ang II in vascular smooth muscle cells by HG.

Higher Circulating Leukocytes in Women with PCOS is Reversed by Aerobic Exercise

PubMed Central

Covington, Jeffrey D.; Tam, Charmaine S.; Pasarica, Magdalena; Redman, Leanne M.

2014-01-01

Polycystic ovary syndrome (PCOS) is characterized by insulin resistance, elevated circulating leukocytes, and hypothesized to have higher adipose tissue inflammation. Aerobic exercise reduces circulating leukocytes and improves insulin sensitivity in obese individuals, but the effect of exercise on inflammation in PCOS is not known. We investigated circulating leukocytes, insulin sensitivity by euglycemic-hyperinsulinemic clamp, serum pro- and anti-inflammatory markers (hsCRP, TNF-α, total and high molecular weight adiponectin), and abdominal subcutaneous adipose tissue (SAT) gene expression of proinflammatory markers in 8 PCOS women and 8 obese control females matched for BMI. Additionally, in a prospective study, the 8 women with PCOS underwent a 16-week aerobic exercise regimen with the same measures performed post-intervention. Compared to controls, white blood cell counts (WBC) were 30% higher (p = 0.04) and circulating total adiponectin levels were 150% lower (p = 0.03) in women with PCOS at baseline/pre-exercise conditions. SAT gene expression of macrophage migration inhibitory factor (MIF, p < 0.01) and interleukin-6 (IL-6, p < 0.05) were also lower in women with PCOS. In response to 16 weeks of aerobic exercise, insulin sensitivity improved (p < 0.01) and WBC counts decreased (p = 0.02). The exercise-induced change in WBC and circulating neutrophils correlated inversely with changes in glucose disposal rate (r= -0.73, p=0.03; and r= -0.82, p=0.01, respectively). Aerobic exercise reduced serum leptin (p < 0.05) after 4 weeks, trended to reduce the ratio of leptin-to-high molecular weight adiponectin (p < 0.1) by the 8th week, and significantly increased serum dehydroepiandrosterone sulfate (DHEA-S, p < 0.001) after 16 weeks. In conclusion, women with PCOS have higher circulating leukocytes compared to controls, which can be reversed by aerobic exercise and is associated with improvements in insulin sensitivity. PMID:25446648

A BAT-Centric Approach to the Treatment of Diabetes: Turn on the Brain.

PubMed

Hankir, Mohammed K; Cowley, Michael A; Fenske, Wiebke K

2016-07-12

The marked (18)F-flurodeoxyglucose uptake by brown adipose tissue (BAT) enabled its identification in human positron emission tomography imaging studies. In this Perspective, we discuss how glucose extraction by BAT and beige adipose tissue (BeAT) sufficiently impacts on glycemic control. We then present a unique overview of the central circuits modulated by gluco-regulatory hormones, temperature, and glucose itself, which converge on sympathetic preganglionic neurons and whose activation syphon circulating glucose into BAT/BeAT. Targeted stimulation of the sympathetic nervous system at specific nodes to selectively recruit BAT/BeAT may represent a safe and effective means of treating diabetes. Copyright © 2016 Elsevier Inc. All rights reserved.

WISP1 is a novel adipokine linked to metabolic parameters in gestational diabetes mellitus.

PubMed

Sahin Ersoy, Gulcin; Altun Ensari, Tugba; Subas, Seda; Giray, Burak; Simsek, Engin Ersin; Cevik, Ozge

2017-04-01

To investigate Wnt1-inducible signaling pathway protein-1 (WISP1) levels and their correlation with metabolic parameters in pregnant women with gestational diabetes mellitus (GDM) and non-GDM healthy pregnant women. In this prospective cross-sectional study, the study group was composed of 62 women with GDM and 73 healthy pregnant women matched for age, body mass index (BMI) and gestational age. Blood samples were collected at 25-29th gestational week. Serum WISP1, betatrophin, glucose, fasting insulin, glycosylated hemoglobin A1c, total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol, C reactive protein, alanine aminotransferase and creatinine levels were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) values was calculated. The level of significance was accepted as p < 0.05. Circulating WISP1 in the GDM group was significantly higher than the control group (p <0.001). Further, WISP1 was positively correlated with BMI, HOMA-IR values and fasting glucose, fasting insulin, triglyceride, betatrophin levels. BMI, HOMA-IR and betatrophin independently and positively predicted WISP1 levels. These results demonstrate a relationship between WISP1 and the metabolic parameters of GDM. And, WISP1 might be involved in the pathophysiology of GDM. As a part of this pathophysiological mechanism, the activation of WISP1 and betatrophin might take place through several ways; WISP1 and betatrophin might either use same signaling pathways and potentiate each other or they might also constitute the sequential steps of a common pathway.

Decreased Glutathione S-transferase Level and Neonatal Hyperbilirubinemia Associated with Glucose-6-phosphate Dehydrogenase Deficiency: A Perspective Review.

PubMed

Al-Abdi, Sameer Yaseen

2017-02-01

Classically, genetically decreased bilirubin conjugation and/or hemolysis account for the mechanisms contributing to neonatal hyperbilirubinemia associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, these mechanisms are not involved in most cases of this hyperbilirubinemia. Additional plausible mechanisms for G6PD deficiency-associated hyperbilirubinemia need to be considered. Glutathione S-transferases (GST) activity depends on a steady quantity of reduced form of glutathione (GSH). If GSH is oxidized, it is reduced back by glutathione reductase, which requires the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). The main source of NADPH is the pentose phosphate pathway, in which G6PD is the first enzyme. Rat kidney GSH, rat liver GST, and human red blood cell GST levels have been found to positively correlate with G6PD levels in their respective tissues. As G6PD is expressed in hepatocytes, it is expected that GST levels would be significantly decreased in hepatocytes of G6PD-deficient neonates. As hepatic GST binds bilirubin and prevents their reflux into circulation, hypothesis that decreased GST levels in hepatocytes is an additional mechanism contributing to G6PD deficiency-associated hyperbilirubinemia seems plausible. Evidence for and against this hypothesis are discussed in this article hoping to stimulate further research on the role of GST in G6PD deficiency-associated hyperbilirubinemia. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Insulin secretion and insulin action in non-insulin-dependent diabetes mellitus: which defect is primary?

PubMed

Reaven, G M

1984-01-01

Defects in both insulin secretion and insulin action exist in patients with non-insulin-dependent diabetes mellitus (NIDDM). The loss of the acute plasma insulin response to intravenous glucose is seen in patients with relatively mild degrees of fasting hyperglycemia, but patients with severe fasting hyperglycemia also demonstrate absolute hypoinsulinemia in response to an oral glucose challenge. In contrast, day-long circulating insulin levels are within normal limits even in severely hyperglycemic patients with NIDDM. The relationship between NIDDM and insulin action in NIDDM is less complex, and is a characteristic feature of the syndrome. This metabolic defect is independent of obesity, and the severity of the resistance to insulin-stimulated glucose uptake increases with magnitude of hyperglycemia. Control of hyperglycemia with exogenous insulin ameliorates the degree of insulin resistance, and reduction of insulin resistance with weight loss in obese patients with NIDDM leads to an enhanced insulin response. Since neither therapeutic intervention is capable of restoring all metabolic abnormalities to normal, these observations do not tell us which of these two defects is primarily responsible for the development of NIDDM. Similarly, the observation that most patients with impaired glucose tolerance are hyperinsulinemic and insulin resistant does not prove that insulin resistance is the primary defect in NIDDM. In conclusion, reduction in both insulin secretion and action is seen in patients with NIDDM, and the relationship between these two metabolic abnormalities is very complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Obese Mice Lacking Inducible Nitric Oxide Synthase Are Sensitized to the Metabolic Actions of Peroxisome Proliferator–Activated Receptor-γ Agonism

PubMed Central

Dallaire, Patrice; Bellmann, Kerstin; Laplante, Mathieu; Gélinas, Stéphanie; Centeno-Baez, Carolina; Penfornis, Patrice; Peyot, Marie-Line; Latour, Martin G.; Lamontagne, Julien; Trujillo, Maria E.; Scherer, Philipp E.; Prentki, Marc; Deshaies, Yves; Marette, André

2008-01-01

OBJECTIVE—Synthetic ligands for peroxisome proliferator–activated receptor-γ (PPAR-γ) improve insulin sensitivity in obesity, but it is still unclear whether inflammatory signals modulate their metabolic actions. In this study, we tested whether targeted disruption of inducible nitric oxide (NO) synthase (iNOS), a key inflammatory mediator in obesity, modulates the metabolic effects of rosiglitazone in obese mice. RESEARCH DESIGN AND METHODS—iNOS−/− and iNOS+/+ were subjected to a high-fat diet or standard diet for 18 weeks and were then treated with rosiglitazone for 2 weeks. Whole-body insulin sensitivity and glucose tolerance were determined and metabolic tissues harvested to assess activation of insulin and AMP-activated protein kinase (AMPK) signaling pathways and the levels of inflammatory mediators. RESULTS—Rosiglitazone was found to similarly improve whole-body insulin sensitivity and insulin signaling to Akt/PKB in skeletal muscle of obese iNOS−/− and obese iNOS+/+ mice. However, rosiglitazone further improved glucose tolerance and liver insulin signaling only in obese mice lacking iNOS. This genotype-specific effect of rosiglitazone on glucose tolerance was linked to a markedly increased ability of the drug to raise plasma adiponectin levels. Accordingly, rosiglitazone increased AMPK activation in muscle and liver only in obese iNOS−/− mice. PPAR-γ transcriptional activity was increased in adipose tissue of iNOS−/− mice. Conversely, treatment of 3T3-L1 adipocytes with a NO donor blunted PPAR-γ activity. CONCLUSIONS—Our results identify the iNOS/NO pathway as a critical modulator of PPAR-γ activation and circulating adiponectin levels and show that invalidation of this key inflammatory mediator improves the efficacy of PPAR-γ agonism in an animal model of obesity and insulin resistance. PMID:18458147

Enhanced glucose metabolism in cultured human skeletal muscle after Roux-en-Y gastric bypass surgery.

PubMed

Nascimento, Emmani B M; Riedl, Isabelle; Jiang, Lake Qunfeng; Kulkarni, Sameer S; Näslund, Erik; Krook, Anna

2015-01-01

Roux-en-Y gastric bypass (RYGB) surgery rapidly increases whole body insulin sensitivity, with changes in several organs including skeletal muscle. Objectives were to determine whether improvements in insulin action in skeletal muscle may occur directly at the level of the myocyte or secondarily from changes in systemic factors associated with weight loss. Myotubes were derived before and after RYGB surgery. The setting was Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden. Eight patients (body mass index (BMI) 41.8 kg/m(2); age 41 yr) underwent RYGB surgery. Before and 6 months after RYGB surgery, skeletal muscle biopsies were collected from vastus lateralis muscle. Satellite cells derived from skeletal muscle biopsies were propagated in vitro as myoblasts and differentiated into myotubes. Expression of myogenic markers is increased in myoblasts derived from biopsies taken 6 months after bypass surgery, compared with their respective presurgery condition. Furthermore, glycogen synthesis, tyrosine phosphorylation of insulin receptor (IRS)-1-Tyr612 and Interleukin (IL)-8 secretion were increased, while fatty acid oxidation and circulating IL8 levels remain unaltered. Myotubes derived from muscle biopsies obtained after RYGB surgery displayed increased insulin-stimulated phosphorylation of protein kinase B (PKB)-Thr308 and proline-rich Akt substrate of 40 kDa (PRAS40)-Thr246. RYGB surgery is accompanied by enhanced glucose metabolism and insulin signaling, altered IL8 secretion and changes in mRNA levels and myogenic markers in cultured skeletal muscle cells. Thus, RYGB surgery involves intrinsic reprogramming of skeletal muscle to increase peripheral insulin sensitivity and glucose metabolism. Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Ketosis and appetite-mediating nutrients and hormones after weight loss.

