Elevated glucose levels in early puerperium, and association with high cortisol levels during parturition.

PubMed

Risberg, Anitha; Sjöquist, Mats; Wedenberg, Kaj; Larsson, Anders

2016-07-01

Background Gestational diabetes is one of the commonest metabolic problems associated with pregnancy and an accurate diagnosis is critical for the care. Research has shown that pregnant women have high levels of cortisol during the last stage of parturition. As cortisol is a diabetogenic hormone causing increased glucose levels, we wanted to study the association between cortisol and glucose levels during parturition. Materials and methods Glucose and cortisol were analyzed during parturition in 50 females divided according to slow (n = 11) and normal labors (n = 39). Blood samples were analyzed three times during the parturition and four times in the first day after delivery. Glucose levels were also measured once in each trimester. Results In the normal group, the glucose concentration increased from 6.2 (IQR 5.6-8.0) mmol/L in the latency phase to 11.6 (10.0-13.3) mmol/L at aftercare (p < 0.05). After parturition the glucose concentrations decreased gradually. There were significant Spearman rank correlations between glucose and cortisol values. Conclusions The changes associated with birth cause significant elevations of cortisol and glucose around parturition.

Red cell distribution width is associated with hemoglobin A1C elevation, but not glucose elevation.

PubMed

Bao, Xue; Wan, Min; Gu, Yeqing; Song, Yanqi; Zhang, Qing; Liu, Li; Meng, Ge; Wu, Hongmei; Xia, Yang; Shi, HongBin; Su, Qian; Fang, Liyun; Yang, Huijun; Yu, Fei; Sun, Shaomei; Wang, Xing; Zhou, Ming; Jia, Qiyu; Song, Kun; Wang, Guolin; Yu, Ming; Niu, Kaijun

2017-10-01

To investigate the association between red cell distribution width (RDW) and elevation of glucose/glycated hemoglobin (HbA1c). An analysis was conducted using data from a prospective cohort study of adults. People without prediabetes or diabetes (n=7,795) were followed for a mean of 2.90years (range: 1-7years, 95% confidence interval: 2.86-2.94years). Glucose elevation is defined as fasting glucose levels exceeding 5.6mmol/l, or 2-hour glucose values in the oral glucose tolerance test exceeding 7.8mmol/l. HbA1c elevation is defined as a HbA1c value exceeding a normal limit of 39mmol/mol (5.7%). Adjusted Cox proportional hazards regression models were used to assess the association between RDW quartiles and elevation of HbA1c/glucose. The multiple-adjusted hazard ratios (95% confidence interval) of HbA1c elevation for increased quartiles of RDW were 1.00 (reference), 1.08 (0.89, 1.30), 1.28 (1.07, 1.54), and 1.54 (1.29, 1.85) (P for trend<0.0001). However, no significant association was observed between RDW and blood glucose (fasting and postprandial). Elevated RDW is independently related to future HbA1c elevation, but not to glucose elevation. This suggests that RDW may associate with HbA1c through a non-glycemic way, which should be taken into consideration when using HbA1c as a diagnostic criterion of prediabetes or diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

Testosterone is protective against impaired glucose metabolism in male intrauterine growth-restricted offspring

PubMed Central

Dasinger, John Henry; Fahling, Joel M.; Backstrom, Miles A.; Alexander, Barbara T.

2017-01-01

Placental insufficiency alters the intrauterine environment leading to increased risk for chronic disease including impaired glucose metabolism in low birth weight infants. Using a rat model of low birth weight, we previously reported that placental insufficiency induces a significant increase in circulating testosterone in male intrauterine growth-restricted offspring (mIUGR) in early adulthood that is lost by 12 months of age. Numerous studies indicate testosterone has a positive effect on glucose metabolism in men. Female growth-restricted littermates exhibit glucose intolerance at 6 months of age. Thus, the aim of this paper was to determine whether mIUGR develop impaired glucose metabolism, and whether a decrease in elevated testosterone levels plays a role in its onset. Male growth-restricted offspring were studied at 6 and 12 months of age. No impairment in glucose tolerance was observed at 6 months of age when mIUGR exhibited a 2-fold higher testosterone level compared to age-matched control. Fasting blood glucose was significantly higher and glucose tolerance was impaired with a significant decrease in circulating testosterone in mIUGR at 12 compared with 6 months of age. Castration did not additionally impair fasting blood glucose or glucose tolerance in mIUGR at 12 months of age, but fasting blood glucose was significantly elevated in castrated controls. Restoration of elevated testosterone levels significantly reduced fasting blood glucose and improved glucose tolerance in mIUGR. Thus, our findings suggest that the endogenous increase in circulating testosterone in mIUGR is protective against impaired glucose homeostasis. PMID:29145418

Effect of GABA receptor agonists or antagonists injected spinally on the blood glucose level in mice.

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; Suh, Hong-Won

2013-05-01

The possible roles of gamma-amino butyric acid (GABA) receptors located in the spinal cord for the regulation of the blood glucose level were studied in ICR mice. We found in the present study that intrathecal (i.t.) injection with baclofen (a GABAB receptor agonist; 1-10 μg/5 μl) or bicuculline (a GABAA receptor antagonist; 1-10 μg/5 μl) caused an elevation of the blood glucose level in a dose-dependent manner. The hyperglycemic effect induced by baclofen was more pronounced than that induced by bicuculline. However, muscimol (a GABAA receptor agonist; 1-5 μg/5 μl) or phaclofen (a GABAB receptor antagonist; 5-10 μg/5 μl) administered i.t. did not affect the blood glucose level. Baclofen-induced elevation of the blood glucose was dose-dependently attenuated by phaclofen. Furthermore, i.t. pretreatment with pertussis toxin (PTX; 0.05 or 0.1 μg/5 μl) for 6 days dose-dependently reduced the hyperglycemic effect induced by baclofen. Our results suggest that GABAB receptors located in the spinal cord play important roles for the elevation of the blood glucose level. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by baclofen. Furthermore, inactivation of GABAA receptors located in the spinal cord appears to be responsible for tonic up-regulation of the blood glucose level.

The relationship between maternal fear of hypoglycaemia and adherence in children with type-1 diabetes.

PubMed

Freckleton, Evril; Sharpe, Louise; Mullan, Barbara

2014-01-01

Regular blood glucose monitoring is important for children with type-1 diabetes; however, the relationship between maternal fear of hypoglycaemia and glycaemic control is not well understood. The relationship between maternal beliefs about diabetes, concerns about glycaemic control and adherence to recommended blood glucose levels in young children with type-1 diabetes were examined in this study. Seventy-one mothers with children under 13 were recruited, and a prospective design was used. Demographics, maternal self-reported hypoglycaemic fear and illness perceptions were measured at baseline. Self-report daily blood sugar levels were recorded over 1 week, and glycosylated haemoglobin (HbA1c) blood glucose levels were collected at baseline and 3 months later. High maternal fears of hypoglycaemia were predictive of suboptimal daily glycaemic control (elevated blood glucose levels), irrespective of illness duration or age at diagnosis. The results suggest that mothers who worry most about hypoglycaemia compensate by maintaining their child's blood glucose levels above recommended levels. Elevated blood glucose levels have important consequences for long-term health, and further research could explore ways to target maternal fear of hypoglycaemia.

Hyperuricemia Is a Risk Factor for the Onset of Impaired Fasting Glucose in Men with a High Plasma Glucose Level: A Community-Based Study

PubMed Central

Miyake, Teruki; Kumagi, Teru; Furukawa, Shinya; Hirooka, Masashi; Kawasaki, Keitarou; Koizumi, Mitsuhito; Todo, Yasuhiko; Yamamoto, Shin; Abe, Masanori; Kitai, Kohichiro; Matsuura, Bunzo; Hiasa, Yoichi

2014-01-01

Background It is not clear whether elevated uric acid is a risk factor for the onset of impaired fasting glucose after stratifying by baseline fasting plasma glucose levels. We conducted a community-based retrospective longitudinal cohort study to clarify the relationship between uric acid levels and the onset of impaired fasting glucose, according to baseline fasting plasma glucose levels. Methods We enrolled 6,403 persons (3,194 men and 3,209 women), each of whom was 18–80 years old and had >2 annual check-ups during 2003–2010. After excluding persons who had fasting plasma glucose levels ≥6.11 mM and/or were currently taking anti-diabetic agents, the remaining 5,924 subjects were classified into quartiles according to baseline fasting plasma glucose levels. The onset of impaired fasting glucose was defined as fasting plasma glucose ≥6.11 mM during the observation period. Results In the quartile groups, 0.9%, 2.1%, 3.4%, and 20.2% of the men developed impaired fasting glucose, respectively, and 0.1%, 0.3%, 0.5%, and 5.6% of the women developed impaired fasting glucose, respectively (P trend <0.001). After adjusting for age, body mass index, systolic blood pressure, triacylglycerols, high density lipoprotein-cholesterol, creatinine, fatty liver, family history of diabetes, alcohol consumption, and current smoking, uric acid levels were positively associated with onset of impaired fasting glucose in men with highest-quartile fasting plasma glucose levels (adjusted hazard ratio, 1.003; 95% confidence interval, 1.0001–1.005, P = 0.041). Conclusions Among men with high fasting plasma glucose, hyperuricemia may be independently associated with an elevated risk of developing impaired fasting glucose. PMID:25237894

Astroglial pentose phosphate pathway rates in response to high-glucose environments

PubMed Central

Takahashi, Shinichi; Izawa, Yoshikane; Suzuki, Norihiro

2012-01-01

ROS (reactive oxygen species) play an essential role in the pathophysiology of diabetes, stroke and neurodegenerative disorders. Hyperglycaemia associated with diabetes enhances ROS production and causes oxidative stress in vascular endothelial cells, but adverse effects of either acute or chronic high-glucose environments on brain parenchymal cells remain unclear. The PPP (pentose phosphate pathway) and GSH participate in a major defence mechanism against ROS in brain, and we explored the role and regulation of the astroglial PPP in response to acute and chronic high-glucose environments. PPP activity was measured in cultured neurons and astroglia by determining the difference in rate of 14CO2 production from [1-14C]glucose and [6-14C]glucose. ROS production, mainly H2O2, and GSH were also assessed. Acutely elevated glucose concentrations in the culture media increased PPP activity and GSH level in astroglia, decreasing ROS production. Chronically elevated glucose environments also induced PPP activation. Immunohistochemical analyses revealed that chronic high-glucose environments induced ER (endoplasmic reticulum) stress (presumably through increased hexosamine biosynthetic pathway flux). Nuclear translocation of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), which regulates G6PDH (glyceraldehyde-6-phosphate dehydrogenase) by enhancing transcription, was also observed in association with BiP (immunoglobulin heavy-chain-binding protein) expression. Acute and chronic high-glucose environments activated the PPP in astroglia, preventing ROS elevation. Therefore a rapid decrease in glucose level seems to enhance ROS toxicity, perhaps contributing to neural damage when insulin levels given to diabetic patients are not properly calibrated and plasma glucose levels are not adequately maintained. These findings may also explain the lack of evidence for clinical benefits from strict glycaemic control during the acute phase of stroke. PMID:22300409

Rice (Oryza sativa japonica) Albumin Suppresses the Elevation of Blood Glucose and Plasma Insulin Levels after Oral Glucose Loading.

PubMed

Ina, Shigenobu; Ninomiya, Kazumi; Mogi, Takashi; Hase, Ayumu; Ando, Toshiki; Matsukaze, Narumi; Ogihara, Jun; Akao, Makoto; Kumagai, Hitoshi; Kumagai, Hitomi

2016-06-22

The suppressive effect of rice albumin (RA) of 16 kDa on elevation of blood glucose level after oral loading of starch or glucose and its possible mechanism were examined. RA suppressed the increase in blood glucose levels in both the oral starch tolerance test and the oral glucose tolerance test. The blood glucose concentrations 15 min after the oral administration of starch were 144 ± 6 mg/dL for control group and 127 ± 4 mg/dL for RA 200 mg/kg BW group, while those after the oral administration of glucose were 157 ± 7 mg/dL for control group and 137 ± 4 mg/dL for RA 200 mg/kg BW group. However, in the intraperitoneal glucose tolerance test, no significant differences in blood glucose level were observed between RA and the control groups, indicating that RA suppresses the glucose absorption from the small intestine. However, RA did not inhibit the activity of mammalian α-amylase. RA was hydrolyzed to an indigestible high-molecular-weight peptide (HMP) of 14 kDa and low-molecular-weight peptides by pepsin and pancreatin. Furthermore, RA suppressed the glucose diffusion rate through a semipermeable membrane like dietary fibers in vitro. Therefore, the indigestible HMP may adsorb glucose and suppress its absorption from the small intestine.

Steroid injection for shoulder pain causes prolonged increased glucose level in type 1 diabetics

PubMed Central

Povlsen, Bo; Povlsen, Sebastian D

2014-01-01

Shoulder pain is very common in diabetic patients and often treated with steroid injections, with subsequent increases in blood glucose levels or the need for additional insulin being questioned. We report a case of significant and prolonged elevation of blood glucose levels and resultant insulin requirement in a type 1 diabetic man after a single 40 mg injection of triamcinolone for shoulder pain. Within 48 h, the shoulder pain as assessed by a visual analogue scale (0–10) was reduced to zero, but the elevated insulin requirements continued for 4 weeks after the injection. This finding suggests that steroid injections for shoulder pain in diabetics may not always be as safe as previously thought. We propose that medical practitioners advise their patients to monitor their glucose levels more carefully after such injections and that caution is exercised when considering administrating these injections to those who have poorly controlled blood glucose levels preinjection to avoid ketoacidosis. PMID:25199186

Steroid injection for shoulder pain causes prolonged increased glucose level in type 1 diabetics.

PubMed

Povlsen, Bo; Povlsen, Sebastian D

2014-09-08

Shoulder pain is very common in diabetic patients and often treated with steroid injections, with subsequent increases in blood glucose levels or the need for additional insulin being questioned. We report a case of significant and prolonged elevation of blood glucose levels and resultant insulin requirement in a type 1 diabetic man after a single 40 mg injection of triamcinolone for shoulder pain. Within 48 h, the shoulder pain as assessed by a visual analogue scale (0-10) was reduced to zero, but the elevated insulin requirements continued for 4 weeks after the injection. This finding suggests that steroid injections for shoulder pain in diabetics may not always be as safe as previously thought. We propose that medical practitioners advise their patients to monitor their glucose levels more carefully after such injections and that caution is exercised when considering administrating these injections to those who have poorly controlled blood glucose levels preinjection to avoid ketoacidosis. 2014 BMJ Publishing Group Ltd.

Synthesis of glycogen from fructose in the presence of elevated levels of glycogen phosphorylase a in rat hepatocytes.

PubMed

Ciudad, C J; Massagué, J; Salavert, A; Guinovart, J J

1980-03-20

Incubation of hepatocytes with glucose promoted the increase in the glycogen synthase (-glucose 6-phosphate/+glucose 6-phosphate) activity ratio, the decrease in the levels of phosphorylase a and a marked increase in the intracellular glycogen level. Incubation with fructose alone promoted the simultaneous activation of glycogen synthase and increase in the levels of phosphorylase a. Strikingly, glycogen deposition occurred in spite of the elevated levels of phosphorylase a. When glucose and fructose were added to the media the activation of glycogen synthase was always higher than when the hexoses were added separately. On the other hand the effects on glycogen phosphorylase were a function of the relative concentrations of both sugars. Inactivation of glycogen phosphorylase occurred when the fructose to glucose ratio was low while activation took place when the ratio was high. The simultaneous presence of glucose and fructose resulted, in all cases, in an enhancement in the deposition of glycogen. The effects described were not limited to fructose as D-glyceraldehyde, dihydroxyacetone, L-sorbose, D-tagatose and sorbitol, compounds metabolically related to fructose, provoked the same behaviour.

Differences in Body Fat Distribution Play a Role in the Lower Levels of Elevated Fasting Glucose amongst Ghanaian Migrant Women Compared to Men.

PubMed

Nicolaou, Mary; Kunst, Anton E; Busschers, Wim B; van Valkengoed, Irene G; Dijkshoorn, Henriette; Boateng, Linda; Brewster, Lizzy M; Snijder, Marieke B; Stronks, Karien; Agyemang, Charles

2013-01-01

Despite higher levels of obesity, West African migrant women appear to have lower rates of type 2 diabetes than their male counterparts. We investigated the role of body fat distribution in these differences. Cross-sectional study of Ghanaian migrants (97 men, 115 women) aged 18-60 years in Amsterdam, the Netherlands. Weight, height, waist and hip circumferences were measured. Logistic regression was used to explore the association of BMI, waist and hip measurements with elevated fasting glucose (glucose≥5.6 mmol/L). Linear regression was used to study the association of the same parameters with fasting glucose. Mean BMI, waist and hip circumferences were higher in women than men while the prevalence of elevated fasting glucose was higher in men than in women, 33% versus 19%. With adjustment for age only, men were non-significantly more likely than women to have an elevated fasting glucose, odds ratio (OR) 1.81, 95% CI: 0.95, 3.46. With correction for BMI, the higher odds among men increased and were statistically significant (OR 2.84, 95% CI: 1.32, 6.10), but with consideration of body fat distribution (by adding both hip and waist in the analysis) differences were no longer significant (OR 1.56 95% CI: 0.66, 3.68). Analysis with fasting glucose as continuous outcome measure showed somewhat similar results. Compared to men, the lower rates of elevated fasting glucose observed among Ghanaian women may be partly due to a more favorable body fat distribution, characterized by both hip and waist measurements.

Lysine acetyltransferase NuA4 and acetyl-CoA regulate glucose-deprived stress granule formation in Saccharomyces cerevisiae

PubMed Central

Huard, Sylvain; Morettin, Alan; Fullerton, Morgan D.; Côté, Jocelyn

2017-01-01

Eukaryotic cells form stress granules under a variety of stresses, however the signaling pathways regulating their formation remain largely unknown. We have determined that the Saccharomyces cerevisiae lysine acetyltransferase complex NuA4 is required for stress granule formation upon glucose deprivation but not heat stress. Further, the Tip60 complex, the human homolog of the NuA4 complex, is required for stress granule formation in cancer cell lines. Surprisingly, the impact of NuA4 on glucose-deprived stress granule formation is partially mediated through regulation of acetyl-CoA levels, which are elevated in NuA4 mutants. While elevated acetyl-CoA levels suppress the formation of glucose-deprived stress granules, decreased acetyl-CoA levels enhance stress granule formation upon glucose deprivation. Further our work suggests that NuA4 regulates acetyl-CoA levels through the Acetyl-CoA carboxylase Acc1. Altogether this work establishes both NuA4 and the metabolite acetyl-CoA as critical signaling pathways regulating the formation of glucose-deprived stress granules. PMID:28231279

Pregnancy Hyperglycaemia and Risk of Prenatal and Postpartum Depressive Symptoms.

PubMed

Huang, Tianyi; Rifas-Shiman, Sheryl L; Ertel, Karen A; Rich-Edwards, Janet; Kleinman, Ken; Gillman, Matthew W; Oken, Emily; James-Todd, Tamarra

2015-07-01

Glucose dysregulation in pregnancy may affect maternal depressive symptoms during the prenatal and postpartum periods via both physiologic and psychological pathways. During mid-pregnancy, a combination of 50-g 1-h non-fasting glucose challenge test (GCT) and 100-g 3-h fasting oral glucose tolerance test was used to determine pregnancy glycaemic status among women participating in Project Viva: normal glucose tolerance (NGT), isolated hyperglycaemia (IHG), impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM). Using the Edinburgh Postnatal Depression Scale (EPDS), we assessed depressive symptoms at mid-pregnancy and again at 6 months postpartum. We used logistic regression, adjusted for sociodemographic, anthropometric and lifestyle factors, to estimate the odds of elevated prenatal and postpartum depressive symptoms (EPDS ≥ 13 on 0-30 scale) in relation to GCT glucose levels and GDM status in separate models. A total of 9.6% of women showed prenatal and 8.4% postpartum depressive symptoms. Women with higher GCT glucose levels were at greater odds of elevated prenatal depressive symptoms [multivariable-adjusted odds ratio (OR) per standard deviation (SD) increase in glucose levels (27 mg/dL): 1.25; 95%: 1.07, 1.48]. Compared with NGT women, the association appeared stronger among women with IHG [OR: 1.80; 95% confidence interval (CI): 1.08, 3.00] than among those with GDM (OR: 1.45; 95% CI: 0.72, 2.91) or IGT (OR: 1.43; 95% CI: 0.59, 3.46). Neither glucose levels assessed from the GCT nor pregnancy glycaemic status were significantly associated with elevated postpartum depressive symptoms. Pregnancy hyperglycaemia was cross-sectionally associated with higher risk of prenatal depressive symptoms, but not with postpartum depressive symptoms. © 2015 John Wiley & Sons Ltd.

Renal hemodynamic response to galanin: importance of elevated plasma glucose.

PubMed

Premen, A J

1989-12-01

Although recent data point to a possible indirect role for galanin in modulating renal blood flow (RBF) and fluid homeostasis in experimental animals, there have been no systematic studies exploring the possible direct effects of the peptide on the mammalian kidney. We ascertained the RBF, glomerular filtration rate (GFR) and plasma glucose responses to direct intrarenal infusion of three progressively increasing doses of synthetic galanin in anesthetized dogs. A 50 ng/kg per min dose (n = 6) failed to affect RBF, GFR or arterial plasma glucose (APG). Yet, a 100 ng/kg per min dose elevated RBF and GFR by 13 and 14%, respectively, while concomitantly increasing APG by 38%. At 200 ng/kg per min, galanin elevated RBF and GFR by 32 and 33%, respectively, while elevating APG by 57%. Intrarenal infusion of glucose (12.5 mg/kg per min; n = 6), reproducing the percentage rise in glucose (62%) elicited by the highest dose of galanin, elevated RBF and GFR by 20 and 23%, respectively. These data indicate that the elevated plasma glucose level, stimulated by galanin infusion, may account for about 63 and 70% of the RBF and GFR responses, respectively, elicited by galanin infusion at the 200 ng dose. The factors mediating the remaining renal hyperemia and hyperfiltration await resolution.

Genistein improves spatial learning and memory in male rats with elevated glucose level during memory consolidation.

PubMed

Kohara, Yumi; Kawaguchi, Shinichiro; Kuwahara, Rika; Uchida, Yutaro; Oku, Yushi; Yamashita, Kimihiro

2015-03-01

Cognitive dysfunction due to higher blood glucose level has been reported previously. Genistein (GEN) is a phytoestrogen that we hypothesized might lead to improved memory, despite elevated blood glucose levels at the time of memory consolidation. To investigate this hypothesis, we compared the effects of orally administered GEN on the central nervous system in normal versus glucose-loaded adult male rats. A battery of behavioral assessments was carried out. In the MAZE test, which measured spatial learning and memory, the time of normal rats was shortened by GEN treatment compared to the vehicle group, but only in the early stages of testing. In the glucose-loaded group, GEN treatment improved performance as mazes were advanced. In the open-field test, GEN treatment delayed habituation to the new environment in normal rats, and increased the exploratory behaviors of glucose-loaded rats. There were no significant differences observed for emotionality or fear-motivated learning and memory. Together, these results indicate that GEN treatment improved spatial learning and memory only in the early stages of testing in the normal state, but improved spatial learning and memory when glucose levels increased during memory consolidation. Copyright © 2014 Elsevier Inc. All rights reserved.

Evaluation of Correlation of Blood Glucose and Salivary Glucose Level in Known Diabetic Patients.

PubMed

Gupta, Anjali; Singh, Siddharth Kumar; Padmavathi, B N; Rajan, S Y; Mamatha, G P; Kumar, Sandeep; Roy, Sayak; Sareen, Mohit

2015-05-01

Diabetes mellitus is a chronic heterogenous disease in which there is dysregulation of carbohydrates, protein and lipid metabolism; leading to elevated blood glucose levels. The present study was conducted to evaluate the correlation between blood glucose and salivary glucose levels in known diabetic patients and control group and also to evaluate salivary glucose level as a diagnostic tool in diabetic patients. A total number of 250 patients were studied, out of which 212 formed the study group and 38 formed the control group. Among 250 patients, correlation was evaluated between blood glucose and salivary glucose values which on analysis revealed Pearson correlation of 0.073. The p-value was 0.247, which was statistically non significant. Salivary glucose values cannot be considered as a diagnostic tool for diabetic individuals.

Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia

PubMed Central

Meek, Thomas H.; Dorfman, Mauricio D.; Matsen, Miles E.; Fischer, Jonathan D.; Cubelo, Alexis; Kumar, Monica R.; Taborsky, Gerald J.

2015-01-01

Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia. PMID:25633417

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.

Corticosterone and exogenous glucose alter blood glucose levels, neurotoxicity, and vascular toxicity produced by methamphetamine.

PubMed

Bowyer, John F; Tranter, Karen M; Sarkar, Sumit; George, Nysia I; Hanig, Joseph P; Kelly, Kimberly A; Michalovicz, Lindsay T; Miller, Diane B; O'Callaghan, James P

2017-10-01

Our previous studies have raised the possibility that altered blood glucose levels may influence and/or be predictive of methamphetamine (METH) neurotoxicity. This study evaluated the effects of exogenous glucose and corticosterone (CORT) pretreatment alone or in combination with METH on blood glucose levels and the neural and vascular toxicity produced. METH exposure consisted of four sequential injections of 5, 7.5, 10, and 10 mg/kg (2 h between injections) D-METH. The three groups given METH in combination with saline, glucose (METH+Glucose), or CORT (METH+CORT) had significantly higher glucose levels compared to the corresponding treatment groups without METH except at 3 h after the last injection. At this last time point, the METH and METH+Glucose groups had lower levels than the non-METH groups, while the METH+CORT group did not. CORT alone or glucose alone did not significantly increase blood glucose. Mortality rates for the METH+CORT (40%) and METH+Glucose (44%) groups were substantially higher than the METH (< 10%) group. Additionally, METH+CORT significantly increased neurodegeneration above the other three METH treatment groups (≈ 2.5-fold in the parietal cortex). Thus, maintaining elevated levels of glucose during METH exposure increases lethality and may exacerbate neurodegeneration. Neuroinflammation, specifically microglial activation, was associated with degenerating neurons in the parietal cortex and thalamus after METH exposure. The activated microglia in the parietal cortex were surrounding vasculature in most cases and the extent of microglial activation was exacerbated by CORT pretreatment. Our findings show that acute CORT exposure and elevated blood glucose levels can exacerbate METH-induced vascular damage, neuroinflammation, neurodegeneration and lethality. Cover Image for this issue: doi. 10.1111/jnc.13819. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

SET8 is involved in the regulation of hyperglycemic memory in human umbilical endothelial cells.

PubMed

Chen, Xiangyuan; Wu, Qichao; Jiang, Hui; Wang, Jiaqiang; Zhao, Yanjun; Xu, Yajun; Zhu, Minmin

2018-05-14

Hyperglycemic memory occurs in diabetic cardiovascular complications, but the underlying mechanism remains to be elucidated. Although the depletion of SET8 leads to increased mitochondrial oxidative stress via increasing cellular reactive oxygen species (ROS) production, the role of SET8 in hyperglycemic memory-induced mitochondrial dysfunction is not well understood. Here, we investigated the role of SET8 in this setting. Our results showed that high glucose-induced vascular inflammation, ROS production and apoptosis remained at high levels even when glucose returned to normal level. Elevated glucose reduced SET8 expression, which also remained at low level after returning to normoglycemia. SET8 overexpression protected cells from elevated glucose and hyperglycemic memory-induced endothelial injury by blocking ROS accumulation, attenuating vascular inflammation, and restoring nitric oxide production. Thus, our results suggest that SET8 may be a key mediator in hyperglycemic memory.

Oxytocin increases extrapancreatic glucagon secretion and glucose production in pancreatectomized dogs

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

Altszuler, N.; Puma, F.; Winkler, B.

1986-05-01

Infusion of oxytocin into normal dogs increases plasma levels of insulin and glucagon and glucose production and uptake. To determine whether infused oxytocin also increases glucagon secretion from extrapancreatic sites, pancreatectomized dogs, off insulin of 18 hr, were infused with oxytocin and plasma glucagon, and glucose production and uptake were measured using the (6-/sup 3/H)glucose primer-infusion technique. The diabetic dogs, in the control period, had elevated plasma glucose and glucagon levels, an increased rate of glucose production, and a relative decrease in glucose uptake (decreased clearance). Infusion of oxytocin (500 ..mu..U/kg/min) caused a rise in plasma glucagon and glucose levels,more » increased glucose production, and further decreased glucose clearance. it is concluded that oxytocin can stimulate secretion of extrapancreatic glucagon, which contributes to the increased glucose production.« less

Exposure to low levels of hydrogen sulfide elevates circulating glucose in maternal rats

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

Hayden, L.J.; Goeden, H.; Roth, S.H.

1990-09-01

Although the lethal effect of hydrogen sulfide (H{sub 2}S) has long been known, the results of exposure to low levels of H{sub 2}S have not been well documented. Rat dams and pups were exposed to low levels of H{sub 2}S (less than or equal to 75 ppm) from d 1 of gestation until d 21 postpartum and analyzed for changes in circulating enzymatic activity and metabolites. Blood glucose was significantly elevated in maternal blood on d 21 postpartum at all exposure levels. This increase in glucose was accompanied by a possible decrease in serum triglyceride in the pups and inmore » the dams on d 21 postpartum. There was no evidence of alterations in serum alkaline phosphatase, lactate dehydrogenase, or serum glutamate oxaloacetate transaminase.« less

Elevation of branched-chain amino acid levels in diabetes and NAFL and changes with antidiabetic drug treatment.

PubMed

Iwasa, Motoh; Ishihara, Tomoaki; Mifuji-Moroka, Rumi; Fujita, Naoki; Kobayashi, Yoshinao; Hasegawa, Hiroshi; Iwata, Kazuko; Kaito, Masahiko; Takei, Yoshiyuki

2015-01-01

Diabetes mellitus (DM), non-alcoholic fatty liver (NAFL), and obesity are associated with elevated branched-chain amino acid (BCAA) levels, but the mechanism and significance of this has not been elucidated. Eighty-four subjects were enrolled including 43 with DM. Serum BCAA levels were positively correlated with waist-hip ratio and ALT. Serum BCAA levels in subjects with DM were higher than non-DM and those in subjects with NAFL were also higher than non-NAFL. Treatment with pioglitazone and alogliptin (19 of 43 DM subjects) improved serum haemoglobin A1c and decreased BCAA levels. The decrease in BCAAs with improved glucose metabolism suggests that abnormal glucose metabolism is also a factor in elevated BCAA levels. Copyright © 2015 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Prognostic Implications of Single-Sample Confirmatory Testing for Undiagnosed Diabetes: A Prospective Cohort Study.

PubMed

Selvin, Elizabeth; Wang, Dan; Matsushita, Kunihiro; Grams, Morgan E; Coresh, Josef

2018-06-19

Current clinical definitions of diabetes require repeated blood work to confirm elevated levels of glucose or hemoglobin A1c (HbA1c) to reduce the possibility of a false-positive diagnosis. Whether 2 different tests from a single blood sample provide adequate confirmation is uncertain. To examine the prognostic performance of a single-sample confirmatory definition of undiagnosed diabetes. Prospective cohort study. The ARIC (Atherosclerosis Risk in Communities) study. 13 346 ARIC participants (12 268 without diagnosed diabetes) with 25 years of follow-up for incident diabetes, cardiovascular outcomes, kidney disease, and mortality. Confirmed undiagnosed diabetes was defined as elevated levels of fasting glucose (≥7.0 mmol/L [≥126 mg/dL]) and HbA1c (≥6.5%) from a single blood sample. Among 12 268 participants without diagnosed diabetes, 978 had elevated levels of fasting glucose or HbA1c at baseline (1990 to 1992). Among these, 39% had both (confirmed undiagnosed diabetes), whereas 61% had only 1 elevated measure (unconfirmed undiagnosed diabetes). The confirmatory definition had moderate sensitivity (54.9%) but high specificity (98.1%) for identification of diabetes cases diagnosed during the first 5 years of follow-up, with specificity increasing to 99.6% by 15 years. The 15-year positive predictive value was 88.7% compared with 71.1% for unconfirmed cases. Confirmed undiagnosed diabetes was significantly associated with cardiovascular and kidney disease and mortality, with stronger associations than unconfirmed diabetes. Lack of repeated measurements of fasting glucose and HbA1c. A single-sample confirmatory definition of diabetes had a high positive predictive value for subsequent diagnosis and was strongly associated with clinical end points. Our results support the clinical utility of using a combination of elevated fasting glucose and HbA1c levels from a single blood sample to identify undiagnosed diabetes in the population. National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute.

Proteins altered by elevated levels of palmitate or glucose implicated in impaired glucose-stimulated insulin secretion

PubMed Central

Sol, E-ri M; Hovsepyan, Meri; Bergsten, Peter

2009-01-01

Background Development of type 2 diabetes mellitus (T2DM) is characterized by aberrant insulin secretory patterns, where elevated insulin levels at non-stimulatory basal conditions and reduced hormonal levels at stimulatory conditions are major components. To delineate mechanisms responsible for these alterations we cultured INS-1E cells for 48 hours at 20 mM glucose in absence or presence of 0.5 mM palmitate, when stimulatory secretion of insulin was reduced or basal secretion was elevated, respectively. Results After culture, cells were protein profiled by SELDI-TOF-MS and 2D-PAGE. Differentially expressed proteins were discovered and identified by peptide mass fingerprinting. Complimentary protein profiles were obtained by the two approaches with SELDI-TOF-MS being more efficient in separating proteins in the low molecular range and 2D-PAGE in the high molecular range. Identified proteins included alpha glucosidase, calmodulin, gars, glucose-6-phosphate dehydrogenase, heterogenous nuclear ribonucleoprotein A3, lon peptidase, nicotineamide adenine dinucleotide hydrogen (NADH) dehydrogenase, phosphoglycerate kinase, proteasome p45, rab2, pyruvate kinase and t-complex protein. The observed glucose-induced differential protein expression pattern indicates enhanced glucose metabolism, defense against reactive oxygen species, enhanced protein translation, folding and degradation and decreased insulin granular formation and trafficking. Palmitate-induced changes could be related to altered exocytosis. Conclusion The identified altered proteins indicate mechanism important for altered β-cell function in T2DM. PMID:19607692

Influence of insulin on beta-endorphin plasma levels in obese and normal weight subjects.

PubMed

Brunani, A; Pincelli, A I; Pasqualinotto, L; Tibaldi, A; Baldi, G; Scacchi, M; Fatti, L M; Cavagnini, F

1996-08-01

To establish the possible role of hyperinsulinemia in the elevation of plasma beta-endorphin (beta-EP) levels observed in obese patients after an oral glucose load. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Two groups of six (age: 22-39 y, BMI: 30-48 kg/m2) and eight obese men (age: 18-37 y, BMI: 35-45 kg/m2), respectively, and five normal weight healthy men (age: 22-30 y, BMI 22-23 kg/m2). Glucose, insulin and beta-EP levels at baseline and every 30 min until 180 min during the OGTT; glucose, insulin, C-peptide and beta-EP concentrations at baseline and in steady state condition (i.e. during the last 30 min of insulin infusion) in the euglycemic-hyperinsulinemic clamp studies. In the six obese patients undergoing the OGTT a significant elevation of beta-EP plasma levels was observed between 60 and 90 min after glucose ingestion. In the clamp studies no significant differences in beta-EP plasma levels, blood glucose and serum insulin were observed between obese and normal weight subjects both at baseline and at steady state. A markedly diminished insulin sensitivity along with a lower inhibition of C-peptide during insulin infusion was observed in obese patients compared to control subjects. A rise in serum insulin levels unaccompanied by a concomitant increase in blood glucose concentration is unable to elicit a beta-EP response in obese patients.

Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

NASA Astrophysics Data System (ADS)

Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A.; Ghosh, Partha Pratim; Mitra, Prasenjit

2016-06-01

Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation.

Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

PubMed Central

Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A; Ghosh, Partha Pratim; Mitra, Prasenjit

2016-01-01

Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation. PMID:27282931

In vitro and In vivo Postprandial Glycemic Activity of Citrus limetta Peel Flour.

PubMed

Flores-Fernández, José Miguel; Barragán-Álvarez, Carla Patricia; Díaz-Martínez, Nestor Emmanuel; Villanueva-Rodríguez, Socorro; Padilla-Camberos, Eduardo

2017-01-01

Previous studies of Citrus spp. peel have shown hypoglycemic and antioxidant activities. Citrus limetta has been studied for its therapeutic properties. Diabetes mellitus (DM) is a health problem in Mexico and worldwide, that takes a vital importance due to its high incidence. Recently, scientists have searched natural sources to control the disease. In this study, we evaluated the in vitro hypoglycemic activity and in vivo postprandial glycemic effect of C. limetta peel flour by glucose adsorption and retardation assays as well as postprandial serum glucose levels using a group of female Balb-c mice, respectively. C. limetta peel flour showed a glucose adsorption capacity of 16.58 mM, having a similar effect regarding the positive control. The glucose diffusion in the dialysate was elevated, with a glucose dialysis retardation index of 33.79% in a period of 3 h, showing similar results to positive control. Postprandial serum glucose levels in the animal group treated with C. limetta peel flour showed a glucose level of 41.4 mg/dL, being this value significantly lower than negative control group and similar to positive control. Toxicity tests showed good tolerance to the dose of 2000 mg/kg. C. limetta peel flour could act as a source of functional compounds for the control of DM. Citrus limetta peel flour showed a glucose adsorption capacity similar to the positive controlThe glucose diffusion in the dialysate was elevated, showing similar results to positive controlPostprandial serum glucose levels in the animal group treated with C. limetta peel flour showed a glucose level significantly lower than negative control group and similar to positive controlToxicity tests showed good tolerance C. limetta peel flour could act as a source of functional compounds for the control of diabetes mellitus. Abbreviations used: CIATEJ: Center for Research and Assistance in Technology and Design of Jalisco; DM: Diabetes mellitus; FGC: Final glucose concentration; GDRI: Glucose dialysis retardation index; IGC: Initial glucose concentration; OECD: Organization for Economic Cooperation and Development.

Early alterations in soleus GLUT-4, glucose transport, and glycogen in voluntary running rats

NASA Technical Reports Server (NTRS)

Henriksen, Erik J.; Halseth, Amy E.

1994-01-01

Voluntary wheel running (WR) by juvenile female rats was used as a noninterventional model of soleus muscle functional overload to study the regulation of insulin-stimulated glucose transport activity by the glucose transporter (GLUT-4 isoform) protein level and glycogen concentration. Soleus total protein content was significantly greater (+18%;P greater than 0.05) than in age-matched controls after 1 wk of WR, and this hypertrophic response continued in weeks 2-4 (+24-32%). GLUT-4 protein was 39% greater than in controls in 1-wk WR soleus, and this adaptation was accompanied by a similar increase in in vitro insulin-stimulated glucose transport activity(+29%). After 2 and 4 wk of WR, however, insulin-stimulated glucose transport activity had returned to control levels, despite a continued elevation (+25-28%) of GLUT-4 protein. At these two time points, glycogen concentration was significantly enhanced in WR soleus (+21-42%), which coincided with significant reductions in glycogen synthase activity ratios (-23 to-41%). These results indicate that, in this model of soleus muscle functional overload, the GLUT-4 protein level may initially regulate insulin-stimulated glucose transport activity in the absence of changes in other modifying factors. However,this regulation of glucose transport activity by GLUT-4 protein may be subsequently overridden by elevated glycogen concentration.

Possible Increase in Serum FABP4 Level Despite Adiposity Reduction by Canagliflozin, an SGLT2 Inhibitor.

PubMed

Furuhashi, Masato; Matsumoto, Megumi; Hiramitsu, Shinya; Omori, Akina; Tanaka, Marenao; Moniwa, Norihito; Yoshida, Hideaki; Ishii, Junnichi; Miura, Tetsuji

2016-01-01

Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) is secreted from adipocytes in association with catecholamine-induced lipolysis, and elevated serum FABP4 level is associated with obesity, insulin resistance and atherosclerosis. Secreted FABP4 as a novel adipokine leads to insulin resistance via increased hepatic glucose production (HGP). Sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease blood glucose level via increased urinary glucose excretion, though HGP is enhanced. Here we investigated whether canagliflozin, an SGLT2 inhibitor, modulates serum FABP4 level. Canagliflozin (100 mg/day) was administered to type 2 diabetic patients (n = 39) for 12 weeks. Serum FABP4 level was measured before and after treatment. At baseline, serum FABP4 level was correlated with adiposity, renal dysfunction and noradrenaline level. Treatment with canagliflozin significantly decreased adiposity and levels of fasting glucose and HbA1c but increased average serum FABP4 level by 10.3% (18.0 ± 1.0 vs. 19.8 ± 1.2 ng/ml, P = 0.008), though elevation of FABP4 level after treatment was observed in 26 (66.7%) out of 39 patients. Change in FABP4 level was positively correlated with change in levels of fasting glucose (r = 0.329, P = 0.044), HbA1c (r = 0.329, P = 0.044) and noradrenaline (r = 0.329, P = 0.041) but was not significantly correlated with change in adiposity or other variables. Canagliflozin paradoxically increases serum FABP4 level in some diabetic patients despite amelioration of glucose metabolism and adiposity reduction, possibly via induction of catecholamine-induced lipolysis in adipocytes. Increased FABP4 level by canagliflozin may undermine the improvement of glucose metabolism and might be a possible mechanism of increased HGP by inhibition of SGLT2. UMIN-CTR Clinical Trial UMIN000018151.

Evaluation of a novel supplement to reduce blood glucose through the use of a modified oral glucose tolerance test

PubMed Central

Smith, Adam J; Giunta, Brian; Shytle, R Douglas; Blum, James M

2011-01-01

Elevated blood glucose is a major component in metabolic syndrome and pre-diabetes, sometimes leading to type 2 diabetes mellitus (DM II). Additionally, it may lead to adipose deposits when left elevated for long periods. The epidemiology of DM II clearly shows that uncontrolled blood glucose levels leads to many adverse conditions including heart disease, retinal damage, renal failure, erectile dysfunction, and other significant medical conditions. Here we conducted a single-center, prospective, randomized, double-blinded, placebo-controlled, parallel-group- clinical trial of a nutraceutical supplement vs. placebo to measure its glucose lowering effect in generally healthy adults before and after a simple sugars meal. Subjects reported to the test clinic on multiple days to receive placebo or treatment, a simple sugars meal, as well as pre-and postprandial blood glucose measurement (modified oral glucose tolerance test). Each subject served as his or her own control and thirty-one subjects completed the trial with at least one oral glucose tolerance test (OGTT) with the nutraceutical supplement and placebo. Statistical analysis revealed the nutraceutical supplement significantly lowered postprandial glucose levels by 36% and 59% at 45 and 60 minutes, respectively (***P<.001). The study was limited by its composition of primarily overweight females. Future studies will be required over longer periods in more heterogeneous and larger groups to determine the long-term effect of this supplement on blood glucose levels in terms of prophylaxis or treatment for DM II. PMID:21416063

High Liver Enzyme Concentrations are Associated with Higher Glycemia, but not with Glycemic Variability, in Individuals without Diabetes Mellitus.

PubMed

Noordam, Raymond; Vermond, Debbie; Drenth, Hermijntje; Wijman, Carolien A; Akintola, Abimbola A; van der Kroef, Sabrina; Jansen, Steffy W M; Huurman, Neline C; Schutte, Bianca A M; Beekman, Marian; Slagboom, P Eline; Mooijaart, Simon P; van Heemst, Diana

2017-01-01

Elevated concentrations of liver enzymes have been associated with an increased risk of developing type 2 diabetes mellitus. However, it remains unclear to which specific aspects of diurnal glucose metabolism these associate most. We aimed to investigate the associations between liver enzyme concentrations and 24 h-glucose trajectories in individuals without diabetes mellitus from three independent cohorts. This cross-sectional study included 436 participants without diabetes mellitus from the Active and Healthy Aging Study, the Switchbox Study, and the Growing Old Together Study. Fasting blood samples were drawn to measure gamma-glutamyltransferase (GGT), alanine transaminase, and aspartate transaminase. Measures of glycemia (e.g., nocturnal and diurnal mean glucose levels) and glycemic variability (e.g., mean amplitude of glucose excursions) were derived from continuous glucose monitoring. Analyses were performed separately for the three cohorts; derived estimates were additionally meta-analyzed. After meta-analyses of the three cohorts, elevated liver enzyme concentrations, and specifically elevated GGT concentrations, were associated with higher glycemia. More specific, participants in the highest GGT tertile (GGT ≥37.9 U/L) had a 0.39 mmol/L (95% confidence interval: 0.23, 0.56) higher mean nocturnal glucose (3:00 to 6:00 a.m.) and a 0.23 mmol/L (0.10, 0.36) higher diurnal glucose (6:00 to 0:00 a.m.) than participants in the lowest GGT tertile (GGT <21.23 U/L). However, elevated liver enzyme concentrations were not associated with a higher glycemic variability. Though elevated liver enzyme concentrations did not associate with higher glycemic variability in participants without diabetes mellitus, specifically, elevated GGT concentrations associated with higher glycemia.

Prolonged fasting impairs neural reactivity to visual stimulation.

PubMed

Kohn, N; Wassenberg, A; Toygar, T; Kellermann, T; Weidenfeld, C; Berthold-Losleben, M; Chechko, N; Orfanos, S; Vocke, S; Laoutidis, Z G; Schneider, F; Karges, W; Habel, U

2016-01-01

Previous literature has shown that hypoglycemia influences the intensity of the BOLD signal. A similar but smaller effect may also be elicited by low normal blood glucose levels in healthy individuals. This may not only confound the BOLD signal measured in fMRI, but also more generally interact with cognitive processing, and thus indirectly influence fMRI results. Here we show in a placebo-controlled, crossover, double-blind study on 40 healthy subjects, that overnight fasting and low normal levels of glucose contrasted to an activated, elevated glucose condition have an impact on brain activation during basal visual stimulation. Additionally, functional connectivity of the visual cortex shows a strengthened association with higher-order attention-related brain areas in an elevated blood glucose condition compared to the fasting condition. In a fasting state visual brain areas show stronger coupling to the inferior temporal gyrus. Results demonstrate that prolonged overnight fasting leads to a diminished BOLD signal in higher-order occipital processing areas when compared to an elevated blood glucose condition. Additionally, functional connectivity patterns underscore the modulatory influence of fasting on visual brain networks. Patterns of brain activation and functional connectivity associated with a broad range of attentional processes are affected by maturation and aging and associated with psychiatric disease and intoxication. Thus, we conclude that prolonged fasting may decrease fMRI design sensitivity in any task involving attentional processes when fasting status or blood glucose is not controlled.

Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia.

PubMed

Meek, Thomas H; Dorfman, Mauricio D; Matsen, Miles E; Fischer, Jonathan D; Cubelo, Alexis; Kumar, Monica R; Taborsky, Gerald J; Morton, Gregory J

2015-07-01

Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia. © 2015 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.

Confirming glycemic status in the Diabetes Prevention Program: implications for diagnosing diabetes in high risk adults.

PubMed

Christophi, C A; Resnick, H E; Ratner, R E; Temprosa, M; Fowler, S; Knowler, W C; Shamoon, H; Barrett-Connor, E; Kahn, S E

2013-01-01

To examine the ability of fasting plasma glucose (FPG) and/or 2-h glucose to confirm diabetes and to determine the proportion of participants with HbA1c ≥6.5%. Diabetes confirmation rates were calculated after a single elevated FPG and/or 2-h glucose on an oral glucose tolerance test (OGTT) using a confirmatory OGTT performed within 6 weeks. 772 (24%) participants had elevated FPG or 2-h glucose on an OGTT that triggered a confirmation visit. There were 101 triggers on FPG alone, 574 on 2-h glucose alone, and 97 on both. Only 47% of participants who triggered had confirmed diabetes. While the confirmation rate for FPG was higher than that for 2-h glucose, the larger number of 2-h glucose triggers resulted in 87% of confirmed cases triggering on 2-h glucose. Confirmation rates increased to 75% among persons with FPG ≥126 mg/dl and HbA1c ≥6.5%. Only half of the persons with elevated FPG and IGT were subsequently confirmed to have diabetes. At current diagnostic levels, more persons trigger on 2-h glucose than on FPG, but fewer of these persons have their diagnoses confirmed. In individuals with FPG ≥126 mg/dl and HbA1c ≥6.5%, the confirmation rate was increased. Copyright © 2013 Elsevier Inc. All rights reserved.

Ondansetron attenuates depression co-morbid with obesity in obese mice subjected to chronic unpredictable mild stress; an approach using behavioral battery tests.

PubMed

Kurhe, Yeshwant; Radhakrishnan, Mahesh; Gupta, Deepali

2014-09-01

The aim of the present work was to investigate the role of ondansetron on the high fat diet (HFD) induced obese mice for behavioral and biochemical alterations using chronic unpredictable mild stress (CUMS) model of depression. Animals were fed with high fat diet for 14 weeks and subjected to different stress procedures for 4 weeks. Treatment with ondansetron was started on day 15. After day 28 behavioral assays and biochemical estimations were performed. Behavioral paradigms viz. sucrose preference test, locomotor score, forced swim test (FST) and elevated plus maze (EPM), whereas biochemical parameters like plasma glucose, total cholesterol, triglycerides and total proteins were estimated. Results examines that in behavioral assays, ondansetron significantly (P < 0.05) increased sucrose consumption, reduced immobility time in FST, increased the percent entries and time in open arm in EPM. In biochemical assessments elevated plasma glucose, total cholesterol, triglycerides and total proteins were significantly (P < 0.05) reversed by ondansetron treatment in HFD obese animals subjected to CUMS. The study indicates that the obese mice subjected to CUMS exhibited severe depressive-like symptoms and ondansetron significantly reversed the behavioral and biochemical alterations. In the present study the plasma glucose level indicates that, it could be "altered glucose level" playing an important role in depression co-morbid with obesity. Ondansetron through allosteric modulation of serotonergic system elevates the serotonin level and thereby regulates the insulin secretion and hence, reversing the "altered glucose level", could be the possible antidepressive-like mechanism against depression co-morbid with obesity.

Gap junctions and other mechanisms of cell-cell communication regulate basal insulin secretion in the pancreatic islet.

PubMed

Benninger, R K P; Head, W Steven; Zhang, Min; Satin, Leslie S; Piston, David W

2011-11-15

Cell-cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca(2+)](i)) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca(2+)](i) ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell-cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36(-/-)), and these results were compared to those obtained using fully isolated β-cells. K(ATP) loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36(-/-) islets, elevations in [Ca(2+)](i) persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36(-/-) islets was minimally altered. [Ca(2+)](i) was further elevated under basal conditions, but insulin release still suppressed in K(ATP) loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell-cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca(2+)](i) signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion.

Dexamethasone and perioperative blood glucose in patients undergoing total joint arthroplasty: A retrospective study.

PubMed

Nurok, Michael; Cheng, Jennifer; Romeo, Giulio R; Vecino, Stephanie M; Fields, Kara G; YaDeau, Jacques T

2017-02-01

Perioperative dexamethasone is commonly used to prevent nausea. It can also increase blood glucose levels, and recent concern about its blood glucose-elevating effect in humans has been raised. This study aimed to demonstrate relationships between dexamethasone administration and elevated perioperative blood glucose in patients undergoing total joint arthroplasty. Retrospective study. Academic, orthopedic hospital. A total of 625 patients (18-99years) who underwent total hip or total knee arthroplasty with an ASA ≤3 were included in the study. Patients who received dexamethasone perioperatively were compared to those who did not receive dexamethasone. The primary outcome, which was any postoperative glucose >200mg/dl, was compared between groups using multiple logistic regression. Demographic information, intraoperative information, incidence of postoperative nausea and vomiting, white blood cell count, medication use, and length of stay were also collected. Perioperative dexamethasone (median [1st quartile, 3rd quartile] dose=4 [4, 8] mg) was administered to 76% of patients. Only 5.6% (95% CI: 3.8-7.5) of patients had postoperative glucose levels >200mg/dl. After covariate adjustment, there was no evidence of a difference in odds of experiencing postoperative glucose levels >200mg/dl (odds ratio [95% CI]: 0.76 [0.28-2.07]; P=0.594) and maximum glucose levels (P=0.518) between groups. Dexamethasone-treated patients had greater changes in white blood cell count between baseline and postoperative days 0-1. There was no evidence of a difference in wound healing and length of stay between groups. There was no evidence of an association between perioperative dexamethasone administration and the odds of having postoperative glucose levels >200mg/dl or higher maximum glucose levels. However, these findings may not be generalizable to patients having different baseline characteristics or procedures. Copyright © 2016 Elsevier Inc. All rights reserved.

Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice.

PubMed

Tsuneki, Hiroshi; Tokai, Emi; Nakamura, Yuya; Takahashi, Keisuke; Fujita, Mikio; Asaoka, Takehiro; Kon, Kanta; Anzawa, Yuuki; Wada, Tsutomu; Takasaki, Ichiro; Kimura, Kumi; Inoue, Hiroshi; Yanagisawa, Masashi; Sakurai, Takeshi; Sasaoka, Toshiyasu

2015-02-01

Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wild-type mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver. © 2015 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.

Confirming Glycemic Status in the Diabetes Prevention Program: Implications for Diagnosing Diabetes in High Risk Adults

PubMed Central

Christophi, C. A.; Resnick, H. E.; Ratner, R. E.; Temprosa, M.; Fowler, S.; Knowler, W. C.; Shamoon, H.; Barrett-Connor, E.; Kahn, S. E.

2012-01-01

Aims To examine the ability of FPG and/or 2-hr glucose to confirm diabetes and to determine the proportion of participants with HbA1c ≥6.5%. Methods Diabetes confirmation rates were calculated after a single elevated FPG and/or 2-hr glucose on an oral glucose tolerance test (OGTT) using a confirmatory OGTT performed within 6 weeks. Results 772 (24%) participants had elevated FPG or 2-hr glucose on an OGTT that triggered a confirmation visit. There were 101 triggers on FPG alone, 574 on 2-hr glucose alone, and 97 on both. Only 47% of participants who triggered had confirmed diabetes. While the confirmation rate for FPG was higher than that for 2-hr glucose, the larger number of 2-hr glucose triggers resulted in 87% of confirmed cases triggering on 2-hr glucose. Confirmation rates increased to 75% among persons with FPG ≥126 mg/dl and HbA1c ≥6.5%. Conclusions Only half of persons with elevated FPG and IGT were subsequently confirmed to have diabetes. At current diagnostic levels, more persons trigger on 2-hr glucose than on FPG, but fewer of these persons have their diagnoses confirmed. In individuals with FPG ≥126 mg/dl and HbA1c ≥6.5%, the confirmation rate was increased. PMID:23140912

In vitro and In vivo Postprandial Glycemic Activity of Citrus limetta Peel Flour

PubMed Central

Flores-Fernández, José Miguel; Barragán-Álvarez, Carla Patricia; Díaz-Martínez, Nestor Emmanuel; Villanueva-Rodríguez, Socorro; Padilla-Camberos, Eduardo

2017-01-01

Background: Previous studies of Citrus spp. peel have shown hypoglycemic and antioxidant activities. Citrus limetta has been studied for its therapeutic properties. Diabetes mellitus (DM) is a health problem in Mexico and worldwide, that takes a vital importance due to its high incidence. Recently, scientists have searched natural sources to control the disease. Materials and Methods: In this study, we evaluated the in vitro hypoglycemic activity and in vivo postprandial glycemic effect of C. limetta peel flour by glucose adsorption and retardation assays as well as postprandial serum glucose levels using a group of female Balb-c mice, respectively. Results: C. limetta peel flour showed a glucose adsorption capacity of 16.58 mM, having a similar effect regarding the positive control. The glucose diffusion in the dialysate was elevated, with a glucose dialysis retardation index of 33.79% in a period of 3 h, showing similar results to positive control. Postprandial serum glucose levels in the animal group treated with C. limetta peel flour showed a glucose level of 41.4 mg/dL, being this value significantly lower than negative control group and similar to positive control. Toxicity tests showed good tolerance to the dose of 2000 mg/kg. Conclusion: C. limetta peel flour could act as a source of functional compounds for the control of DM. SUMMARY Citrus limetta peel flour showed a glucose adsorption capacity similar to the positive controlThe glucose diffusion in the dialysate was elevated, showing similar results to positive controlPostprandial serum glucose levels in the animal group treated with C. limetta peel flour showed a glucose level significantly lower than negative control group and similar to positive controlToxicity tests showed good toleranceC. limetta peel flour could act as a source of functional compounds for the control of diabetes mellitus. Abbreviations used: CIATEJ: Center for Research and Assistance in Technology and Design of Jalisco; DM: Diabetes mellitus; FGC: Final glucose concentration; GDRI: Glucose dialysis retardation index; IGC: Initial glucose concentration; OECD: Organization for Economic Cooperation and Development. PMID:29200722

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

Edwards, Joshua R.; Prozialeck, Walter C.

Recent epidemiological studies suggest a positive association between exposure to the environmental pollutant cadmium (Cd) and the incidence and severity of diabetes. In this review, we examine the literature suggesting a relationship between Cd exposure, elevated blood glucose levels, and the development of diabetes. In addition we review human and animal studies indicating that Cd potentiates or exacerbates diabetic nephropathy. We also review the various possible cellular mechanisms by which Cd may alter blood glucose levels. In addition, we present some novel findings from our own laboratories showing that Cd elevates fasting blood glucose levels in an animal model ofmore » subchronic Cd exposure before overt signs of renal dysfunction are evident. These studies also show that Cd reduces insulin levels and has direct cytotoxic effects on the pancreas. Together, these findings indicate that Cd may be a factor in the development of some types of diabetes and they raise the possibility that Cd and diabetes-related hyperglycemia may act synergistically to damage the kidney.« less

Alterations in brain glucose utilization accompanying elevations in blood ethanol and acetate concentrations in the rat.

PubMed

Pawlosky, Robert J; Kashiwaya, Yoshihiro; Srivastava, Shireesh; King, Michael T; Crutchfield, Calvin; Volkow, Nora; Kunos, George; Li, Ting-Kai; Veech, Richard L

2010-02-01

Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. Rats were infused with solutions of sodium acetate, ethanol, or saline containing (13)C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs' cycle, acyl-coenzyme A (CoA) compounds, and amino acids. Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of (13)C-glucose into the brain compared to controls and the concentration of brain (13)C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg(2+) in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, alpha-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD(+)]/[NADH] was lower, the free mitochondrial [NAD(+)]/[NADH] and [CoQ]/[CoQH(2)] were oxidized and the DeltaG' of ATP lowered by acetate infusion from -61.4 kJ to -59.9 kJ/mol. Animals with elevated levels of blood ethanol or acetate had decreased (13)C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in (13)C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in DeltaG' of ATP was similar to administration of uncoupling agents indicating that the metabolism of acetate in brain caused the mitochondrial voltage dependent pore to form.

Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat

PubMed Central

Pawlosky, Robert J.; Kashiwaya, Yoshihiro; Srivastava, Shireesh; King, Michael T.; Crutchfield, Calvin; Volkow, Nora; Kunos, George; Li, Ting-Kai; Veech, Richard L.

2010-01-01

Background Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. Methods Rats were infused with solutions of sodium acetate, ethanol, or saline containing 13C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs’ cycle, acyl-coenzyme A (CoA) compounds, and amino acids. Results Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of 13C-glucose into the brain compared to controls and the concentration of brain 13C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg2+ in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, α-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD+]/[NADH] was lower, the free mitochondrial [NAD+]/[NADH] and [CoQ]/[CoQH2] were oxidized and the ΔG′ of ATP lowered by acetate infusion from −61.4 kJ to −59.9 kJ/mol. Conclusions Animals with elevated levels of blood ethanol or acetate had decreased 13C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in 13C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in ΔG′ of ATP was similar to administration of uncoupling agents indicating that the metabolism of acetate in brain caused the mitochondrial voltage dependent pore to form. PMID:19951290

Somatostatin promotes glucose generation of Ca2+oscillations in pancreatic islets both in the absence and presence of tolbutamide.

PubMed

Hellman, Bo; Dansk, Heléne; Grapengiesser, Eva

2018-06-01

Many cellular processes, including pulsatile release of insulin, are triggered by increase of cytoplasmic Ca 2+ . This study examines how somatostatin affects glucose generation of cytoplasmic Ca 2+ oscillations in mouse islets in absence and presence of tolbutamide blockade of the K ATP channels. Ca 2+ was measured with dual wavelength microflurometry in isolated islets loaded with the indicator Fura-2. Rise of glucose from 3 to 20 mM evoked introductory lowering of Ca 2+ prolonged by activation of somatostatin receptors. During continued superfusion exposure to somatostatin triggered oscillations mediated by periodic increase from the basal level (absence of tolbutamide) or by periodic interruption of an elevated level (presence of tolbutamide). In the latter situation the oscillations were transformed into sustained elevation by activation of muscarinic receptors (acetylcholine) or increase of cyclic AMP (IBMX, 8-bromo-cyclic AMP, forskolin). The observed effect of cyclic AMP raises the question whether high proportions of the glucagon-producing α-cells promote steady-state elevation of Ca 2+ . In support for this idea somatostatin was found to trigger glucose-induced Ca 2+ oscillations essentially in small islets that contain very few α-cells. The results indicate that somatostatin promotes glucose generation of Ca 2+ oscillations with similar characteristics both in the absence and presence of functional K ATP channels. Copyright © 2018. Published by Elsevier Ltd.

Dirty Electricity Elevates Blood Sugar Among Electrically Sensitive Diabetics and May Explain Brittle Diabetes

PubMed Central

Havas, Magda

2008-01-01

Transient electromagnetic fields (dirty electricity), in the kilohertz range on electrical wiring, may be contributing to elevated blood sugar levels among diabetics and prediabetics. By closely following plasma glucose levels in four Type 1 and Type 2 diabetics, we find that they responded directly to the amount of dirty electricity in their environment. In an electromagnetically clean environment, Type 1 diabetics require less insulin and Type 2 diabetics have lower levels of plasma glucose. Dirty electricity, generated by electronic equipment and wireless devices, is ubiquitous in the environment. Exercise on a treadmill, which produces dirty electricity, increases plasma glucose. These findings may explain why brittle diabetics have difficulty regulating blood sugar. Based on estimates of people who suffer from symptoms of electrical hypersensitivity (3–35%), as many as 5–60 million diabetics worldwide may be affected. Exposure to electromagnetic pollution in its various forms may account for higher plasma glucose levels and may contribute to the misdiagnosis of diabetes. Reducing exposure to electromagnetic pollution by avoidance or with specially designed GS filters may enable some diabetics to better regulate their blood sugar with less medication and borderline or pre-diabetics to remain non diabetic longer. PMID:18568931

Insulin secretion at high altitude in man

NASA Astrophysics Data System (ADS)

Sawhney, R. C.; Malhotra, A. S.; Singh, T.; Rai, R. M.; Sinha, K. C.

1986-09-01

The effect of hypoxia on circulatory levels of insulin, its response to oral glucose administration (100 g) and changes in circadian rhythms of glucose as well as insulin were evaluated in euglycemic males at sea level (SL, 220 m) during their stay at high altitude (3500 m, SJ) and in high altitude natives (HAN). Basal glucose levels were not altered at high altitude but the rise in glucose (δ glucose) after glucose load was significantly higher in SJ and HAN (p<0.01) as compared to SL values. An increase (p<0.01) both in basal as well as glucose induced rise in insulin secretion (δ insulin) was observed at HA. The rise in insulin in SJ was significantly higher (p<0.01) than in HAN. This elevation in glucose and insulin levels was also evident at different times of the day. The circadian rhythmicity of glucose as well as insulin was altered by the altitude stress. The findings of the study show a rise in insulin level at HA but the hyperglycemia in the face of hyper-insulinism require the presumption of a simultaneous and dispropotionate rise of insulin antagonistic hormones upsetting the effect of insulin on glucose metabolism.

Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 in livers of zucker diabetic fatty rats.

PubMed

Jain, Sushil K; Croad, Jennifer L; Velusamy, Thirunavukkarasu; Rains, Justin L; Bull, Rebeca

2010-09-01

Chromium and cysteine supplementation can improve glucose metabolism in animal studies. This study examined the hypothesis that a cysteinate complex of chromium is significantly beneficial than either of them in lowering blood glucose and vascular inflammation markers in Zucker diabetic fatty (ZDF) rats. Starting at the age of 6 wk, ZDF rats were supplemented orally (daily gavages for 8 more weeks) with saline-placebo (D) or chromium (400 microg Cr/Kg body weight) as chromium dinicocysteinate (CDNC), chromium dinicotinate (CDN) or chromium picolinate (CP) or equimolar L-cysteine (LC, img/Kg body weight), and fed Purina 5008 diet for 8 wk. ZDF rats of 6 wk age before any supplementations and onset of diabetes were considered as baseline. D rats showed elevated levels of fasting blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and oxidative stress (lipid peroxidation) and lower adiponectin and vitamin C, when compared with baseline rats. In comparison to D group, CDNC group had significantly lower blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and lipid peroxidation and increased vitamin C and adiponectin levels. CDN, CP or LC showed significantly less or no effect on these biomarkers. Only CDNC lowered blood creatinine levels in comparison to D. While CDN and CP had no effect, activation of NFkappaB, Akt and glucose transporter-2 levels were decreased, insulin receptor substrate 1 (IRS-1) activation increased in livers of CDNC-rats. CDNC effect on glycemia, NFkappaB, Akt and IRS-1 in liver was significantly greater compared with LC. Blood chromium levels did not differ between Cr-groups. Exogenous vitamin C supplementation significantly inhibited MCP-1 secretion in U937 monocytes cultured in high-glucose-medium. CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats.

Cardiovascular Risk Factors in Severely Obese Adolescents

PubMed Central

Michalsky, Marc P.; Inge, Thomas H.; Simmons, Mark; Jenkins, Todd M.; Buncher, Ralph; Helmrath, Michael; Brandt, Mary L.; Harmon, Carroll M.; Courcoulas, Anita; Chen, Michael; Horlick, Mary; Daniels, Stephen R.; Urbina, Elaine M.