PubMed

Sumithran, P; Prendergast, L A; Delbridge, E; Purcell, K; Shulkes, A; Kriketos, A; Proietto, J

2013-07-01

Diet-induced weight loss is accompanied by compensatory changes, which increase appetite and encourage weight regain. There is some evidence that ketogenic diets suppress appetite. The objective is to examine the effect of ketosis on a number of circulating factors involved in appetite regulation, following diet-induced weight loss. Of 50 non-diabetic overweight or obese subjects who began the study, 39 completed an 8-week ketogenic very-low-energy diet (VLED), followed by 2 weeks of reintroduction of foods. Following weight loss, circulating concentrations of glucose, insulin, non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHB), leptin, gastrointestinal hormones and subjective ratings of appetite were compared when subjects were ketotic, and after refeeding. During the ketogenic VLED, subjects lost 13% of initial weight and fasting BHB increased from (mean±s.e.m.) 0.07±0.00 to 0.48±0.07 mmol/l (P<0.001). BHB fell to 0.19±0.03 mmol/l after 2 weeks of refeeding (P<0.001 compared with week 8). When participants were ketotic, the weight loss induced increase in ghrelin was suppressed. Glucose and NEFA were higher, and amylin, leptin and subjective ratings of appetite were lower at week 8 than after refeeding. The circulating concentrations of several hormones and nutrients which influence appetite were altered after weight loss induced by a ketogenic diet, compared with after refeeding. The increase in circulating ghrelin and subjective appetite which accompany dietary weight reduction were mitigated when weight-reduced participants were ketotic.

Thyroid function and insulin sensitivity before and after bilio-pancreatic diversion.

PubMed

Gniuli, Donatella; Leccesi, Laura; Guidone, Caterina; Iaconelli, Amerigo; Chiellini, Chiara; Manto, Andrea; Castagneto, Marco; Ghirlanda, Giovanni; Mingrone, Geltrude

2010-01-01

Bilio-pancreatic diversion (BPD) induces permanent weight loss in previously severe obese patients through a malabsorptive mechanism. The aim of the study was to evaluate the modifications of circulating thyroid hormones after BPD, a surgical procedure which interferes with the entero-hepatic circulation of biliary metabolites. Forty-five patients were studied before and 2 years after BPD. Thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), anti-thyroid antibodies, iodine urinary excretion, lipid profile, insulin and glucose plasma levels were assessed. The insulin-resistance HOMA IR index was calculated, and colour Doppler ultrasonography of the neck was performed. The subjects (23%) had subclinical hypothyroidism prior to BPD (TSH levels above the normal range with normal fT3 and fT4 levels). After 2 years 40.42% of the population showed subclinical hypothyroidism, while 6.3% became frankly hypothyroid, all of them with no evidence of auto-immune thyroiditis. Most of the patients, who became sub-clinically hypothyroid only following BPD, had already thyroid alterations at the sonogram (multi-nodular euthyroid goiter and thyroidal cysts) prior to surgery. BPD increases the prevalence of subclinical or even frank hypothyroidism, without causing a defect in thyroid function itself, through several integrated mechanisms. (1) It induces iodine malabsorption, which is partially compensated by iodine excretion contraction. (2) The entero-hepatic open circulation determines fT3 loss, which induces subclinical or frank hypothyroidism in patients with pre-existing thyroid alterations, interfering also with the weight loss progress. Iodine supplementation should be recommended in those patients reporting thyroid alterations at the sonogram prior to BPD, LT4 therapy should be strictly monitored in patients suffering of subclinical hypopthiroidism and T3 therapy should eventually be considered for patients diagnosed with frank hypothyroidism prior to BPD.

Thiamine and its phosphate esters in relation to cardiometabolic risk factors in Saudi Arabs.

PubMed

Al-Daghri, Nasser M; Al-Attas, Omar S; Alkharfy, Khalid M; Alokail, Majed S; Abd-Alrahman, Sherif H; Sabico, Shaun

2013-09-23

Thiamine deficiency has suggested to be linked to several insulin-resistance complications. In this study, we aim to associate circulating thiamine levels among cardiometabolic parameters in an Arab cohort using a simple, sensitive, rapid and selective high-performance liquid chromatography (HPLC) method that has recently been developed. A total of 236 randomly selected, consenting Saudi adult participants (166 males and 70 females) were recruited and screened for the presence of the metabolic syndrome (MetS) using the modified National Cholesterol Education Program-Adult Treatment Panel III definition. Blood thiamine and its derivatives were quantified using HPLC. A total of 140 participants (53.9%) had MetS. The levels of thiamine and its derivatives of those with MetS were not significantly different from those without. However, hypertensive subjects had significantly higher urinary thiamine (P = 0.03) as well as significantly lower levels of thiamine diphosphate (TDP) (P = 0.01) and total thiamine (P = 0.02) than the normotensive subjects, even after adjusting for age and body mass index (BMI). Furthermore, age- and BMI-matched participants with elevated blood glucose levels had significantly lower levels of thiamine monophosphate (P = 0.020), TDP (P < 0.001) and total thiamine (P < 0.001) and significantly elevated levels of urinary thiamine (P = 0.005) compared to normoglycemic participants. Low thiamine levels are associated with elevated blood glucose and hypertension in Saudi adults. Determination of thiamine status may be considered and corrected among patients with, or at high risk for, MetS, but the question whether thiamine deficiency correction translates to improved cardiometabolic status needs further longitudinal investigation.

The Effect of Coenzyme Q10 Supplementation on Circulating Levels of Novel Adipokine Adipolin/CTRP12 in Overweight and Obese Patients with Type 2 Diabetes.

PubMed

Mehrdadi, P; Kolahdouz Mohammadi, R; Alipoor, E; Eshraghian, M R; Esteghamati, A; Hosseinzadeh-Attar, M J

2017-03-01

Background: Adipolin, the novel adipokine that is proposed to be reduced in diabetes, obesity and inflammation, may improve glycemic control. It is known that coenzyme Q10 could improve insulin sensitivity. The aim of the current study was to investigate the effect of Q10 supplementation on adipolin concentration and glucose metabolism in overweight and obese diabetic patients. Material & Methods: Sixty four patients with type 2 diabetes and 25

Association of CDH13 Genotypes/Haplotypes with Circulating Adiponectin Levels, Metabolic Syndrome, and Related Metabolic Phenotypes: The Role of the Suppression Effect

PubMed Central

Teng, Ming-Sheng; Hsu, Lung-An; Wu, Semon; Sun, Yu-Chen; Juan, Shu-Hui; Ko, Yu-Lin

2015-01-01

Objective Previous genome-wide association studies have indicated an association between CDH13 genotypes and adiponectin levels. In this study, we used mediation analysis to assess the statistical association between CDH13 locus variants and adiponectin levels, metabolic syndrome, and related metabolic phenotypes. Methods and results A sample population of 530 Taiwanese participants was enrolled. Four CDH13 gene variants in the promoter and intron 1 regions were genotyped. After adjustment for clinical covariates, the CDH13 genotypes/haplotypes exhibited an association with the adiponectin levels (lowest P = 1.95 × 10−11 for rs4783244 and lowest P = 3.78 × 10−13 for haplotype ATTT). Significant correlations were observed between the adiponectin levels and the various metabolic syndrome-related phenotypes (all P ≤ 0.005). After further adjustment for the adiponectin levels, participants with a minor allele of rs12051272 revealed a considerable association with a more favorable metabolic profile, including higher insulin sensitivity, high-density lipoprotein cholesterol levels, lower diastolic blood pressure, circulating levels of fasting plasma glucose, and triglycerides, and as a lower risk of metabolic syndrome (all P < 0.05). The mediation analysis further revealed a suppression effect of the adiponectin levels on the association between CDH13 genotypes and metabolic syndrome and its related phenotypes (Sobel test; all P < 0.001). Conclusion The genetic polymorphisms at the CDH13 locus independently affect the adiponectin levels, whereas the adiponectin levels exhibit a suppressive effect on the association between CDH13 locus variants and various metabolic phenotypes and metabolic syndrome. In addition, these results provide further evidence of the association between the CDH13 gene variants and the risks of metabolic syndrome and atherosclerotic cardiovascular disease. PMID:25875811

Ghrelin Gene Variants Influence on Metabolic Syndrome Components in Aged Spanish Population.

PubMed

Mora, Mireia; Adam, Victoria; Palomera, Elisabet; Blesa, Sebastian; Díaz, Gonzalo; Buquet, Xavier; Serra-Prat, Mateu; Martín-Escudero, Juan Carlos; Palanca, Ana; Chaves, Javier Felipe; Puig-Domingo, Manuel

2015-01-01

The role of genetic variations within the ghrelin gene on cardiometabolic profile and nutritional status is still not clear in humans, particularly in elderly people. We investigated six SNPs of the ghrelin gene and their relationship with metabolic syndrome (MS) components. 824 subjects (413 men/411 women, age 77.31±5.04) participating in the Mataró aging study (n = 310) and the Hortega study (n = 514) were analyzed. Anthropometric variables, ghrelin, lipids, glucose and blood pressure levels were measured, and distribution of SNPs -994CT (rs26312), -604GA (rs27647), -501AC (rs26802), R51Q (rs34911341), M72L (rs696217) and L90G (rs4684677) of the ghrelin gene evaluated. Genotypes were determined by multiplex PCR and SNaPshot minisequencing. MS (IDF criteria) was found in 54.9%. No association between any of the SNPs and levels of total fasting circulating ghrelin levels was found. C/A-A/A genotype of M72L was associated with increased risk of central obesity according to IDF criteria, while G/A-G/G genotypes of -604GA with reduced risk. A/A genotype of -501AC polymorphism was associated to decreased BMI. In relation to lipid profile, the same genotypes of -604GA were associated with increased total cholesterol and LDL-cholesterol and -501AC with reduced triglycerides. There were no associations with systolic or diastolic blood pressure levels or with hypertension, glucose levels or diabetes and ghrelin polymorphisms. However, G/G genotype of -604GA was associated with glucose >100 mg/dL. Haplotype analysis showed that only one haplotype is associated with increased risk of waist circumference and central obesity. The analysis of subjects by gender showed an important and different association of these polymorphisms regarding MS parameters. Ghrelin gene variants -604GA, -501AC and M72L are associated with certain components of MS, in particular to BMI and lipid profile in elderly Spanish subjects.

Infusion of fluoxetine, a serotonin reuptake inhibitor, in the shell region of the nucleus accumbens increases blood glucose concentrations in rats.

PubMed

Diepenbroek, C; Rijnsburger, M; Eggels, L; van Megen, K M; Ackermans, M T; Fliers, E; Kalsbeek, A; Serlie, M J; la Fleur, S E

2017-01-10

The brain is well known to regulate blood glucose, and the hypothalamus and hindbrain, in particular, have been studied extensively to understand the underlying mechanisms. Nuclei in these regions respond to alterations in blood glucose concentrations and can alter glucose liver output or glucose tissue uptake to maintain blood glucose concentrations within strict boundaries. Interestingly, several cortico-limbic regions also respond to alterations in glucose concentrations and have been shown to project to hypothalamic nuclei and glucoregulatory organs. For instance, electrical stimulation of the shell of the nucleus accumbens (sNAc) results in increased circulating concentrations of glucose and glucagon and activation of the lateral hypothalamus (LH). Whether this is caused by the simultaneous increase in serotonin release in the sNAc remains to be determined. To study the effect of sNAc serotonin on systemic glucose metabolism, we implanted bilateral microdialysis probes in the sNAc of male Wistar rats and infused fluoxetine, a serotonin reuptake inhibitor, or vehicle after which blood glucose, endogenous glucose production (EGP) and glucoregulatory hormones were measured. Fluoxetine in the sNAc for 1h significantly increased blood glucose concentrations without an effect on glucoregulatory hormones. This increase was accompanied by a higher EGP in the fluoxetine infused rats compared to the controls. These data provide further evidence for a role of sNAc-serotonin in the regulation of glucose metabolism. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cattle temperament influences metabolism: 1. Metabolic response to a glucose tolerance test in beef steers

USDA-ARS?s Scientific Manuscript database

Temperamental cattle are behaviorally, physiologically, and immunologically different in comparison to calm cattle. Recently, the metabolic differences between temperamental and calm cattle have begun to be explored; temperamental cattle maintain greater circulating concentrations of non-esterified ...

Asprosin is a centrally acting orexigenic hormone

USDA-ARS?s Scientific Manuscript database

Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood–brain barrier and directly activates orexigenic AgRP+ neurons via a cAMPdependent pathway. This signaling results in inhibition o...