2015-01-01

IMPORTANCE Severe obesity is increasingly common in the adolescent population but, as of yet, very little information exists regarding cardiovascular disease (CVD) risks in this group. OBJECTIVE To assess the baseline prevalence and predictors of CVD risks among severely obese adolescents undergoing weight-loss surgery. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study was conducted from February 28, 2007, to December 30, 2011, at the following 5 adolescent weight-loss surgery centers in the United States: Nationwide Children’s Hospital in Columbus, Ohio; Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio; Texas Children’s Hospital in Houston; University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania; and Children’s Hospital of Alabama in Birmingham. Consecutive patients aged 19 years or younger were offered enrollment in a long-term outcome study; the final analysis cohort consisted of 242 participants. MAIN OUTCOMES AND MEASURES This report examined the preoperative prevalence of CVD risk factors (ie, fasting hyperinsulinemia, elevated high-sensitivity C-reactive protein levels, impaired fasting glucose levels, dyslipidemia, elevated blood pressure, and diabetes mellitus) and associations between risk factors and body mass index (calculated as weight in kilograms divided by height in meters squared), age, sex, and race/ethnicity. Preoperative data were collected within 30 days preceding bariatric surgery. RESULTS The mean (SD) age was 17 (1.6) years and median body mass index was 50.5. Cardiovascular disease risk factor prevalence was fasting hyperinsulinemia (74%), elevated high-sensitivity C-reactive protein levels (75%), dyslipidemia (50%), elevated blood pressure (49%), impaired fasting glucose levels (26%), and diabetes mellitus (14%). The risk of impaired fasting glucose levels, elevated blood pressure, and elevated high-sensitivity C-reactive protein levels increased by 15%, 10%, and 6%, respectively, per 5-unit increase in body mass index (P < .01). Dyslipidemia (adjusted relative risk = 1.60 [95% CI, 1.26–2.03]; P < .01) and elevated blood pressure (adjusted relative risk = 1.48 [95% CI, 1.16–1.89]; P < .01) were more likely in adolescent boys compared with adolescent girls. White individuals were at greater risk of having elevated triglyceride levels (adjusted relative risk = 1.76 [95% CI, 1.14–2.72]; P = .01) but were less likely to have impaired fasting glucose levels (adjusted relative risk = 0.58 [95% CI, 0.38–0.89]; P = .01). CONCLUSIONS AND RELEVANCE Numerous CVD risk factors are apparent in adolescents undergoing weight-loss surgery. Increasing body mass index and male sex increase the relative risk of specific CVD risk factors. These data suggest that even among severely obese adolescents, recognition and treatment of CVD risk factors is important to help limit further progression of disease. PMID:25730293

Cardiovascular Risk Factors in Severely Obese Adolescents: The Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Study.

PubMed

Michalsky, Marc P; Inge, Thomas H; Simmons, Mark; Jenkins, Todd M; Buncher, Ralph; Helmrath, Michael; Brandt, Mary L; Harmon, Carroll M; Courcoulas, Anita; Chen, Michael; Horlick, Mary; Daniels, Stephen R; Urbina, Elaine M

2015-05-01

Severe obesity is increasingly common in the adolescent population but, as of yet, very little information exists regarding cardiovascular disease (CVD) risks in this group. To assess the baseline prevalence and predictors of CVD risks among severely obese adolescents undergoing weight-loss surgery. A prospective cohort study was conducted from February 28, 2007, to December 30, 2011, at the following 5 adolescent weight-loss surgery centers in the United States: Nationwide Children's Hospital in Columbus, Ohio; Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio; Texas Children's Hospital in Houston; University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania; and Children's Hospital of Alabama in Birmingham. Consecutive patients aged 19 years or younger were offered enrollment in a long-term outcome study; the final analysis cohort consisted of 242 participants. This report examined the preoperative prevalence of CVD risk factors (ie, fasting hyperinsulinemia, elevated high-sensitivity C-reactive protein levels, impaired fasting glucose levels, dyslipidemia, elevated blood pressure, and diabetes mellitus) and associations between risk factors and body mass index (calculated as weight in kilograms divided by height in meters squared), age, sex, and race/ethnicity. Preoperative data were collected within 30 days preceding bariatric surgery. The mean (SD) age was 17 (1.6) years and median body mass index was 50.5. Cardiovascular disease risk factor prevalence was fasting hyperinsulinemia (74%), elevated high-sensitivity C-reactive protein levels (75%), dyslipidemia (50%), elevated blood pressure (49%), impaired fasting glucose levels (26%), and diabetes mellitus (14%). The risk of impaired fasting glucose levels, elevated blood pressure, and elevated high-sensitivity C-reactive protein levels increased by 15%, 10%, and 6%, respectively, per 5-unit increase in body mass index (P < .01). Dyslipidemia (adjusted relative risk = 1.60 [95% CI, 1.26-2.03]; P < .01) and elevated blood pressure (adjusted relative risk = 1.48 [95% CI, 1.16-1.89]; P < .01) were more likely in adolescent boys compared with adolescent girls. White individuals were at greater risk of having elevated triglyceride levels (adjusted relative risk = 1.76 [95% CI, 1.14-2.72]; P = .01) but were less likely to have impaired fasting glucose levels (adjusted relative risk = 0.58 [95% CI, 0.38-0.89]; P = .01). Numerous CVD risk factors are apparent in adolescents undergoing weight-loss surgery. Increasing body mass index and male sex increase the relative risk of specific CVD risk factors. These data suggest that even among severely obese adolescents, recognition and treatment of CVD risk factors is important to help limit further progression of disease.

Arsenate-induced maternal glucose intolerance and neural tube defects in a mouse model

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

Hill, Denise S.; Wlodarczyk, Bogdan J.; Mitchell, Laura E.

Background: Epidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals. Objectives: We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic's teratogenicity in early neurodevelopment. Methods: We evaluated maternal intraperitoneal (IP) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selectedmore » compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), L-methionine (L-Met), N-tert-Butyl-{alpha}-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate's effects. Results: Arsenate caused significant glucose elevation during an IP glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p = 0.0260). Arsenate caused NTDs (100%, p < 0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%. Conclusions: IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin's success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.« less

Long-term exposure to high glucose induces changes in the content and distribution of some exocytotic proteins in cultured hippocampal neurons.

PubMed

Gaspar, J M; Castilho, Á; Baptista, F I; Liberal, J; Ambrósio, A F

2010-12-29

A few studies have reported the existence of depletion of synaptic vesicles, and changes in neurotransmitter release and in the content of exocytotic proteins in the hippocampus of diabetic rats. Recently, we found that diabetes alters the levels of synaptic proteins in hippocampal nerve terminals. Hyperglycemia is considered the main trigger of diabetic complications, although other factors, such as low insulin levels, also contribute to diabetes-induced changes. Thus, the aim of this work was to evaluate whether long-term elevated glucose per se, which mimics prolonged hyperglycemia, induces significant changes in the content and localization of synaptic proteins involved in exocytosis in hippocampal neurons. Hippocampal cell cultures were cultured for 14 days and were exposed to high glucose (50 mM) or mannitol (osmotic control; 25 mM plus 25 mM glucose), for 7 days. Cell viability and nuclear morphology were evaluated by MTT and Hoechst assays, respectively. The protein levels of vesicle-associated membrane protein-2 (VAMP-2), synaptosomal-associated protein-25 (SNAP-25), syntaxin-1, synapsin-1, synaptophysin, synaptotagmin-1, rabphilin 3a, and also of vesicular glutamate and GABA transporters (VGluT-1 and VGAT), were evaluated by immunoblotting, and its localization was analyzed by immunocytochemistry. The majority of the proteins were not affected. However, elevated glucose decreased the content of SNAP-25 and increased the content of synaptotagmin-1 and VGluT-1. Moreover, there was an accumulation of syntaxin-1, synaptotagmin-1 and VGluT-1 in the cell body of some hippocampal neurons exposed to high glucose. No changes were detected in mannitol-treated cells. In conclusion, elevated glucose per se did not induce significant changes in the content of the majority of the synaptic proteins studied in hippocampal cultures, with the exception of SNAP-25, synaptotagmin-1 and VGluT-1. However, there was an accumulation of some proteins in cell bodies of hippocampal neurons exposed to elevated glucose, suggesting that the trafficking of these proteins to the synapse may be compromised. Moreover, these results also suggest that other factors, in addition to hyperglycemia, certainly contribute to alterations detected in synaptic proteins in diabetic animals. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

The modulatory role of spinally located histamine receptors in the regulation of the blood glucose level in d-glucose-fed mice.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Suh, Hong-Won

2014-02-01

The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (α-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with α-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, α-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.

AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice

PubMed Central

Nakano, Kazuhiro; Takeshita, Sen; Kawasaki, Noriko; Miyanaga, Wataru; Okamatsu, Yoriko; Dohi, Mizuki; Nakagawa, Tadakiyo

2017-01-01

Impaired glycogen synthesis and turnover are common in insulin resistance and type 2 diabetes. As glycogen synthase (GS) is a key enzyme involved in the synthetic process, it presents a promising therapeutic target for the treatment of type 2 diabetes. In the present study, we identified a novel, potent and orally available GS activator AJS1669 {sodium 2-[[5-[[4-(4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl]furan-2-carbonyl]-(2-furylmethyl)amino] acetate}. In vitro, we performed a glycogen synthase 1 (GYS1) activation assay for screening GS activators and identified that the activity of AJS1669 was further potentiated in the presence of glucose-6-phosphate (G6P). In vivo, we used ob/ob mice to evaluate the novel anti-diabetic effects of AJS1669 by measuring basal blood glucose levels, glucose tolerance and body fat mass index. Repeated administration of AJS1669 over 4 weeks reduced blood glucose and hemoglobin A1c (HbA1c) levels in ob/ob mice. AJS1669 also improved glucose tolerance in a dose-dependent manner, and decreased body fat mass. The mRNA levels of genes involved in mitochondrial fatty acid oxidation and mitochondrial biogenesis were elevated in skeletal muscle tissue following AJS1669 treatment. Hepatic tissue of treated mice also exhibited elevated expression of genes associated with fatty acid oxidation. In contrast to ob/ob mice, in C57Bl/6 mice AJS1669 administration did not alter body weight or reduce glucose levels. These results demonstrate that pharmacological agents that activate GYS1, the main GS subtype found in skeletal muscle, have potential for use as novel treatments for diabetes that improve glucose metabolism in skeletal muscle. PMID:28290602

AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice.

PubMed

Nakano, Kazuhiro; Takeshita, Sen; Kawasaki, Noriko; Miyanaga, Wataru; Okamatsu, Yoriko; Dohi, Mizuki; Nakagawa, Tadakiyo

2017-04-01

Impaired glycogen synthesis and turnover are common in insulin resistance and type 2 diabetes. As glycogen synthase (GS) is a key enzyme involved in the synthetic process, it presents a promising therapeutic target for the treatment of type 2 diabetes. In the present study, we identified a novel, potent and orally available GS activator AJS1669 {sodium 2-[[5-[[4-(4,5-difluoro-2-methylsulfanyl-phenyl)phenoxy] methyl]furan-2-carbonyl]-(2-furylmethyl)amino] acetate}. In vitro, we performed a glycogen synthase 1 (GYS1) activation assay for screening GS activators and identified that the activity of AJS1669 was further potentiated in the presence of glucose-6-phosphate (G6P). In vivo, we used ob/ob mice to evaluate the novel anti-diabetic effects of AJS1669 by measuring basal blood glucose levels, glucose tolerance and body fat mass index. Repeated administration of AJS1669 over 4 weeks reduced blood glucose and hemoglobin A1c (HbA1c) levels in ob/ob mice. AJS1669 also improved glucose tolerance in a dose-dependent manner, and decreased body fat mass. The mRNA levels of genes involved in mitochondrial fatty acid oxidation and mitochondrial biogenesis were elevated in skeletal muscle tissue following AJS1669 treatment. Hepatic tissue of treated mice also exhibited elevated expression of genes associated with fatty acid oxidation. In contrast to ob/ob mice, in C57Bl/6 mice AJS1669 administration did not alter body weight or reduce glucose levels. These results demonstrate that pharmacological agents that activate GYS1, the main GS subtype found in skeletal muscle, have potential for use as novel treatments for diabetes that improve glucose metabolism in skeletal muscle.

Brain glucose metabolism in an animal model of depression.

PubMed

Detka, J; Kurek, A; Kucharczyk, M; Głombik, K; Basta-Kaim, A; Kubera, M; Lasoń, W; Budziszewska, B

2015-06-04

An increasing number of data support the involvement of disturbances in glucose metabolism in the pathogenesis of depression. We previously reported that glucose and glycogen concentrations in brain structures important for depression are higher in a prenatal stress model of depression when compared with control animals. A marked rise in the concentrations of these carbohydrates and glucose transporters were evident in prenatally stressed animals subjected to acute stress and glucose loading in adulthood. To determine whether elevated levels of brain glucose are associated with a change in its metabolism in this model, we assessed key glycolytic enzymes (hexokinase, phosphofructokinase and pyruvate kinase), products of glycolysis, i.e., pyruvate and lactate, and two selected enzymes of the tricarboxylic acid cycle (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the hippocampus and frontal cortex. Additionally, we assessed glucose-6-phosphate dehydrogenase activity, a key enzyme in the pentose phosphate pathway (PPP). Prenatal stress increased the levels of phosphofructokinase, an important glycolytic enzyme, in the hippocampus and frontal cortex. However, prenatal stress had no effect on hexokinase or pyruvate kinase levels. The lactate concentration was elevated in prenatally stressed rats in the frontal cortex, and pyruvate levels remained unchanged. Among the tricarboxylic acid cycle enzymes, prenatal stress decreased the level of pyruvate dehydrogenase in the hippocampus, but it had no effect on α-ketoglutarate dehydrogenase. Like in the case of glucose and its transporters, also in the present study, differences in markers of glucose metabolism between control animals and those subjected to prenatal stress were not observed under basal conditions but in rats subjected to acute stress and glucose load in adulthood. Glucose-6-phosphate dehydrogenase activity was not reduced by prenatal stress but was found to be even higher in animals exposed to all experimental conditions, i.e., prenatal stress, acute stress, and glucose administration. Our data indicate that glycolysis is increased and the Krebs cycle is decreased in the brain of a prenatal stress animal model of depression. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

The biphasic effect of extracellular glucose concentration on carbachol-induced fluid secretion from mouse submandibular glands.

PubMed

Terachi, Momomi; Hirono, Chikara; Kitagawa, Michinori; Sugita, Makoto

2018-06-01

Cholinergic agonists evoke elevations of the cytoplasmic free-calcium concentration ([Ca 2+ ] i ) to stimulate fluid secretion in salivary glands. Salivary flow rates are significantly reduced in diabetic patients. However, it remains elusive how salivary secretion is impaired in diabetes. Here, we used an ex vivo submandibular gland perfusion technique to characterize the dependency of salivary flow rates on extracellular glucose concentration and activities of glucose transporters expressed in the glands. The cholinergic agonist carbachol (CCh) induced sustained fluid secretion, the rates of which were modulated by the extracellular glucose concentration in a biphasic manner. Both lowering the extracellular glucose concentration to less than 2.5 mM and elevating it to higher than 5 mM resulted in decreased CCh-induced fluid secretion. The CCh-induced salivary flow was suppressed by phlorizin, an inhibitor of the sodium-glucose cotransporter 1 (SGLT1) located basolaterally in submandibular acinar cells, which is altered at the protein expression level in diabetic animal models. Our data suggest that SGLT1-mediated glucose uptake in acinar cells is required to maintain the fluid secretion by sustaining Cl - secretion in real-time. High extracellular glucose levels may suppress the CCh-induced secretion of salivary fluid by altering the activities of ion channels and transporters downstream of [Ca 2+ ] i signals. © 2018 Eur J Oral Sci.

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.

Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes.

PubMed

Xu, Ning; Chua, Angela K; Jiang, Hong; Liu, Ning-Ai; Goodarzi, Mark O

2014-08-01

Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study.

Early Embryonic Androgen Exposure Induces Transgenerational Epigenetic and Metabolic Changes

PubMed Central

Xu, Ning; Chua, Angela K.; Jiang, Hong; Liu, Ning-Ai

2014-01-01

Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study. PMID:24992182

Muscle-specific inflammation induced by MCP-1 overexpression does not affect whole-body insulin sensitivity in mice.

PubMed

Evers-van Gogh, Inkie J A; Oteng, Antwi-Boasiako; Alex, Sheril; Hamers, Nicole; Catoire, Milene; Stienstra, Rinke; Kalkhoven, Eric; Kersten, Sander

2016-03-01

Obesity is associated with a state of chronic low-grade inflammation that is believed to contribute to the development of skeletal muscle insulin resistance. However, the extent to which local and systemic elevation of cytokines, such as monocyte chemoattractant protein 1 (MCP-1), interferes with the action of insulin and promotes insulin resistance and glucose intolerance in muscle remains unclear. Here, we aim to investigate the effect of muscle-specific overexpression of MCP-1 on insulin sensitivity and glucose tolerance in lean and obese mice. We used Mck-Mcp-1 transgenic (Tg) mice characterised by muscle-specific overexpression of Mcp-1 (also known as Ccl2) and elevated plasma MCP-1 levels. Mice were fed either chow or high-fat diet for 10 weeks. Numerous metabolic variables were measured, including glucose and insulin tolerance tests, muscle insulin signalling and plasma NEFA, triacylglycerol, cholesterol, glucose and insulin. Despite clearly promoting skeletal muscle inflammation, muscle-specific overexpression of Mcp-1 did not influence glucose tolerance or insulin sensitivity in either lean chow-fed or diet-induced obese mice. In addition, plasma NEFA, triacylglycerol, cholesterol, glucose and insulin were not affected by MCP-1 overexpression. Finally, in vivo insulin-induced Akt phosphorylation in skeletal muscle did not differ between Mcp-1-Tg and wild-type mice. We show that increased MCP-1 production in skeletal muscle and concomitant elevated MCP-1 levels in plasma promote inflammation in skeletal muscle but do not influence insulin signalling and have no effect on insulin resistance and glucose tolerance in lean and obese mice. Overall, our data argue against MCP-1 promoting insulin resistance in skeletal muscle and raise questions about the impact of inflammation on insulin sensitivity in muscle.

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.

An incubation medium for the elevation of adenosine triphosphate and 2,3-diphosphoglycerate in fresh and long-preserved human erythrocytes.

PubMed

Rubinstein, D; Warrendorf, E

1975-06-01

The levels of adenosine triphosphate (ATP) and 2,3-diphosphoglycerate in freshly drawn human erythrocytes can be tripled by a 2 h incubation at 37 degrees C in a medium containing 21 mM glucose, 1.8 mM adenine, 5 mM pyruvate, 10 mM inosine, and 96 mM phosphate. Similar incubation conditions will restore the levels of ATP and 2,3-diphosphoglycerate in erythrocytes from blood levels preserved for 12 and 15 weeks, respectively, to those of fresh cells. Omission of pyruvate from the incubation medium further increases the level of ATP slightly, but there is little elevation of 2,3-diphosphoglycerate. Under these conditions labelled pyruvate and lactate production from [14-C]glucose or [14-C]inosine is not diminished, but labelled fructose 1,6-diphosphate, rather than 2,3-diphosphoglycerate, accumulates. In addition, omission of pyruvate from the incubation medium, with a concomitant decrease in accumulation of 2,3-diphosphoglycerate, diminishes the concentration of inorganic phosphate required for optimal ATP elevation. A 5 h incubation in the glucose-adenine-pyruvate-inosine-phosphate medium elevates the levels of ATP and 2,3-diphosphoglycerate in erythrocytes from blood preserved in the cold for 15 weeks to twice that of fresh cells, indicating that the cells retain their metabolic potential even after prolonged storage at 2 degrees C. The medium may provide a method of rejuvenating 10-12 week cold-preserved erythrocytes for transfusion purposes, by a 1 h incubation at 37 degrees C.

Evaluation of the influence of blood glucose level on oral candidal colonization in complete denture wearers with Type-II Diabetes Mellitus: An in vivo Study.

PubMed

Ganapathy, Dhanraj Muthuveera; Joseph, Sajeesh; Ariga, Padma; Selvaraj, Anand

2013-01-01

Candidal colonization in complete denture wearers is a commonly encountered condition that worsens in the presence of untreated Diabetes Mellitus. The aim of this study was to evaluate the correlation between oral candidiasis in denture-bearing mucosa and elevated blood glucose levels in complete denture wearers and to evaluate the effect of oral hypoglycemic drug therapy in controlling oral candidal colonization in denture-bearing mucosa of complete denture wearers with Type II Diabetes Mellitus. This prospective observational study involved the participation of 15 complete denture wearers with Type II Diabetes Mellitus. The sample collection was made prior and after oral hypoglycaemic drug intervention, by swabbing the rugal surfaces of palatal mucosa, cultured and the density of the candidal colony formed was analyzed and interpreted as colony forming units (CFU) per mL. The candidal samples CFU and corresponding pre- and post-prandial blood glucose levels were estimated, analyzed and compared using Karl Pearson correlation analysis and paired t-test (α = 0.05). The Karl Pearson correlation analysis showed that there was a positive correlation between the blood glucose levels (PPS and FBS) and the candidal colonization (CFU) (P < 0.05). The mean values of all the variables were analyzed using the paired t-test. There was significant reduction in the mean values of blood glucose levels (P < 0.001) and the mean values of the CFU (P < 0.001) following oral hypoglycemic drug therapy. Positive correlation was observed between oral candidiasis in complete denture-bearing mucosa and elevated blood glucose levels and oral hypoglycemic drug therapy has a positive effect in controlling oral candidal colonization in complete denture wearers with Type II Diabetes Mellitus.

Non-high-density lipoprotein cholesterol and other lipid indices vs elevated glucose risk in Arab adolescents.

PubMed

Al-Daghri, Nasser M; Aljohani, Naji J; Al-Attas, Omar S; Al-Saleh, Yousef; Wani, Kaiser; Alnaami, Abdullah M; Alfawaz, Hanan; Al-Ajlan, Abdulrahman S M; Kumar, Sudhesh; Chrousos, George P; Alokail, Majed S

2015-01-01

Non-high-density lipoprotein cholesterol (non-HDL-C) has been identified as a significant predictor of various cardiovascular events in adults. Limited studies have been conducted in the pediatric population with diverse results, depending on ethnic origin. None has been conducted in the Arabic adolescent population so far; this study aims to fill this gap. In this cross-sectional study, 1690 Saudi school adolescents (968 boys [mean age 14.8 ± 1.7] and 722 girls [mean age 14.6 ± 1.7]) were recruited. Anthropometrics were obtained. Fasting blood glucose and lipid profiles were quantified routinely. Non-HDL-C was calculated and screening was done for dyslipidemia using cutoffs obtained from the cohort and elevated fasting glucose. Using the 90th percentile cutoff obtained, the overall prevalence of high non-HDL-C (≥4.26 mmol/L) was 10.1%. Prevalence was slightly higher in girls (10.5%) than boys (9.9%). Non-HDL-C was similar to other lipids in terms of significant associations with anthropometric measures and glucose in both boys and girls. Elevated triglycerides was most predictive of elevated glucose in both girls (odds ratio 2.41; confidence interval 1.43-4.08; P = .001) and boys (odds ratio 2.61; confidence interval 1.70-4.0); P < .001). Non-HDL-C appears to be gender-specific and is cardiometabolically more associated with Saudi boys, despite higher levels in girls. It is inferior compared with triglycerides in assessing elevated glucose risk. Further investigations may provide a more definite value for non-HDL-C use as a biomarker in assessing cardiometabolic risk in the Arab adolescent population. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Admission hyperglycemia predicts poorer short- and long-term outcomes after primary percutaneous coronary intervention for ST-elevation myocardial infarction.

PubMed

Chen, Pei-Chi; Chua, Su-Kiat; Hung, Huei-Fong; Huang, Chung-Yen; Lin, Chiu-Mei; Lai, Shih-Ming; Chen, Yen-Ling; Cheng, Jun-Jack; Chiu, Chiung-Zuan; Lee, Shih-Huang; Lo, Huey-Ming; Shyu, Kou-Gi

2014-02-12

Admission hyperglycemia is associated with poor outcome in patients with myocardial infarction. The present study evaluated the relationship between admission glucose level and other clinical variables in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The 959 consecutive STEMI patients undergoing primary PCI were divided into five groups based on admission glucose levels of <100, 100-139, 140-189, 190-249 and ≥250 mg/dL. Their short- and long-term outcomes were compared. Higher admission glucose levels were associated with significantly higher in-hospital morbidity and mortality, the overall mortality rate at follow up, and the incidence of reinfarction or heart failure requiring admission or leading to mortality at follow up. The odds ratios (95% confidence interval) for in-hospital morbidity, in-hospital mortality, mortality at follow up and re-infarction or heart failure or mortality at follow up of patients with admission glucose levels ≥190 mg/dL, compared with those with admission glucose levels <190 mg/dL, were 2.12 (1.3-3.4, P = 0.001), 2.74 (1.4-5.5, P = 0.004), 2.52 (1.2-5.1, P = 0.01) and 1.70 (1.03-2.8, P = 0.04), respectively. Previously non-diabetic patients with admission glucose levels ≥250 mg/dL had significantly higher in-hospital morbidity or mortality (44 vs 70%, P = 0.03). Known diabetic patients had higher rates of reinfarction, heart failure or mortality at follow up in the 100-139 mg/dL (8 vs 27%, P = 0.04) and 140-189 mg/dL (11 vs 26%, P = 0.02) groups. Admission hyperglycemia, especially at glucose levels ≥190 mg/dL, is a predictor of poor prognosis in STEMI patients undergoing primary PCI.

Elevated α-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents.

PubMed

Tricò, Domenico; Prinsen, Hetty; Giannini, Cosimo; de Graaf, Robin; Juchem, Christoph; Li, Fangyong; Caprio, Sonia; Santoro, Nicola; Herzog, Raimund I

2017-07-01

Traditional risk factors for type 2 diabetes mellitus are weak predictors of changes in glucose tolerance and insulin sensitivity in youth. To identify early metabolic features of insulin resistance (IR) in youth and whether they predict deterioration of glycemic control. A cross-sectional and longitudinal study was conducted at the Yale Pediatric Obesity Clinic. Concentrations of α-hydroxybutyrate, β-hydroxybutyrate, lactate, and branched-chain amino acids (BCAAs) were measured by nuclear magnetic resonance spectroscopy in 78 nondiabetic adolescents during an oral glucose tolerance test (OGTT). Associations between baseline metabolic alterations and longitudinal changes in glucose control were tested in 16 subjects after a mean follow-up of 2.3 years. The relationship between metabolite levels, parameters of IR, and glycemic control, and their progression over time. Elevated fasting α-hydroxybutyrate levels were observed in adolescents with reduced insulin sensitivity after adjusting for age, sex, ethnicity, Tanner stage, and body mass index z-score (P = 0.014). Plasma α-hydroxybutyrate and BCAAs were increased throughout the course of the OGTT in this group (P < 0.03). Notably, borderline IR was associated with a progressive α-hydroxybutyrate decrease from elevated baseline concentrations to normal levels (P = 0.02). Increased baseline α-hydroxybutyrate concentrations were further associated with progressive worsening of glucose tolerance and disposition index. α-Hydroxybutyrate and BCAA concentrations during an OGTT characterize insulin-resistant youth and predict worsening of glycemic control. These findings provide potential biomarkers for risk assessment of type 2 diabetes and new insights into IR pathogenesis. Copyright © 2017 Endocrine Society

High glucose environment inhibits cranial neural crest survival by activating excessive autophagy in the chick embryo

PubMed Central

Wang, Xiao-Yu; Li, Shuai; Wang, Guang; Ma, Zheng-Lai; Chuai, Manli; Cao, Liu; Yang, Xuesong

2015-01-01

High glucose levels induced by maternal diabetes could lead to defects in neural crest development during embryogenesis, but the cellular mechanism is still not understood. In this study, we observed a defect in chick cranial skeleton, especially parietal bone development in the presence of high glucose levels, which is derived from cranial neural crest cells (CNCC). In early chick embryo, we found that inducing high glucose levels could inhibit the development of CNCC, however, cell proliferation was not significantly involved. Nevertheless, apoptotic CNCC increased in the presence of high levels of glucose. In addition, the expression of apoptosis and autophagy relevant genes were elevated by high glucose treatment. Next, the application of beads soaked in either an autophagy stimulator (Tunicamycin) or inhibitor (Hydroxychloroquine) functionally proved that autophagy was involved in regulating the production of CNCC in the presence of high glucose levels. Our observations suggest that the ERK pathway, rather than the mTOR pathway, most likely participates in mediating the autophagy induced by high glucose. Taken together, our observations indicated that exposure to high levels of glucose could inhibit the survival of CNCC by affecting cell apoptosis, which might result from the dysregulation of the autophagic process. PMID:26671447

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

PubMed Central

Olivier, Alicia K.; Yi, Yaling; Sun, Xingshen; Sui, Hongshu; Liang, Bo; Hu, Shanming; Xie, Weiliang; Fisher, John T.; Keiser, Nicholas W.; Lei, Diana; Zhou, Weihong; Yan, Ziying; Li, Guiying; Evans, Turan I.A.; Meyerholz, David K.; Wang, Kai; Stewart, Zoe A.; Norris, Andrew W.; Engelhardt, John F.

2012-01-01

Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas. PMID:22996690

[The impaired glucose tolerance in the pathogenesis of dyslipidemia].

PubMed

Ikoue, I; Takahashi, K; Katayama, S

1996-10-01

It is well known that hyperlipidemia is often present in patient with impaired glucose tolerance, obesity and/or hypertension. All of these are risk factors for coronary artery disease (CAD). The coexistence of these risk factors markedly increase the likelihood of CAD. Recently, it has been reported that the impaired glucose tolerance and insulin resistence are associated with the increased proinsulin, which is linked to the risk of CAD. We review that the impaired glucose tolerance is an important factor causing dyslipidemia. The characteristic of dyslipidemia associated with the impaired glucose tolerance include hypertriglyceridemia, high level of VLDL and low level of HDL cholesterol. They also associate with accumulation of remnant lipoproteins and appearance of small dense LDL. In addition, we pointed out that the increased number of risk factors is associated with elevated insulin and proinsulin level.

Carbon Disulfide (CS2) Interference in Glucose Metabolism from Unconventional Oil and Gas Extraction and Processing Emissions.

PubMed

Rich, Alisa L; Patel, Jay T; Al-Angari, Samiah S

2016-01-01

Carbon disulfide (CS2) has been historically associated with the manufacturing of rayon, cellophane, and carbon tetrachloride production. This study is one of the first to identify elevated atmospheric levels of CS2 above national background levels and its mechanisms to dysregulate normal glucose metabolism. Interference in glucose metabolism can indirectly cause other complications (diabetes, neurodegenerative disease, and retinopathy), which may be preventable if proper precautions are taken. Rich et al found CS2 and 12 associated sulfide compounds present in the atmosphere in residential areas where unconventional shale oil and gas extraction and processing operations were occurring. Ambient atmospheric concentrations of CS2 ranged from 0.7 parts per billion by volume (ppbv) to 103 ppbv over a continuous 24-hour monitoring period. One-hour ambient atmospheric concentrations ranged from 3.4 ppbv to 504.6 ppbv. Using the U.S. Environmental Protection Agency Urban Air Toxic Monitoring Program study as a baseline comparison for atmospheric CS2 concentrations found in this study, it was determined that CS2 atmospheric levels were consistently elevated in areas where unconventional oil and gas extraction and processing occurred. The mechanisms by which CS2 interferes in normal glucose metabolism by dysregulation of the tryptophan metabolism pathway are presented in this study. The literature review found an increased potential for alteration of normal glucose metabolism in viscose rayon occupational workers exposed to CS2. Occupational workers in the energy extraction industry exposed to CS2 and other sulfide compounds may have an increased potential for glucose metabolism interference, which has been an indicator for diabetogenic effect and other related health impacts. The recommendation of this study is for implementation of regular monitoring of blood glucose levels in CS2-exposed populations as a preventative health measure.

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.

Increased SHP-1 Protein Expression by High Glucose Levels Reduces Nephrin Phosphorylation in Podocytes*

PubMed Central

Denhez, Benoit; Lizotte, Farah; Guimond, Marie-Odile; Jones, Nina; Takano, Tomoko; Geraldes, Pedro

2015-01-01

Nephrin, a critical podocyte membrane component that is reduced in diabetic nephropathy, has been shown to activate phosphotyrosine signaling pathways in human podocytes. Nephrin signaling is important to reduce cell death induced by apoptotic stimuli. We have shown previously that high glucose level exposure and diabetes increased the expression of SHP-1, causing podocyte apoptosis. SHP-1 possesses two Src homology 2 domains that serve as docking elements to dephosphorylate tyrosine residues of target proteins. However, it remains unknown whether SHP-1 interacts with nephrin and whether its elevated expression affects the nephrin phosphorylation state in diabetes. Here we show that human podocytes exposed to high glucose levels exhibited elevated expression of SHP-1, which was associated with nephrin. Coexpression of nephrin-CD16 and SHP-1 reduced nephrin tyrosine phosphorylation in transfected human embryonic kidney 293 cells. A single tyrosine-to-phenylalanine mutation revealed that rat nephrin Tyr1127 and Tyr1152 are required to allow SHP-1 interaction with nephrin. Overexpression of dominant negative SHP-1 in human podocytes prevented high glucose-induced reduction of nephrin phosphorylation. In vivo, immunoblot analysis demonstrated that nephrin expression and phosphorylation were decreased in glomeruli of type 1 diabetic Akita mice (Ins2+/C96Y) compared with control littermate mice (Ins2+/+), and this was associated with elevated SHP-1 and cleaved caspase-3 expression. Furthermore, immunofluorescence analysis indicated increased colocalization of SHP-1 with nephrin in diabetic mice compared with control littermates. In conclusion, our results demonstrate that high glucose exposure increases SHP-1 interaction with nephrin, causing decreased nephrin phosphorylation, which may, in turn, contribute to diabetic nephropathy. PMID:25404734

Hepatocyte growth factor is elevated in amniotic fluid from obese women and regulates placental glucose and fatty acid metabolism.

PubMed

Visiedo, F; Bugatto, F; Carrasco-Fernández, C; Sáez-Benito, A; Mateos, R M; Cózar-Castellano, I; Bartha, J L; Perdomo, G

2015-04-01

To evaluate the impact of the pro-inflammatory cytokine hepatocyte growth factor (HGF) on the regulation of glucose and lipid placental metabolism. HGF levels were quantified in amniotic fluid and placenta from control and obese women. 2-deoxy-glucose (2-DOG) uptake, glycolysis, fatty acid oxidation (FAO), fatty acid esterification, de novo fatty acid synthesis, triglyceride levels and carnitine palmitoyltransferase activities (CPT) were measured in placental explants upon addition of pathophysiological HGF levels. In obese women, total- and -activated-HGF levels in amniotic fluid were elevated ∼24%, and placental HGF levels were ∼3-fold higher than in control women. At a similar dose to that present in amniotic fluid of obese women, HGF (30 ng/mL) increased Glut-1 levels and 2-DOG uptake by ∼25-30% in placental explants. HGF-mediated effect on 2-DOG uptake was dependent on the activation of phosphatidylinositol 3-kinase signaling pathway. In addition, HGF decreased ∼20% FAO, whereas esterification and de novo fatty acid synthesis increased ∼15% and ∼25% respectively, leading to 2-fold triglyceride accumulation in placental explants. In parallel, HGF reduced CPT-I activity ∼70%. HGF is a cytokine elevated in amniotic fluid and placental tissue of obese women, which through its ability to stimulate 2-DOG uptake and metabolism impairs FAO and enhances esterification and de novo fatty acid synthesis, leading to accumulation of placental triglycerides. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkB, Akt, and Glut-2 in livers of Zucker diabetic fatty rats

PubMed Central

Jain, Sushil K.; Croad, Jennifer L.; Velusamy, Thirunavukkarasu; Rains, Justin L.; Bull, Rebeca

2011-01-01

Aim Chromium and cysteine supplementation can improve glucose metabolism in animal studies. This study examined the hypothesis that a cysteinate complex of chromium is significantly beneficial than either of them in lowering blood glucose and vascular inflammation markers in ZDF rats. Methods Starting at the age of 6 wks, ZDF rats were supplemented orally (daily gavages for 8 more wks) with saline-placebo (D) or chromium (400µg Cr/KgBW) as chromium-dinicocysteinate (CDNC), chromium-dinicotinate (CDN), or chromium-picolinate (CP) or equimolar L-cysteine (LC, img/Kg BW), and fed Purina 5008 diet for 8 wks. ZDF rats of 6 wks age before any supplementations and onset of diabetes were considered as baseline (BL). Results D rats showed elevated levels of fasting blood glucose, HbA1, CRP, MCP-1, ICAM-1 and oxidative stress (LP) and lower adiponectin and vitamin C, when compared to BL rats. In comparison to D group, CDNC group had significantly lower blood glucose, HbA1, CRP, MCP-1, ICAM-1 and LP and increased vitamin C and adiponectin levels. CDN, CP or LC showed significantly less or no effect on these biomarkers. Only CDNC lowered blood creatinine levels in comparison to D. While CDN and CP had no effect, activation of NFkB, Akt and GLUT-2 levels were decreased, IRS-1 activation increased in livers of CDNC-rats. CDNC effect on glycemia, NFkB, Akt and IRS-1 in liver was significantly greater compared with LC. Blood chromium levels did not differ between Cr-groups. Exogenous vitamin C supplementation significantly inhibited MCP-1 secretion in U937 monocytes cultured in high-glucose-medium. Conclusions CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats. PMID:20306473

How sensitive and specific is urinalysis 'dipstick' testing for detection of hyperglycaemia and ketosis? An audit of findings from coronial autopsies.

PubMed

Mitchell, Rebecca; Thomas, Sunethra Devika; Langlois, Neil E I

2013-10-01

Biochemical analysis of glucose and ketones in the vitreous humour obtained at post-mortem examination is representative of the levels in the blood prior to death. Elevated levels can be indicative of conditions including diabetic ketoacidosis, which can be a cause for unexpected death. A rapid screening test for such conditions can be performed during the autopsy through urinalysis using test strips (urine 'dipstick' testing). The aim of this study was to assess the utility of urinalysis testing for post-mortem detection of derangements of glucose and ketone levels. The results of vitreous biochemical analysis and urinalysis were collated from 188 forensic autopsy cases. A vitreous glucose result of above 10 mmol/L was regarded as high. When this was compared to urinalysis results it was found that any urinalysis result above negative had a sensitivity of 0.83 and a specificity of 0.93. A vitreous ketone level of above 5 mmol/L was regarded as significantly elevated; a urinalysis result above negative had a sensitivity of 1, but a specificity of 0.12. Urinalysis ('dipstick' testing) for glucose has a good sensitivity and specificity for high vitreous glucose levels, which are regarded as indicative of pathological hyperglycaemia during life. It was found that urine testing for ketones either has an excellent sensitivity with low specificity or a poor sensitivity with a good specificity; however, this finding has to be viewed in the context of uncertainty of the biochemical level of significant ketosis.

Single Cell "Glucose Nanosensor" Verifies Elevated Glucose Levels in Individual Cancer Cells.

PubMed

Nascimento, Raphael A S; Özel, Rıfat Emrah; Mak, Wai Han; Mulato, Marcelo; Singaram, Bakthan; Pourmand, Nader

2016-02-10

Because the transition from oxidative phosphorylation to anaerobic glycolytic metabolism is a hallmark of cancer progression, approaches to identify single living cancer cells by their unique glucose metabolic signature would be useful. Here, we present nanopipettes specifically developed to measure glucose levels in single cells with temporal and spatial resolution, and we use this technology to verify the hypothesis that individual cancer cells can indeed display higher intracellular glucose levels. The nanopipettes were functionalized as glucose nanosensors by immobilizing glucose oxidase (GOx) covalently to the tip so that the interaction of glucose with GOx resulted in a catalytic oxidation of β-d-glucose to d-gluconic acid, which was measured as a change in impedance due to drop in pH of the medium at the nanopipette tip. Calibration studies showed a direct relationship between impedance changes at the tip and glucose concentration in solution. The glucose nanosensor quantified single cell intracellular glucose levels in human fibroblasts and the metastatic breast cancer lines MDA-MB-231 and MCF7 and revealed that the cancer cells expressed reproducible and reliable increases in glucose levels compared to the nonmalignant cells. Nanopipettes allow repeated sampling of the same cell, as cells remain viable during and after measurements. Therefore, nanopipette-based glucose sensors provide an approach to compare changes in glucose levels with changes in proliferative or metastatic state. The platform has great promise for mechanistic investigations, as a diagnostic tool to distinguish cancer cells from nonmalignant cells in heterogeneous tissue biopsies, as well as a tool for monitoring cancer progression in situ.

Atypical antipsychotic medications increase postprandial triglyceride and glucose levels in male rats: relationship with stearoyl-CoA desaturase activity.

PubMed

McNamara, Robert K; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Cole-Strauss, Allyson; Lipton, Jack W

2011-06-01

Recent preclinical and clinical evidence suggests that the stearoyl-CoA desaturase-1 (Scd1) enzyme plays a key role in the regulation of triglyceride (TG) biosynthesis and insulin sensitivity, and in vitro studies have found that antipsychotic medications up-regulate Scd1 mRNA expression. To investigate these effects in vivo, rats were treated with risperidone (1.5, 3, and 6mg/kg/d), paliperidone (1.5, 3, and 6mg/kg/d), olanzapine (2.5, 5, and 10mg/kg/d), quetiapine (5, 10, and 20mg/kg/d), haloperidol (1, and 3mg/kg/d) or vehicle through their drinking water for 40days. Effects on liver Scd1 mRNA expression and an index of Scd1 activity (the plasma 18:1/18:0 ratio, 'desaturation index') were determined, as were postprandial plasma triglyceride (TG), glucose, insulin, and polyunsaturated fatty acid (PUFA) levels. All atypical antipsychotics increased the plasma 18:1/18:0 ratio, but not liver Scd1 mRNA expression, at doses found to also increase plasma TG levels. Among all rats (n=122), the plasma 18:1/18:0 ratio accounted for 56% of the variance in TG concentrations. The plasma 18:1/18:0 ratio was also positively associated with erythrocyte and heart membrane phospholipid 18:1n-9 composition. All antipsychotics except risperidone increased glucose levels at specific doses, and none of the antipsychotics significantly altered insulin levels. The plasma 18:1/18:0 ratio accounted for 20% of the variance in glucose levels. Plasma omega-3 and omega-6 PUFA levels were inversely correlated with the plasma 18:1/18:0 ratio and TG and glucose levels. These in vivo data demonstrate that different atypical antipsychotic medications increase the plasma 18:1/18:0 ratio in association with elevations in postprandial TG and glucose levels, and that concomitant elevations in PUFA biosynthesis oppose these effects. Copyright © 2011 Elsevier B.V. All rights reserved.

Correlation of the association of serum lactate, random blood sugar, and revised trauma score as predictors of outcome in hemodynamically unstable abdominal emergencies.

PubMed

Allwell-Brown, E; Afuwape, O O; Ayandipo, O; Alonge, T

2016-01-01

Elevated levels of serum lactate and glucose during resuscitation have been demonstrated to be predictors of morbidity and mortality in hemodynamically unstable patients with surgical abdominal conditions. However, the rate of return to normal levels of both lactate and blood glucose may be better predictors of mortality and morbidity. The aims of this study are: (I) To determine the pattern of serum lactate and glucose changes in patients with surgical abdominal conditions requiring resuscitation within 48 hours of presentation. (II) To correlate the predictive capability of these two independent parameters. (III) To correlate the predictive values of these parameters with the revised trauma score (RTS). This is a prospective observational study conducted over three months. The patients admitted by the general surgery division requiring resuscitation from shock was included in this study. Resuscitation was carried out with crystalloids. The estimation of serum lactate and glucose levels was done at presentation (0 hours), 12, 24 and 48 hours after admission. The revised trauma score (RTS) was calculated for each patient at presentation and at 12, 24 and 48 hours subsequently. The patients were followed up four weeks or when death occurred within four weeks of presentation. Forty four patients were recruited in the study. There were seven mortalities. The mean serum levels of Plasma glucose and lactate of all the patients were elevated at presentation in the emergency department. Survival was better with a return to normal serum lactate within 12 hours. On the other hand the random plasma glucose (RPG) levels may not be useful in prognosticating patients. However a combination of serum lactate, RTS (at 24 and 48 hours) and RPG at 48 hours may improve predictive parameters in trauma related cases.

[Relationship between activity of fibrinolysis, parameters of lipid spectrum and carbohydrate metabolism].

PubMed

Ratnikova, L A; Metel'skaia, V A; Shal'nova, S A; Perova, N V; Deev, A D; Shkol'nikova, M A; Shkol'nikov, V M

2010-01-01

In this work analysis of results of a prospective populational cohort study "Stress and health in Russia" is presented. We included in the study inhabitants of Moscow randomly sampled from the population of men and women aged > or =55 years. Aim of the present work consisted in the study of relationship of activity of fibrinolysis and main parameters of the system of lipoproteines providing transport of lipids in blood serum and system controlling utilization of glucose by tissues. In dependence on fibrinolytic activity all examined persons were divided into 3 groups: with hypofibrinolysis (group 1, n=41.5%), with normofybrinolysis (group 2, n=41.9%), and hyperfibrinolysis (group 3, n=16.6%). In persons of group 1 low fibrinolytic activity and high level of fibrinogen were combined with atherogenic spectrum of blood serum lipids and elevated level of insulin at normal level of glucose. In patients of group 3 elevated fibrinolytic activity was combined with more favorable composition of blood lipids, lower levels of insulin and glucose and absence of obesity. At study of relation between fibrinoltic activity and a row of clinical states by the method of logistic regression a tendency to elevation of prevalence of myocardial infarction in persons with hypofibrinolysis was found while in persons with hyperfibrinolysis a significant lowering of prevalence of arterial hypertension, ischemic heart disease, and angina pectoris was observed.

Binge drinking and total alcohol consumption from 16 to 43 years of age are associated with elevated fasting plasma glucose in women: results from the northern Swedish cohort study.

PubMed

Nygren, Karina; Hammarström, Anne; Rolandsson, Olov

2017-06-08

Studies have indicated that moderate alcohol consumption is associated with lower incidence of diabetes in women. However, not only the amount but also the drinking pattern could be of importance when assessing the longitudinal relation between alcohol and glucose. Also, there is a lack of studies on alcohol use beginning in adolescence on adult glucose levels. The aim was to examine the association between total alcohol consumption and binge drinking between ages 16 and 43 and fasting plasma glucose at age 43. Data were retrieved from a 27-year prospective cohort study, the Northern Swedish Cohort. In 1981, all 9th grade students (n = 1083) within a municipality in Sweden were invited to participate. There were re-assessments at ages 18, 21, 30 and 43. This particular study sample consisted of 897 participants (82.8%). Fasting plasma glucose (mmol/L) was measured at a health examination at age 43. Total alcohol consumption (in grams) and binge drinking were calculated from alcohol consumption data obtained from questionnaires. Descriptive analyses showed that men had higher levels of fasting plasma glucose as compared to women. Men also reported higher levels of alcohol consumption and binge drinking behavior. Linear regressions showed that total alcohol consumption in combination with binge drinking between ages 16 and 43 was associated with elevated fasting plasma glucose at age 43 in women (beta = 0.14, p = 0.003) but not in men after adjustment for BMI, hypertension and smoking at age 43. Our findings indicate that reducing binge drinking and alcohol consumption among young and middle-aged women with the highest consumption might be metabolically favorable for their future glucose metabolism.

Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose.

PubMed

Maiello, M; Boeri, D; Podesta, F; Cagliero, E; Vichi, M; Odetti, P; Adezati, L; Lorenzi, M

1992-08-01

In diabetic patients, elevated plasma levels of t-PA and PAI-1 accompany impaired fibrinolysis. To identify mechanisms for these abnormalities, we examined whether vascular endothelial cells exposed to high glucose upregulate t-PA and PAI-1 production and whether ambient PA activity is decreased concomitantly. In 17 cultures of human umbilical vein endothelial cells grown to confluency in 30 mM glucose, the t-PA antigen released to the medium in 24 h was (median) 52 ng/10(6) cells (range 10-384) and the PAI-1 antigen was 872 ng/10(6) cells (range 217-2074)--both greater (P less than 0.02) than the amounts released by paired control cultures grown in 5 mM glucose--29 ng/10(6) cells (range 7.5-216) and 461 ng/10(6) cells (range 230-3215), respectively. In the presence of high glucose, the steady-state levels of t-PA and PAI-1 mRNAs were increased correspondingly (median 142 and 183% of control, respectively, P less than 0.05); high glucose per se and hypertonicity contributed to the upregulation in additive fashion. The PA activity of conditioned medium from cultures exposed to high glucose was 0.4 IU/ml (range 0.2-0.6), which was significantly lower (P less than 0.02) than the PA activity of control medium (0.5 IU/ml, range 0.2-0.9). No difference was observed when comparing the PA activities of acidified conditioned media, expected to be depleted of inhibitors. Thus, high glucose coordinately upregulates endothelial t-PA and PAI-1 expression through effects exerted at the pretranslational level and enhanced by even mild degrees of hypertonicity.(ABSTRACT TRUNCATED AT 250 WORDS)

[Puerariae Lobatae Radix elevated expression levels of OB-R, IRS2, GLUT1 and GLUT2 to regulate glucose metabolism in insulin-resistance HepG2 cells].

PubMed

Li, Yu; Luo, Xin-Xin; Yan, Feng-Dong; Wei, Zhang-Bin; Tu, Jun

2017-05-01

To observe the anti-hyperglycemic effect of Puerariae Lobatae Radix in hepatocyte insulin resistance(IR) models, and investigate its preliminary molecular mechanism. IR-HepG2 cell model was stably established with 1×10-9 mol•L⁻¹ insulin plus 3.75×10-6 mol•L-1 dexamethasone treatment for 48 h according to optimized protocol in our research group. After IR-HepG2 cells were treated with different concentrations(5%,10% and 15%) of Puerariae Lobatae Radix-containing serum, cell viability was detected by CCK-8 assay; the glucose consumptions in IR-HepG2 cells were separately detected at different time points (12, 15, 18, 21, 24, 30, 36 h) by using glucose oxidase method; intracellular glycogen content was detected by anthrone method; and the protein expression levels of leptin receptor (Ob-R), insulin receptor substrate-2 (IRS2), glucose transporter 1(GLUT1) and GLUT2 were detected by Western blot assay. The results showed that Puerariae Lobatae Radix-containing serum (5%, 10% and 15%) had no significant effect on IR-HepG2 cell viability; 5% and 10% Puerariae Lobatae Radix-containing serum significantly increased glucose consumption of IR-HepG2 cells (P<0.01) at 18, 21 and 24 h; 15% Puerariae Lobatae Radix-containing serum elevated the glucose consumption of IR-HepG2 cells at 15 h (P<0.05), and significantly elevated the glucose consumption at 18, 21, 24 and 30 h (P<0.01) in a dose-dependent manner. The optimized time of anti-hyperglycemic effect was defined as 24 h, and further study showed that Puerariae Lobatae Radix-containing serum could increase intracellular glycogen content after 24 h treatment (P<0.01), and up-regulate IRS2, Ob-R, GLUT1 and GLUT2 protein expression levels. Our results indicated that Puerariae Lobatae Radix-containing serum could achieve the anti-hyperglycemic effect through important PI3K/PDK signaling pathway partially by up-regulating the expression levels of Ob-R and IRS2, GLUT1 and GLUT2 in IR-HepG2 cells, accelerating the glucose transport into hepatocytes and increasing hepatic glycogen synthesis to enhance the anti-hyperglycemic effect of IR-HepG2 cells. Copyright© by the Chinese Pharmaceutical Association.

Flight is the key to postprandial blood glucose balance in the fruit bats Eonycteris spelaea and Cynopterus sphinx.

PubMed

Peng, Xingwen; He, Xiangyang; Liu, Qi; Sun, Yunxiao; Liu, Hui; Zhang, Qin; Liang, Jie; Peng, Zhen; Liu, Zhixiao; Zhang, Libiao

2017-11-01

Excessive sugar consumption could lead to high blood glucose levels that are harmful to mammalian health and life. Despite consuming large amounts of sugar-rich food, fruit bats have a longer lifespan, raising the question of how these bats overcome potential hyperglycemia. We investigated the change of blood glucose level in nectar-feeding bats ( Eonycteris spelaea ) and fruit-eating bats ( Cynopterus sphinx ) via adjusting their sugar intake and time of flight. We found that the maximum blood glucose level of C. sphinx was higher than 24 mmol/L that is considered to be pathological in other mammals. After C. sphinx bats spent approximately 75% of their time to fly, their blood glucose levels dropped markedly, and the blood glucose of E. spelaea fell to the fast levels after they spent 70% time of fly. Thus, the level of blood glucose elevated with the quantity of sugar intake but declined with the time of flight. Our results indicate that high-intensive flight is a key regulator for blood glucose homeostasis during foraging. High-intensive flight may confer benefits to the fruit bats in foraging success and behavioral interactions and increases the efficiency of pollen and seed disposal mediated by bats.

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

Transient elevation of glycolysis confers radio-resistance by facilitating DNA repair in cells.

PubMed

Bhatt, Anant Narayan; Chauhan, Ankit; Khanna, Suchit; Rai, Yogesh; Singh, Saurabh; Soni, Ravi; Kalra, Namita; Dwarakanath, Bilikere S

2015-05-01

Cancer cells exhibit increased glycolysis for ATP production (the Warburg effect) and macromolecular biosynthesis; it is also linked with therapeutic resistance that is generally associated with compromised respiratory metabolism. Molecular mechanisms underlying radio-resistance linked to elevated glycolysis remain incompletely understood. We stimulated glycolysis using mitochondrial respiratory modifiers (MRMs viz. di-nitro phenol, DNP; Photosan-3, PS3; Methylene blue, MB) in established human cell lines (HEK293, BMG-1 and OCT-1). Glucose utilization and lactate production, levels of glucose transporters and glycolytic enzymes were investigated as indices of glycolysis. Clonogenic survival, DNA repair and cytogenetic damage were studied as parameters of radiation response. MRMs induced the glycolysis by enhancing the levels of two important regulators of glucose metabolism GLUT-1 and HK-II and resulted in 2 fold increase in glucose consumption and lactate production. This increase in glycolysis resulted in resistance against radiation-induced cell death (clonogenic survival) in different cell lines at an absorbed dose of 5 Gy. Inhibition of glucose uptake and glycolysis (using fasentin, 2-deoxy-D-glucose and 3-bromopyruvate) in DNP treated cells failed to increase the clonogenic survival of irradiated cells, suggesting that radio-resistance linked to inhibition of mitochondrial respiration is glycolysis dependent. Elevated glycolysis also facilitated rejoining of radiation-induced DNA strand breaks by activating both non-homologous end joining (NHEJ) and homologous recombination (HR) pathways of DNA double strand break repair leading to a reduction in radiation-induced cytogenetic damage (micronuclei formation) in these cells. These findings suggest that enhanced glycolysis generally observed in cancer cells may be responsible for the radio-resistance, partly by enhancing the repair of DNA damage.

A multiscale, model-based analysis of the multi-tissue interplay underlying blood glucose regulation in type I diabetes.

PubMed

Wadehn, Federico; Schaller, Stephan; Eissing, Thomas; Krauss, Markus; Kupfer, Lars

2016-08-01

A multiscale model for blood glucose regulation in diabetes type I patients is constructed by integrating detailed metabolic network models for fat, liver and muscle cells into a whole body physiologically-based pharmacokinetic/pharmacodynamic (pBPK/PD) model. The blood glucose regulation PBPK/PD model simulates the distribution and metabolization of glucose, insulin and glucagon on an organ and whole body level. The genome-scale metabolic networks in contrast describe intracellular reactions. The developed multiscale model is fitted to insulin, glucagon and glucose measurements of a 48h clinical trial featuring 6 subjects and is subsequently used to simulate (in silico) the influence of geneknockouts and drug-induced enzyme inhibitions on whole body blood glucose levels. Simulations of diabetes associated gene knockouts and impaired cellular glucose metabolism, resulted in elevated whole body blood-glucose levels, but also in a metabolic shift within the cell's reaction network. Such multiscale models have the potential to be employed in the exploration of novel drug-targets or to be integrated into control algorithms for artificial pancreas systems.

An elevated gap between admission and A1C-derived average glucose levels is associated with adverse outcomes in diabetic patients with pyogenic liver abscess.

PubMed

Liao, Wen-I; Sheu, Wayne Huey-Herng; Chang, Wei-Chou; Hsu, Chin-Wang; Chen, Yu-Long; Tsai, Shih-Hung

2013-01-01

To assess whether chronic glycemic control and stress-induced hyperglycemia, determined by the gap between admission glucose levels and A1C-derived average glucose (ADAG) levels adversely affects outcomes in diabetic patients with pyogenic liver abscess (PLA). Clinical, laboratory, and multi-detector computed tomography (MDCT) findings of 329 PLA patients (2004-2010) were retrospectively reviewed. HbA1C levels were used to determine long-term glycemic control status, which were then converted to estimated average glucose values. For the gap between admission glucose levels and ADAG levels, we used receiver operating characteristic (ROC) curve to determine the optimal cut-off values predicting adverse outcomes. Univariate and multivariate logistic regressions were used to identify predictors of adverse outcomes. Diabetic PLA patients with poorer glycemic control had significantly higher Klebsiella pneumoniae (KP) infection rates, lower albumin levels, and longer hospital stays than those with suboptimal and good glycemic control. The ROC curve showed that a glycemic gap of 72 mg/dL was the optimal cut-off value for predicting adverse outcomes and showed a 22.3% relative increase in adverse outcomes compared with a glycemic gap<72 mg/dL. Multivariate analysis revealed that an elevated glycemic gap≥72 mg/dL was important predictor of adverse outcomes. A glycemic gap≥72 mg/dL, rather than admission hyperglycemia or chronic glycemic control, was significantly correlated with adverse outcomes in diabetic PLA patients. Poorer chronic glycemic control in diabetic PLA patients is associated with high incidence of KP infection, hypoalbuminemia and longer hospital stay.

Brain interstitial fluid TNF-α after subarachnoid hemorrhage

PubMed Central

Hanafy, Khalid A.; Grobelny, Bartosz; Fernandez, Luis; Kurtz, Pedro; Connolly, ES; Mayer, Stephan A.; Schindler, Christian; Badjatia, Neeraj

2010-01-01

Objective: TNF-α is an inflammatory cytokine that plays a central role in promoting the cascade of events leading to an inflammatory response. Recent studies have suggested that TNF-α may play a key role in the formation and rupture of cerebral aneurysms, and that the underlying cerebral inflammatory response is a major determinate of outcome following subrarachnoid hemorrhage (SAH). Methods: We studied 14 comatose SAH patients who underwent multimodality neuromonitoring with intracranial pressure (ICP) and cerebral microdialysis as part of their clinical care. Continuous physiological variables were time-locked every 8 hours and recorded at the same point that brain interstitial fluid TNF-α was measured in brain microdialysis samples. Significant associations were determined using generalized estimation equations. Results: Each patient had a mean of 9 brain tissue TNF-α measurements obtained over an average of 72 hours of monitoring. TNF-α levels rose progressively over time. Predictors of elevated brain interstitial TNF-α included higher brain interstitial fluid glucose levels (β=0.066, P<0.02), intraventricular hemorrhage (β=0.085, P<0.021), and aneurysm size >6 mm (β=0.14, p<0.001). There was no relationship between TNF-α levels and the burden of cisternal SAH; concurrent measurements of serum glucose, or lactate-pyruvate ratio. Interpretation: Brain interstitial TNF-α levels are elevated after SAH, and are associated with large aneurysm size, the burden of intraventricular blood, and elevation brain interstitial glucose levels. PMID:20110094

[Influence and mechanism of a tight control of blood glucose by intensive insulin therapy on human sepsis].

PubMed

Yu, Wen-kui; Li, Wei-qin; Wang, Xiao-dong; Yan, Xiao-wen; Qi, Xiao-ping; Li, Ning; Li, Jie-shou

2005-01-01

To investigate the effect of a tight control of blood glucose by intensive insulin therapy on human sepsis, and to explore the potential mechanism of the intensive insulin therapy. Eligible patients were randomized by a blinded pharmacist to receive tight control of blood glucose by intensive insulin therapy (maintenance of blood glucose at a level between 4.4 and 6.1 mmol/L) or to receive conventional treatment (maintenance of glucose at a level between 10.0 and 11.1 mmol/L). The expression of HLA-DR on peripheral monocytes was measured in 54 patients by flow cytometry on 24 h, 3 d, 5 d, 7 d, 10 d and 14 d of intensive care in parallel with serum c-reactive protein (CRP), severity of the disease (APACHE II score, SOFA score) and clinical data collection. Patients receiving intensive insulin therapy were less likely to require prolonged mechanical ventilation. Tight control of blood glucose significantly reduced the number of days during which leukopenia or leukocytosis and the days with hypo- or hyperthermia (P < 0.05). Hypoglycemia occurred in 3 patients (10.7%) in the tight control of blood glucose group. There were no instance of hemodynamic deterioration or convulsions. Compared with the conventional treatment, tight control of blood glucose also increased the HLA-DR expression of peripheral monocytes, and there were significantly difference on 3 d, 5 d and 7 d (P < 0.05). Whereas it suppressed the elevated serum CRP concentrations, there was significantly difference on 7 d (P < 0.05). Tight control of blood glucose by intensive insulin therapy expedited healing of human sepsis, and increased the HLA-DR expression of peripheral and suppressed the elevated serum CRP. So, it is necessary to use insulin to strict control the glucose levels in human sepsis.

Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.

PubMed

Jacobson, Peer B; von Geldern, Thomas W; Ohman, Lars; Osterland, Marie; Wang, Jiahong; Zinker, Bradley; Wilcox, Denise; Nguyen, Phong T; Mika, Amanda; Fung, Steven; Fey, Thomas; Goos-Nilsson, Annika; Grynfarb, Marlena; Barkhem, Tomas; Marsh, Kennan; Beno, David W A; Nga-Nguyen, Bach; Kym, Philip R; Link, James T; Tu, Noah; Edgerton, Dale S; Cherrington, Alan; Efendic, Suad; Lane, Benjamin C; Opgenorth, Terry J

2005-07-01

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.

Glucose-Sensing Receptor T1R3: A New Signaling Receptor Activated by Glucose in Pancreatic β-Cells.

PubMed

Kojima, Itaru; Nakagawa, Yuko; Hamano, Kunihisa; Medina, Johan; Li, Longfei; Nagasawa, Masahiro

2015-01-01

Subunits of the sweet taste receptors T1R2 and T1R3 are expressed in pancreatic β-cells. Compared with T1R3, mRNA expression of T1R2 is considerably lower. At the protein level, expression of T1R2 is undetectable in β-cells. Accordingly, a major component of the sweet taste-sensing receptor in β-cells may be a homodimer of T1R3 rather than a heterodimer of T1R2/T1R3. Inhibition of this receptor by gurmarin or deletion of the T1R3 gene attenuates glucose-induced insulin secretion from β-cells. Hence the T1R3 homodimer functions as a glucose-sensing receptor (GSR) in pancreatic β-cells. When GSR is activated by the T1R3 agonist sucralose, elevation of intracellular ATP concentration ([ATP]i) is observed. Sucralose increases [ATP]i even in the absence of ambient glucose, indicating that sucralose increases [ATP]i not simply by activating glucokinase, a rate-limiting enzyme in the glycolytic pathway. In addition, sucralose augments elevation of [ATP]i induced by methylsuccinate, suggesting that sucralose activates mitochondrial metabolism. Nonmetabolizable 3-O-methylglucose also increases [ATP]i and knockdown of T1R3 attenuates elevation of [ATP]i induced by high concentration of glucose. Collectively, these results indicate that the T1R3 homodimer functions as a GSR; this receptor is involved in glucose-induced insulin secretion by activating glucose metabolism probably in mitochondria.

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.

A Tele-Behavioral Health Intervention to Reduce Depression, Anxiety, and Stress and Improve Diabetes Self-Management.

PubMed

Mochari-Greenberger, Heidi; Vue, Lee; Luka, Andi; Peters, Aimee; Pande, Reena L

2016-08-01

Depression is prevalent among individuals with diabetes and associated with suboptimal self-management. Little is known about the feasibility and potential impact of tele-behavioral therapy to improve depressive symptoms and self-management among diabetes patients. This was a retrospective observational study of consecutive graduates enrolled in a national 8-week diabetes behavioral telehealth program between August 1, 2014, and January 31, 2015 (N = 466; mean age 56.8 ± 5.0 years; 56% female). Participant characteristics (demographics, comorbidities) were obtained by standardized questionnaire. Depression, anxiety, and stress symptoms (DASS; validated Depression Anxiety and Stress Scale 21 survey), and glucose self-testing frequency and values (point-of-care monitor) were measured at program start and completion. Changes in DASS severity and glucose self-testing frequency were assessed by chi-square tests. Changes in DASS and blood glucose levels were evaluated by paired t-tests. At baseline, approximately one in three participants had elevated depression (32%), anxiety (33%), or stress (31%) scores. Significant reductions in average DASS, depression (-8.8), anxiety (-6.9), and stress (-9.9), scores were observed at graduation among those with elevated baseline scores (p < 0.0001); most (≥80%) improved to less severe depression, anxiety, or stress categories. Improved glucose self-testing frequency (69% vs. 60% tested ≥once per week; p = 0.0005) and significant reductions in mean morning glucose levels (-12.3 mg/dL; p = 0.0002) were observed from baseline to graduation. Participants with normal versus non-normal depression scores were more likely to have lower (

Radiation from wireless technology elevates blood glucose and body temperature in 40-year-old type 1 diabetic male.

PubMed

Kleiber, Catherine E

2017-01-01

A type 1 diabetic male reports multiple instances when his blood glucose was dramatically elevated by the presence of microwave radiation from wireless technology and plummeted when the radiation exposure ended. In one instance, his body temperature elevated in addition to his blood glucose. Both remained elevated for nearly 48 h after exposure with the effect gradually decreasing. Possible mechanisms for microwave radiation elevating blood glucose include effects on glucose transport proteins and ion channels, insulin conformational changes and oxidative stress. Temperature elevation may be caused by microwave radiation-triggered Ca 2+ efflux, a mechanism similar to malignant hyperthermia. The potential for radiation from wireless technology to cause serious biological effects has important implications and necessitates a reevaluation of its near-ubiquitous presence, especially in hospitals and medical facilities.