Androidal fat dominates in predicting cardiometabolic risk in postmenopausal women

USDA-ARS?s Scientific Manuscript database

We hypothesized that soy isoflavones would attenuate the anticipated increase in androidal fat mass in postmenopausal women during the 36-month treatment, and thereby favorably modify the circulating cardiometabolic risk factors: triacylglycerol, LDLC, HDL-C, glucose, insulin, uric acid, C-reactive ...

The Relationship between Serum Zonulin Level and Clinical and Laboratory Parameters of Childhood Obesity.

PubMed

Küme, Tuncay; Acar, Sezer; Tuhan, Hale; Çatlı, Gönül; Anık, Ahmet; Gürsoy Çalan, Özlem; Böber, Ece; Abacı, Ayhan

2017-03-01

To investigate the relationship between zonulin levels and clinical and laboratory parameters of childhood obesity. The study included obese children with a body mass index (BMI) >95 th percentile and healthy children who were of similar age and gender distribution. Clinical (BMI, waist circumferences, mid-arm circumference, triceps skinfold, percentage of body fat, systolic blood pressure, diastolic blood pressure) and biochemical (glucose, insulin, lipid levels, thyroid function tests, cortisol, zonulin and leptin levels) parameters were measured. A total of 43 obese subjects (23 males, mean age: 11.1±3.1 years) and 37 healthy subjects (18 males, mean age: 11.5±3.5 years) were included in this study. Obese children had significantly higher insulin, homeostasis model assessment of insulin resistance, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), zonulin and leptin levels than healthy children (p<0.05), while glucose levels were not different (p>0.05). Comparison of the obese children with and without insulin resistance showed no statistically significant differences for zonulin levels (p>0.05). Zonulin levels were found to negatively correlate with HDL-C and positively correlate with leptin levels, after adjusting for age and BMI. To the best of our knowledge, this is the first study investigating the relationship between circulating zonulin level (as a marker of intestinal permeability) and insulin resistance and leptin (as markers of metabolic disturbances associated with obesity) in childhood obesity. The results showed that zonulin was significantly higher in obese children when compared to healthy children, a finding indicating a potential role of zonulin in the etiopathogenesis of obesity and related disturbances.

Low-protein diet induces, whereas high-protein diet reduces hepatic FGF21 production in mice, but glucose and not amino acids up-regulate FGF21 in cultured hepatocytes.

PubMed

Chalvon-Demersay, Tristan; Even, Patrick C; Tomé, Daniel; Chaumontet, Catherine; Piedcoq, Julien; Gaudichon, Claire; Azzout-Marniche, Dalila

2016-10-01

Fibroblast growth factor 21 (FGF21) is a polypeptide secreted by the liver and involved in several metabolic processes such as thermogenesis and lipid oxidation. The nutritional mechanisms controlling FGF21 production are poorly understood. This study aimed to investigate how dietary carbohydrates and proteins impact FGF21 production and how in turn, FGF21 is involved in the metabolic adaptation to changes in the carbohydrate and protein contents of the diet. For that purpose, we fed 25 male C57BL/6 mice diets composed of different protein and carbohydrate contents (normal-protein and carbohydrate diet (N=9, NPNC), low-protein high-carbohydrate diet (N=8, LPHC), high-protein low-carbohydrate diet (N=8, HPLC) for 3 weeks. We measured liver Fgf21 gene expression, synthesis and secretion as well as different parameters related to energy and glucose metabolism. We also investigated the direct role of amino acids and glucose in the control of Fgf21 gene expression in hepatocyte primary cultures (n=6). In vivo, FGF21 responds acutely to LPHC intake whereas under an HPLC diet, plasma FGF21 circulating levels are low in the fasted and refed states. In hepatocytes, Fgf21 expression was controlled by glucose but not amino acids. Both diets increased the thermic effect of feeding (TEF) and ketogenesis was increased in fasted HPLC mice. The results presented suggest that dietary glucose, rather than amino acids, directly controls FGF21 secretion, and that FGF21 may be involved in the increased TEF response to LPHC. The effects of the HPLC diet on ketogenesis and TEF are probably controlled by other metabolic pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Replacing with whole grains and legumes reduces Lp-PLA2 activities in plasma and PBMCs in patients with prediabetes or T2D1

PubMed Central

Kim, Minjoo; Jeung, Se Ri; Jeong, Tae-Sook; Lee, Sang-Hyun; Lee, Jong Ho

2014-01-01

To determine dietary effects on circulating lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and enzyme activity in peripheral blood mononuclear cells (PBMCs), 99 patients with impaired fasting glucose, impaired glucose tolerance, or newly-diagnosed T2D were randomly assigned to either a control group (usual diet with refined rice) or the whole grain and legume group. Substitution of whole grains and legumes for refined rice was associated with the replacement of 7% of energy from carbohydrates with energy from protein (about 4%) and fat. After 12 weeks, the whole grain and legume group showed a significant decrease in fasting glucose, insulin, homeostasis model assessment-insulin resistance, hemoglobin A1c, malondialdehyde, plasma Lp-PLA2 activity, and oxidized LDL (ox-LDL), and an increase in LDL particle size. The changes (Δs) in these variables in the whole grain and legume group were significantly different from those in controls after adjustment for the baseline levels. When all subjects were considered, Δ plasma Lp-PLA2 positively correlated with Δ glucose, Δ PBMC Lp-PLA2, Δ ox-LDL, and Δ urinary 8-epi-prostaglandin F2α after being adjusted for confounding factors. The Δ PBMC Lp-PLA2 correlated positively with Δ glucose and Δ ox-LDL, and negatively with Δ LDL particle size and baseline PBMC Lp-PLA2. The substitution of whole grains and legumes for refined rice resulted in a reduction in Lp-PLA2 activities in plasma and PBMCs partly through improved glycemic control, increased consumption of protein relative to carbohydrate, and reduced lipid peroxides. PMID:24904022

A Novel, Ecologically Relevant, Highly Preferred, and Non-invasive Means of Oral Substance Administration for Rodents

PubMed Central

Sobolewski, Marissa; Allen, Joshua L.; Morris-Schaffer, Keith; Klocke, Carolyn; Conrad, Katherine; Cory-Slechta, Deborah A.

2017-01-01

Prenatal stress and nutrition are well-known to alter a broad range of physiological systems, notably metabolic, endocrine and neurobehavioral function. Commonly used methods for oral administration of xenobiotics can, by acting as a stressor or altering normal nutrition intake, alter these physiological systems as well. Taken together, oral administration methods may unintentionally introduce confounding physiological effects that can mask or enhance toxicity of xenobiotics, particularly if they share biological targets. Consequently, it should be preferable to develop alternative methods without these potential confounds. The aim of this study was to determine the suitability of mealworms as an alternative treat-based method to deliver xenobiotics via the orogastric route. Accurate oral administration is contingent on motivation and preference; mice reliably preferred mealworms over wafer cookie treats. Further, ingestion of wafer cookies significantly increased mouse blood glucose levels, whereas unaltered mealworms produced no such change. Mealworms functioned effectively to orally administer glucose, as glucose-spiked mealworms produced a rise in blood glucose equivalent to the ingestion of the wafer cookie. Mealworms did not interfere with the physiological function of orally administered d-amphetamine, as both mealworm and oral gavage administered d-amphetamine showed similar alterations in locomotor behavior (mice did not fully consume d-amphetamine-dosed cookies and thus could not be compared). Collectively, the findings indicate that mealworms are a preferred and readily consumed treat, which importantly mimics environmental-relevant nutritional intake, and mealworms per se do not alter glucose metabolic pathways. Additionally, mealworms accurately delivered xenobiotics into blood circulation and did not interfere with the physiological function of administered xenobiotics. Thus mealworm-based oral administration may be a preferable and accurate route of xenobiotic administration that eliminates physiological alterations associated with other methods of delivery. PMID:27094606

A novel, ecologically relevant, highly preferred, and non-invasive means of oral substance administration for rodents.

PubMed

Sobolewski, Marissa; Allen, Joshua L; Morris-Schaffer, Keith; Klocke, Carolyn; Conrad, Katherine; Cory-Slechta, Deborah A

2016-01-01

Prenatal stress and nutrition are well-known to alter a broad range of physiological systems, notably metabolic, endocrine and neurobehavioral function. Commonly used methods for oral administration of xenobiotics can, by acting as a stressor or altering normal nutrition intake, alter these physiological systems as well. Taken together, oral administration methods may unintentionally introduce confounding physiological effects that can mask or enhance toxicity of xenobiotics, particularly if they share biological targets. Consequently, it should be preferable to develop alternative methods without these potential confounds. The aim of this study was to determine the suitability of mealworms as an alternative treat-based method to deliver xenobiotics via the orogastric route. Accurate oral administration is contingent on motivation and preference; mice reliably preferred mealworms over wafer cookie treats. Further, ingestion of wafer cookies significantly increased mouse blood glucose levels, whereas unaltered mealworms produced no such change. Mealworms functioned effectively to orally administer glucose, as glucose-spiked mealworms produced a rise in blood glucose equivalent to the ingestion of the wafer cookie. Mealworms did not interfere with the physiological function of orally administered d-amphetamine, as both mealworm and oral gavage administered d-amphetamine showed similar alterations in locomotor behavior (mice did not fully consume d-amphetamine-dosed cookies and thus could not be compared). Collectively, the findings indicate that mealworms are a preferred and readily consumed treat, which importantly mimics environmental-relevant nutritional intake, and mealworms per se do not alter glucose metabolic pathways. Additionally, mealworms accurately delivered xenobiotics into blood circulation and did not interfere with the physiological function of administered xenobiotics. Thus mealworm-based oral administration may be a preferable and accurate route of xenobiotic administration that eliminates physiological alterations associated with other methods of delivery. Copyright © 2016. Published by Elsevier Inc.

Circulating 25-Hydroxyvitamin D Concentrations Are Correlated With Cardiometabolic Risk Among American Black and White Adolescents Living in a Year-Round Sunny Climate

PubMed Central

Parikh, Samip; Guo, De-huang; Pollock, Norman K.; Petty, Karen; Bhagatwala, Jigar; Gutin, Bernard; Houk, Chris; Zhu, Haidong; Dong, Yanbin

2012-01-01

OBJECTIVE Low vitamin D status is common among healthy black and white adolescents residing at southern U.S. latitudes with a year-round sunny climate. Thus we aimed to study the relationships between circulating 25-hydroxyvitamin D [25(OH)D] and cardiometabolic risk factors in this population. RESEARCH DESIGN AND METHODS 25(OH)D concentrations were measured with liquid chromatography tandem mass spectroscopy in 701 girls and boys (14–18 years old, 54% blacks, 49% females). Cardiometabolic risk was indexed by adipokines, inflammatory markers, fasting glucose, homeostatic model assessment-insulin resistance (HOMA-IR), lipid profile, and blood pressure (BP). RESULTS Controlling for age, sex, race, sexual maturation, season, physical activity, and percent body fat, 25(OH)D concentrations were significantly correlated with adiponectin (r = 0.06, P = 0.05), leptin (r = −0.32, P < 0.01), fibrinogen (r = −0.05, P = 0.03), glucose (r = −0.16, P = 0.02), HOMA-IR (r = −0.17, P < 0.01), HDL cholesterol (r = 0.14, P = 0.02), systolic BP (r = −0.10, P = 0.02), and diastolic BP (r = −0.21, P < 0.01). When 25(OH)D concentrations were stratified into increasing tertiles, there were significant linear upward trends for adiponectin (P = 0.01) and HDL cholesterol (P = 0.04), but significant linear down trends for glucose (P < 0.01), HOMA-IR (P < 0.01), and systolic BP (P < 0.01), after adjusting for the above covariates. CONCLUSIONS Circulating 25(OH)D concentrations are associated with various adverse cardiometabolic risk factors, independent of adiposity. Clinical trials addressing the effects of vitamin D supplementation on cardiometabolic risk are warranted in adolescents irrespective of their geographical regions. PMID:22410810

Drosophila glucome screening identifies Ck1alpha as a regulator of mammalian glucose metabolism

PubMed Central

Ugrankar, Rupali; Berglund, Eric; Akdemir, Fatih; Tran, Christopher; Kim, Min Soo; Noh, Jungsik; Schneider, Rebekka; Ebert, Benjamin; Graff, Jonathan M.