Glucose Levels and Risk of Frailty.

PubMed

Zaslavsky, Oleg; Walker, Rod L; Crane, Paul K; Gray, Shelly L; Larson, Eric B

2016-09-01

The association between glucose levels and incident frailty in older persons remains unclear. We examined the extent to which higher glucose levels in older adults with and without diabetes are related to risk of frailty. The data are from the Adult Changes in Thought study. We identified 1,848 individuals aged 65+ without dementia for whom glucose levels from laboratory measurements of glucose and glycated hemoglobin were available. Physical frailty using modified Fried's criteria was determined from biennial assessments. Frailty hazard was modeled as a function of time-varying measures of diabetes and average glucose levels using Cox regression. A total of 578 incident frailty cases (94 with diabetes, 484 without) occurred during a median follow-up of 4.8 years. The adjusted hazard ratio for frailty comparing those with and without diabetes was 1.52 (95% confidence interval = 1.19-1.94). In participants without diabetes, modeling suggested elevated frailty risk with greater average glucose levels (p = .019); for example, a glucose level of 110mg/dL compared with 100mg/dL yielded a hazard ratio of 1.32 (95% confidence interval = 1.09-1.59). In participants with diabetes, glucose levels less than 160mg/dL and greater than 180mg/dL were related to increased risk of frailty (p = .001). Higher glucose levels may be a risk factor for frailty in older adults without diabetes. The apparent U-shape association between glucose levels and frailty in people with diabetes is consistent with the literature on glycemia and mortality and deserves further examination. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Interleukin-1β (IL-1β) increases pain behavior and the blood glucose level: possible involvement of sympathetic nervous system.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kang, Yu-Jung; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Suh, Hong-Won

2012-07-01

The relationship between interleukin-1β (IL-1β)-induced nociception and the blood glucose level was studied in ICR mice. We found in the present study that intrathecal (i.t.) injection of IL-1β increased pain behavior. In addition, i.t. IL-1β injection caused an elevation of the blood glucose level. The time-course study showed that maximal blood glucose level was observed 30 and 60 min after i.t. IL-1β administration. Furthermore, i.t. injection of IL-1β enhanced the blood glucose level when mice were orally fed with d-glucose. The i.t. administration of IL-1β antagonist (AF12198) inhibited the hyperglycemia and pain behaviors induced by IL-1β. We found in the present study that adrenal tyrosine hydroxylase (TH) mRNA level was also increased by i.t. IL-1β injection. Furthermore, intraperitoneal (i.p.) pretreatment with phentolamine (an α(1)-adrenergic blocker) or yohimbine (an α(2)-adrenergic blocker) significantly attenuated the blood glucose level and pain behavior induced by IL-1β administered i.t. However, the blood glucose level and pain behavior were not affected by butoxamine (a β(2)-adrenergic blocker), whereas metoprolol (a β(2)-adrenergic blocker) enhanced IL-1β-induced blood glucose level and pain behavior in mice fed with d-glucose. However, its effect was not statistically significant. Our results suggest that IL-1β administered i.t. increases the blood glucose level via an activation of α adrenergic nervous system. Copyright © 2012 Elsevier Inc. All rights reserved.

Hyperglycaemia does not affect antigen-specific activation and cytolytic killing by CD8+ T cells in vivo.

PubMed

Recino, Asha; Barkan, Kerry; Wong, F Susan; Ladds, Graham; Cooke, Anne; Wallberg, Maja

2017-08-31

Metabolism is of central importance for T cell survival and differentiation. It is well known that T cells cannot function in the absence of glucose, but it is less clear how they respond to excessive levels of glucose. In the present study, we investigated how increasing levels of glucose affect T-cell-mediated immune responses. We examined the effects of increased levels of glucose on CD8 + T-cell behaviour in vitro by assessing activation and cytokine production, as well as oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and intracellular signalling. In addition, we assessed in vivo proliferation, cytokine production and cytolytic activity of cells in chemically induced diabetic C57BL/6 mice. Elevated levels of glucose in in vitro cultures had modest effects on proliferation and cytokine production, while in vivo hyperglycaemia had no effect on CD8 + T-cell proliferation, interferon γ (IFNγ) production or cytolytic killing. © 2017 The Author(s).

Effect of pertussis toxin pretreated centrally on blood glucose level induced by stress.

PubMed

Suh, Hong-Won; Sim, Yun-Beom; Park, Soo-Hyun; Sharma, Naveen; Im, Hyun-Ju; Hong, Jae-Seung

2016-09-01

In the present study, we examined the effect of pertussis toxin (PTX) administered centrally in a variety of stress-induced blood glucose level. Mice were exposed to stress after the pretreatment of PTX (0.05 or 0.1 µg) i.c.v. or i.t. once for 6 days. Blood glucose level was measured at 0, 30, 60 and 120 min after stress stimulation. The blood glucose level was increased in all stress groups. The blood glucose level reached at maximum level after 30 min of stress stimulation and returned to a normal level after 2 h of stress stimulation in restraint stress, physical, and emotional stress groups. The blood glucose level induced by cold-water swimming stress was gradually increased up to 1 h and returned to the normal level. The intracerebroventricular (i.c.v.) or intrathecal (i.t.) pretreatment with PTX, a Gi inhibitor, alone produced a hypoglycemia and almost abolished the elevation of the blood level induced by stress stimulation. The central pretreatment with PTX caused a reduction of plasma insulin level, whereas plasma corticosterone level was further up-regulated in all stress models. Our results suggest that the hyperglycemia produced by physical stress, emotional stress, restraint stress, and the cold-water swimming stress appear to be mediated by activation of centrally located PTX-sensitive G proteins. The reduction of blood glucose level by PTX appears to due to the reduction of plasma insulin level. The reduction of blood glucose level by PTX was accompanied by the reduction of plasma insulin level. Plasma corticosterone level up-regulation by PTX in stress models may be due to a blood glucose homeostatic mechanism.

Glycogen Supercompensation in the Rat Brain After Acute Hypoglycemia is Independent of Glucose Levels During Recovery.

PubMed

Duarte, João M N; Morgenthaler, Florence D; Gruetter, Rolf

2017-06-01

Patients with diabetes display a progressive decay in the physiological counter-regulatory response to hypoglycemia, resulting in hypoglycemia unawareness. The mechanism through which the brain adapts to hypoglycemia may involve brain glycogen. We tested the hypothesis that brain glycogen supercompensation following hypoglycemia depends on blood glucose levels during recovery. Conscious rats were submitted to hypoglycemia of 2 mmol/L for 90 min and allowed to recover at different glycemia, controlled by means of i.v. glucose infusion. Brain glycogen concentration was elevated above control levels after 24 h of recovery in the cortex, hippocampus and striatum. This glycogen supercompensation was independent of blood glucose levels in the post-hypoglycemia period. In the absence of a preceding hypoglycemia insult, brain glycogen concentrations were unaltered after 24 h under hyperglycemia. In the hypothalamus, which controls peripheral glucose homeostasis, glycogen levels were unaltered. Overall, we conclude that post-hypoglycemia glycogen supercompensation occurs in several brain areas and its magnitude is independent of plasma glucose levels. By supporting brain metabolism during recurrent hypoglycemia periods, glycogen may have a role in the development of hypoglycemia unawareness.

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.

Hypoglycemic and hypolipidemic effects of Aronia melanocarpa fruit juice in streptozotocin-induced diabetic rats.

PubMed

Valcheva-Kuzmanova, S; Kuzmanov, K; Tancheva, S; Belcheva, A

2007-03-01

Aronia melanocarpa fruit juice (AMFJ) is rich in phenolic antioxidants, especially flavonoids from the anthocyanin subclass. The aim of the present study was to investigate the influence of AMFJ on plasma glucose and lipids in diabetic rats. Diabetes was induced by an intraperitoneal injection of streptozotocin (50 mg/kg). AMFJ was applied by gavage at doses of 10 and 20 ml/kg for 6 weeks to normal and diabetic rats. Streptozotocin caused a significant elevation of plasma glucose by 141% and of plasma triglycerides (TG) by 64% in comparison with normal control rats and induced statistically insignificant elevations of total cholesterol and LDL-cholesterol and a reduction of HDL-cholesterol. Applied to normal rats, AMFJ did not influence plasma glucose and lipid levels. Applied to diabetic rats, AMFJ (10 and 20 ml/kg) significantly reduced plasma glucose by 44% and 42% and TG by 35% and 39%, respectively, to levels that did not significantly differ from those of the normal control rats and counteracted the influence of streptozotocin on total cholesterol, LDL-cholesterol and HDL-cholesterol. In conclusion, AMFJ significantly decreased the streptozotocin-induced abnormalities in blood glucose and TG in diabetic rats and might be useful in prevention and control of diabetes mellitus and diabetes-associated complications. Copyright 2007 Prous Science.

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.

Anti-obesity and anti-diabetic effects of ethanol extract of Artemisia princeps in C57BL/6 mice fed a high-fat diet.

PubMed

Yamamoto, Norio; Kanemoto, Yuki; Ueda, Manabu; Kawasaki, Kengo; Fukuda, Itsuko; Ashida, Hitoshi

2011-01-01

Artemisia princeps is commonly used as a food ingredient and in traditional Asian medicine. In this study, we examined the effects of long-term administration of an ethanol extract of A. princeps (APE) on body weight, white adipose tissue, blood glucose, insulin, plasma and hepatic lipids, and adipocytokines in C57BL/6 mice fed a high-fat diet. Daily feeding of a 1% APE diet for 14 weeks normalized elevated body weight, white adipose tissue, and plasma glucose and insulin levels, and delayed impaired glucose tolerance in mice a fed high-fat diet. These events were not observed in mice fed a control diet containing 1% APE. Liver triglyceride and cholesterol levels were similar in mice fed a 1% APE-diet and those fed a control diet. In the high-fat diet groups, APE inhibited hepatic fatty acid synthase (FAS) and suppressed the elevation of plasma leptin, but had no effect on adiponectin levels. These findings suggest that the regulation of leptin secretion by APE may inhibit FAS activity with subsequent suppression of triglyceride accumulation in the liver and adipose tissues. Inhibition of lipid accumulation can, in turn, lead to improvements in impaired glucose tolerance.

Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes.

PubMed

Moran, A; Phillips, J; Milla, C

2001-10-01

Insulin and glucose levels in response to premeal insulin lispro or repaglinide were evaluated in adult patients with cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia. Seven patients with CFRD were fed 1,000-kcal liquid mixed meals. Three study conditions were administered in random order on separate mornings: 1) no premeal diabetes medication, 2) insulin lispro, 0.1 unit/kg body wt premeal and 3) repaglinide 1 mg premeal. Glucose and insulin levels were measured every 20 min for 5 h. Fasting insulin and glucose levels were normal in patients with CFRD, but the peak glucose level was elevated. Insulin lispro significantly decreased the peak glucose level (P = 0.0004) and the 2-h (P = 0.001) and 5-h (P < 0.0001) glucose area under the curve (AUC). Repaglinide significantly decreased the 5-h glucose AUC (P = 0.03). Neither drug completely normalized cystic fibrosis glucose excursion at the doses used for this study. Insulin lispro significantly increased the 5-h insulin AUC (P = 0.04). In response to subcutaneous insulin lispro, postprandial glucose excursion was significantly diminished and insulin secretion was enhanced compared with a control meal in which no medication was given to patients with CFRD. The oral agent repaglinide resulted in lesser corrections in these parameters. Neither drug completely normalized glucose or insulin levels, suggesting that the doses chosen for this study were suboptimal. Placebo-controlled longitudinal studies comparing the effectiveness of repaglinide and insulin on glucose metabolic control as well as overall nutrition and body weight are needed to help determine optimal medical treatment of CFRD.

Uteroplacental insufficiency after bilateral uterine artery ligation in the rat: impact on postnatal glucose and lipid metabolism and evidence for metabolic programming of the offspring by sham operation.

PubMed

Nüsken, Kai-Dietrich; Dötsch, Jörg; Rauh, Manfred; Rascher, Wolfgang; Schneider, Holm

2008-03-01

Ligation of the uterine arteries (LIG) in rats serves as a model of intrauterine growth restriction and subsequent developmental programming of impaired glucose tolerance, hyperinsulinemia, and adiposity in the offspring. Its impact on lipid metabolism has been less well investigated. We compared parameters of glucose and lipid metabolism and glucocorticoid levels in the offspring of dams that underwent either LIG or sham operation (SOP) with those of untreated controls. Blood parameters including insulin, leptin, and visfatin as well as body weight, food intake, and creatinine clearance were recorded up to an age of 30 wk. Glucose tolerance tests were performed, and both leptin and visfatin expression in liver, muscle, and epididymal and mesenteric fat was quantified by RT-PCR. After catch-up growth, weight gain of all groups was similar, despite lower food intake of the LIG rats. LIG offspring showed impaired glucose tolerance from the age of 15 wk as well as elevated glycosylated hemoglobin and corticosterone levels. However, the body fat content of both LIG and SOP animals increased relative to controls, and both showed elevated triglyceride, total cholesterol, and leptin levels as well as a reduced proportion of high-density lipoprotein cholesterol. Thus, use of the LIG model requires both SOP and untreated controls. Although only LIG is associated with impaired glucose tolerance, pathogenic programming of the lipid metabolism can also be induced by SOP. Visfatin does not appear to be involved in the disturbed glucose metabolism after intrauterine growth restriction and may represent only a marker of fat accumulation.

The antidiabetic action of camel milk in experimental type 2 diabetes mellitus: an overview on the changes in incretin hormones, insulin resistance, and inflammatory cytokines.

PubMed

Korish, A A

2014-06-01

Folk medicine stories accredited the aptitude of camel milk (CMK) as a hypoglycemic agent and recent studies have confirmed this in the diabetic patients and experimental animals. However, the mechanism(s) by which CMK influences glucose homeostasis is yet unclear. The current study investigated the changes in the glucose homeostatic parameters, the incretin hormones, and the inflammatory cytokines in the CMK-treated diabetic animals. A model of type 2 diabetes mellitus was induced in rats by intraperitoneal injection of streptozotocin 40 mg/kg/day for 4 repeated doses. Camel milk treatment was administered for 8 weeks. The changes in glucagon like peptide-1 (GLP-1), glucose dependent insulinotropic peptide (GIP), glucose tolerance, fasting and glucose-stimulated insulin secretion, insulin resistance (IR), TNF-α, TGF-β1, lipid profile, atherogenic index (AI), and body weight were investigated. The untreated diabetic animals showed hyperglycemia, increased HOMA-IR, hyperlipidemia, elevated AI, high serum incretins [GLP-1 and GIP], TNF-α, and TGF-β1 levels and weight loss as compared with the control group. Camel milk treatment to the diabetic animals resulted in significant lowered fasting glucose level, hypolipidemia, decreased HOMA-IR, recovery of insulin secretion, weight gain, and no mortality during the study. Additionally, CMK inhibits the diabetes-induced elevation in incretin hormones, TNF-α and TGF-β1 levels. The increase in glucose-stimulated insulin secretion, decreased HOMA-IR, modulation of the secretion and/or the action of incretins, and the anti-inflammatory effect are anticipated mechanisms to the antidiabetic effect of CMK and suggest it as a valuable adjuvant antidiabetic therapy. © Georg Thieme Verlag KG Stuttgart · New York.

[Metabolic changes associated with obesity in adults].

PubMed

Rincón, E; Ryder, E; Valbuena, H; García de Zambrano, N; Campos, G; Morales, L M; Semprún de Fereira, M; Wilhelm, I

1989-01-01

In order to find if the metabolic disorders more frequently found in our obese population were similar to the ones reported in the literature for other countries, a study was conducted in a group of 34 obese subjects (10 men and 24 women) whose only apparent alteration was a body mass index above 30 (mean value: 36.8 +/- 4.6) to obtain the relation between anthropometric measurements (Quetelet index, skinfold measures and waist/hip ratio) and plasma levels of nine biochemical parameters (including lipids, lipoproteins and glucose and insulin levels after an oral glucose load). The results revealed a tendency to the android distribution of fat in the female population, a significantly elevated triglyceride and total lipids levels and a decreased in HDL-cholesterol in both sexes. Hypercholesterolemia was present mainly in the male population. The most frequent dyslipidemia was Type IV (23%) followed by type IIb (15%). Practically none of the subjects had abnormal glycemic values after the glucose load, however the insulin levels were highly elevated in 80% of the patients, resulting in a great insulin/glucose ratios. Correlation analysis showed no association of the BMI with any biochemical parameter; only the insulin area was positively associated with anthropometric measures (mainly waist/hip ratio) and with the most altered biochemical parameter, the triglycerides. Variance analysis showed that only low HDL-cholesterol values were significantly different in patients presenting high blood pressure and familiar history of diabetes.

Effect of pertussis and cholera toxins administered supraspinally on CA3 hippocampal neuronal cell death and the blood glucose level induced by kainic acid in mice.

PubMed

Kim, Chea-Ha; Park, Soo-Hyun; Sim, Yun-Beom; Sharma, Naveen; Kim, Sung-Su; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

2014-12-01

The effect of cholera toxin (CTX) or pertussis toxin (PTX) administered supraspinally on hippocampal neuronal cell death in CA3 region induced by kainic acid (KA) was examined in mice. After the pretreatment with either PTX or CTX intracerebroventricularly (i.c.v.), mice were administered i.c.v. with KA. The i.c.v. treatment with KA caused a neuronal cell death in CA3 region and PTX, but not CTX, attenuated the KA-induced neuronal cell death. In addition, i.c.v. treatment with KA caused an elevation of the blood glucose level. The i.c.v. PTX pretreatment alone caused a hypoglycemia and inhibited KA-induced hyperglycemic effect. However, i.c.v. pretreatment with CTX did not affect the basal blood glucose level and KA-induced hyperglycemic effect. Moreover, KA administered i.c.v. caused an elevation of corticosterone level and reduction of the blood insulin level. Whereas, i.c.v. pretreatment with PTX further enhanced KA-induced up-regulation of corticosterone level. Furthermore, i.c.v. administration of PTX alone increased the insulin level and KA-induced hypoinsulinemic effect was reversed. In addition, PTX pretreatment reduces the KA-induced seizure activity. Our results suggest that supraspinally administered PTX, exerts neuroprotective effect against KA-induced neuronal cells death in CA3 region and neuroprotective effect of PTX is mediated by the reduction of KA-induced blood glucose level. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men.

PubMed

Riales, R; Albrink, M J

1981-12-01

Chromium deficiency may cause insulin resistance, hyperinsulinemia, impaired glucose tolerance, and hyperlipidemia, recovered by chromium supplementation. The effect of chromium supplementation on serum lipids and glucose tolerance was tested in a double-blind 12-wk study of 23 healthy adult men aged 31 to 60 yr. Either 200 micrograms trivalent chromium in 5 ml water (Cr) or 5 ml plain water (W) was ingested daily 5 days each week. Half the subjects volunteered for glucose tolerance tests with insulin levels. At 12 wk high-density lipoprotein cholesterol increased in the Cr group from 35 to 39 mg/dl (p less than 0.05) but did not change in the water group (34 mg/dl). The largest increase in high-density lipoprotein cholesterol and decreases in insulin and glucose were found in those subjects having normal glucose levels together with elevated insulin levels at base-line. The data are thus consistent with the hypothesis that Cr supplementation raises high-density lipoprotein cholesterol and improves insulin sensitivity in those with evidence of insulin resistance but normal glucose tolerance.

Elevated IGFBP3 levels in diabetic tears: a negative regulator of IGF-1 signaling in the corneal epithelium.

PubMed

Wu, Yu-Chieh; Buckner, Benjamin R; Zhu, Meifang; Cavanagh, H Dwight; Robertson, Danielle M

2012-04-01

To determine the ratio of IGFBP3:IGF-1 in normal and diabetic human tears, and in telomerase-immortalized human corneal epithelial cells (hTCEpi) cultured under elevated glucose conditions and to correlate these changes with total and phosphorylated levels of IGF-1R. Tear samples were collected noninvasively from diabetic subjects and non-diabetic controls; corneal sensitivity was assessed using a Cochet-Bonnet Aesthesiometer. Conditioned media were collected following culture of hTCEpi cells in normal (5 mM) and elevated (25 mM) glucose conditions; mannitol was used as an osmotic control. IGFBP3, IGF-1, and phosphorylated IGF-1R levels were assessed by ELISA. IGFBP3 and IGF-1R mRNA were assessed by real-time polymerase chain reaction (PCR). Total and phosphorylated IGF-1R expression in whole cell lysates was assessed by western blot. There was a 2.8-fold increase in IGFBP3 in diabetic tears compared to non-diabetic controls (P=0.006); IGF-1 levels were not significantly altered. No difference in corneal sensitivity was detected between groups. The concentration of IGFBP3 in tears was independent of IGF-1. Consistent with human tear measurements in vivo, IGFBP3 secretion was increased 2.2 fold (P<0.001) following culture of hTCEpi cells under elevated glucose conditions in vitro. Treatment with glucose and the mannitol control reduced IGFBP3 mRNA (P<0.001). Total IGF-1R levels were unchanged. The increase in the IGFBP3:IGF-1 ratio detected in diabetic tears compared to normal controls blocked phosphorylation of the IGF-1R by IGF-1 (P<0.001) when tested in vitro. Taken together, these in vivo and confirmatory in vitro findings suggest that the observed increase in IGFBP3 found in human tears may attenuate IGF-1R signaling in the diabetic cornea. A long-term increase in IGFBP3 may contribute to epithelial compromise and the pathogenesis of ocular surface complications reported in diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

Elevated IGFBP3 levels in diabetic tears: a negative regulator of IGF-1 signaling in the corneal epithelium

PubMed Central

Wu, Yu-Chieh; Buckner, Benjamin R.; Zhu, Meifang; Cavanagh, H. Dwight; Robertson, Danielle M.

2012-01-01

Purpose To determine the ratio of IGFBP3:IGF-1 in normal and diabetic human tears, and in telomerase-immortalized human corneal epithelial cells (hTCEpi) cultured under elevated glucose conditions and to correlate these changes with total and phosphorylated levels of IGF-1R. Methods Tear samples were collected noninvasively from diabetic subjects and non-diabetic controls; corneal sensitivity was assessed using a Cochet-Bonnet Aesthesiometer. Conditioned media were collected following culture of hTCEpi cells in normal (5 mM) and elevated (25 mM) glucose conditions; mannitol was used as an osmotic control. IGFBP3, IGF-1, and phosphorylated IGF-1R levels were assessed by ELISA. IGFBP3 and IGF-1R mRNA were assessed by real time polymerase chain reaction (PCR). Total and phosphorylated IGF-1R expression in whole cell lysates was assessed by western blot. Results There was a 2.8-fold increase in IGFBP3 in diabetic tears compared to non-diabetic controls (P=0.006); IGF-1 levels were not significantly altered. No difference in corneal sensitivity was detected between groups. The concentration of IGFBP3 in tears was independent of IGF-1. Consistent with human tear measurements in vivo, IGFBP3 secretion was increased 2.2 fold (P<0.001) following culture of hTCEpi cells under elevated glucose conditions in vitro. Treatment with glucose and the mannitol control reduced IGFBP3 mRNA (P<0.001). Total IGF-1R levels were unchanged. The increase in the IGFBP3:IGF-1 ratio detected in diabetic tears compared to normal controls blocked phosphorylation of the IGF-1R by IGF-1 (P<0.001) when tested in vitro. Conclusions Taken together, these in vivo and confirmatory in vitro findings suggest that the observed increase in IGFBP3 found in human tears may attenuate IGF-1R signaling in the diabetic cornea. A long-term increase in IGFBP3 may contribute to epithelial compromise and the pathogenesis of ocular surface complications reported in diabetes. PMID:22482470

Antidiabetic effect of Cinnamomum cassia and Cinnamomum zeylanicum in vivo and in vitro.

PubMed

Verspohl, Eugen J; Bauer, Katrin; Neddermann, Eckhard

2005-03-01

Rats were given Cinnamomum cassia bark or extracts from Cinnamomum cassia and zeylanicum to evaluate blood glucose and plasma insulin levels in rats under various conditions. The cassia extract was superior to the zeylanicum extract. The cassia extract was slightly more efficacious than the equivalent amount of Cassia bark. A decrease in blood glucose levels was observed in a glucose tolerance test (GTT), whereas it was not obvious in rats that were not challenged by a glucose load. The elevation in plasma insulin was direct since a stimulatory in vitro effect of insulin release from INS-1 cells (an insulin secreting cell line) was observed. Thus the cassia extract has a direct antidiabetic potency. Copyright 2005 John Wiley & Sons, Ltd.

The effects of glucose ingestion and glucose regulation on memory performance in older adults with mild cognitive impairment.

PubMed

Riby, L M; Marriott, A; Bullock, R; Hancock, J; Smallwood, J; McLaughlin, J

2009-04-01

Previous research investigating the impact of glucose ingestion and/or improvements in glucose regulation has found selective cognitive facilitation on episodic memory tasks in successful ageing and dementia. The present study aimed to extend this research to mild cognitive impairment (MCI). In a repeated-measures design, 24 older adults with and 24 older adults without MCI performed a battery of memory and attention tasks after 25 g of glucose or a sweetness matched placebo. In addition, to assess the impact of individual differences in glucose regulation, blood glucose measurements were taken throughout the testing session. Consistent with previous research, cognitive facilitation was observed for episodic memory tasks only in both successful ageing and MCI. Older adults with MCI had a similar glucose regulatory response as controls but their fasting levels were elevated. Notably, higher levels of blood glucose were associated with impaired memory performance in both the glucose and placebo conditions. Importantly, both blood glucose and memory performance indices were significant predictors of MCI status. The utility of glucose supplementation and the use of glucose regulation as a biological marker are discussed in relation to these data.

Lower extremity weakness is associated with elevated blood and cerebrospinal fluid glucose levels following multibranched endovascular aortic aneurysm repair.

PubMed

Hiramoto, Jade S; Fernandez, Charlene; Gasper, Warren; Vartanian, Shant; Reilly, Linda; Chuter, Timothy

2017-02-01

Hyperglycemia is associated with worsened clinical outcomes after central nervous system injury. The purpose of this study was to examine the association between lower extremity weakness (LEW) and the glucose levels of blood and cerebrospinal fluid (CSF) in patients undergoing multibranched endovascular aneurysm repair (MBEVAR) of thoracoabdominal and pararenal aortic aneurysms. Blood and CSF samples were collected preoperatively, immediately after aneurysm repair, and on postoperative day 1 in 21 patients undergoing MBEVAR. Data on demographics, operative repair, complications, and outcomes were collected prospectively. There were 21 patients who underwent successful MBEVAR. Two patients had pre-existing paraplegia from prior open aortic surgery and were excluded from the current analysis. The mean age was 73 ± 8 years, and 15 of 19 (79%) were men. In the postoperative period, 7 of 19 (37%) patients developed LEW. This was temporary in 5 of 19 (26%) patients and permanent in 2 of 19 (11%) patients. The LEW group was older than the non-LEW group (77 ± 6 vs 70 ± 9 years, respectively; P = .10), had a lower preoperative glomerular filtration rate (58.6 ± 18.5 vs 71.4 ± 23.5 mL/min per 1.73 m 2 ; P = .24), and was more likely to be taking a statin (100% vs 67%, respectively; P = .13), but these did not reach statistical significance. There was no significant difference in the prevalence of diabetes mellitus, hypertension, coronary artery disease, lung disease, or peripheral artery disease between the LEW and non-LEW groups. There was also no difference in operative time, blood loss, contrast material volume, or fluoroscopy times between the two groups. Preoperative blood and CSF glucose levels were similar in those with and without LEW. During the postoperative period, glucose values in the blood and CSF were significantly higher in those patients who developed LEW compared with those who did not develop LEW. In all patients with LEW, the elevation in the blood or CSF glucose level preceded the development of LEW. In a multivariable logistic regression model, CSF glucose concentration on postoperative day 1 was significantly and independently associated with the development of LEW (odds ratio, 2.30 [1.03-5.14] per 10 mg/dL increase in CSF glucose; P = .04). Elevated blood glucose and CSF glucose levels are associated with postoperative LEW in patients undergoing MBEVAR. The protective effect of euglycemia deserves further study in patients at risk for spinal cord ischemia. Copyright © 2016 Society for Vascular Surgery. All rights reserved.

Fluoride Alteration of [3H]Glucose Uptake in Wistar Rat Brain and Peripheral Tissues.

PubMed

Rogalska, Anna; Kuter, Katarzyna; Żelazko, Aleksandra; Głogowska-Gruszka, Anna; Świętochowska, Elżbieta; Nowak, Przemysław

2017-04-01

The present study was designed to investigate the role of postnatal fluoride intake on [3H]glucose uptake and transport in rat brain and peripheral tissues. Sodium fluoride (NaF) in a concentration of 10 or 50 ppm was added to the drinking water of adult Wistar rats. The control group received distilled water. After 4 weeks, respective plasma fluoride levels were 0.0541 ± 0.0135 μg/ml (control), 0.0596 ± 0.0202 μg/ml (10 ppm), and 0.0823 ± 0.0199 μg/ml (50 ppm). Although plasma glucose levels were not altered in any group, the plasma insulin level in the fluoride (50 ppm) group was elevated (0.72 ± 0.13 μg/ml) versus the control group (0.48 ± 0.24 μg/ml) and fluoride (10 ppm) group. In rats receiving fluoride for 4 weeks at 10 ppm in drinking water, [3H]glucose uptake was unaltered in all tested parts of the brain. However, in rats receiving fluoride at 50 ppm, [3H]glucose uptake in cerebral cortex, hippocampus, and thalamus with hypothalamus was elevated, versus the saline group. Fluoride intake had a negligible effect on [3H]glucose uptake by peripheral tissues (liver, pancreas, stomach, small intestine, atrium, aorta, kidney, visceral tissue, lung, skin, oral mucosa, tongue, salivary gland, incisor, molars, and jawbone). In neither fluoride group was glucose transporter proteins 1 (GLUT 1) or 3 (GLUT 3) altered in frontal cortex and striatum versus control. On the assumption that increased glucose uptake (by neural tissue) reasonably reflects neuronal activity, it appears that fluoride damage to the brain results in a compensatory increase in glucose uptake and utilization without changes in GLUT 1 and GLUT 3 expression.

Postnatal Pancreatic Islet β Cell Function and Insulin Sensitivity at Different Stages of Lifetime in Rats Born with Intrauterine Growth Retardation

PubMed Central

Liu, Cuiping; Xu, Kuanfeng; Mao, Xiaodong; Liu, Chao

2011-01-01

Epidemiological studies have linked intrauterine growth retardation (IUGR) to the metabolic diseases, consisting of insulin resistance, type 2 diabetes, obesity and coronary artery disease, during adult life. To determine the internal relationship between IUGR and islet β cell function and insulin sensitivity, we established the IUGR model by maternal nutrition restriction during mid- to late-gestation. Glucose tolerance test and insulin tolerance test(ITT) in vivo and glucose stimulated insulin secretion(GSIS) test in vitro were performed at different stages in IUGR and normal groups. Body weight, pancreas weight and pancreas/body weight of IUGR rats were much lower than those in normal group before 3 weeks of age. While the growth of IUGR rats accelerated after 3 weeks, pancreas weight and pancreas/body weight remained lower till 15 weeks of age. In the newborns, the fasting glucose and insulin levels of IUGR rats were both lower than those of controls, whereas glucose levels at 120 and 180 min after glucose load were significantly higher in IUGR group. Between 3 and 15 weeks of age, both the fasting glucose and insulin levels were elevated and the glucose tolerance was impaired with time in IUGR rats. At age 15 weeks, the area under curve of insulin(AUCi) after glucose load in IUGR rats elevated markedly. Meanwhile, the stimulating index of islets in IUGR group during GSIS test at age 15 weeks was significantly lower than that of controls. ITT showed no significant difference in two groups before 7 weeks of age. However, in 15-week-old IUGR rats, there was a markedly blunted glycemic response to insulin load compared with normal group. These findings demonstrate that IUGR rats had both impaired pancreatic development and deteriorated glucose tolerance and insulin sensitivity, which would be the internal causes why they were prone to develop type 2 diabetes. PMID:22022381

Fasting glucose, NT-proBNP, treatment with eptifibatide, and outcomes in non-ST-segment elevation acute coronary syndromes: An analysis from EARLY ACS.