2015-01-01

Circulating carbohydrates are an essential energy source, perturbations in which are pathognomonic of various diseases, diabetes being the most prevalent. Yet many of the genes underlying diabetes and its characteristic hyperglycaemia remain elusive. Here we use physiological and genetic interrogations in D. melanogaster to uncover the ‘glucome', the complete set of genes involved in glucose regulation in flies. Partial genomic screens of ∼1,000 genes yield ∼160 hyperglycaemia ‘flyabetes' candidates that we classify using fat body- and muscle-specific knockdown and biochemical assays. The results highlight the minor glucose fraction as a physiological indicator of metabolism in Drosophila. The hits uncovered in our screen may have conserved functions in mammalian glucose homeostasis, as heterozygous and homozygous mutants of Ck1alpha in the murine adipose lineage, develop diabetes. Our findings demonstrate that glucose has a role in fly biology and that genetic screenings carried out in flies may increase our understanding of mammalian pathophysiology. PMID:25994086

The orphan nuclear receptor small heterodimer partner is required for thiazolidinedione effects in leptin-deficient mice.

PubMed

Tseng, Hsiu-Ting; Park, Young Joo; Lee, Yoon Kwang; Moore, David D

2015-05-08

Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp(-/-)) double mutant mice. Both ob/ob and double mutant ob/ob;Shp(-/-) mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp(-/-) mice. PPARγ2 mRNA levels were markedly lower in ob/ob;Shp(-/-) liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp(-/-) mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp(-/-) mice. Moreover, overexpression of SHP by adenovirus infection increased PPARγ2 mRNA levels in mouse primary hepatocytes. Our results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARγ expression.

Effect of cholera toxin administered supraspinally or spinally on the blood glucose level in pain and d-glucose fed animal models.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kang, Yu-Jung; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Choi, Seong-Soo; Suh, Hong-Won

2013-04-01

In the present study, the effect of intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration with cholera toxin (CTX) on the blood glucose level was examined in ICR mice. The i.t. treatment with CTX alone for 24 h dose-dependently increased the blood glucose level. However, i.c.v. treatment with CTX for 24 h did not affect the blood glucose level. When mice were orally fed with D-glucose (2 g/kg), the blood glucose level reached to a maximum level at 30 min and almost returned to the control level at 120 min after D-glucose feeding. I.c.v. pretreatment with CTX increased the blood glucose level in a potentiative manner, whereas i.t. pretreatment with CTX increased the blood glucose level in an additive manner in a D-glucose fed group. In addition, the blood glucose level was increased in formalin-induced pain animal model. I.c.v. pretreatment with CTX enhanced the blood glucose level in a potentiative manner in formalin-induced pain animal model. On the other hand, i.t. pretreatment with CTX increased the blood glucose level in an additive manner in formalin-induced pain animal model. Our results suggest that CTX administered supraspinally or spinally differentially modulates the regulation of the blood glucose level in D-glucose fed model as well as in formalin-induced pain model.

Analysis of blood glucose distribution characteristics in a health examination population in Chengdu (2007-2015).

PubMed

Huang, Wenxia; Xu, Wangdong; Zhu, Ping; Yang, Hanwei; Su, Linchong; Tang, Huairong; Liu, Yi

2017-12-01

With socioeconomic growth and cultural changes in China, the level of blood glucose may have changed in recent years. This study aims to detect the blood glucose distribution characteristics with a large size of health examination population.A total of 641,311 cases (360,259 males and 281,052 females) more than 18 years old during 2007 to 2015 were recruited from the Health Examination Center at West China hospital, Sichuan University.The percentage of cases with abnormal glucose level and the mean level of glucose were significantly increased since 2007 to 2015 overall. The percentage of cases with abnormal glucose level in males was significantly higher than that in females every year, and the percentage of cases with abnormal glucose level in aged population was higher than the young population. In addition, the mean level of glucose was higher in aged population with normal level of glucose than the young population with normal level of glucose, and the mean level of glucose was higher in males with normal level of glucose than the females with normal level of glucose.The population showed an increased level of blood glucose. Some preventive action may be adopted early and more attention can be paid to them.

Portosystemic shunt as a cause of congenital hyperinsulinemic hypoglycemia.

PubMed

Yoshii, Keisuke; Noda, Masahiro; Naiki, Yasuhiro; Horikawa, Reiko

2017-04-01

Congenital hyperinsulinemic hypoglycemia (CHH) is characterized by the inappropriate secretion of insulin from pancreatic beta cells in the presence of hypoglycemia. We herein describe the case of a 5-month-old boy with CHH due to congenital portosystemic shunt (CPSS). Insulin secreted from pancreatic beta cells flows into the portal vein and is first metabolized in the liver. First-pass elimination of insulin in the liver leads to great decrease in insulin concentration by approximately 40-80% in humans. CPSS accounts for a large quantity of insulin delivery into the systemic circulation due to the lack of hepatic first-pass elimination. Hypoglycemia can result from consistently high levels of insulin after reaching normal glucose level. CPSS therefore should be considered as a rare cause of CHH, especially in the case of post-prandial hyperinsulinemic hypoglycemia. © 2017 Japan Pediatric Society.

The modulatory role of alpha-melanocyte stimulating hormone administered spinally in the regulation of blood glucose level in d-glucose-fed and restraint stress mouse models.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

2014-08-01

Alpha-melanocyte stimulating hormone (α-MSH) is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of α-MSH located in the spinal cord in the regulation of the blood glucose level were investigated in d-glucose-fed and immobilization stress (IMO) mouse models. We found in the present study that intrathecal (i.t.) injection with α-MSH alone did not affect the blood glucose level. However, i.t. administration with α-MSH reduced the blood glucose level in d-glucose-fed model. The plasma insulin level was increased in d-glucose-fed model and was further increased by α-MSH, whereas α-MSH did not affect plasma corticosterone level in d-glucose-fed model. In addition, i.t. administration with glucagon alone enhanced blood glucose level and, i.t. injection with glucagon also increased the blood glucose level in d-glucose-fed model. In contrasted to results observed in d-glucose-fed model, i.t. treatment with α-MSH caused enhancement of the blood glucose level in IMO model. The plasma insulin level was increased in IMO model. The increased plasma insulin level by IMO was reduced by i.t. treatment with α-MSH, whereas i.t. pretreatment with α-MSH did not affect plasma corticosterone level in IMO model. Taken together, although spinally located α-MSH itself does not alter the blood glucose level, our results suggest that the activation of α-MSH system located in the spinal cord play important modulatory roles for the reduction of the blood glucose level in d-glucose fed model whereas α-MSH is responsible for the up-regulation of the blood glucose level in IMO model. The enhancement of insulin release may be responsible for modulatory action of α-MSH in down-regulation of the blood glucose in d-glucose fed model whereas reduction of insulin release may be responsible for modulatory action of α-MSH in up-regulation of the blood glucose in IMO model. Copyright © 2014 Elsevier Ltd. All rights reserved.

Utilization of oral sucrose load during exercise in humans. Effect of the alpha-glucosidase inhibitor acarbose.

PubMed

Gerard, J; Jandrain, B; Pirnay, F; Pallikarakis, N; Krzentowski, G; Lacroix, M; Mosora, F; Luyckx, A S; Lefèbvre, P J

1986-11-01

We investigated the hormonal and metabolic response to a 100-g sucrose load given 15 min after adaptation to moderate-intensity (50% VmaxO2) long-duration (4-h) exercise in healthy volunteers. The effect of a 100-mg dose of the alpha-glucosidase inhibitor Acarbose ingested with the sucrose load was also investigated. "Naturally labeled [13C] sucrose" was used to follow the conversion to expired-air CO2 of the sugar ingested by isotope-ratio mass spectrometry. Circulating hormone and metabolite data were obtained in nine subjects, and indirect calorimetry and stable isotope methodology were applied to six of them. Under placebo, 93 +/- 4 g sucrose were entirely oxidized during the 4 h of exercise, total carbohydrate utilization was 235 +/- 14 g, endogenous carbohydrate utilization was 142 +/- 13 g, and total lipid oxidation was 121 +/- 7 g. A single oral dose of 100 mg Acarbose ingested with the sucrose load did not significantly modify total carbohydrate (239 +/- 2 g/4 h) or lipid (122 +/- 6 g/4 h) oxidation. In contrast, sucrose oxidation was reduced to 53 +/- 6 g/4 h and endogenous carbohydrate utilization increased to 186 +/- 7 g/4 h. Reduction of the rises in blood glucose and fructose and of the increases in plasma insulin and C peptide under Acarbose confirmed these effects, whereas lower circulating levels of alanine suggested a higher rate of gluconeogenesis. These data show that a 100-g glucose load ingested soon after initiation of exercise is a perfect available metabolic substrate.(ABSTRACT TRUNCATED AT 250 WORDS)

CXC chemokine ligand 16 is increased in gestational diabetes mellitus and preeclampsia and associated with lipoproteins in gestational diabetes mellitus at 5 years follow-up.

PubMed

Lekva, Tove; Michelsen, Annika E; Aukrust, Pål; Paasche Roland, Marie Cecilie; Henriksen, Tore; Bollerslev, Jens; Ueland, Thor

2017-11-01

Women with a history of gestational diabetes mellitus and preeclampsia are at increased risk of cardiovascular disease later in life, but the mechanism remains unclear. The aim of the study was to evaluate the association between CXC chemokine ligand 16 and indices of glucose metabolism, dyslipidemia and systemic inflammation in gestational diabetes mellitus and preeclampsia. This sub-study of the population-based prospective cohort included 310 women. Oral glucose tolerance test was performed during pregnancy and 5 years later along with lipid analysis. CXC chemokine ligand 16 was measured in plasma (protein) and peripheral blood mononuclear cells (messenger RNA) during pregnancy and at follow-up. Circulating CXC chemokine ligand 16 was higher in gestational diabetes mellitus women early in pregnancy and at follow-up, while higher in preeclampsia women late in pregnancy compared to control women. Messenger RNA of CXC chemokine ligand 16 in peripheral blood mononuclear cells were lower in gestational diabetes mellitus and preeclampsia women compared to control women. Increased circulating CXC chemokine ligand 16 level was associated with a higher apolipoprotein B and low-density lipoprotein cholesterol in gestational diabetes mellitus women but not in normal pregnancy at follow-up. Our study shows that women with gestational diabetes mellitus and preeclampsia had a dysregulated CXC chemokine ligand 16 during pregnancy, and in gestational diabetes mellitus, the increase in CXC chemokine ligand 16 early in pregnancy and after 5 years was strongly associated with their lipid profile.

Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels.

PubMed

Pedraza-Arévalo, S; Córdoba-Chacón, J; Pozo-Salas, A I; L-López, F; de Lecea, L; Gahete, M D; Castaño, J P; Luque, R M

2015-06-01

Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of various endocrine secretions. In particular, SST and CORT are two primary negative regulators of GH secretion. Consequently, single SST or CORT knockout mice exhibit elevated GH levels; however, this does not lead to increased IGF-1 levels or somatic growth. This apparent lack of correspondence has been suggested to result from compensatory mechanisms between both peptides. To test this hypothesis, in this study we explored, for the first time, the consequences of simultaneously deleting endogenous SST and CORT by generating a double SST/CORT knockout mouse model and exploring its endocrine and metabolic phenotype. Our results demonstrate that simultaneous deletion of SST and CORT induced a drastic elevation of endogenous GH levels, which, surprisingly, did not lead to changes in growth rate or IGF-1 levels, suggesting the existence of additional factors/systems that, in the absence of endogenous SST and CORT, could counteract GH actions. Notably, elevation in circulating GH levels were not accompanied by changes in pituitary GH expression or by alterations in the expression of its main regulators (GHRH and ghrelin) or their receptors (GHRH receptor, GHS receptor, or SST/CORT receptors) at the hypothalamic or pituitary level. However, although double-SST/CORT knockout male mice exhibited normal glucose and insulin levels, they had improved insulin sensitivity compared with the control mice. Therefore, these results suggest the existence of an intricate interplay among the known (SST/CORT), and likely unknown, inhibitory components of the GH/IGF-1 axis to regulate somatic growth and glucose/insulin homeostasis.