PubMed

Farhan, Serdar; Clare, Robert M; Jarai, Rudolf; Giugliano, Robert P; Lokhnygina, Yuliya; Harrington, Robert A; Kristin Newby, L; Huber, Kurt

2017-04-01

Higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels have been linked to a more favorable glucometabolic profile. Little is known about the interaction of NT-proBNP and fasting glucose in non-ST-segment elevation acute coronary syndrome (NSTE ACS). Fasting glucose and NT-proBNP were measured in 2240 patients enrolled in the EARLY ACS trial. Multivariable Cox models were used to assess associations between fasting glucose and NT-proBNP and a 96-hour composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout; 30-day death or MI; and 1-year mortality. In adjusted Cox models, neither NT-proBNP nor fasting glucose was associated with the 96-hour endpoint (p=0.95 and p=0.87). NT-proBNP was associated with 30-day death or MI (hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.02-1.22, p=0.02) and 1-year mortality (HR 1.63, 95% CI 1.42-1.89, p<0.0001), but fasting glucose was associated only with 1-year death (HR 1.53, 95% CI 1.08-2.16, p=0.02). NT-proBNP×glucose interaction terms were non-significant in all models. As fasting glucose levels increased, the risk of 96-hour and 30-day endpoints increased among patients who received early eptifibatide but not delayed, provisional use (p int =0.035 and p int =0.029). Higher NT-proBNP levels were associated with greater 30-day death or MI among patients who received early eptifibatide but not delayed, provisional use (p int =0.045). NT-proBNP and fasting glucose concentrations were associated with intermediate-term ischemic outcomes and may identify differential response to treatment with eptifibatide. CLINICALTRIALS. NCT00089895. Copyright © 2017. Published by Elsevier B.V.

Pleocytosis is not fully responsible for low CSF glucose in meningitis.

PubMed

Baud, Maxime O; Vitt, Jeffrey R; Robbins, Nathaniel M; Wabl, Rafael; Wilson, Michael R; Chow, Felicia C; Gelfand, Jeffrey M; Josephson, S Andrew; Miller, Steve

2018-01-01

The mechanism of hypoglycorrhachia-low CSF glucose-in meningitis remains unknown. We sought to evaluate the relative contribution of CSF inflammation vs microorganisms (bacteria and fungi) in lowering CSF glucose levels. We retrospectively categorized CSF profiles into microbial and aseptic meningitis and analyzed CSF leukocyte count, glucose, and protein concentrations. We assessed the relationship between these markers using multivariate and stratified linear regression analysis for initial and repeated CSF sampling. We also calculated the receiver operating characteristics of CSF glucose and CSF-to-serum glucose ratios to presumptively diagnose microbial meningitis. We found that increasing levels of CSF inflammation were associated with decreased CSF glucose levels in the microbial but not aseptic category. Moreover, elevated CSF protein levels correlated more strongly than the leukocyte count with low CSF glucose levels on initial ( R 2 = 36%, p < 0.001) and repeated CSF sampling ( R 2 = 46%, p < 0.001). Hypoglycorrhachia (<40 mg/dL) was observed in 50.1% of microbial cases, but only 9.6% of aseptic cases, most of which were neurosarcoidosis. Absolute CSF glucose and CSF-to-serum glucose ratios had similar low sensitivity and moderate-to-high specificity in diagnosing microbial meningitis at thresholds commonly used. The main driver of hypoglycorrhachia appears to be a combination of microbial meningitis with moderate to high degrees of CSF inflammation and proteins, suggesting that the presence of microorganisms capable of catabolizing glucose is a determinant of hypoglycorrhachia in meningitis. A major notable exception is neurosarcoidosis. Low CSF glucose and CSF-to-serum glucose ratios are useful markers for the diagnosis of microbial meningitis.

Relationship between admission blood glucose level and prognosis in elderly patients without previously known diabetes who undergo emergency non-cardiac surgery.

PubMed

Ma, Jinling; He, Lei; Wang, Xiujie; Gao, Meng; Zhao, Yuexiang; Liu, Jie

2015-08-01

Elevated blood glucose levels on admission are important as a marker for adverse events in patients who undergo surgery. This study aims to evaluate the relationship between admission glucose level and adverse outcome during the 30-day follow-up period in elderly patients without previously known diabetes who undergo emergency non-cardiac surgery. The primary and secondary end points were all-cause and major adverse cardiac event (MACE) mortalities, respectively, during the 30-day postoperative follow-up period. Higher 30-day all-cause (24.1 %) and MACE (13.7 %) mortalities were observed in patients with an admission glucose ≥ 11.1 mmol/L than in patients with admission glucose <11.1 mmol/L (p < 0.001). Multivariate logistic regression analysis shows that an higher admission blood glucose level is an independent predictor for the development of the 30-day all-cause mortality [odds ratio (OR), 1.91; 95 % confidence interval (CI), 1.746-2.082; p < 0.001) and cardiac mortality (OR 1.97, 95 % CI 1.774-2.191; p < 0.001] after adjusting for age, gender, body mass index, comorbidities, and medication before admission. Kaplan-Meier event-free survival curves demonstrate that an admission blood glucose level ≥ 11.1 mmol/L has worse event-free survival than an admission blood glucose level <11.1 mmol/L.

Hyperglycemia and adverse pregnancy outcome study: neonatal glycemia.

PubMed

Metzger, Boyd E; Persson, Bengt; Lowe, Lynn P; Dyer, Alan R; Cruickshank, J Kennedy; Deerochanawong, Chaicharn; Halliday, Henry L; Hennis, Anselm J; Liley, Helen; Ng, Pak C; Coustan, Donald R; Hadden, David R; Hod, Moshe; Oats, Jeremy J N; Trimble, Elisabeth R

2010-12-01

The goal was to describe the temporal pattern of neonatal plasma glucose levels and associations with maternal glucose levels, cord serum C-peptide levels, and neonatal size and adiposity. A total of 17,094 mothers and infants were included in the Hyperglycemia and Adverse Pregnancy Outcome Study (15 centers in 9 countries). Mothers underwent a 75-g, 2-hour, oral glucose tolerance test (OGTT) at 24 to 32 weeks of gestation. Cord blood and neonatal blood samples were collected. Biochemical neonatal hypoglycemia was defined as glucose levels of <10th percentile (2.2 mmol/L). Clinically identified hypoglycemia was ascertained through medical record review and associations were assessed. Plasma glucose concentrations were stable during the first 5 hours after birth. Maternal glucose levels were weakly positively associated with biochemical neonatal hypoglycemia (odds ratios: 1.07-1.14 for 1-SD higher OGTT glucose levels). Frequency of neonatal hypoglycemia was higher with higher cord C-peptide levels (odds ratio: 11.6 for highest versus lowest C-peptide category). Larger and/or fatter infants were more likely to have hypoglycemia (P < .001), and infants with hypoglycemia tended to have a higher frequency of cord C-peptide levels of >90th percentile. Mean neonatal plasma glucose concentrations varied little in the first 5 hours after birth, which suggests normal postnatal adjustment. Biochemical and clinical hypoglycemia were weakly related to maternal OGTT glucose measurements but were strongly associated with elevated cord serum C-peptide levels. Larger and/or fatter infants were more likely to develop hypoglycemia and hyperinsulinemia. These relationships suggest physiologic relationships between maternal glycemia and fetal insulin production.

Blood glucose regulation mechanism in depressive disorder animal model during hyperglycemic states.

PubMed

Lim, Su-Min; Park, Soo-Hyun; Sharma, Naveen; Kim, Sung-Su; Lee, Jae-Ryeong; Jung, Jun-Sub; Suh, Hong-Won

2016-06-01

Depression is more common among diabetes people than in the general population. In the present study, blood glucose change in depression animal model was characterized by various types of hyperglycemia models such as d-glucose-fed-, immobilization stress-, and drug-induced hyperglycemia models. First, the ICR mice were enforced into chronic restraint stress for 2h daily for 2 weeks to produce depression animal model. The animals were fed with d-glucose (2g/kg), forced into restraint stress for 30min, or administered with clonidine (5μg/5μl) supraspinally or spinally to produce hyperglycemia. The blood glucose level in depression group was down-regulated compared to that observed in the normal group in d-glucose-fed-, restraint stress-, and clonidine-induced hyperglycemia models. The up-regulated corticosterone level induced by d-glucose feeding or restraint stress was reduced in the depression group while the up-regulation of plasma corticosterone level is further elevated after i.t. or i.c.v. clonidine administration in the depression group. The up-regulated insulin level induced by d-glucose feeding or restraint stress was reduced in the depression group. On the other hand, blood corticosterone level in depression group was up-regulated compared to the normal group after i.t. or i.c.v. clonidine administration. Whereas the insulin level in depression group was not altered when mice were administered clonidine i.t. or i.c.v. Our results suggest that the blood glucose level in depression group is down-regulated compared to the normal group during d-glucose-fed-, immobilization stress-, and clonidine-induced hyperglycemia in mice. The down-regulation of the blood glucose level might be one of the important pathophysiologic changes in depression. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Hyperosmolar sodium chloride is toxic to cultured neurons and causes reduction of glucose metabolism and ATP levels, an increase in glutamate uptake, and a reduction in cytosolic calcium.

PubMed

Morland, Cecilie; Pettersen, Mi Nguyen; Hassel, Bjørnar

2016-05-01

Elevation of serum sodium, hypernatremia, which may occur during dehydration or treatment with sodium chloride, may cause brain dysfunction and damage, but toxic mechanisms are poorly understood. We found that exposure to excess NaCl, 10-100mmol/L, for 20h caused cell death in cultured cerebellar granule cells (neurons). Toxicity was due to Na(+), since substituting excess Na(+) with choline reduced cell death to control levels, whereas gluconate instead of excess Cl(-) did not. Prior to cell death from hyperosmolar NaCl, glucose consumption and lactate formation were reduced, and intracellular aspartate levels were elevated, consistent with reduced glycolysis or glucose uptake. Concomitantly, the level of ATP became reduced. Pyruvate, 10mmol/L, reduced NaCl-induced cell death. The extracellular levels of glutamate, taurine, and GABA were concentration-dependently reduced by excess NaCl; high-affinity glutamate uptake increased. High extracellular [Na(+)] caused reduction in intracellular free [Ca(2+)], but a similar effect was seen with mannitol, which was not neurotoxic. We suggest that inhibition of glucose metabolism with ensuing loss of ATP is a neurotoxic mechanism of hyperosmolar sodium, whereas increased uptake of extracellular neuroactive amino acids and reduced intracellular [Ca(2+)] may, if they occur in vivo, contribute to the cerebral dysfunction and delirium described in hypernatremia. Copyright © 2016. Published by Elsevier B.V.

Uncovering the Path That Leads to Diabetes | Center for Cancer Research

Cancer.gov

The origins of diabetes have been the subject of intense scientific research, but the genetic factors that cause certain people to develop the disease have remained elusive. In healthy individuals, glucose levels in the bloodstream are transiently elevated after a meal. The increase in glucose triggers β cells in the pancreatic islet to release the hormone insulin. Insulin is

Urea loading enhances freezing survival and postfreeze recovery in a terrestrially hibernating frog.

PubMed

Costanzo, Jon P; Lee, Richard E

2008-09-01

We tested the hypothesis that urea, an osmolyte accumulated early in hibernation, functions as a cryoprotectant in the freeze-tolerant wood frog, Rana sylvatica. Relative to saline-treated, normouremic (10 micromol ml(-1)) frogs, individuals rendered hyperuremic (70 micromol ml(-1)) by administration of an aqueous urea solution exhibited significantly higher survival (100% versus 64%) following freezing at -4 degrees C, a potentially lethal temperature. Hyperuremic frogs also had lower plasma levels of intracellular proteins (lactate dehydrogenase, creatine kinase, hemoglobin), which presumably escaped from damaged cells, and more quickly recovered neurobehavioral functions following thawing. Experimental freezing-thawing did not alter tissue urea concentrations, but did elevate glucose levels in the blood and organs of all frogs. When measured 24 h after thawing commenced, glucose concentrations were markedly higher in urea-loaded frogs as compared to saline-treated ones, possibly because elevated urea retarded glucose clearance. Like other low-molecular-mass cryoprotectants, urea colligatively reduces both the amount of ice forming within the body and the osmotic dehydration of cells. In addition, by virtue of certain non-colligative properties, it may bestow additional protection from freeze-thaw damage not afforded by glucose.

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.

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.

Atypical Antipsychotic Medications Increase Postprandial Triglyceride and Glucose Levels in Male Rats: Relationship with Stearoyl-CoA Desaturase Activity

PubMed Central

McNamara, Robert K.; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Cole-Strauss, Allyson; Lipton, Jack W.

2011-01-01

Recent preclinical and clinical evidence suggests that the stearoyl-CoA desaturase-1 (Scd1) enzyme plays a key role in the regulation of triglyceride (TG) biosynthesis and insulin sensitivity, and in vitro studies have found that antipsychotic medications up-regulate Scd1 mRNA expression. To investigate these effects in vivo, rats were treated with risperidone (1.5, 3, 6 mg/kg/d), paliperidone (1.5, 3, 6 mg/kg/d), olanzapine (2.5, 5, 10 mg/kg/d), quetiapine (5, 10, 20 mg/kg/d), haloperidol (1, 3 mg/kg/d) or vehicle through their drinking water for 40 d. Effects on liver Scd1 mRNA expression and an index of Scd1 activity (the plasma 18:1/18:0 ratio, ‘deaturation index’) were determined, as were postprandial plasma triglyceride (TG), glucose, insulin, and polyunsaturated fatty acid (PUFA) levels. All atypical antipsychotics increased the plasma 18:1/18:0 ratio, but not liver Scd1 mRNA expression, at doses found to also increase plasma TG levels. Among all rats (n=122), the plasma 18:1/18:0 ratio accounted for 56% of the variance in TG concentrations. The plasma 18:1/18:0 ratio was also positively associated with erythrocyte and heart membrane phospholipid 18:1n-9 composition. All antipsychotics except risperidone increased glucose levels at specific doses, and none of the antipsychotics significantly altered insulin levels. The plasma 18:1/18:0 ratio accounted for 20% of the variance in glucose levels. Plasma omega-3 and omega-6 PUFA levels were inversely correlated with the plasma 18:1/18:0 ratio and TG and glucose levels. These in vivo data demonstrate that different atypical antipsychotic medications increase the plasma 18:1/18:0 ratio in association with elevations in postprandial TG levels, and that concomitant elevations in PUFA biosynthesis oppose these effects. PMID:21474290

Thymoquinone, a bioactive component of Nigella sativa, normalizes insulin secretion from pancreatic β-cells under glucose overload via regulation of malonyl-CoA

PubMed Central

Gray, Joshua P.; Zayasbazan Burgos, Delaine; Yuan, Tao; Seeram, Navindra; Rebar, Rebecca; Follmer, Rebecca

2015-01-01

Thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) is a major bioactive component of Nigella sativa, a plant used in traditional medicine to treat a variety of symptoms, including elevated blood glucose levels in type 2 diabetic patients. Normalization of elevated blood glucose depends on both glucose disposal by peripheral tissues and glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. We employed clonal β-cells and rodent islets to investigate the effects of thymoquinone (TQ) and Nigella sativa extracts (NSEs) on GSIS and cataplerotic metabolic pathways implicated in the regulation of GSIS. TQ and NSE regulated NAD(P)H/NAD(P)+ ratios via a quinone-dependent redox cycling mechanism. TQ content was positively correlated with the degree of redox cycling activity of NSE extracts, suggesting that TQ is a major component engaged in mediating NSE-dependent redox cycling. Both acute and chronic exposure to TQ and NSE enhanced GSIS and were associated with the ability of TQ and NSE to increase the ATP/ADP ratio. Furthermore, TQ ameliorated the impairment of GSIS following chronic exposure of β-cells to glucose overload. This protective action was associated with the TQ-dependent normalization of chronic accumulation of malonyl-CoA, elevation of acetyl-CoA carboxylase (ACC), fatty acid synthase, and fatty acid-binding proteins following chronic glucose overload. Together, these data suggest that TQ modulates the β-cell redox circuitry and enhances the sensitivity of β-cell metabolic pathways to glucose and GSIS under normal conditions as well as under hyperglycemia. This action is associated with the ability of TQ to regulate carbohydrate-to-lipid flux via downregulation of ACC and malonyl-CoA. PMID:26786775

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.

Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease.

PubMed

Varbo, Anette; Benn, Marianne; Smith, George Davey; Timpson, Nicholas J; Tybjaerg-Hansen, Anne; Nordestgaard, Børge G

2015-02-13

Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se. To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein. Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively. The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss. © 2014 American Heart Association, Inc.

Effects of organophosphorus anticholinesterase compounds on brain glucose and energy metabolism. Annual summary report, 1 October 1982-29 February 1984

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

Medina, M.A.; Miller, A.L.

1984-09-01

The effects of paraoxon and Soman on glucose utilization and of Soman on the levels of intermediary metabolites were investigated in rat brain. The rate of glucose utilization and the levels of intermediary metabolites were determined in six brain areas at varying time periods after administration of 0.5 or 0.8 of the paraoxon or Soman LD50. Behavioral changes were observed only with the 0.8 LD50 dose of both compounds and some of the animals exhibited convulsive activity with this dose of Soman. Brain glucose utilization tended to be decreased by 0.8 LD50 paraoxon and 0.5 LD50 Soman. Some alterations inmore » metabolite levels were observed but these were not consistent and could not be correlated with the rate of glucose utilization. In animals with Soman-induced convulsions, glucose utilization and lactate levels were elevated only in the cortex and thalamus/basal ganglia. ATP, creatine phosphate and glucose levels were decreased in the cortex but not in other brain areas, suggesting the possibility of uncoupling of oxidative phosphorylation. Pretreatment with atropine prevented the behavioral responses and the changes in glucose utilization previously observed with 0.8 Soman LD50. Our results in convulsing animals are similar to those which have been observed with the excitatorytoxins kainic acid and bicuculline.« less

Effects of hydrogen sulfide on high glucose-induced glomerular podocyte injury in mice

PubMed Central

Liu, Ye; Zhao, Huichen; Qiang, Ye; Qian, Guanfang; Lu, Shengxia; Chen, Jicui; Wang, Xiangdong; Guan, Qingbo; Liu, Yuantao; Fu, Yuqin

2015-01-01

The aim of this study was to assess the effects of hydrogen sulfide on high glucose-induced mouse podocyte (MPC) injury and the underlying mechanisms. Mouse podocytes were randomly divided into 4 groups, including high glucose (HG), normal glucose (NG), normal glucose + DL-propargylglycine (PPG), and high glucose + NaHS (HG + NaHS) groups for treatment. Then, ZO-2, nephrin, β-catenin, and cystathionine γ-lyase (CSE) protein expression levels were determined by western blot. We found that high glucose significantly reduced nephrin, ZO-2, and CSE expression levels (P<0.05), and overtly elevated β-catenin amounts (P<0.05), in a time-dependent manner. Likewise, PPG at different concentrations in normal glucose resulted in significantly lower CSE, ZO-2, and nephrin levels (P<0.05), and increased β-catenin amounts (P<0.05). Interestingly, significantly increased ZO-2 and nephrin levels, and overtly reduced β-catenin amounts were observed in the HG + NaHS group compared with HG treated cells (P<0.01). Compared with NG treated cells, decreased ZO-2 and nephrin levels and higher β-catenin amounts were obtained in the HG + NaHS group. In conclusion,CSE downregulation contributes to hyperglycemia induced podocyte injury, which is alleviated by exogenous H2S possibly through ZO-2 upregulation and the subsequent suppression of Wnt/β-catenin pathway. PMID:26261567

Bats: Body mass index, forearm mass index, blood glucose levels and SLC2A2 genes for diabetes

PubMed Central

Meng, Fanxing; Zhu, Lei; Huang, Wenjie; Irwin, David M.; Zhang, Shuyi

2016-01-01

Bats have an unusually large volume of endocrine tissue, with a large population of beta cells, and an elevated sensitivity to glucose and insulin. This makes them excellent animal models for studying diabetes mellitus. We evaluated bats as models for diabetes in terms of lifestyle and genetic factors. For lifestyle factors, we generated data sets of 149 body mass index (BMI) and 860 forearm mass index (FMI) measurements for different species of bats. Both showed negative inter-species correlations with blood glucose levels in sixteen bats examined. The negative inter-species correlations may reflect adaptation of a small insectivorous ancestor to a larger frugivore. We identified an 11 bp deletion in the proximal promoter of SLC2A2 that we predicted would disrupt binding sites for the transcription repressor ZNF354C. In frugivorous bats this could explain the relatively high expression of this gene, resulting in a better capacity to absorb glucose and decrease blood glucose levels. PMID:27439361

Resveratrol prevents insulin resistance caused by short-term elevation of free fatty acids in vivo.

PubMed

Pereira, Sandra; Park, Edward; Moore, Jessy; Faubert, Brandon; Breen, Danna M; Oprescu, Andrei I; Nahle, Ashraf; Kwan, Denise; Giacca, Adria; Tsiani, Evangelia

2015-11-01

Elevated levels of plasma free fatty acids (FFA), which are commonly found in obesity, induce insulin resistance. FFA activate protein kinases including the proinflammatory IκBα kinase β (IKKβ), leading to serine phosphorylation of insulin receptor substrate 1 (IRS-1) and impaired insulin signaling. To test whether resveratrol, a polyphenol found in red wine, prevents FFA-induced insulin resistance, we used a hyperinsulinemic-euglycemic clamp with a tracer to assess hepatic and peripheral insulin sensitivity in overnight-fasted Wistar rats infused for 7 h with saline, Intralipid plus 20 U·mL(-1) heparin (IH; triglyceride emulsion that elevates FFA levels in vivo; 5.5 μL·min(-1)) with or without resveratrol (3 mg·kg(-1)·h(-1)), or resveratrol alone. Infusion of IH significantly decreased glucose infusion rate (GIR; P < 0.05) and peripheral glucose utilization (P < 0.05) and increased endogenous glucose production (EGP; P < 0.05) during the clamp compared with saline infusion. Resveratrol co-infusion, however, completely prevented the effects induced by IH infusion: it prevented the decreases in GIR (P < 0.05 vs. IH), peripheral glucose utilization (P < 0.05 vs. IH), and insulin-induced suppression of EGP (P < 0.05 vs. IH). Resveratrol alone had no effect. Furthermore, IH infusion increased serine (307) phosphorylation of IRS-1 in soleus muscle (∼30-fold, P < 0.001), decreased total IRS-1 levels, and decreased IκBα content, consistent with activation of IKKβ. Importantly, all of these effects were abolished by resveratrol (P < 0.05 vs. IH). These results suggest that resveratrol prevents FFA-induced hepatic and peripheral insulin resistance and, therefore, may help mitigate the health consequences of obesity.

Caffeic acid as active principle from the fruit of Xanthium strumarium to lower plasma glucose in diabetic rats.

PubMed

Hsu, F L; Chen, Y C; Cheng, J T

2000-04-01

The antihyperglycemic effect of caffeic acid, one of the phenolic compounds contained in the fruit of Xanthium strumarium, was investigated. After an intravenous injection of caffeic acid into diabetic rats of both streptozotocin-induced and insulin-resistant models, a dose-dependent decrease of plasma glucose was observed. However, a similar effect was not produced in normal rats. An insulin-independent action of caffeic acid can thus be considered. Otherwise, this compound reduced the elevation of plasma glucose level in insulin-resistant rats receiving a glucose challenge test. Also, glucose uptake into the isolated adipocytes was raised by caffeic acid in a concentration-dependent manner. Increase of glucose utilization by caffeic acid seems to be responsible for the lowering of plasma glucose.

Interleukin-1β (IL-1β) increases pain behavior and the blood glucose level: possible involvement of glucocorticoid system.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kang, Yu-Jung; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Choi, Seong-Soo; Suh, Hong-Won

2013-10-01

The possible involvement of glucocorticoid system in interleukin-1β (IL-1β)-induced nociception and the blood glucose level was studied in ICR mice. In the first experiment, mice were treated intrathecally (i.t.) with IL-1β (100 pg). Corticotrophin releasing hormone (CRH) mRNA (hypothalamus) and c-Fos mRNA (pituitary gland, spinal cord, and the adrenal gland) levels were measured at 30, 60 and 120 min after IL-1β administration. We found that i.t. injection with IL-1β increased CRH mRNA level in the hypothalamus. The IL-1β administered i.t. elevated c-Fos mRNA levels in the spinal cord, pituitary and adrenal glands. Furthermore, i.t. administration of IL-1β significantly increased the plasma corticosterone level up to 60 min. In addition, the adrenalectomy caused the reductions of the blood glucose level and pain behavior induced by IL-1β injected i.t. in normal and D-glucose-fed groups. Furthermore, intraperitoneal (i.p.) pretreatment with RU486 (100mg/kg) attenuated the blood glucose level and pain behavior induced by IL-1β administered i.t. in normal and D-glucose-fed groups. Our results suggest that IL-1β administered i.t. increases the blood glucose level and pain behavior via an activation of the glucocorticoid system. Copyright © 2013 Elsevier Ltd. All rights reserved.

Characterization of the physiological stress response in lingcod

USGS Publications Warehouse

Milston, R.H.; Davis, M.W.; Parker, S.J.; Olla, B.L.; Clements, S.; Schreck, C.B.

2006-01-01

The goal of this study was to describe the duration and magnitude of the physiological stress response in lingcod Ophiodon elongatus after exposure to brief handling and sublethal air stressors. The response to these stressors was determined during a 24-h recovery period by measuring concentrations of plasma cortisol, lactate, glucose, sodium, and potassium. Lingcod were subjected to brief handling followed by either a 15-min or a 45-min air stressor in the laboratory. After the 15-min stressor, an increase in cortisol or glucose could not be detected until after 5 min of recovery. Peak concentrations were measured after 30 min for cortisol and after 60 min for glucose and lactate. Glucose and lactate had returned to basal levels after 12 h, whereas cortisol did not return to basal levels until after 24 h of recovery. Immediately following a 45-min air stressor, all measured parameters were significantly elevated over levels in prestressor control fish. Cortisol concentrations tended to increase and reached a measured peak after 8 h of recovery, whereas glucose and lactate reached a measured peak after 1 h of recovery. Cortisol and lactate returned to basal levels within 24 h. Glucose, however, remained elevated even after 24 h of recovery. Plasma ions initially increased during the first hour of recovery, and the concentrations then declined to a level below that measured in control fish for the remainder of the 24-h recovery period. In addition, we evaluated the effect of fish size on the stress response. There was no significant difference between the stress response of smaller (41-49-cm [total length] and larger (50-67-cm) lingcod after 45 min air exposure. In general, both the magnitude and duration of the primary and secondary stress responses in lingcod are comparable to those of salmonids. ?? Copyright by the American Fisheries Society 2006.

Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women.

PubMed

Hwang, Janice J; Johnson, Andrea; Cline, Gary; Belfort-DeAguiar, Renata; Snegovskikh, Denis; Khokhar, Babar; Han, Christina S; Sherwin, Robert S

2015-01-01

Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000 th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose → sorbitol → fructose) contributes to brain exposure to fructose. In this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF), maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM) undergoing spinal anesthesia and elective cesarean section. As expected, CSF glucose was ~ 60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001), and CSF sorbitol was ~ 9-times higher than plasma levels (p < 0.001). Moreover, CSF fructose correlated positively with CSF glucose (ρ 0.45, p = 0.02) and sorbitol levels (ρ 0.75, p < 0.001). Cord blood sorbitol was also ~ 7-fold higher than maternal plasma sorbitol levels (p = 0.001). There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups. These data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption.

Efficacy of a church-based lifestyle intervention programme to control high normal blood pressure and/or high normal blood glucose in church members: a randomized controlled trial in Pretoria, South Africa.

PubMed

Pengpid, Supa; Peltzer, Karl; Skaal, Linda

2014-06-06

In persons 15 years and above in South Africa the prevalence of pre-diabetes and diabetes has been estimated at 9.1% and 9.6%, respectively, and the prevalence of systolic prehypertension and hypertension, 38.2% and 24.6%, respectively. Elevated blood glucose and elevated blood pressure are prototype of preventable chronic cardiovascular disease risk factors.Lifestyle interventions have been shown to control high normal blood pressure and/or high normal blood glucose. This study proposes to evaluate the efficacy of a community (church)-based lifestyle intervention programme to control high normal blood pressure and/or high normal blood glucose in church members in a randomized controlled trial in Gauteng, South Africa. The objectives are to: (1) measure non-communicable diseases profile, including hypertension and diabetes, health behaviours, weight management and psychological distress of church members; (2) measure the reduction of blood glucose and blood pressure levels after the intervention; (3) prevent the development of impaired glucose tolerance; (4) compare health behaviours, weight management and psychological distress, blood glucose and blood pressure levels between intervention and control groups, and within group during 6, 12, 24 and 36 months during and post intervention. The study will use a group-randomized design, recruiting 300 church members from 12 churches. Churches will be randomly assigned to experimental and control conditions. Lifestyle interventions may prevent from the development of high blood pressure and/or diabetes. The findings will impact public health and will enable the health ministry to formulate policy related to lifestyle interventions to control blood pressure and glucose. PACTR201105000297151.

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.

Oral Lactobacillus reuteri GMN-32 treatment reduces blood glucose concentrations and promotes cardiac function in rats with streptozotocin-induced diabetes mellitus.

PubMed

Lin, Chih-Hsueh; Lin, Cheng-Chieh; Shibu, Marthandam Asokan; Liu, Chiu-Shong; Kuo, Chia-Hua; Tsai, Fuu-Jen; Tsai, Chang-Hai; Hsieh, Cheng-Hong; Chen, Yi-Hsing; Huang, Chih-Yang

2014-02-01

Impaired regulation of blood glucose levels in diabetes mellitus (DM) patients and the associated elevation of blood glucose levels are known to increase the risk of diabetic cardiomyopathy (DC). In the present study, a probiotic bacterium, Lactobacillus reuteri GMN-32, was evaluated for its potential to reduce blood glucose levels and to provide protection against DC risks in streptozotocin (STZ)-induced DM rats. The blood glucose levels of the STZ-induced DM rats when treated with L. reuteri GMN-32 decreased from 4480 to 3620 mg/l (with 10⁷ colony-forming units (cfu)/d) and 3040 mg/l (with 10⁹ cfu/d). Probiotic treatment also reduced the changes in the heart caused by the effects of DM. Furthermore, the Fas/Fas-associated protein with death domain pathway-induced caspase 8-mediated apoptosis that was observed in the cardiomyocytes of the STZ-induced DM rats was also found to be controlled in the probiotic-treated rats. The results highlight that L. reuteri GMN-32 treatment reduces blood glucose levels, inhibits caspase 8-mediated apoptosis and promotes cardiac function in DM rats as observed from their ejection fraction and fractional shortening values. In conclusion, the administration of L. reuteri GMN-32 probiotics can regulate blood glucose levels, protect cardiomyocytes and prevent DC in DM rats.

Impaired glucose tolerance in patients with amyotrophic lateral sclerosis.

PubMed

Pradat, Pierre-Francois; Bruneteau, Gaelle; Gordon, Paul H; Dupuis, Luc; Bonnefont-Rousselot, Dominique; Simon, Dominique; Salachas, Francois; Corcia, Philippe; Frochot, Vincent; Lacorte, Jean-Marc; Jardel, Claude; Coussieu, Christiane; Le Forestier, Nadine; Lacomblez, Lucette; Loeffler, Jean-Philippe; Meininger, Vincent

2010-01-01

Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine potential association with parameters of lipid metabolism and clinical features. Glucose tolerance was assessed by the oral glucose tolerance test in 21 non-diabetic ALS patients and compared with 21 age- and sex-matched normal subjects. Lipids and lactate/pyruvate ratio, levels of pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and adipocytokines (leptin and adiponectin) were also measured in ALS patients. Mann-Whitney U-tests analysed continuous data and Fisher's exact tests assessed categorical data. Blood glucose determined 120 min after the glucose bolus was significantly higher in patients with ALS (7.41 mmol/l+/-1.68) compared to controls (6.05+/-1.44, p=0.006). ALS patients with impaired glucose tolerance (IGT) according to WHO criteria (n=7, 33%) were more likely to have elevated free fatty acids (FFA) levels compared to patients with normal glucose tolerance (0.77 nmol/l+/-0.30 vs. 0.57+/-0.19, p=0.04). IGT was not associated with disease duration or severity. In conclusion, patients with ALS show abnormal glucose tolerance that could be associated with increased FFA levels, a key determinant of insulin resistance. The origin of glucose homeostasis abnormalities in ALS may be multifactorial and deserves further investigation.

The effect of prolactin levels on MPV in women with PCOS.

PubMed

Yilmaz, Özgür; Calan, Mehmet; Kume, Tuncay; Temur, Muzaffer; Yesil, Pınar; Senses, Mehmet Y

2015-05-01

Polycystic ovary syndrome (PCOS) is associated with cardiovascular risk factors including hypertension, obesity, hyperlipidaemia and glucose intolerance. Several studies demonstrated the link between PCOS and an increased risk of cardiovascular disease. Platelets play a crucial role in the development of atherothrombotic disease. Mean platelet volume (MPV) is a marker of platelet size that reflects its activity. Research points to a link between prolactin (PRL) and platelet activation. The purpose of this study was to investigate whether prolactin levels are associated with MPV in women with PCOS. The research was designed as a cross-sectional study. Participants were divided into three groups-PCOS patients with mildly elevated PRL levels (n = 72), patients with PCOS with normal PRL levels (n = 207) and healthy controls (n = 90). They were body mass index and age-matched and consecutively recruited. Complete blood counts, serum glucose, prolactin, insulin, lipids, high-sensitivity C-reactive protein and free-testosterone levels were measured. Among the three groups, MPV levels were higher in women with PCOS having mildly elevated PRL levels (P < 0·001) and MPV was found to be correlated with PRL levels (r = 0·387, P < 0·001). Multiple regression analysis showed that PRL levels were associated with MPV levels (R(2) = 0·239, β = 0·354, P < 0·001). Mean platelet volume levels are significantly increased in women with PCOS having mildly elevated PRL. Our results suggest that there is a link between prolactin and MPV levels. In women with PCOS, elevated PRL levels may increase the risk of developing atherothrombotic events via the activation of platelets. © 2014 John Wiley & Sons Ltd.

Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions.

PubMed

Connolly, Niamh M C; D'Orsi, Beatrice; Monsefi, Naser; Huber, Heinrich J; Prehn, Jochen H M

2016-01-01

Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK), re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity. The model further correctly predicted an excitotoxicity-induced elevation of intracellular glucose, and well resembled the delayed recovery and cell-to-cell heterogeneity of experimentally measured glucose dynamics. The model also predicted necrotic bioenergetic collapse and altered calcium dynamics following more severe excitotoxic insults. In conclusion, our data suggest that a minimal set of critical reactions may determine the acute bioenergetic response to transient excitotoxicity and that an AMPK-mediated increase in intracellular glucose may be sufficient to rapidly recover ATP levels following an excitotoxic insult.

Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions

PubMed Central

Connolly, Niamh M. C.; D’Orsi, Beatrice; Monsefi, Naser; Huber, Heinrich J.; Prehn, Jochen H. M.

2016-01-01

Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK), re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity. The model further correctly predicted an excitotoxicity-induced elevation of intracellular glucose, and well resembled the delayed recovery and cell-to-cell heterogeneity of experimentally measured glucose dynamics. The model also predicted necrotic bioenergetic collapse and altered calcium dynamics following more severe excitotoxic insults. In conclusion, our data suggest that a minimal set of critical reactions may determine the acute bioenergetic response to transient excitotoxicity and that an AMPK-mediated increase in intracellular glucose may be sufficient to rapidly recover ATP levels following an excitotoxic insult. PMID:26840769

The effect of intraoperative administration of dexamethasone for PONV prophylaxis on perioperative blood glucose level in obese and normal weight children.

PubMed

Gnatzy, Richard; Hempel, Gunther; Kaisers, Udo X; Höhne, Claudia

2015-11-01

The incidence of postoperative nausea and vomiting (PONV) can be reduced by dexamethasone. Single-dose administration may cause elevated blood glucose levels in obese adults. No data are available for children. The aim was to evaluate perioperative blood glucose changes related to body weight in children who received dexamethasone. This prospective observational study included 62 children. All patients received total intravenous anesthesia and a single dose of dexamethasone (0.15 mg/kg, maximum 8 mg). Blood glucose levels were measured up to 6 h. Standard deviation scores (SDS) were calculated using age- and gender-specific body mass index (BMI) percentiles, p<0.05. A total of 62 children (11.5±2.9 years, median SDS 0.43, 29% overweight/obese) were included. Blood glucose levels increased from 5.52±0.52 to 6.74±0.84 mmol/L 6 h after dexamethasone without correlation to the BMI-SDS. This study showed an increase of perioperative blood glucose (normoglycemic ranges) after single dose of dexamethasone, but no BMI-dependent effect was observed in children. Therefore, low-dose dexamethasone may be used in obese children for PONV prophylaxis.

An elevated blood glucose level and increased incidence of gestational diabetes mellitus in pregnant women with latent toxoplasmosis.

PubMed

Kankova, Sarka; Flegr, Jaroslav; Calda, Pavel

2015-09-21

About 30-50% of the world human population are infected with the protozoan parasite Toxoplasma gondii (Nicolle et Manceaux, 1908). Latent toxoplasmosis has many specific behavioural and physiological effects on the human body and influences the course of pregnancy, including secondary sex ratio of children of infected mothers. It was suggested that an increased concentration of glucose could be the proximate cause of increased sex ratio. There are some indirect indications of possible association between toxoplasmosis and certain forms of diabetes. Here we searched for a possible link between latent toxoplasmosis and the level of glucose in the blood. In a cross-sectional study, we found that pregnant women with latent toxoplasmosis had significantly higher blood glucose levels during the oral glucose tolerance test (n = 191, p = 0.010; the level of fasting plasma glucose: mean = 5.04 mmol/l vs mean = 4.88 mmol/l; blood glucose level at 1 hour mean = 7.73 mmol/l vs mean = 6.89 mmol/l and blood glucose level at two hours mean = 6.43 mmol/l vs mean = 5.74 mmol/l) and higher prevalence (19.5 %) of gestational diabetes mellitus (n = 532, p = 0.033, odds ratio = 1.78) in the 24-28th gestational weeks than T. gondii-free women (12.0 %). Increased level of glucose and increased incidence of gestational diabetes mellitus could have considerable clinical impact as contributors to the development of the metabolic syndrome and type 2 diabetes in T. gondii-infected women. Our results also brought the first empirical support for the hypothesis that the glucose concentration may play a role in T. gondii-associated offspring sex ratio shifts.

Glucose Oscillations Can Activate an Endogenous Oscillator in Pancreatic Islets

PubMed Central

Mukhitov, Nikita; Roper, Michael G.; Bertram, Richard

2016-01-01

Pancreatic islets manage elevations in blood glucose level by secreting insulin into the bloodstream in a pulsatile manner. Pulsatile insulin secretion is governed by islet oscillations such as bursting electrical activity and periodic Ca2+ entry in β-cells. In this report, we demonstrate that although islet oscillations are lost by fixing a glucose stimulus at a high concentration, they may be recovered by subsequently converting the glucose stimulus to a sinusoidal wave. We predict with mathematical modeling that the sinusoidal glucose signal’s ability to recover islet oscillations depends on its amplitude and period, and we confirm our predictions by conducting experiments with islets using a microfluidics platform. Our results suggest a mechanism whereby oscillatory blood glucose levels recruit non-oscillating islets to enhance pulsatile insulin output from the pancreas. Our results also provide support for the main hypothesis of the Dual Oscillator Model, that a glycolytic oscillator endogenous to islet β-cells drives pulsatile insulin secretion. PMID:27788129

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

Glyceollin-containing fermented soybeans improve glucose homeostasis in diabetic mice.

PubMed

Park, Sunmin; Kim, Da Sol; Kim, Jeong Hwan; Kim, Jong Sang; Kim, Hyo Jung

2012-02-01

Our previous in vitro study demonstrated that glyceollins help normalize glucose homeostasis by potentiating β-cell function and survival in insulinoma cells as well as improving glucose utilization in adipocytes. Here, we investigated whether fermented soybeans containing glyceollins had an antidiabetic action in type 2 diabetic animals. The diabetic mice, their diabetes induced by intraperitoneal injections of streptozotocin (20 mg/kg bw), were administered a high fat diet with no soybeans (control), 10% unfermented soybeans and 10% fermented soybeans containing glyceollins, respectively, (FSG) for 8 weeks. As positive controls, rosiglitazone (20 mg/kg/bw) was given to diabetic mice fed a no soybean diet and non-diabetic mice were also placed on the same diet. Among the diabetic mice, FSG-treated mice exhibited the lowest peak for blood glucose levels with an elevation of serum insulin levels during the first part of oral glucose tolerance testing. FSG also made blood glucose levels drop quickly after the peak and it decreased blood glucose levels more than the control during insulin tolerance testing. This improvement was associated with increased hepatic glycogen accumulation and decreased triglyceride storage. The phosphorylation of Akt, AMP-kinase, and acetyl-CoA carboxylase in the liver was potentiated by FSG, whereas phosphoenolpyruvate carboxykinase expression decreased. The enhancement of glucose homeostasis was comparable to the effect induced by rosiglitazone, a commercial peroxisome proliferator-activated receptor-γ agonist, but it did not match the level of glucose homeostasis in the non-diabetic mice. Glyceollin-containing FSG improves glucose homeostasis, partly by enhancing hepatic insulin sensitivity in type 2 diabetic mice. Copyright © 2012 Elsevier Inc. All rights reserved.

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.

Influence of elastin-derived peptides, glucose, LDL and oxLDL on nitric oxide synthase expression in human umbilical artery endothelial cells.

PubMed

Garczorz, Wojciech; Francuz, Tomasz; Gmiński, Jan; Likus, Wirginia; Siemianowicz, Krzysztof; Jurczak, Teresa; Strzałka-Mrozik, Barbara

2011-01-01

Endothelial dysfunction plays an important role in the development of atherosclerosis. Elastin-derived peptides (EDP), hyperglycemia, hypercholesterolemia and oxidized LDL have a proven proatherosclerotic potential. Nitric oxide generated by endothelial nitric oxide synthase (eNOS; EC 1.14.13.39) is an important vasorelaxant. Here we studied the influence of those proatherosclerotic factors on eNOS gene and protein expression in artery-derived endothelial cells. Human umbilical artery endothelial cells (HUAEC) were incubated with or without: glucose (270 mg/dl), LDL (200 mg/dl), oxidized LDL (oxLDL 25 mg/dl) or κ-elastin (0.5 and 2.5 µg/ml). Gene expression was assessed by real time RT-PCR, whilst the eNOS protein by ELISA. In cells incubated with 2.5 µg/ml of κ-elastin, a 31 % increase of eNOS mRNA expression was observed, but the protein level remained unchanged. OxLDL, LDL and glucose decreased the eNOS protein level by 74 %, 37 % and 29 %, respectively. OxLDL decreased eNOS mRNA by 42 %. LDL non-significantly decreased eNOS mRNA expression. An elevated glucose level did not affect the eNOS mRNA expression. Hyperglycemia and an elevated level of LDL, particularly oxLDL, decreased the level of eNOS protein in endothelial cells. As κ-elastin did not decrease the expression of eNOS gene in HUAEC, the proatherogenic properties of elastin-derived peptides are unlikely to be due to their influence on eNOS.

Metabolic profiling of muscle contraction in lean compared with obese rodents.

PubMed

Thyfault, John P; Cree, Melanie G; Tapscott, Edward B; Bell, Jill A; Koves, Timothy R; Ilkayeva, Olga; Wolfe, Robert R; Dohm, G Lynis; Muoio, Deborah M

2010-09-01

Interest in the pathophysiological relevance of intramuscular triacylglycerol (IMTG) accumulation has grown from numerous studies reporting that abnormally high glycerolipid levels in tissues of obese and diabetic subjects correlate negatively with glucose tolerance. Here, we used a hindlimb perfusion model to examine the impact of obesity and elevated IMTG levels on contraction-induced changes in skeletal muscle fuel metabolism. Comprehensive lipid profiling was performed on gastrocnemius muscles harvested from lean and obese Zucker rats immediately and 25 min after 15 min of one-legged electrically stimulated contraction compared with the contralateral control (rested) limbs. Predictably, IMTG content was grossly elevated in control muscles from obese rats compared with their lean counterparts. In muscles of obese (but not lean) rats, contraction resulted in marked hydrolysis of IMTG, which was then restored to near resting levels during 25 min of recovery. Despite dramatic phenotypical differences in contraction-induced IMTG turnover, muscle levels of diacylglycerol (DAG) and long-chain acyl-CoAs (LCACoA) were surprisingly similar between groups. Tissue profiles of acylcarnitine metabolites suggested that the surfeit of IMTG in obese rats fueled higher rates of fat oxidation relative to the lean group. Muscles of the obese rats had reduced lactate levels immediately following contraction and higher glycogen resynthesis during recovery, consistent with a lipid-associated glucose-sparing effect. Together, these findings suggest that contraction-induced mobilization of local lipid reserves in obese muscles promotes beta-oxidation, while discouraging glucose utilization. Further studies are necessary to determine whether persistent oxidation of IMTG-derived fatty acids contributes to systemic glucose intolerance in other physiological settings.

Discrimination, Psychosocial Stress, and Health among Latin American Immigrants in Oregon

PubMed Central

McClure, Heather H.; Snodgrass, J. Josh; Martinez, Charles R.; Eddy, J. Mark; Jiménez, Roberto A.; Isiordia, Laura E.

2009-01-01

Chronic psychosocial stress related to discrimination has been shown to be associated with biological measures such as elevated systolic blood pressure (SBP), increased body fat, and higher fasting glucose levels. Few studies have examined this relationship in immigrant populations. The present study recruited a sample of 132 Oregon Latino immigrant adults in order to investigate the relationships between perceived discrimination and several health measures (blood pressure, body mass index [BMI], and fasting glucose). Results indicate that perceived discrimination stress predicted elevated SBP among men but not among women. Perceived discrimination was significantly higher among obese women than among women of normal BMI. The same pattern was not observed for men. Further, a strong trend relationship was detected: the higher women’s reported discrimination stress, the higher their fasting glucose levels. Again, this pattern was not observed for men. These results suggest that chronic psychosocial stress plays an important role in disease risk among Latin American immigrants, and that male and female immigrants may have distinctive physiological responses. If confirmed, these findings may have important clinical and public health implications for chronic disease prevention among Latinos. PMID:19844904

Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese BL/6J mice[S

PubMed Central

Tripathy, Sasmita; Torres-Gonzalez, Moises; Jump, Donald B.

2010-01-01

Elevated hepatic fatty acid elongase-5 (Elovl5) activity lowers blood glucose in fasted chow-fed C57BL/6J mice. As high-fat diets induce hyperglycemia and suppress hepatic Elovl5 activity, we tested the hypothesis that elevated hepatic Elovl5 expression attenuates hyperglycemia in high-fat-diet-induced obese mice. Increasing hepatic Elovl5 activity by a recombinant adenoviral approach restored blood glucose and insulin, HOMA-IR, and glucose tolerance to normal values in obese mice. Elevated Elovl5 activity increased hepatic content of Elovl5 products (20:3,n-6, 22:4,n-6) and suppressed levels of enzymes (Pck1, G6Pc) and transcription factors (FoxO1 and PGC1α, but not CRTC2) involved in gluconeogenesis. Effects of Elovl5 on FoxO1 nuclear abundance correlated with increased phosphorylation of FoxO1, Akt, and the catalytic unit of PP2A, as well as a decline in cellular abundance of TRB3. Such changes are mechanistically linked to the regulation of FoxO1 nuclear abundance and gluconeogenesis. These results show that Elovl5 activity impacts the hepatic abundance and phosphorylation status of multiple proteins involved in gluconeogenesis. Our findings establish a link between fatty acid elongation and hepatic glucose metabolism and suggest a role for regulators of Elovl5 activity in the treatment of diet-induced hyperglycemia. PMID:20488798

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.

The impact of blood glucose levels on stimulated adrenocorticotropin hormone and growth hormone release in healthy subjects.

PubMed

Jakobsdóttir, S; Twisk, J W R; Drent, M L

2009-12-01

In studies investigating the influence of glucose levels on the pituitary function the methods used have been variable and mainly focused on the change in function as a reaction to unphysiological low or high blood glucose levels. In the present study the impact of physiological and elevated blood glucose levels on adrenocorticotropin hormone (ACTH) and growth hormone release are investigated. The euglycaemic and hyperglycaemic clamp techniques were used to reach stable levels of 4, 8 and 12 mmol/l blood glucose levels. After a stabilization phase of 2 h, a corticotropin releasing hormone (CRH) or a growth hormone releasing hormone (GHRH) stimulation test was performed. Seven and eight healthy male volunteers, belonging to two groups, participated in this study. The area under the curve (AUC), peak values and time to peak of ACTH, cortisol and growth hormone were calculated to evaluate the response to the CRH and GHRH stimulation test. The peak values of ACTH, cortisol and growth hormone seemed to be the highest during the 4 mmol/l clamp sessions, compared with the 8 and 12 mmol/l clamps, although the differences were not statistically significant when analysed for every subject individually. The AUC and time to peak measurements were comparable during the three clamp procedures. The pituitary reaction on CRH and GHRH was not significantly changed by various blood glucose levels. © 2009 Blackwell Publishing Ltd.

Fructose Levels Are Markedly Elevated in Cerebrospinal Fluid Compared to Plasma in Pregnant Women

PubMed Central

Hwang, Janice J.; Johnson, Andrea; Cline, Gary; Belfort-DeAguiar, Renata; Snegovskikh, Denis; Khokhar, Babar; Han, Christina S.; Sherwin, Robert S.

2015-01-01

Background Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose→sorbitol→fructose) contributes to brain exposure to fructose. Methods In this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF), maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM) undergoing spinal anesthesia and elective cesarean section. Results As expected, CSF glucose was ~60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001), and CSF sorbitol was ~9-times higher than plasma levels (p < 0.001). Moreover, CSF fructose correlated positively with CSF glucose (ρ 0.45, p = 0.02) and sorbitol levels (ρ 0.75, p < 0.001). Cord blood sorbitol was also ~7-fold higher than maternal plasma sorbitol levels (p = 0.001). There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups. Conclusions These data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption. PMID:26035307

Beta-endorphin-induced inhibition and stimulation of insulin secretion in normal humans is glucose dependent.

PubMed

Giugliano, D; Cozzolino, D; Salvatore, T; Torella, R; D'Onofrio, F

1988-09-01

This study evaluated the effect of human beta-endorphin on pancreatic hormone levels and their responses to nutrient challenges in normal subjects. Infusion of 0.5 mg/h beta-endorphin caused a significant rise in plasma glucose concentrations preceded by a significant increase in peripheral glucagon levels. No changes occurred in the plasma concentrations of insulin and C-peptide. Acute insulin and C-peptide responses to intravenous pulses of different glucose amounts (0.33 g/kg and 5 g) and arginine (3 g) were significantly reduced by beta-endorphin infusion (P less than .01). This effect was associated with a significant reduction of the glucose disappearance rates, suggesting that the inhibition of insulin was of biological relevance. beta-Endorphin also inhibited glucose suppression of glucagon levels and augmented the glucagon response to arginine. To verify whether the modification of prestimulus glucose level could be important in these hormonal responses to beta-endorphin, basal plasma glucose concentrations were raised by a primed (0.5 g/kg) continuous (20 mg kg-1.min-1) glucose infusion. After stabilization of plasma glucose levels (350 +/- 34 mg/dl, t = 120 min), beta-endorphin infusion caused an immediate and marked increase in plasma insulin level (peak response 61 +/- 9 microU/ml, P less than .01), which remained elevated even after the discontinuation of opioid infusion. Moreover, the acute insulin response to a glucose pulse (0.33 g/kg i.v.) given during beta-endorphin infusion during hyperglycemia was significantly higher than the response obtained during euglycemia (171 +/- 32 vs. 41 +/- 7 microU/ml, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic glucose-6-phosphatase-α deficiency leads to metabolic reprogramming in glycogen storage disease type Ia.

PubMed

Cho, Jun-Ho; Kim, Goo-Young; Mansfield, Brian C; Chou, Janice Y

2018-04-15

Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in endogenous glucose production. This autosomal recessive disorder is characterized by impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC). We have shown that hepatic G6Pase-α deficiency-mediated steatosis leads to defective autophagy that is frequently associated with carcinogenesis. We now show that hepatic G6Pase-α deficiency also leads to enhancement of hepatic glycolysis and hexose monophosphate shunt (HMS) that can contribute to hepatocarcinogenesis. The enhanced hepatic glycolysis is reflected by increased lactate accumulation, increased expression of many glycolytic enzymes, and elevated expression of c-Myc that stimulates glycolysis. The increased HMS is reflected by increased glucose-6-phosphate dehydrogenase activity and elevated production of NADPH and the reduced glutathione. We have previously shown that restoration of hepatic G6Pase-α expression in G6Pase-α-deficient liver corrects metabolic abnormalities, normalizes autophagy, and prevents HCA/HCC development in GSD-Ia. We now show that restoration of hepatic G6Pase-α expression normalizes both glycolysis and HMS in GSD-Ia. Moreover, the HCA/HCC lesions in L-G6pc-/- mice exhibit elevated levels of hexokinase 2 (HK2) and the M2 isoform of pyruvate kinase (PKM2) which play an important role in aerobic glycolysis and cancer cell proliferation. Taken together, hepatic G6Pase-α deficiency causes metabolic reprogramming, leading to enhanced glycolysis and elevated HMS that along with impaired autophagy can contribute to HCA/HCC development in GSD-Ia. Published by Elsevier Inc.

Sarcopenia is a risk factor for elevated aminotransferase in men independently of body mass index, dietary habits, and physical activity.

PubMed

Yoo, Ki Deok; Jun, Dae Won; Lee, Kang Nyeong; Lee, Hang Lak; Lee, Oh Young; Yoon, Byung Chul; Choi, Ho Soon

2015-04-01

Aminotransferase activity is a surrogate marker of liver injury showing strong correlations with obesity and metabolic syndrome. However, elevated aminotransferase activity is not uncommon in non-obese and non-alcoholic patients in clinical practice. To examine the relationship between sarcopenia and aminotransferase activity in a large population-based cohort. Data from the Korean National Health and Nutrition Examinations were used. A total of 13,431 subjects were included. A whole-body dual X-ray absorptiometry scan was performed on each patient to measure total and regional muscle mass. Appendicular skeletal muscle mass indices were also obtained. The prevalence of sarcopenia was significantly higher in the group with elevated aminotransferase levels than in the normal liver enzyme group (males: 26.5% vs. 16.9%; females: 38.3% vs. 22.1%, p<0.05). The skeletal muscle index was negatively correlated with most cardiometabolic risk factors, including fasting glucose and cholesterol levels. The frequency of elevated aminotransferase increased in male patients with sarcopenia after adjusting for potential confounding factors including age, body mass index, fasting glucose level, dietary, and exercise habits. However, the correlation was no longer observed in women after adjusting for body mass index. Sarcopenia is a risk factor for elevated aminotransferase in men, independently of body mass index, dietary habits, and physical activity. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Diet reduction to requirements in obese/overfed ewes from early gestation prevents glucose/insulin dysregulation and returns fetal adiposity and organ development to control levels

PubMed Central

Tuersunjiang, Nuermaimaiti; Odhiambo, John F.; Long, Nathan M.; Shasa, Desiree R.; Nathanielsz, Peter W.

2013-01-01

Obesity at conception and excess gestational weight gain pose significant risks for adverse health consequences in human offspring. This study evaluated the effects of reducing dietary intake of obese/overfed ewes beginning in early gestation on fetal development. Sixty days prior to conception, ewes were assigned to a control diet [CON: 100% of National Research Council (NRC) recommendations], a diet inducing maternal obesity (MO: 150% of NRC recommendations), or a maternal obesity intervention diet (MOI: 150% of NRC recommendations to day 28 of gestation, then 100% NRC) until necropsy at midgestation (day 75) or late (day 135) gestation. Fetal size and weight, as well as fetal organ weights, were greater (P < 0.05) at midgestation in MO ewes than those of CON and MOI ewes. By late gestation, whereas fetal size and weight did not differ among dietary groups, cardiac ventricular weights and wall thicknesses as well as liver and perirenal fat weights remained elevated in fetuses from MO ewes compared with those from CON and MOI ewes. MO ewes and fetuses exhibited elevated (P < 0.05) plasma concentrations of triglycerides, cholesterol, insulin, glucose, and cortisol at midgestation compared with CON and MOI ewes and fetuses. In late gestation, whereas plasma triglycerides and cholesterol, insulin, and cortisol remained elevated in MO vs. CON and MOI ewes and fetuses, glucose concentrations were elevated in both MO and MOI fetuses compared with CON fetuses, which was associated with elevated placental GLUT3 expression in both groups. These data are consistent with the concept that reducing maternal diet of obese/overfed ewes to requirements from early gestation can prevent subsequent alterations in fetal growth, adiposity, and glucose/insulin dynamics. PMID:23921140

Diet reduction to requirements in obese/overfed ewes from early gestation prevents glucose/insulin dysregulation and returns fetal adiposity and organ development to control levels.

PubMed

Tuersunjiang, Nuermaimaiti; Odhiambo, John F; Long, Nathan M; Shasa, Desiree R; Nathanielsz, Peter W; Ford, Stephen P

2013-10-01

Obesity at conception and excess gestational weight gain pose significant risks for adverse health consequences in human offspring. This study evaluated the effects of reducing dietary intake of obese/overfed ewes beginning in early gestation on fetal development. Sixty days prior to conception, ewes were assigned to a control diet [CON: 100% of National Research Council (NRC) recommendations], a diet inducing maternal obesity (MO: 150% of NRC recommendations), or a maternal obesity intervention diet (MOI: 150% of NRC recommendations to day 28 of gestation, then 100% NRC) until necropsy at midgestation (day 75) or late (day 135) gestation. Fetal size and weight, as well as fetal organ weights, were greater (P < 0.05) at midgestation in MO ewes than those of CON and MOI ewes. By late gestation, whereas fetal size and weight did not differ among dietary groups, cardiac ventricular weights and wall thicknesses as well as liver and perirenal fat weights remained elevated in fetuses from MO ewes compared with those from CON and MOI ewes. MO ewes and fetuses exhibited elevated (P < 0.05) plasma concentrations of triglycerides, cholesterol, insulin, glucose, and cortisol at midgestation compared with CON and MOI ewes and fetuses. In late gestation, whereas plasma triglycerides and cholesterol, insulin, and cortisol remained elevated in MO vs. CON and MOI ewes and fetuses, glucose concentrations were elevated in both MO and MOI fetuses compared with CON fetuses, which was associated with elevated placental GLUT3 expression in both groups. These data are consistent with the concept that reducing maternal diet of obese/overfed ewes to requirements from early gestation can prevent subsequent alterations in fetal growth, adiposity, and glucose/insulin dynamics.

Modulation of Glucose Transporter 1 (GLUT1) Expression Levels Alters Mouse Mammary Tumor Cell Growth In Vitro and In Vivo

PubMed Central

Young, Christian D.; Lewis, Andrew S.; Rudolph, Michael C.; Ruehle, Marisa D.; Jackman, Matthew R.; Yun, Ui J.; Ilkun, Olesya; Pereira, Renata; Abel, E. Dale; Anderson, Steven M.

2011-01-01

Tumor cells exhibit an altered metabolism characterized by elevated aerobic glycolysis and lactate secretion which is supported by an increase in glucose transport and consumption. We hypothesized that reducing or eliminating the expression of the most prominently expressed glucose transporter(s) would decrease the amount of glucose available to breast cancer cells thereby decreasing their metabolic capacity and proliferative potential. Of the 12 GLUT family glucose transporters expressed in mice, GLUT1 was the most abundantly expressed at the RNA level in the mouse mammary tumors from MMTV-c-ErbB2 mice and cell lines examined. Reducing GLUT1 expression in mouse mammary tumor cell lines using shRNA or Cre/Lox technology reduced glucose transport, glucose consumption, lactate secretion and lipid synthesis in vitro without altering the concentration of ATP, as well as reduced growth on plastic and in soft agar. The growth of tumor cells with reduced GLUT1 expression was impaired when transplanted into the mammary fat pad of athymic nude mice in vivo. Overexpression of GLUT1 in a cell line with low levels of endogenous GLUT1 increased glucose transport in vitro and enhanced growth in nude mice in vivo as compared to the control cells with very low levels of GLUT1. These studies demonstrate that GLUT1 is the major glucose transporter in mouse mammary carcinoma models overexpressing ErbB2 or PyVMT and that modulation of the level of GLUT1 has an effect upon the growth of mouse mammary tumor cell lines in vivo. PMID:21826239

A natural protective mechanism against hyperglycaemia in vascular endothelial and smooth-muscle cells: role of glucose and 12-hydroxyeicosatetraenoic acid.

PubMed Central

Alpert, Evgenia; Gruzman, Arie; Totary, Hanan; Kaiser, Nurit; Reich, Reuven; Sasson, Shlomo

2002-01-01

Bovine aortic endothelial and smooth-muscle cells down-regulate the rate of glucose transport in the face of hyperglycaemia, thus providing protection against deleterious effects of increased intracellular glucose levels. When exposed to high glucose concentrations these cells reduced the mRNA and protein content of their typical glucose transporter, GLUT-1, as well as its plasma-membrane abundance. Inhibition of the lipoxygenase (LO) pathway, and particularly 12-LO, reversed this glucose-induced down-regulatory process and restored the rate of hexose transport to the level seen in vascular cells exposed to normal glucose levels. This reversal was accompanied by increased levels of GLUT-1 mRNA and protein, as well as of its plasma-membrane content. Exposure of the vascular cells to elevated glucose concentrations increased by 2-3-fold the levels of cell-associated and secreted 12-hydroxyeicosatetraenoic acid (12-HETE), the product of 12-LO. Inhibition of 15- and 5-LO, cyclo-oxygenases 1 and 2, and eicosanoid-producing cytochrome P450 did not modify the hexose-transport system in vascular cells. These results suggest a role for HETEs in the autoregulation of hexose transport in vascular cells. 8-Iso prostaglandin F(2alpha), a non-enzymic oxidation product of arachidonic acid, had no effect on the hexose-transport system in vascular cells exposed to hyperglycaemic conditions. Taken together, these findings show that hyperglycaemia increases the production rate of 12-HETE, which in turn mediates the down-regulation of GLUT-1 expression and the glucose-transport system in vascular endothelial and smooth-muscle cells. PMID:11853550

Comparison of diagnostic criteria to detect undiagnosed diabetes in hyperglycaemic patients with acute coronary syndrome.

PubMed

de Mulder, Maarten; Oemrawsingh, Rohit M; Stam, Frank; Boersma, Eric; Umans, Victor A

2012-01-01

Elevated plasma glucose levels on admission (APG) are very common in patients with acute coronary syndrome (ACS) and can be the first indication of diabetes mellitus. To provide insight into the prevalence of previously undiagnosed diabetes and to compare different methods of diagnosing diabetes in patients with ACS. Patients with ACS with elevated APG who participated in the BIOMArCS 2 glucose trial underwent an oral glucose tolerance test (OGTT) prior to discharge. 130 patients were included who underwent metabolic assessment. Of these, 109 had an OGTT and 13 patients had pre-existing diabetes. The OGTT results were categorised as (previously) undiagnosed diabetes in 35% of patients (fasting plasma glucose (FPG) ≥7.0 mmol/l or 2-h post-load glucose ≥11.1 mmol/l) and impaired glucose metabolism in 44% (FPG 6.1-6.9 mmol/l or post-load glucose 7.8-11.0 mmol/l), so only 21% had a normal glucose metabolism. Undiagnosed diabetes could not be adequately predicted with APG, FPG or HbA1c (area under the ROC curve 0.61, 0.75 and 0.72, respectively). Patients with abnormal glucose metabolism were significantly older, had higher admission HbA1c values, a higher Killip classification and more often had a prior stroke than patients with normal glucose metabolism. 79% of hyperglycaemic patients with ACS were found to have abnormal glucose metabolism. As APG, HbA1c and FPG had a low sensitivity to detect undiagnosed diabetes, an OGTT appears to be the best test to assess the presence of previously undiagnosed diabetes or impaired glucose metabolism in hyperglycaemic patients with ACS.

Reciprocal regulation of insulin and plasma 5'-AMP in glucose homeostasis in mice.

PubMed

Xia, Lin; Wang, Zhongqiu; Zhang, Ying; Yang, Xiao; Zhan, Yibei; Cheng, Rui; Wang, Shiming; Zhang, Jianfa

2015-03-01

A previous investigation has demonstrated that plasma 5'-AMP (pAMP) exacerbates and causes hyperglycemia in diabetic mice. However, the crosstalk between pAMP and insulin signaling to regulate glucose homeostasis has not been investigated in depth. In this study, we showed that the blood glucose level was more dependent on the ratio of insulin to pAMP than on the absolute level of these two factors. Administration of 5'-AMP significantly attenuated the insulin-stimulated insulin receptor (IR) autophosphorylation in the liver and muscle tissues, resulting in the inhibition of downstream AKT phosphorylation. A docking analysis indicated that adenosine was a potential inhibitor of IR tyrosine kinase. Moreover, the 5'-AMP treatment elevated the ATP level in the pancreas and in the isolated islets, stimulating insulin secretion and increasing the plasma level of insulin. The insulin administration decreased the 5'-AMP-induced hyper-adenosine level by the up-regulation of adenosine kinase activities. Our results indicate that blood glucose homeostasis is reciprocally regulated by pAMP and insulin. © 2015 Society for Endocrinology.

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells.

PubMed

Hamano, Kunihisa; Nakagawa, Yuko; Ohtsu, Yoshiaki; Li, Longfei; Medina, Johan; Tanaka, Yuji; Masuda, Katsuyoshi; Komatsu, Mitsuhisa; Kojima, Itaru

2015-07-01

Glucose activates the glucose-sensing receptor T1R3 and facilitates its own metabolism in pancreatic β-cells. An inhibitor of this receptor would be helpful in elucidating the physiological function of the glucose-sensing receptor. The present study was conducted to examine whether or not lactisole can be used as an inhibitor of the glucose-sensing receptor. In MIN6 cells, in a dose-dependent manner, lactisole inhibited insulin secretion induced by sweeteners, acesulfame-K, sucralose and glycyrrhizin. The IC50 was ∼4 mmol/l. Lactisole attenuated the elevation of cytoplasmic Ca2+ concentration ([Ca2+]c) evoked by sucralose and acesulfame-K but did not affect the elevation of intracellular cAMP concentration ([cAMP]c) induced by these sweeteners. Lactisole also inhibited the action of glucose in MIN6 cells. Thus, lactisole significantly reduced elevations of intracellular [NADH] and intracellular [ATP] induced by glucose, and also inhibited glucose-induced insulin secretion. To further examine the effect of lactisole on T1R3, we prepared HEK293 cells stably expressing mouse T1R3. In these cells, sucralose elevated both [Ca2+]c and [cAMP]c. Lactisole attenuated the sucralose-induced increase in [Ca2+]c but did not affect the elevation of [cAMP]c. Finally, lactisole inhibited insulin secretion induced by a high concentration of glucose in mouse islets. These results indicate that the mouse glucose-sensing receptor was inhibited by lactisole. Lactisole may be useful in assessing the role of the glucose-sensing receptor in mouse pancreatic β-cells. © 2015 Society for Endocrinology.