Effect of flow velocity on the photoacoustic detection for glucose aqueous solutions

NASA Astrophysics Data System (ADS)

Ren, Zhong; Liu, Guodong; Ding, Yu; Yao, Qingkai

2018-01-01

The blood glucose non-invasive detection has become the research hot-spot. The photoacoustic spectroscopy is a well-promising, high-efficient and noninvasive detection method because it combines the advantages of the pure optic and pure ultrasonic. In practice, the photoacoustic detection of blood glucose is impacted by many factors because the human body is a complicated bio-system. To study the effect of flow velocity in the blood vessel on the photoacoustic detection of blood glucose, a photoacoustic detection system based on optical parameter oscillator (OPO) pulsed laser induced ultrasonic was established. In this system, a 532nm pumped Nd: YAG OPO pulsed laser was used as the excitation source, and the photoacoustic signals of glucose were captured by ultrasonic transducer. Moreover, a set of blood circulation system was built to simulate the real blood flow situation in the human body. The experiments of the photoacoustic detection of glucose aqueous solutions with different concentrations at different flow velocities were experimentally investigated. Experimental results show that the photoacoustic peak-to-peak value linearly increases with the glucose concentration, but it decreases with the increase of the flow velocity although the profiles of photoacoustic signals don't change.

Excess cholesterol inhibits glucose-stimulated fusion pore dynamics in insulin exocytosis.

PubMed

Xu, Yingke; Toomre, Derek K; Bogan, Jonathan S; Hao, Mingming

2017-11-01

Type 2 diabetes is caused by defects in both insulin sensitivity and insulin secretion. Glucose triggers insulin secretion by causing exocytosis of insulin granules from pancreatic β-cells. High circulating cholesterol levels and a diminished capacity of serum to remove cholesterol from β-cells are observed in diabetic individuals. Both of these effects can lead to cholesterol accumulation in β-cells and contribute to β-cell dysfunction. However, the molecular mechanisms by which cholesterol accumulation impairs β-cell function remain largely unknown. Here, we used total internal reflection fluorescence microscopy to address, at the single-granule level, the role of cholesterol in regulating fusion pore dynamics during insulin exocytosis. We focused particularly on the effects of cholesterol overload, which is relevant to type 2 diabetes. We show that excess cholesterol reduced the number of glucose-stimulated fusion events, and modulated the proportion of full fusion and kiss-and-run fusion events. Analysis of single exocytic events revealed distinct fusion kinetics, with more clustered and compound exocytosis observed in cholesterol-overloaded β-cells. We provide evidence for the involvement of the GTPase dynamin, which is regulated in part by cholesterol-induced phosphatidylinositol 4,5-bisphosphate enrichment in the plasma membrane, in the switch between full fusion and kiss-and-run fusion. Characterization of insulin exocytosis offers insights into the role that elevated cholesterol may play in the development of type 2 diabetes. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Prolonged sitting and markers of cardiometabolic disease risk in children and youth: a randomized crossover study.

PubMed

Saunders, Travis J; Chaput, Jean-Philippe; Goldfield, Gary S; Colley, Rachel C; Kenny, Glen P; Doucet, Eric; Tremblay, Mark S

2013-10-01

Recent evidence suggests that short bouts of uninterrupted sedentary behavior reduce insulin sensitivity and glucose tolerance while increasing triglyceride levels in both healthy and overweight/obese adults. To date no study has examined the acute impact of uninterrupted sitting in children and youth. The objective of the present study was to determine whether 8 h of uninterrupted sitting increases markers of cardiometabolic disease risk in healthy children and youth, in comparison to 8 h of sitting interrupted by light intensity walk breaks or structured physical activity. 11 healthy males and 8 healthy females between the ages of 10 and 14 years experienced 3 conditions in random order: (1) 8 h of uninterrupted sitting (Sedentary); (2) 8 h of sitting interrupted with a 2-min light-intensity walk break every 20 min (Breaks); and (3) 8 h of sitting interrupted with a 2-min light-intensity walk break every 20 min as well as 2×20 min of moderate-intensity physical activity (Breaks+Physical Activity). Insulin, glucose, triglyceride, HDL and LDL cholesterol area under the curve were calculated for each condition. We observed no significant differences in the area under the curve for any marker of cardiometabolic disease risk across the 3 study conditions (all p>0.09). These results suggest that in comparison to interrupted sitting or structured physical activity, a single bout of 8 h of uninterrupted sitting does not result in measurable changes in circulating levels of insulin, glucose, or lipids in healthy children and youth. Copyright © 2013 Elsevier Inc. All rights reserved.

Temperament alters the metabolic response to glucose and insulin challenges and feed restriction in steers

USDA-ARS?s Scientific Manuscript database

Recently the dramatic metabolic differences between Temperamental and Calm cattle have been elucidated; Temperamental cattle maintain greater circulating concentrations of non-esterified fatty acids (NEFA) when compared to Calm cattle, which may influence other metabolic parameters including glucos...

Glucan-MOS® improved growth and innate immunity in pacu stressed and experimentally infected with Aeromonas hydrophila.

PubMed

Soares, Michelly Pereira; Oliveira, Fulvia Cristina; Cardoso, Israel Luz; Urbinati, Elisabeth Criscuolo; Meldau de Campos, Cristiane; Hisano, Hamilton

2018-02-01

We tested the efficacy of a commercial product (Glucan-MOS ® ) derived from yeast Saccharomyces cerevisiae, containing two combined products, β-1,3-1,6 glucans and mannans on the growth, feed efficiency, stress and innate immune responses of juvenile pacu (Piaractus mesopotamicus) after a stressful handling and bacterial inoculation. For this, we evaluated the serum cortisol and plasma glucose levels, the respiratory activity of leukocytes, the serum lysozyme levels, as well as the number of circulating erythrocytes and leukocytes of fish fed during 30 days with diets containing increased levels of Glucan-MOS (0.0, 0.1, 0.2, 0.4 and 0.8%). The supplementation of 0.1% improved weight gain, feed conversion and the protein efficiency ratio compared to a control diet. The 0.2 and 0.4% Glucan-MOS ® diets were sufficient to increase the respiratory burst of leukocytes and lysozyme activity, the number of thrombocytes, neutrophils and monocytes in the blood after a stressful handling and bacterial challenge, and minimized stress response as shown by decreased cortisol and glucose levels when compared to the control. The results of this work reinforce the benefits of the adoption of feeding strategies including combination of both β-1,3-1,6 glucans and mannans as a dietary supplement in periods prior to intensive management. The 30-day period was sufficient to stimulate growth performance, improve nutrient utilization, minimize stress response and modulate innate immunity responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evidence in obese children: contribution of hyperlipidemia, obesity-inflammation, and insulin sensitivity.

PubMed

Chang, Chi-Jen; Jian, Deng-Yuan; Lin, Ming-Wei; Zhao, Jun-Zhi; Ho, Low-Tone; Juan, Chi-Chang

2015-01-01

Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, and insulin sensitivity in overweight/obese children. We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-α, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits. Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-α and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%). Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future.

A Thyroid Hormone Challenge in Hypothyroid Rats Identifies T3 Regulated Genes in the Hypothalamus and in Models with Altered Energy Balance and Glucose Homeostasis

PubMed Central

Herwig, Annika; Campbell, Gill; Mayer, Claus-Dieter; Boelen, Anita; Anderson, Richard A.; Ross, Alexander W.; Mercer, Julian G.

2014-01-01

Background: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms. Methods: Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA. Results: Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (±1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic ventricular ependymal layer and differentially expressed in animal models of long- and short-term body weight regulation. Conclusion: This study identified genes regulated by T3 in the hypothalamus, a key area of the brain involved in homeostasis and neuroendocrine functions. These include genes hitherto not known to be regulated by thyroid status. PMID:25087834

Depletion of norepinephrine of the central nervous system Down-regulates the blood glucose level in d-glucose-fed and restraint stress models.

PubMed

Park, Soo-Hyun; Kim, Sung-Su; Lee, Jae-Ryeong; Sharma, Naveen; Suh, Hong-Won

2016-05-04

DSP-4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] is a neurotoxin that depletes norepinephrine. The catecholaminergic system has been implicated in the regulation of blood glucose level. In the present study, the effect of DSP-4 administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on blood glucose level was examined in d-glucose-fed and restraint stress mice models. Mice were pretreated once i.c.v. or i.t. with DSP-4 (10-40μg) for 3days, and d-glucose (2g/kg) was fed orally. Blood glucose level was measured 0 (prior to glucose feeding or restraint stress), 30, 60, and 120min after d-glucose feeding or restraint stress. The i.c.v. or i.t. pretreatment with DSP-4 attenuated blood glucose level in the d-glucose-fed model. Plasma corticosterone level was downregulated in the d-glucose-fed model, whereas plasma insulin level increased in the d-glucose-fed group. The i.c.v. or i.t. pretreatment with DSP-4 reversed the downregulation of plasma corticosterone induced by feeding d-glucose. In addition, the d-glucose-induced increase in plasma insulin was attenuated by the DSP-4 pretreatment. Furthermore, i.c.v. or i.t. pretreatment with DSP-4 reduced restraint stress-induced increases in blood glucose levels. Restraint stress increased plasma corticosterone and insulin levels. The i.c.v. pretreatment with DSP-4 attenuated restraint stress-induced plasma corticosterone and insulin levels. Our results suggest that depleting norepinephrine at the supraspinal and spinal levels appears to be responsible for downregulating blood glucose levels in both d-glucose-fed and restraint stress models. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Developmental Programming in Response to Intrauterine Growth Restriction Impairs Myoblast Function and Skeletal Muscle Metabolism

PubMed Central

Yates, D. T.; Macko, A. R.; Nearing, M.; Chen, X.; Rhoads, R. P.; Limesand, S. W.

2012-01-01

Fetal adaptations to placental insufficiency alter postnatal metabolic homeostasis in skeletal muscle by reducing glucose oxidation rates, impairing insulin action, and lowering the proportion of oxidative fibers. In animal models of intrauterine growth restriction (IUGR), skeletal muscle fibers have less myonuclei at birth. This means that myoblasts, the sole source for myonuclei accumulation in fibers, are compromised. Fetal hypoglycemia and hypoxemia are complications that result from placental insufficiency. Hypoxemia elevates circulating catecholamines, and chronic hypercatecholaminemia has been shown to reduce fetal muscle development and growth. We have found evidence for adaptations in adrenergic receptor expression profiles in myoblasts and skeletal muscle of IUGR sheep fetuses with placental insufficiency. The relationship of β-adrenergic receptors shifts in IUGR fetuses because Adrβ2 expression levels decline and Adrβ1 expression levels are unaffected in myofibers and increased in myoblasts. This adaptive response would suppress insulin signaling, myoblast incorporation, fiber hypertrophy, and glucose oxidation. Furthermore, this β-adrenergic receptor expression profile persists for at least the first month in IUGR lambs and lowers their fatty acid mobilization. Developmental programming of skeletal muscle adrenergic receptors partially explains metabolic and endocrine differences in IUGR offspring, and the impact on metabolism may result in differential nutrient utilization. PMID:22900186

Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling.

PubMed

Chen, Vicky Ping; Gao, Yang; Geng, Liyi; Brimijoin, Stephen

2017-10-10

The worldwide prevalence of obesity is increasing at an alarming rate but treatment options remain limited. Despite initial success, weight loss by calorie restriction (CR) often fails because of rebound weight gain. Postdieting hyperphagia along with altered hypothalamic neuro-architecture appears to be one direct cause of this undesirable outcome. In response to calorie deficiency the circulating levels of the appetite-promoting hormone, acyl-ghrelin, rise sharply. We hypothesize that proper modulation of acyl-ghrelin and its receptor's sensitivity will favorably impact energy intake and reprogram the body weight set point. Here we applied viral gene transfer of the acyl-ghrelin hydrolyzing enzyme, butyrylcholinesterase (BChE), in a mouse model of diet-induced obesity. Our results confirmed that BChE overexpression decreased circulating acyl-ghrelin levels, suppressed CR-provoked ghrelin signaling, and restored central ghrelin sensitivity. In addition to maintaining healthy body weights, BChE treated mice had modest postdieting food intake and showed normal glucose homeostasis. Spontaneous activity and energy expenditure did not differ significantly between treated and untreated mice after body weight rebound, suggesting that BChE gene transfer did not alter energy expenditure in the long term. These findings indicate that combining BChE treatment with CR could be an effective approach in treating human obesity and aiding lifelong weight management.

Metabolic Profiling of Adiponectin Levels in Adults: Mendelian Randomization Analysis.

PubMed

Borges, Maria Carolina; Barros, Aluísio J D; Ferreira, Diana L Santos; Casas, Juan Pablo; Horta, Bernardo Lessa; Kivimaki, Mika; Kumari, Meena; Menon, Usha; Gaunt, Tom R; Ben-Shlomo, Yoav; Freitas, Deise F; Oliveira, Isabel O; Gentry-Maharaj, Aleksandra; Fourkala, Evangelia; Lawlor, Debbie A; Hingorani, Aroon D

2017-12-01

Adiponectin, a circulating adipocyte-derived protein, has insulin-sensitizing, anti-inflammatory, antiatherogenic, and cardiomyocyte-protective properties in animal models. However, the systemic effects of adiponectin in humans are unknown. Our aims were to define the metabolic profile associated with higher blood adiponectin concentration and investigate whether variation in adiponectin concentration affects the systemic metabolic profile. We applied multivariable regression in ≤5909 adults and Mendelian randomization (using cis -acting genetic variants in the vicinity of the adiponectin gene as instrumental variables) for analyzing the causal effect of adiponectin in the metabolic profile of ≤37 545 adults. Participants were largely European from 6 longitudinal studies and 1 genome-wide association consortium. In the multivariable regression analyses, higher circulating adiponectin was associated with higher high-density lipoprotein lipids and lower very-low-density lipoprotein lipids, glucose levels, branched-chain amino acids, and inflammatory markers. However, these findings were not supported by Mendelian randomization analyses for most metabolites. Findings were consistent between sexes and after excluding high-risk groups (defined by age and occurrence of previous cardiovascular event) and 1 study with admixed population. Our findings indicate that blood adiponectin concentration is more likely to be an epiphenomenon in the context of metabolic disease than a key determinant. © 2017 The Authors.

Inhibiting LDL glycation ameliorates increased cholesteryl ester synthesis in macrophages and hypercholesterolemia and aortic lipid peroxidation in streptozotocin diabetic rats

PubMed Central

Cohen, Margo P.; Shea, Elizabeth A.; Wu, Van-Yu

2009-01-01

Increased nonenzymatic glycation of apoB-containing lipoproteins impairs uptake and metabolism by the high affinity low density lipoprotein (LDL) receptor, and is one of the post-secretory modifications contributory to accelerated atherosclerosis in diabetes. The present study evaluated in vitro and in vivo effects of 2,2-chlorophenylaminophenylacetate (CAP22) to probe the influence of glycated lipoprotein on cholesterol homeostasis. This compound prevented the increased formation of glycated products in LDL incubated with 200 mM glucose and the increased cholesteryl ester synthesis in THP-1 macrophages induced by apoB-containing lipoproteins preincubated with high glucose concentration. The elevated circulating concentrations of glycated lipoprotein and cholesterol and higher vascular levels of lipid peroxidation products observed in streptozotocin diabetic rats compared to nondiabetic controls were significantly reduced in diabetic animals treated for six months with test compound. These results are the first to demonstrate that inhibiting nonenzymatic glycation of apoB-containing lipoproteins ameliorates abnormalities contributory to hypercholesterolemia and atherogenic risk in diabetes. PMID:19922964

The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.

PubMed

White, Phillip J; McGarrah, Robert W; Grimsrud, Paul A; Tso, Shih-Chia; Yang, Wen-Hsuan; Haldeman, Jonathan M; Grenier-Larouche, Thomas; An, Jie; Lapworth, Amanda L; Astapova, Inna; Hannou, Sarah A; George, Tabitha; Arlotto, Michelle; Olson, Lyra B; Lai, Michelle; Zhang, Guo-Fang; Ilkayeva, Olga; Herman, Mark A; Wynn, R Max; Chuang, David T; Newgard, Christopher B

2018-06-05

Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-β transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity. Copyright © 2018 Elsevier Inc. All rights reserved.

Transcriptional regulation of pancreas development and β-cell function [Review].

PubMed

Fujitani, Yoshio

2017-05-30

A small number of cells in the adult pancreas are endocrine cells. They are arranged in clusters called islets of Langerhans. The islets make insulin, glucagon, and other endocrine hormones, and release them into the blood circulation. These hormones help control the level of blood glucose. Therefore, a dysfunction of endocrine cells in the pancreas results in impaired glucose homeostasis, or diabetes mellitus. The pancreas is an organ that originates from the evaginations of pancreatic progenitor cells in the epithelium of the foregut endoderm. Pancreas organogenesis and maturation of the islets of Langerhans occurs via a coordinated and complex interplay of transcriptional networks and signaling molecules, which guide a stepwise and repetitive process of the propagation of progenitor cells and their maturation, eventually resulting in a fully functional organ. Increasing our understanding of the extrinsic, as well as intrinsic mechanisms that control these processes should facilitate the efforts to generate surrogate β cells from ES or iPS cells, or to reactivate the function of important cell types within pancreatic islets that are lost in diabetes.

Signals for glucagon secretion.

PubMed

Bloom, S R

1977-01-01

The normal physiological role of glucagon is in controlling hepatic glucose output. Glucagon subserves the role of homeostasis by maintaining plasma glucose and of a stress hormone by producing hyperglycaemia. While control of glucagon release by circulating metabolites and also other hormones is clearly important, it seems likely that the nervous system exerts an over-riding influence. The parasympathetic nervous system maintains homeostasis and the sympathetic acts in stress. Glucagon levels are found to be high in cirrhosis and also after acute hepatic failure. It is likely that these changes in glucagon concentration are secondary to metabolic abnormalities. While some glucagon is cleared by the liver, a similar clearance is seen by many other tissues and it is not likely that the elevation of glucagon seen in liver failure is due solely to a gross deficiency of glucagon clearance. No liver abnormality is seen in the glucagonoma syndrome, where glucagon concentration are chronically high, or in patients who have had a total pancreatectomy, where plasma glucagon is undetectably low. It thus seems unlikely that liver mass is importantly controlled by glucagon.

Fat body glycogen serves as a metabolic safeguard for the maintenance of sugar levels in Drosophila.

PubMed

Yamada, Takayuki; Habara, Okiko; Kubo, Hitomi; Nishimura, Takashi

2018-03-14

Adapting to changes in food availability is a central challenge for survival. Glucose is an important resource for energy production, and therefore many organisms synthesize and retain sugar storage molecules. In insects, glucose is stored in two different forms: the disaccharide trehalose and the branched polymer glycogen. Glycogen is synthesized and stored in several tissues, including in muscle and the fat body. Despite the major role of the fat body as a center for energy metabolism, the importance of its glycogen content remains unclear. Here, we show that glycogen metabolism is regulated in a tissue-specific manner under starvation conditions in the fruit fly Drosophila The mobilization of fat body glycogen in larvae is independent of Adipokinetic hormone (Akh, the glucagon homolog) but is regulated by sugar availability in a tissue-autonomous manner. Fat body glycogen plays a crucial role in the maintenance of circulating sugars, including trehalose, under fasting conditions. These results demonstrate the importance of fat body glycogen as a metabolic safeguard in Drosophila . © 2018. Published by The Company of Biologists Ltd.

Short-term fasting promotes insulin expression in rat hypothalamus.

PubMed

Dakic, Tamara B; Jevdjovic, Tanja V; Peric, Mina I; Bjelobaba, Ivana M; Markelic, Milica B; Milutinovic, Bojana S; Lakic, Iva V; Jasnic, Nebojsa I; Djordjevic, Jelena D; Vujovic, Predrag Z

2017-07-01

In the hypothalamus, insulin takes on many roles involved in energy homoeostasis. Therefore, the aim of this study was to examine hypothalamic insulin expression during the initial phase of the metabolic response to fasting. Hypothalamic insulin content was assessed by both radioimmunoassay and Western blot. The relative expression of insulin mRNA was examined by qPCR. Immunofluorescence and immunohistochemistry were used to determine the distribution of insulin immunopositivity in the hypothalamus. After 6-h fasting, both glucose and insulin levels were decreased in serum but not in the cerebrospinal fluid. Our study showed for the first time that, while the concentration of circulating glucose and insulin decreased, both insulin mRNA expression and insulin content in the hypothalamic parenchyma were increased after short-term fasting. Increased insulin immunopositivity was detected specifically in the neurons of the hypothalamic periventricular nucleus and in the ependymal cells of fasting animals. These novel findings point to the complexity of mechanisms regulating insulin expression in the CNS in general and in the hypothalamus in particular. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The Activation by Glucose of Liver Membrane Nitric Oxide Synthase in the Synthesis and Translocation of Glucose transporter-4 in the Production of Insulin in the Mice Hepatocytes

PubMed Central

Bhattacharya, Suman; Ghosh, Rajeshwary; Maiti, Smarajit; Khan, Gausal Azam; Sinha, Asru K.

2013-01-01

Introduction Glucose has been reported to have an essential role in the synthesis and secretion of insulin in hepatocytes. As the efflux of glucose is facilitated from the liver cells into the circulation, the mechanism of transportation of glucose into the hepatocytes for the synthesis of insulin was investigated. Methods Grated liver suspension (GLS) was prepared by grating intact liver from adult mice by using a grater. Nitric oxide (NO) was measured by methemoglobin method. Glucose transporter-4 (Glut-4) was measured by immunoblot technique using Glut-4 antibody. Results Incubation of GLS with different amounts of glucose resulted in the uptake of glucose by the suspension with increased NO synthesis due to the stimulation of a glucose activated nitric oxide synthase that was present in the liver membrane. The inhibition of glucose induced NO synthesis resulted in the inhibition of glucose uptake. Glucose at 0.02M that maximally increased NO synthesis in the hepatocytes led to the translocation and increased synthesis of Glut-4 by 3.3 fold over the control that was inhibited by the inhibition of NO synthesis. The glucose induced NO synthesis was also found to result in the synthesis of insulin, in the presence of glucose due to the expression of both proinsulin genes I and II in the liver cells. Conclusion It was concluded that glucose itself facilitated its own transportation in the liver cells both via Glut-4 and by the synthesis of NO which had an essential role for insulin synthesis in the presence of glucose in these cells. PMID:24349154

Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis.

PubMed

Rao, Rajesh R; Long, Jonathan Z; White, James P; Svensson, Katrin J; Lou, Jesse; Lokurkar, Isha; Jedrychowski, Mark P; Ruas, Jorge L; Wrann, Christiane D; Lo, James C; Camera, Donny M; Lachey, Jenn; Gygi, Steven; Seehra, Jasbir; Hawley, John A; Spiegelman, Bruce M

2014-06-05

Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

BCAA Metabolism and Insulin Sensitivity - Dysregulated by Metabolic Status?

PubMed

Gannon, Nicholas P; Schnuck, Jamie K; Vaughan, Roger A

2018-03-01

Branched-chain amino acids (BCAAs) appear to influence several synthetic and catabolic cellular signaling cascades leading to altered phenotypes in mammals. BCAAs are most notably known to increase protein synthesis through modulating protein translation, explaining their appeal to resistance and endurance athletes for muscle hypertrophy, expedited recovery, and preservation of lean body mass. In addition to anabolic effects, BCAAs may increase mitochondrial content in skeletal muscle and adipocytes, possibly enhancing oxidative capacity. However, elevated circulating BCAA levels have been correlated with severity of insulin resistance. It is hypothesized that elevated circulating BCAAs observed in insulin resistance may result from dysregulated BCAA degradation. This review summarizes original reports that investigated the ability of BCAAs to alter glucose uptake in consequential cell types and experimental models. The review also discusses the interplay of BCAAs with other metabolic factors, and the role of excess lipid (and possibly energy excess) in the dysregulation of BCAA catabolism. Lastly, this article provides a working hypothesis of the mechanism(s) by which lipids may contribute to altered BCAA catabolism, which often accompanies metabolic disease. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mediastinal germ cell tumour causing superior vena cava tumour thrombosis.

PubMed

Karanth, Suman S; Vaid, Ashok K; Batra, Sandeep; Sharma, Devender

2015-03-25

We report a rare case of a 35-year-old man who presented with a 1-week history of retrosternal chest pain of moderate intensity. A positron emission tomography CT (PET-CT) showed a large fluorodeoxy-glucose (FDG)-avid heterogeneously enhancing necrotic mass in the anterosuperior mediastinum with a focal FDG-avid thrombosis of the superior vena cava (SVC) suggestive of tumour thrombus and vascular invasion. α-Fetoprotein levels were raised (5690 IU/L). Image guided biopsy of the mediastinal mass was suggestive of non-seminomatous germ cell tumour (NSGCT). The patient received four cycles of BEP (bleomycin, etoposide and cisplatin) along with therapeutic anticoagulation with low-molecular-weight heparin. Follow-up whole body PET-CT revealed complete resolution of mediastinal mass and SVC tumour thrombosis. The documentation of FDG-PET-avid tumour thrombus resolving with chemotherapy supports the concept of circulating tumour cells being important not only in common solid tumours such as breast and colon cancer but also in relatively less common tumours such as NSGCT. The detection of circulating tumour cells could help deploy aggressive regimens upfront. 2015 BMJ Publishing Group Ltd.

Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes.

PubMed

Ortega, Francisco J; Mercader, Josep M; Moreno-Navarrete, José M; Sabater, Mónica; Pueyo, Neus; Valdés, Sergio; Ruiz, Bartomeu; Luche, Elodie; Serino, Matteo; Naon, Deborah; Ricart, Wifredo; Botas, Patricia; Delgado, Elias; Burcelin, Remy; Frühbeck, Gema; Bosch, Fatima; Mingrone, Gertrude; Zorzano, Antonio; Fernández-Real, José M

2013-04-01

Calgranulin B (S100A9) was recognized as a candidate type 2 diabetes (T2D) gene in the genomic profiling of muscle from a rodent model of T2D and identifying the human orthologs of genes localized in T2D susceptibility regions. Circulating and S100A9 expressions in muscle and adipose tissue, isolated fat cells, and mouse models were evaluated. A common 5'-upstream single-nucleotide polymorphism (SNP; rs3014866) for S100A9 was analyzed, as well as the effects of weight loss and treatments in vitro with recombinant S100A9. S100a9 expression was increased in muscle of diabetic mice (1.6-fold, p = 0.002), and in muscle from subjects with impaired glucose tolerance (∼4-fold, p = 0.028; n = 34). The rs3014866 SNP was associated with circulating S100A9 and the risk of T2D, having TT carriers at 28 % (p = 0.03) lower risk (n = 1,450). Indeed, increased circulating S100A9 (∼4-fold, p = 0.03; n = 206) and subcutaneous (2-fold, p = 0.01) and omental (1.4-fold, p = 0.04) S100A9 gene expressions (n = 83) in TT carriers run in parallel to decreased fasting glucose and glycated hemoglobin. Accordingly, metformin led to increased S100A9 mRNA in ex vivo-treated adipose tissue explants (n = 5/treatment). Otherwise, obese subjects showed a compensatory increase in circulating and S100A9 expressions in adipose (n = 126), as further demonstrated by decreased levels after diet- (-34 %, p = 0.002; n = 20) and surgery-induced (-58 %, p = 0.02; n = 8) weight loss. Lipopolysaccharide led to increased S100A9 in adipose from mice (n = 5/treatment) while recombinant S100A9 downregulated inflammation in adipocytes (n = 3/treatment). Current findings support the strategy of testing differentially expressed genes in mice and human orthologs associated with T2D. The increased S100A9 reported for obesity and insulin resistance may be envisioned as a compensatory mechanism for inflammation.

Polyunsaturated fatty acids reduce insulin and very low density lipoprotein levels in broiler chickens.

PubMed

Crespo, N; Esteve-Garcia, E

2003-07-01

An experiment was conducted to study the effect of different dietary fatty acid profiles on plasma levels of insulin, very low density lipoproteins (VLDL), cholesterol, and glucose. Diets with four types of fat (tallow, olive, sunflower, and linseed oils) at an inclusion level of 10% and a basal diet without additional fat were administered to female broiler chickens. Serum insulin, cholesterol, and plasma VLDL were affected by the different treatments; however, glucose concentrations were similar among treatments. In the fasted state, broilers fed diets with sunflower or linseed oil presented lower levels of insulin and cholesterol with respect to those fed tallow or olive oil (P < 0.05). VLDL in the fasted state was reduced in broilers fed sunflower and linseed oils (P < 0.05) with respect to those fed tallow, olive oil, or the basal diet. Plasma levels of VLDL were only significantly correlated with abdominal fat in birds fed the basal diet, in the fed and in the fasted state, and in those fed linseed oil in the fed state (P < 0.05). Results of this experiment suggest that higher insulin levels in broilers fed diets rich in saturated fatty acids could be related to higher fat deposition. Fat deposition in birds fed high fat diets was not correlated with circulating VLDL, which suggested direct dietary fat deposition, except for birds fed linseed oil diets. Although birds fed linseed oil diets presented lower levels of VLDL than those fed tallow, olive oil, or the basal diet, the higher correlation with abdominal fat suggests that in these birds, fat deposition is more dependent on hepatic VLDL secretion, despite the high dietary fat level.

Cinnamon extract regulates plasma levels of adipose-derived factors and expression of multiple genes related to carbohydrate metabolism and lipogenesis in adipose tissue of fructose-fed rats.

PubMed

Qin, B; Polansky, M M; Anderson, R A

2010-03-01

We reported earlier that dietary cinnamon extract (CE) improves systemic insulin sensitivity and dyslipidemia by enhancing insulin signaling. In the present study, we have examined the effects of CE on several biomarkers including plasma levels of adipose-derived adipokines, and the potential molecular mechanisms of CE in epididymal adipose tissue (EAT). In Wistar rats fed a high-fructose diet (HFD) to induce insulin resistance, supplementation with a CE (Cinnulin PF, 50 mg/kg daily) for 8 weeks reduced blood glucose, plasma insulin, triglycerides, total cholesterol, chylomicron-apoB48, VLDL-apoB100, and soluble CD36. CE also inhibited plasma retinol binding protein 4 (RBP4) and fatty acid binding protein 4 (FABP4) levels. CE-induced increases in plasma adiponectin were not significant. CE did not affect food intake, bodyweight, and EAT weight. In EAT, there were increases in the insulin receptor ( IR) and IR substrate 2 ( IRS2) mRNA, but CE-induced increases in mRNA expression of IRS1, phosphoinositide-3-kinase, AKT1, glucose transporters 1 and 4 , and glycogen synthase 1 expression and decreased trends in mRNA expression of glycogen synthase kinase 3beta were not statistically significant. CE also enhanced the mRNA levels of ADIPOQ, and inhibited sterol regulatory element binding protein-1c mRNA levels. mRNA and protein levels of fatty acid synthase and FABP4 were inhibited by CE and RBP4, and CD36 protein levels were also decreased by CE. These results suggest that CE effectively ameliorates circulating levels of adipokines partially mediated via regulation of the expression of multiple genes involved in insulin sensitivity and lipogenesis in the EAT.

Increased follistatin levels after oral contraceptive treatment in obese and non-obese women with polycystic ovary syndrome.

PubMed

Chen, Mei-Jou; Yang, Wei-Shiung; Chen, Hsin-Fu; Kuo, Jahn-Jahn; Ho, Hong-Nerng; Yang, Yu-Shih; Chen, Shee-Uan

2010-03-01

Follistatin levels have recently been considered as a marker for inflammation. Our objective was to evaluate the level of circulating follistatin and high-sensitivity C-reactive protein (hsCRP) in women with polycystic ovary syndrome (PCOS) after oral contraceptive (OC) treatment. A total of 56 Taiwanese women with PCOS were enrolled in this prospective observational study in which they were treated for 3 months with OCs (ethinyl estradiol-cyproterone acetate). Blood samples were taken at baseline after treatment during the withdrawal bleed. Body mass index (BMI), lipid profiles, plasma follistatin, hsCRP, fasting glucose, insulin for the homeostasis model assessment of insulin resistance (HOMA-IR) and hormone profiles were measured and analyzed. Total testosterone, free androgen index (FAI), dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol levels were significantly lower, but total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, circulating follistatin and hsCRP were significantly higher than baseline in women with PCOS after treatment with OCs. An elevation of fasting insulin, HOMA-IR and hsCRP after OC treatment was more evident in non-obese than obese women, whereas the elevation of follistatin was significant in both obese and non-obese women. Follistatin and hsCRP levels all showed significant correlations with each other at baseline and after treatment. The differences in follistatin and hsCRP levels from baseline to after OC treatment were significantly associated with the difference in triglyceride levels. Both hsCRP and follistatin levels increase after OC treatment in women with PCOS. Follistatin seems more sensitive than hsCRP alone to represent the aggravated low-grade inflammatory status after OC treatment in obese and non-obese women with PCOS.

Comparison of serum vaspin levels and vaspin expression in adipose tissue and smooth muscle tissue in pregnant women with and without gestational diabetes.

PubMed

Tang, Yuping; Qiao, Ping; Qu, Xiaoxian; Bao, Yirong; Li, Yuhong; Liao, Yini; Ying, Hao

2017-10-01

Vaspin is associated with metabolic parameters and insulin resistance. However, the expression of vaspin in visceral adipose tissue (VAT) in pregnant women with gestational diabetes mellitus (GDM) has not been fully explored, and the contribution of vaspin to the biological mechanisms underlying GDM remains unclear. This study aimed to compare circulating vaspin levels and its expression in different insulin target tissues including subcutaneous adipose tissue (SAT), VAT and smooth muscle tissue (SMT) in pregnant women with and without GDM. A total of 37 women with GDM (GDM group) and 37 normal pregnant women (control group) were selected. Fasting plasma glucose (FPG), fasting insulin (FINS) and serum vaspin levels were quantified at term, and homeostasis model of assessment2-insulin resistance (HOMA2-IR) values were calculated. RT-qPCR and Western blotting were used to measure mRNA and protein levels of vaspin in VAT, SAT and SMT of 15 GDM women and normal pregnant women. In the GDM group, serum vaspin concentrations were significantly higher than in the control group. Serum vaspin levels were positively correlated with HOMA2-IR in the GDM group but not in the control group. In the GDM group, vaspin mRNA and protein expression levels in SAT and VAT were both significantly higher than in controls, but no difference was found in SMT. Moreover, relative mRNA but not protein expression levels of vaspin in SAT were highest among the three tissues in both groups. Circulating vaspin levels and expression of vaspin in SAT and VAT were higher in GDM women than in normal pregnant women. However, the specific role of vaspin from SAT and VAT in the pathogenesis of GDM needs further study. © 2017 John Wiley & Sons Ltd.

Gold nanorods in an oil-base formulation for transdermal treatment of type 1 diabetes in mice

NASA Astrophysics Data System (ADS)

Nose, Keisuke; Pissuwan, Dakrong; Goto, Masahiro; Katayama, Yoshiki; Niidome, Takuro

2012-05-01

Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients.Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr30651d

Betatrophin: no relation to glucose metabolism or weight status in obese children before and after lifestyle intervention.

PubMed

Roth, Christian L; Elfers, Clinton; Lass, Nina; Reinehr, Thomas

2017-09-01

The influences of obesity, glucose metabolism, gender, and puberty on betatrophin levels and the longitudinal relationships between weight loss, metabolic changes and betatrophin have not yet been studied in childhood. Cross-sectional and longitudinal analysis of weight status (standard deviation score-body mass index (SDS-BMI)), homeostasis model assessment insulin resistance (HOMA-IR), gender, and pubertal stage were evaluated in 69 obese children (51% female, age 11.9 ± 2.0 years) participating in lifestyle intervention over a 1-year period. An oral glucose tolerance test was performed in 53 of the 69 children. Twenty normal weight children (50% female, age 12.3 ± 3.0 years) served as controls. Circulating betatrophin did not differ significantly between obese and lean children (1.99 ± 0.90 vs 2.35 ± 0.28, mean ± SD, P = .155). At baseline, betatrophin did not differ in obese patients with vs without glucose intolerance (1.89 ± 0.96 vs 2.031 ± 0.91 ng/mL; P = .591) and obese with (delta SDS-BMI >0.4) vs without successful obesity intervention (1.89 ± 0.94 vs. 2.07 ± 0.87 ng/mL; P = 0.396). In multiple linear regression analyses, pubertal stage was associated with betatrophin (b: 0.48, P = .027), while gender, age, BMI, blood pressure, fasting glucose, HOMA-IR, triglycerides, LDL- and HDL-cholesterol were not related to betatrophin at baseline. At the end of the 1-year intervention, changes of betatrophin were not significantly associated with any parameter after controlling for multiple covariates including age and changes of pubertal stages. Our data do not support a relationship between betatrophin and weight status or glucose tolerance, insulin resistance, and lipid metabolism in children. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Glucose regulates hypothalamic long-chain fatty acid metabolism via AMP-activated kinase (AMPK) in neurons and astrocytes.

PubMed

Taïb, Bouchra; Bouyakdan, Khalil; Hryhorczuk, Cécile; Rodaros, Demetra; Fulton, Stephanie; Alquier, Thierry

2013-12-27

Hypothalamic controls of energy balance rely on the detection of circulating nutrients such as glucose and long-chain fatty acids (LCFA) by the mediobasal hypothalamus (MBH). LCFA metabolism in the MBH plays a key role in the control of food intake and glucose homeostasis, yet it is not known if glucose regulates LCFA oxidation and esterification in the MBH and, if so, which hypothalamic cell type(s) and intracellular signaling mechanisms are involved. The aim of this study was to determine the impact of glucose on LCFA metabolism, assess the role of AMP-activated Kinase (AMPK), and to establish if changes in LCFA metabolism and its regulation by glucose vary as a function of the kind of LCFA, cell type, and brain region. We show that glucose inhibits palmitate oxidation via AMPK in hypothalamic neuronal cell lines, primary hypothalamic astrocyte cultures, and MBH slices ex vivo but not in cortical astrocytes and slice preparations. In contrast, oleate oxidation was not affected by glucose or AMPK inhibition in MBH slices. In addition, our results show that glucose increases palmitate, but not oleate, esterification into neutral lipids in neurons and MBH slices but not in hypothalamic astrocytes. These findings reveal for the first time the metabolic fate of different LCFA in the MBH, demonstrate AMPK-dependent glucose regulation of LCFA oxidation in both astrocytes and neurons, and establish metabolic coupling of glucose and LCFA as a distinguishing feature of hypothalamic nuclei critical for the control of energy balance.

Effects of sugar-sweetened beverages on plasma acylation stimulating protein, leptin, and adiponectin: Relationships with metabolic outcomes

USDA-ARS?s Scientific Manuscript database

OBJECTIVE: The effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity were determined. DESIGN AND METHODS: Thirty two over...

Development of insulin resistance in dairy cows by 150 days of lactation does not alter oocyte quality in smaller follicles.

PubMed

Oliveira, L H; Nascimento, A B; Monteiro, P L J; Guardieiro, M M; Wiltbank, M C; Sartori, R

2016-11-01

The objective of this study was to test the hypothesis that high-producing dairy cows become increasingly resistant to insulin throughout lactation and that, consequently, oocyte quality is compromised. We used Holstein cows at 50 (51.5±3.7; n=30), 100 (102.3±9.4; n=30), and 150 (154.5±18.9; n=30) days in milk (DIM). We measured circulating insulin and glucose and performed a glucose tolerance test (GTT) after 5h of fasting. To evaluate oocyte quality, we performed ovum pickup on the day before the GTT (581 oocytes). We performed statistical analyses using the MIXED procedure of SAS. The model included the fixed effects of DIM, period, time, parity, and an interaction between DIM and time. We observed no difference in the GTT between groups for any variable related to circulating glucose (for example, glucose peak=203.3±7.2, 208.8±6.3, and 194.3±5.9mg/dL). However, various measures of circulating insulin were different in cows at 150 DIM compared with 50 or 100 DIM: higher basal insulin (8.8±0.9, 8.8±0.8, and 11.9±0.8 µIU/mL), peak insulin (61.9±6.2 , 69.1±5.7, and 89.0±6.1 µIU/mL), delta maximum insulin (51.1±5.5 , 59.4±5.0, and 73.5±5.4 µIU/mL), and area under the curve 5-60 (1,874.8±171.0 , 2,189.5±157.8, and 2,610.5±174.0 µIU/mL × min). Nevertheless, we observed no difference among groups in the number of viable oocytes (3.2±0.7, 3.9±0.7, and 3.6±0.7 per cow per ovum pickup) or percentage of viable oocytes (49.3, 52.2, and 51.8%). Increased circulating insulin before and throughout the GTT in cows at 150 DIM indicates that cows develop increasing insulin resistance with increasing DIM; however, increased insulin resistance was not associated with a detectable alteration in the quality of oocytes aspirated from small and medium-sized follicles. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Differential Effects of Oral and Intravenous Lipid Administration on Key Molecules Related to Energy Homeostasis

PubMed Central

Vamvini, Maria T.; Hamnvik, Ole-Petter; Sahin-Efe, Ayse; Gavrieli, Anna; Dincer, Fadime; Farr, Olivia M.

2016-01-01

Context: The spectrum of lipid-induced changes in the secretion of hormones important in energy homeostasis has not yet been fully elucidated. Objective: To identify potential incretin-like effects in response to lipid administration, we examined the short-term effect of iv vs oral lipids on key molecules regulating energy homeostasis. Design, Intervention, and Participants: After a 10-hour overnight fast, 26 subjects were randomized to receive an oral lipid load, a 10% iv lipid emulsion, a 20% iv lipid emulsion, or an iv saline infusion. We obtained blood samples at 30-minute intervals for the first 2 hours and hourly thereafter for a total of 6 hours. Main Outcome Measures: Circulating levels of insulin, glucose, c-peptide, free fatty acids, incretins (glucagon-like peptide-1, gastric inhibitory polypeptide), glucagon, peptide YY, ghrelin, fibroblast growth factor 21, fetuin A, irisin, omentin, and adiponectin were measured. Results: Oral lipid ingestion resulted in higher glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, and peptide YY levels, compared with the other three groups (incremental area under the curve P = .003, P < .001, P < .001, P < .001, respectively). The 20% lipid emulsion, leading to higher free fatty acid levels, resulted in greater insulin, c-peptide, and fibroblast growth factor 21 responses compared with placebo and the other two groups (incremental area under the curve P = .002, P = .005, P < .001, P < .001, respectively). Omentin, adiponectin, fetuin A, and irisin levels were not affected by either mode of lipid administration. Conclusions: Metabolic responses to lipids depend on the route of administration. Only iv lipids trigger a dose-dependent fibroblast growth factor 21 secretion, which is nonglucagon mediated. Intravenous lipids also induce hyperinsulinemia without concurrent decreases in glucose, a phenomenon observed in insulin-resistant states. Orally administered lipids mostly affect gastrointestinal tract-secreted molecules important in glucose and energy homeostasis such as glucagon, incretins, and peptide YY. PMID:26964729

Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism.

PubMed

Pollin, Toni I; Jablonski, Kathleen A; McAteer, Jarred B; Saxena, Richa; Kathiresan, Sekar; Kahn, Steven E; Goldberg, Ronald B; Altshuler, David; Florez, Jose C

2011-07-01

Glucokinase regulatory protein (GCKR) regulates the trafficking and enzymatic activity of hepatic glucokinase, the rate-limiting enzyme in glycogen synthesis and glycolysis. The intronic single-nucleotide polymorphism (SNP) rs780094 (intron 16) and the missense SNP rs1260326 (P446L) in the GCKR gene are strongly associated with increased circulating triglyceride and C-reactive protein levels and, paradoxically, reductions in diabetes incidence, fasting glucose levels, and insulin resistance. OBJECTIVE, SETTING, AND PATIENTS: We sought to replicate these associations and evaluate interactions with lifestyle and metformin interventions in the multiethnic Diabetes Prevention Program (DPP). We genotyped the two GCKR SNP in 3346 DPP participants and evaluated association with progression to diabetes and both baseline levels and changes in triglycerides, homeostasis model assessment of insulin resistance (HOMA-IR), oral disposition index, and inflammatory markers along with their interactions with DPP interventions. GCKR variation did not predict development of type 2 diabetes. At baseline, the 446L allele was associated with higher triglyceride and C-reactive protein levels (both P < 0.0001) and lower fasting glucose (P = 0.001) and HOMA-IR (P = 0.06). The lifestyle intervention was associated with a decrease in magnitude of the effect of the 446L allele on triglyceride levels (interaction P = 0.04). Metformin was more effective in reducing HOMA-IR in carriers of the P446 allele (interaction P = 0.05). Intensive lifestyle intervention appears to partially mitigate the effect of the 446L allele on higher triglycerides, whereas the P446 allele appears to enhance responsiveness to the HOMA-IR-lowering effect of metformin.

Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet.

PubMed

Douris, Nicholas; Melman, Tamar; Pecherer, Jordan M; Pissios, Pavlos; Flier, Jeffrey S; Cantley, Lewis C; Locasale, Jason W; Maratos-Flier, Eleftheria

2015-10-01

Ingestion of very low-carbohydrate ketogenic diets (KD) is associated with weight loss, lowering of glucose and insulin levels and improved systemic insulin sensitivity. However, the beneficial effects of long-term feeding have been the subject of debate. We therefore studied the effects of lifelong consumption of this diet in mice. Complete metabolic analyses were performed after 8 and 80weeks on the diet. In addition we performed a serum metabolomic analysis and examined hepatic gene expression. Lifelong consumption of KD had no effect on morbidity or mortality (KD vs. Chow, 676 vs. 630days) despite hepatic steatosis and inflammation in KD mice. The KD fed mice lost weight initially as previously reported (Kennnedy et al., 2007) and remained lighter and had less fat mass; KD consuming mice had higher levels of energy expenditure, improved glucose homeostasis and higher circulating levels of β-hydroxybutyrate and triglycerides than chow-fed controls. Hepatic expression of the critical metabolic regulators including fibroblast growth factor 21 were also higher in KD-fed mice while expression levels of lipogenic enzymes such as stearoyl-CoA desaturase-1 was reduced. Metabolomic analysis revealed compensatory changes in amino acid metabolism, primarily involving down-regulation of catabolic processes, demonstrating that mice eating KD can shift amino acid metabolism to conserve amino acid levels. Long-term KD feeding caused profound and persistent metabolic changes, the majority of which are seen as health promoting, and had no adverse effects on survival in mice. Copyright © 2015. Published by Elsevier B.V.

Lower dipeptidyl peptidase-4 following exercise training plus weight loss is related to increased insulin sensitivity in adults with metabolic syndrome.

PubMed

Malin, Steven K; Huang, Hazel; Mulya, Anny; Kashyap, Sangeeta R; Kirwan, John P

2013-09-01

Dipeptidyl peptidase-4 (DPP-4) is a circulating glycoprotein that impairs insulin-stimulated glucose uptake and is linked to obesity and metabolic syndrome. However, the effect of exercise on plasma DPP-4 in adults with metabolic syndrome is unknown. Therefore, we determined the effect of exercise on DPP-4 and its role in explaining exercise-induced improvements in insulin sensitivity. Fourteen obese adults (67.9±1.2 years, BMI: 34.2±1.1kg/m(2)) with metabolic syndrome (ATP III criteria) underwent a 12-week supervised exercise intervention (60min/day for 5 days/week at ∼85% HRmax). Plasma DPP-4 was analyzed using an enzyme-linked immunosorbent assay. Insulin sensitivity was measured using the euglycemic-hyperinsulinemic clamp (40mU/m(2)/min) and estimated by HOMA-IR. Visceral fat (computerized tomography), 2-h glucose levels (75g oral glucose tolerance), and basal fat oxidation as well as aerobic fitness (indirect calorimetry) were also determined before and after exercise. The intervention reduced visceral fat, lowered blood pressure, glucose and lipids, and increased aerobic fitness (P<0.05). Exercise improved clamp-derived insulin sensitivity by 75% (P<0.001) and decreased HOMA-IR by 15% (P<0.05). Training decreased plasma DPP-4 by 10% (421.8±30.1 vs. 378.3±32.5ng/ml; P<0.04), and the decrease in DPP-4 was associated with clamp-derived insulin sensitivity (r=-0.59; P<0.04), HOMA-IR (r=0.59; P<0.04) and fat oxidation (r=-0.54; P<0.05). Increased fat oxidation also correlated with lower 2-h glucose levels (r=-0.64; P<0.02). Exercise training reduces plasma DPP-4, which may be linked to elevated insulin sensitivity and fat oxidation. Maintaining low plasma DPP-4 concentrations is a potential mechanism whereby exercise plus weight loss prevents/delays the onset of type 2 diabetes in adults with metabolic syndrome. Copyright © 2013 Elsevier Inc. All rights reserved.