Slightly elevated high-sensitivity C-reactive protein (hsCRP) concentrations are associated with carotid atherosclerosis in women with varying degrees of glucose tolerance.

PubMed

Prahl, Ulrica; Wikstrand, John; Bergström, Göran M L; Behre, Carl Johan; Hulthe, Johannes; Fagerberg, Björn

2010-11-01

We examined whether high-sensitivity C-reactive protein (hsCRP) ≥2.0 mg/L was associated with increased intima-media thickness (IMT), plaque burden, and plaque echolucency in carotid arteries. Women (n = 635) from a population sample of 64-year-old females with varying degrees of glucose tolerance underwent risk factor assessment, measurement of hsCRP, and ultrasound examinations of the carotid arteries. Participants with hsCRP levels ≥2.0 mg/L had elevated carotid bulb IMT independently of other cardiovascular risk factors compared with those with hsCRP <2.0 mg/L. The participants with plaques in the highhsCRP group had larger total plaque area compared to those with plaque in the lower hsCRP group. Plaque echolucency did not differ between groups. High-sensitivity CRP levels ≥2.0 mg/L were accompanied by elevated IMT in the carotid bulbs independently of other cardiovascular risk factors. Total plaque area was larger among women with plaques in the high hsCRP group versus the lower hsCRP group.

MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

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

Bagge, Annika; Clausen, Trine R.; Larsen, Sylvester

Highlights: Black-Right-Pointing-Pointer MicroRNA-29a (miR-29a) levels are increased by glucose in human and rat islets and INS-1E cells. Black-Right-Pointing-Pointer miR-29a increases proliferation of INS-1E beta-cells. Black-Right-Pointing-Pointer Forced expression of miR-29a decreases glucose-stimulated insulin secretion (GSIS). Black-Right-Pointing-Pointer Depletion of beta-cell miR-29a improves GSIS. Black-Right-Pointing-Pointer miR-29a may be a mediator of glucose toxicity in beta-cells. -- Abstract: Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate the impact of glucose on miR-29a levels in INS-1E beta-cellsmore » and in human islets of Langerhans and furthermore to evaluate the impact of miR-29a on beta-cell function and proliferation. Increased glucose levels up-regulated miR-29a in beta-cells and human and rat islets of Langerhans. Glucose-stimulated insulin-secretion (GSIS) of INS-1E beta-cells was decreased by forced expression of miR-29a, while depletion of endogenous miR-29a improved GSIS. Over-expression of miR-29a increased INS-1E proliferation. Thus, miR-29a up-regulation is involved in glucose-induced proliferation of beta-cells. Furthermore, as depletion of miR-29a improves beta-cell function, miR-29a is a mediator of glucose-induced beta-cell dysfunction. Glucose-induced up-regulation of miR-29a in beta-cells could be implicated in progression from impaired glucose tolerance to type 2 diabetes.« less

Improved Properties of Baker's Yeast Mutants Resistant to 2-Deoxy-d-Glucose

PubMed Central

Rincón, Ana M.; Codón, Antonio C.; Castrejón, Francisco; Benítez, Tahía

2001-01-01

We isolated spontaneous mutants from Saccharomyces cerevisiae (baker's yeast V1) that were resistant to 2-deoxy-d-glucose and had improved fermentative capacity on sweet doughs. Three mutants could grow at the same rate as the wild type in minimal SD medium (0.17% Difco yeast nitrogen base without amino acids and ammonium sulfate, 0.5% ammonium sulfate, 2% glucose) and had stable elevated levels of maltase and/or invertase under repression conditions but lower levels in maltose-supplemented media. Two of the mutants also had high levels of phosphatase active on 2-deoxy-d-glucose-6-phosphate. Dough fermentation (CO2 liberation) by two of the mutants was faster and/or produced higher final volumes than that by the wild type, both under laboratory and industrial conditions, when the doughs were supplemented with glucose or sucrose. However, the three mutants were slower when fermenting plain doughs. Fermented sweet bakery products obtained with these mutants were of better quality than those produced by the wild type, with regard to their texture and their organoleptic properties. PMID:11526034

GLUT4 in the endocrine pancreas--indicating an impact in pancreatic islet cell physiology?

PubMed

Bähr, I; Bazwinsky-Wutschke, I; Wolgast, S; Hofmann, K; Streck, S; Mühlbauer, E; Wedekind, D; Peschke, E

2012-06-01

The glucose transporter GLUT4 is well known to facilitate the transport of blood glucose into insulin-sensitive muscle and adipose tissue. In this study, molecular, immunohistochemical, and Western blot investigations revealed evidence that GLUT4 is also located in the mouse, rat, and human endocrine pancreas. In addition, high glucose decreased and insulin elevated the GLUT4 expression in pancreatic α-cells. In contrast, high glucose increased GLUT4 expression, whereas insulin led to a reduced expression level of the glucose transporter in pancreatic β-cells. In vivo experiments showed that in pancreatic tissue of type 2 diabetic rats as well as type 2 diabetic patients, the GLUT4 expression is significantly increased compared to the nondiabetic control group. Furthermore, type 1 diabetic rats exhibited reduced GLUT4 transcript levels in pancreatic tissue, whereas insulin treatment of type 1 diabetic animals enhanced the GLUT4 expression back to control levels. These data provide evidence for the existence of GLUT4 in the endocrine pancreas and indicate a physiological relevance of this glucose transporter as well as characteristic changes in diabetic disease. © Georg Thieme Verlag KG Stuttgart · New York.

Aqueous fraction of Beta vulgaris ameliorates hyperglycemia in diabetic mice due to enhanced glucose stimulated insulin secretion, mediated by acetylcholine and GLP-1, and elevated glucose uptake via increased membrane bound GLUT4 transporters.

PubMed

Ul Kabir, Ashraf; Samad, Mehdi Bin; Ahmed, Arif; Jahan, Mohammad Rajib; Akhter, Farjana; Tasnim, Jinat; Hasan, S M Nageeb; Sayfe, Sania Sarker; Hannan, J M A

2015-01-01

The study was designed to investigate the probable mechanisms of anti-hyperglycemic activity of B. Vulgaris. Aqueous fraction of B. Vulgaris extract was the only active fraction (50mg/kg). Plasma insulin level was found to be the highest at 30 mins after B. Vulgaris administration at a dose of 200mg/kg. B. Vulgaris treated mice were also assayed for plasma Acetylcholine, Glucagon Like Peptide-1 (GLP-1), Gastric Inhibitory Peptide (GIP), Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase-Activating Peptide (PACAP), Insulin Like Growth Factor-1 (IGF-1), Pancreatic Polypeptides (PP), and Somatostatin, along with the corresponding insulin levels. Plasma Acetylcholine and GLP-1 significantly increased in B. Vulgaris treated animals and were further studied. Pharmacological enhancers, inhibitors, and antagonists of Acetylcholine and GLP-1 were also administered to the test animals, and corresponding insulin levels were measured. These studies confirmed the role of acetylcholine and GLP-1 in enhanced insulin secretion (p<0.05). Principal signaling molecules were quantified in isolated mice islets for the respective pathways to elucidate their activities. Elevated concentrations of Acetylcholine and GLP-1 in B. Vulgaris treated mice were found to be sufficient to activate the respective pathways for insulin secretion (p<0.05). The amount of membrane bound GLUT1 and GLUT4 transporters were quantified and the subsequent glucose uptake and glycogen synthesis were assayed. We showed that levels of membrane bound GLUT4 transporters, glucose-6-phosphate in skeletal myocytes, activity of glycogen synthase, and level of glycogen deposited in the skeletal muscles all increased (p<0.05). Findings of the present study clearly prove the role of Acetylcholine and GLP-1 in the Insulin secreting activity of B. Vulgaris. Increased glucose uptake in the skeletal muscles and subsequent glycogen synthesis may also play a part in the anti-hyperglycemic activity of B. Vulgaris.

In vivo Investigation of Anti-diabetic Properties of Ripe Onion Juice in Normal and Streptozotocin-induced Diabetic Rats

PubMed Central

Lee, Chul-Won; Lee, Hyung-Seok; Cha, Yong-Jun; Joo, Woo-Hong; Kang, Dae-Ook; Moon, Ja-Young

2013-01-01

The acute and subacute hypoglycemic and antihyperglycemic effects of drinkable ripe onion juice (Commercial product name is “Black Onion Extract”) were investigated in normal and streptozotocin-induced diabetic rats. For tests of acute and subacute hypoglycemic effects, ripe onion juice (5 and 15 mL/kg b.w.) was administered by oral gavage to normal Sprague Dawley rats and measurements of fasting glucose levels and oral glucose tolerance tests were performed. Tolbutamide was used as a reference drug at a single oral dose of 250 mg/kg b.w. To test anti-hyper-glycemic activity, the ripe onion juice was administered to streptozotocin-induced diabetic rats by oral gavage at single dose of 15 mL/kg b.w. per day for 7 consecutive days. Oral administration of the ripe onion juice at either dosed level of 5 or 15 mL/kg b.w. showed no remarkable acute hypoglycemic effect in normal rats. The two dosed levels caused a relatively small reduction, only 18% and 12% (5 and 15 mL/kg b.w., respectively) decrease in glucose levels at 2 h after glucose loading in normal rats. However, at 3 h after glucose loading, blood glucose levels in the ripe onion juice-dosed rats were decreased to the corresponding blood glucose level in tolbutamide-dosed rats. Although showing weak hypoglycemic potential compared to that of tolbutamide, oral administration of ripe onion juice (15 mL/kg b.w.) for a short period (8 days) resulted in a slight reduction in the blood glucose levels that had elevated in Streptozotocin-induced diabetic rats. In conclusion, these results suggest that the commercial product “Black Onion Extract” may possess anti-hyperglycemic potential in diabetes. PMID:24471128

Fluctuations in Nucleus Accumbens Extracellular Glutamate and Glucose during Motivated Glucose-drinking Behavior: Dissecting the Neurochemistry of Reward

PubMed Central

Wakabayashi, Ken T.; Myal, Stephanie E.; Kiyatkin, Eugene A.

2015-01-01

While motivated behavior involves multiple neurochemical systems, few studies have focused on the role of glutamate, the brain’s excitatory neurotransmitter, and glucose, the energetic substrate of neural activity in reward-related neural processes. Here, we used high-speed amperometry with enzyme-based substrate-sensitive and control, enzyme-free biosensors to examine second-scale fluctuations in the extracellular levels of these substances in the nucleus accumbens shell during glucose-drinking behavior in trained rats. Glutamate rose rapidly after the presentation of a glucose-containing cup and before the initiation of drinking (reward seeking), decreased more slowly to levels below baseline during consumption (sensory reward), and returned to baseline when the ingested glucose reached the brain (metabolic reward). When water was substituted for glucose, glutamate rapidly increased with cup presentation and in contrast to glucose drinking, increased above baseline after rats tasted the water and refused to drink further. Therefore, extracellular glutamate show distinct changes associated with key events of motivated drinking behavior and opposite dynamics during sensory and metabolic components of reward. In contrast to glutamate, glucose increased at each stimulus and behavioral event, showing a sustained elevation during the entire behavior and a robust post-ingestion rise that correlated with the gradual return of glutamate levels to their baseline. By comparing active drinking with passive intra-gastric glucose delivery, we revealed that fluctuations in extracellular glucose are highly dynamic, reflecting a balance between rapid delivery due to neural activity, intense metabolism, and the influence of ingested glucose reaching the brain. PMID:25393775

Effect of Chronic Administration of Forskolin on Glycemia and Oxidative Stress in Rats with and without Experimental Diabetes

PubMed Central

Ríos-Silva, Mónica; Trujillo, Xóchitl; Trujillo-Hernández, Benjamín; Sánchez-Pastor, Enrique; Urzúa, Zorayda; Mancilla, Evelyn; Huerta, Miguel

2014-01-01

Forskolin is a diterpene derived from the plant Coleus forskohlii. Forskolin activates adenylate cyclase, which increases intracellular cAMP levels. The antioxidant and antiinflammatory action of forskolin is due to inhibition of macrophage activation with a subsequent reduction in thromboxane B2 and superoxide levels. These characteristics have made forskolin an effective medication for heart disease, hypertension, diabetes, and asthma. Here, we evaluated the effects of chronic forskolin administration on blood glucose and oxidative stress in 19 male Wistar rats with streptozotocin-induced diabetes compared to 8 healthy male Wistar rats. Rats were treated with forskolin, delivered daily for 8 weeks. Glucose was assessed by measuring fasting blood glucose in diabetic rats and with an oral glucose tolerance test (OGTT) in healthy rats. Oxidative stress was assessed by measuring 8-hydroxydeoxyguanosine (8‑OHdG) in 24-h urine samples. In diabetic rats, without forskolin, fasting blood glucose was significantly higher at the end than at the beginning of the experiment (8 weeks). In both healthy and diabetic rats, forskolin treatment lowered the fasting glucose at the end of the experiment but no effect was found on oral glucose tolerance. The 8-OHdG levels tended to be less elevated in forskolin-treated than in untreated group. Our results showed that chronic administration of forskolin decreased fasting blood glucose levels; however, the reductions of 8-OHdG were not statistically significant. PMID:24688307

Effect of chronic administration of forskolin on glycemia and oxidative stress in rats with and without experimental diabetes.

PubMed

Ríos-Silva, Mónica; Trujillo, Xóchitl; Trujillo-Hernández, Benjamín; Sánchez-Pastor, Enrique; Urzúa, Zorayda; Mancilla, Evelyn; Huerta, Miguel

2014-01-01

Forskolin is a diterpene derived from the plant Coleus forskohlii. Forskolin activates adenylate cyclase, which increases intracellular cAMP levels. The antioxidant and antiinflammatory action of forskolin is due to inhibition of macrophage activation with a subsequent reduction in thromboxane B2 and superoxide levels. These characteristics have made forskolin an effective medication for heart disease, hypertension, diabetes, and asthma. Here, we evaluated the effects of chronic forskolin administration on blood glucose and oxidative stress in 19 male Wistar rats with streptozotocin-induced diabetes compared to 8 healthy male Wistar rats. Rats were treated with forskolin, delivered daily for 8 weeks. Glucose was assessed by measuring fasting blood glucose in diabetic rats and with an oral glucose tolerance test (OGTT) in healthy rats. Oxidative stress was assessed by measuring 8-hydroxydeoxyguanosine (8‑OHdG) in 24-h urine samples. In diabetic rats, without forskolin, fasting blood glucose was significantly higher at the end than at the beginning of the experiment (8 weeks). In both healthy and diabetic rats, forskolin treatment lowered the fasting glucose at the end of the experiment but no effect was found on oral glucose tolerance. The 8-OHdG levels tended to be less elevated in forskolin-treated than in untreated group. Our results showed that chronic administration of forskolin decreased fasting blood glucose levels; however, the reductions of 8-OHdG were not statistically significant.

Plasma selenium levels and nonalcoholic fatty liver disease in Chinese adults: a cross-sectional analysis

PubMed Central

Yang, Zhen; Yan, Chonghuai; Liu, Gang; Niu, Yixin; Zhang, Weiwei; Lu, Shuai; Li, Xiaoyong; Zhang, Hongmei; Ning, Guang; Fan, Jiangao; Qin, Li; Su, Qing

2016-01-01

Selenium exposure can induce liver insulin resistance and increased liver triglyceride concentrations in animals, which may link to an increased risk of nonalcoholic fatty liver disease (NAFLD). However, epidemiological studies investigating the association between elevated plasma selenium levels and NAFLD were not available. We aimed to investigate the association of selenium levels with the prevalence of NAFLD in Chinese adults. This was a cross-sectional study of 8550 Chinese adults aged 40 yr or older in Shanghai, China. A questionnaire, anthropometric measurements, and laboratory tests were conducted. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases. Plasma selenium concentration was assessed by inductively coupled plasma mass spectroscopy. The median concentration of plasma selenium was 213.0 μg/L. Elevated plasma selenium levels were associated with higher triglycerides, LDL-cholesterol, fasting plasma glucose, post-loading plasma glucose, A1c, HOMA-IR, as well as ALT, AST and γ-GT (all P < 0.05). The odds ratios were substantially higher for NAFLD (OR = 1.54, 95% CI 1.13–2.18) in the highest selenium quartile compared with those in the lowest quartile, after adjustment for potential cofounder. The results of this study provided epidemiological evidence that increased plasma selenium level is associated with elevated prevalence of NAFLD. PMID:27853246

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

Yu, Shu; Cheng, Qiong; Li, Lu

Salidroside is proven to be a neuroprotective agent of natural origin, and its analog, 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-D-pyranoside (named SalA-4 g), has been synthesized in our lab. In this study, we showed that SalA-4 g promoted neuronal survival and inhibited neuronal apoptosis in primary hippocampal neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to ischemia by transient middle cerebral artery occlusion (MCAO), respectively, and that SalA-4 g was more neuroprotective than salidroside. We further found that SalA-4 g elevated glucose uptake in OGD-injured primary hippocampal neurons and increased the expression and recruitment of glucose transporter 3 (GLUT3) in ischemicmore » brain. Signaling analysis revealed that SalA-4 g triggered the phosphorylation of CREB, and increased the expression of PKA RII in primary hippocampal neurons exposed to OGD injury, while inhibition of PKA/CREB by H-89 alleviated the elevation in glucose uptake and GLUT3 expression, and blocked the protective effects of SalA-4 g. Moreover, SalA-4 g was noted to inhibit intracellular Ca{sup 2+} influx and calpain1 activation in OGD-injured primary hippocampal neurons. Our results suggest that SalA-4 g neuroprotection might be mediated by increased glucose uptake and elevated GLUT3 expression through calpain1/PKA/CREB pathway. - Highlights: • A salidroside (Sal) analog (SalA-4 g) is prepared to be more neuroprotective than Sal. • SalA-4 g protected hippocampal neurons from oxygen and glucose deprivation insult. • SalA-4 g reduced ischemic injury after transient middle cerebral artery occlusion in rats. • Neuroprotection of SalA-4 g was mediated by GLUT3 level via calpain/PKA/CREB pathway.« less

Gintonin enhances performance of mice in rotarod test: Involvement of lysophosphatidic acid receptors and catecholamine release.

PubMed

Lee, Byung-Hwan; Kim, Jisu; Lee, Ra Mi; Choi, Sun-Hye; Kim, Hyeon-Joong; Hwang, Sung-Hee; Lee, Myung Koo; Bae, Chun-Sik; Kim, Hyoung-Chun; Rhim, Hyewon; Lim, Kiwon; Nah, Seung-Yeol

2016-01-26

Ginseng has a long history of use as a tonic for restoration of vigor. One example of ginseng-derived tonic effect is that it can improve physical stamina under conditions of stress. However, the active ingredient and the underlying molecular mechanism responsible for the ergogenic effect are unknown. Recent studies show that ginseng contains a novel ingredient, gintonin, which consists of a unique class of herbal-medicine lysophosphatidic acids (LPAs). Gintonin activates G protein-coupled LPA receptors to produce a transient [Ca(2+)]i signal, which is coupled to diverse intra- and inter-cellular signal transduction pathways that stimulate hormone or neurotransmitter release. However, relatively little is known about how gintonin-mediated cellular modulation is linked to physical endurance. In the present study, systemic administration of gintonin, but not ginsenosides, in fasted mice increased blood glucose concentrations in a dose-dependent manner. Gintonin treatment elevated blood glucose to a maximum level after 30min. This elevation in blood glucose level could be abrogated by the LPA1/3 receptor antagonist, Ki16425, or the β-adrenergic receptor antagonist, propranolol. Furthermore, gintonin-dependent enhanced performance of fasted mice in rotarod test was likewise abrogated by Ki16425. Gintonin also elevated plasma epinephrine and norepinephrine concentrations. The present study shows that gintonin mediates catecholamine release through activation of the LPA receptor and that activation of the β-adrenergic receptor is coupled to liver glycogenolysis, thereby increasing the supply of glucose and enhancing performance in the rotarod test. Thus, gintonin acts via the LPA-catecholamine-glycogenolysis axis, representing a candidate mechanism that can explain how ginseng treatment enhances physical stamina. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Preventing exercise-induced hypoglycemia in type 1 diabetes using real-time continuous glucose monitoring and a new carbohydrate intake algorithm: an observational field study.

PubMed

Riddell, Michael C; Milliken, Jill

2011-08-01

Real-time (RT) continuous glucose monitoring (CGM) offers the possibility to better manage glucose levels during exercise in active individuals with type 1 diabetes mellitus (T1DM). However, studies have yet to determine the appropriate actions to take when glucose levels are trending toward hypoglycemia. The purpose of this observational field study was to test the effectiveness of RT-GCM and a new carbohydrate intake algorithm designed for maintaining euglycemia during sports. During a 2-week sports camp, 25 adolescents (8-17 years old) with T1DM were fitted with a RT-CGM device and instructed to ingest fast-acting carbohydrates (8-20 g, depending on the concentration of glucose at the time of RT-CGM alert and rates of change in glycemia) when glucose levels were trending toward hypoglycemia. Rates of change in glucose were measured before and after algorithm use, and the incidence of hypoglycemia was documented. With RT-CGM and algorithm use, euglycemia was largely maintained with modest amounts of carbohydrate intake, even when glucose levels were initially dropping at an elevated rate (>0.55 mmol/L per 5 min). Mild biochemical hypoglycemia (3.0-3.9 mmol/L) occurred just twice out of 22 uses of the algorithm (9%) when trend arrows alerted the subjects that glucose levels were dropping. When glucose levels were already below target (<5.0 mmol/L), mild hypoglycemia occurred five times out of 13 events (38%), despite 16 g of carbohydrate being ingested. Average glucose levels during sports in the 60 min following algorithm use were 5.8 ± 1.2 mmol/L, 5.3 ± 1.0 mmol/L, and 6.2 ± 0.8 mmol/L in the 20-, 16-, and 8-g carbohydrate intake protocols when glucose levels were initially on target but dropping toward hypoglycemia. When coupled with RT-CGM, a new carbohydrate intake algorithm prevents hypoglycemia and maintains euglycemia during exercise, particularly if patients ingest carbohydrate when trend arrows alert them of a drop in glycemia.

Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy.

PubMed

Hadigan, C; Meigs, J B; Corcoran, C; Rietschel, P; Piecuch, S; Basgoz, N; Davis, B; Sax, P; Stanley, T; Wilson, P W; D'Agostino, R B; Grinspoon, S

2001-01-01

We evaluated metabolic and clinical features of 71 HIV-infected patients with lipodystrophy by comparing them with 213 healthy control subjects, matched for age and body mass index, from the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were compared separately with 90 matched control subjects from the Framingham Offspring Study. Fasting glucose, insulin, and lipid levels; glucose and insulin response to standard oral glucose challenge; and anthropometric measurements were determined. HIV-infected patients with lipodystrophy demonstrated significantly increased waist-to-hip ratios, fasting insulin levels, and diastolic blood pressure compared with controls. Patients with lipodystrophy were more likely to have impaired glucose tolerance, diabetes, hypertriglyceridemia, and reduced levels of high-density lipoprotein (HDL) cholesterol than were controls. With the exception of HDL cholesterol level, these risk factors for cardiovascular disease (CVD) were markedly attenuated in patients without lipodystrophy and were not significantly different in comparison with controls. These data demonstrate a metabolic syndrome characterized by profound insulin resistance and hyperlipidemia. CVD risk factors are markedly elevated in HIV-infected patients with fat redistribution.

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.

Carbohydrate management, anaerobic metabolism, and adenosine levels in the armoured catfish, Liposarcus pardalis (castelnau), during hypoxia.

PubMed

Maccormack, Tyson James; Lewis, Johanne Mari; Almeida-Val, Vera Maria Fonseca; Val, Adalberto Luis; Driedzic, William Robert

2006-04-01

The armoured catfish, Liposarcus pardalis, tolerates severe hypoxia at high temperatures. Although this species can breathe air, it also has a strong anaerobic metabolism. We assessed tissue to plasma glucose ratios and glycogen and lactate in a number of tissues under "natural" pond hypoxia, and severe aquarium hypoxia without aerial respiration. Armour lactate content and adenosine in brain and heart were also investigated. During normoxia, tissue to plasma glucose ratios in gill, brain, and heart were close to one. Hypoxia increased plasma glucose and decreased tissue to plasma ratios to less than one, suggesting glucose phosphorylation is activated more than uptake. High normoxic white muscle glucose relative to plasma suggests gluconeogenesis or active glucose uptake. Excess muscle glucose may serve as a metabolic reserve since hypoxia decreased muscle to plasma glucose ratios. Mild pond hypoxia changed glucose management in the absence of lactate accumulation. Lactate was elevated in all tissues except armour following aquarium hypoxia; however, confinement in aquaria increased armour lactate, even under normoxia. A stress-associated acidosis may contribute to armour lactate sequestration. High plasma lactate levels were associated with brain adenosine accumulation. An increase in heart adenosine was triggered by confinement in aquaria, although not by hypoxia alone.

Unhealthy Phenotype as Indicated by Salivary Biomarkers: Glucose, Insulin, VEGF-A, and IL-12p70 in Obese Kuwaiti Adolescents

PubMed Central

Hartman, Mor-Li; Goodson, J. Max; Shi, Ping; Vargas, Jorel; Yaskell, Tina; Stephens, Danielle; Cugini, Maryann; Hasturk, Hatice; Barake, Roula; Alsmadi, Osama; Al-Mutawa, Sabiha; Ariga, Jitendra; Soparkar, Pramod; Behbehani, Jawad; Behbehani, Kazem; Welty, Francine

2016-01-01

Objective. Here, we investigated the relationships between obesity and the salivary concentrations of insulin, glucose, and 20 metabolic biomarkers in Kuwaiti adolescents. Previously, we have shown that certain salivary metabolic markers can act as surrogates for blood concentrations. Methods. Salivary samples of whole saliva were collected from 8,317 adolescents. Salivary glucose concentration was measured by a high-sensitivity glucose oxidase method implemented on a robotic chemical analyzer. The concentration of salivary insulin and 20 other metabolic biomarkers was assayed in 744 randomly selected saliva samples by multiplexed bead-based immunoassay. Results. Obesity was seen in 26.5% of the adolescents. Salivary insulin predicting hyperinsulinemia occurred in 4.3% of normal-weight adolescents, 8.3% of overweight adolescents, and 25.7% of obese adolescents (p < 0.0001). Salivary glucose predicting hyperglycemia was found in only 3% of obese children and was not predictive (p = 0.89). Elevated salivary glucose and insulin occurring together was associated with elevated vascular endothelial growth factor and reduced salivary interleukin-12. Conclusion. Considering the surrogate nature of salivary insulin and glucose, this study suggests that elevated insulin may be a dominant sign of metabolic disease in adolescent populations. It also appears that a proangiogenic environment may accompany elevated glucose in obese adolescents. PMID:27069678

Glycaemic indices and non-traditional biochemical cardiovascular disease markers in a diabetic population in Nigeria.

PubMed

Ogbera, Okeoghene Anthonia; Okeoghene, Ogbera Anthonia; Azenabor, Alfred

2011-08-01

To determine the frequency of hyperfibrinogenaemia, elevated C-reactive protein, hyperuricaemia and elevated lipoprotein A in a clinic population of patients with type 2 Diabetes mellitus (DM) compared with healthy controls; and determine the interrelationship between fasting plasma glucose levels and indices of long-term glycaemic control (fructosamine and glycosylated haemoglobin) in DM. Cross-sectional, analytical study. The study was conducted at the Lagos State University Teaching Hospital, Ikeja, from April to June 2009. A total of 200 patients with type 2 DM and 100 age and gender matched healthy controls were recruited for the study. Glycaemic control was assessed using fasting blood glucose, fructosamine and glycosylated haemoglobin levels. The non-traditional risk factors studied included C-reactive protein (CRP), Lipoprotein a (Lpa), serum uric acid (SUA), microalbuminuria and fibrinogen. Mann-whitney, chi-square and Pearson's correlation tests were used for analysis as applicable. Hyperfibrinoginaemia, elevated CRP, LPa, microalbuminuria and hyperuricaemia were present in 3.5%, 65%, 12%, 6% and 57% respectively in type 2 DM. The mean levels of these CV risk factors were significantly higher in subjects with type 2 DM than that of the control subject. There was a positive and significant correlation between HbA1c and FBS (r=0.46, p=0.0001) and HbA1c and fructosamine (r=0.49, p=0.0001). All studied CVS risk factors were related to indices of glycaemic control which were found to be interrelated. Fasting blood glucose significantly correlated with both HbA1c and fructosamine but HbA1c showed better correlation to FPG than fructosamine (r=0.51 vs. 0.32). Glycosylated haemoglobin and fasting plasma glucose but not fructosamine are significantly associated with microalbuminuria, fibrinogen SUA and CRP in type 2 DM. HbA1c was found to be better than fructosamine in monitoring overall long-term glycaemic control.

Antiproliferative effect of elevated glucose in human microvascular endothelial cells

NASA Technical Reports Server (NTRS)

Kamal, K.; Du, W.; Mills, I.; Sumpio, B. E.

1998-01-01

Diabetic microangiopathy has been implicated as a fundamental feature of the pathological complications of diabetes including retinopathy, neuropathy, and diabetic foot ulceration. However, previous studies devoted to examining the deleterious effects of elevated glucose on the endothelium have been performed largely in primary cultured cells of macrovessel origin. Difficulty in the harvesting and maintenance of microvascular endothelial cells in culture have hindered the study of this relevant population. Therefore, the objective of this study was to characterize the effect of elevated glucose on the proliferation and involved signaling pathways of an immortalized human dermal microvascular endothelial cell line (HMEC-1) that possess similar characteristics to their in vivo counterparts. Human dermal microvascular endothelial cells (HMEC-1) were grown in the presence of normal (5 mM) or high D-glucose (20 mM) for 14 days. The proliferative response of HMEC-1 was compared under these conditions as well as the cAMP and PKC pathways by in vitro assays. Elevated glucose significantly inhibited (P < 0.05) HMEC-1 proliferation after 7, 10, and 14 days. This effect was not mimicked by 20 mM mannitol. The antiproliferative effect was more pronounced with longer exposure (1-14 days) to elevated glucose and was irreversible 4 days after a 10-day exposure. The antiproliferative effect was partially reversed in the presence of a PKA inhibitor, Rp-cAMP (10-50 microM), and/or a PKC inhibitor, Calphostin C (10 nM). HMEC-1 exposed to elevated glucose (20 mM) for 14 days caused an increase in cyclic AMP accumulation, PKA, and PKC activity but was not associated with the activation of downstream events such as CRE and AP-1 binding activity. These data support the hypothesis that HMEC-1 is a suitable model to study the deleterious effects of elevated glucose on microvascular endothelial cells. Continued studies with HMEC-1 may prove advantageous in delineation of the molecular pathophysiology associated with diabetic microangiopathy.

Effect of Exercise Training on Cardiac Biomarkers in At-Risk Populations: A Systematic Review.

PubMed

Glenney, Susan Sullivan; Brockemer, Derrick Paul; Ng, Andy C; Smolewski, Michael A; Smolgovskiy, Vladimir M; Lepley, Adam S

2017-12-01

Studies have demonstrated beneficial effects of exercise on cardiovascular disease biomarkers for healthy individuals; however, a comprehensive review regarding the effect of exercise on cardiovascular disease biomarkers in at-risk populations is lacking. A literature search was performed to identify studies meeting the following criteria: randomized controlled study, participants with pathology/activity limitations, biomarker outcome (total cholesterol, high-density lipoprotein, low-density lipoprotein, C-reactive protein, insulin, triglycerides, or glucose), and exercise intervention. Means and standard deviations from each biomarker were used to calculate standardized Cohen's d effect sizes with 95% confidence intervals. In total, 37 articles were included. The majority (44/57; 77%) of data points demonstrated moderate to strong effects for the reduction in total cholesterol, triglycerides, and low-density lipoprotein, and elevation in high-density lipoprotein following exercise. The majority of data points demonstrated strong effects for reductions in blood glucose (24/30; 80%) and insulin (23/24; 96%) levels following exercise intervention. Evidence is heterogeneous regarding the influence of exercise on cardiovascular disease biomarkers in at-risk patients, which does not allow a definitive conclusion. Favorable effects include reductions in triglycerides, total cholesterol, low-density lipoprotein, glucose, and insulin, and elevation in high-density lipoprotein following exercise intervention. The strongest evidence indicates that exercise is favorable for the reduction in glucose and cholesterol levels among obese patients, and reduction of insulin regardless of population.

Generation of an immortalized mesenchymal stem cell line producing a secreted biosensor protein for glucose monitoring

PubMed Central

Weisman, Itamar; Romano, Jacob; Ivics, Zoltán; Izsvák, Zsuzsanna; Barkai, Uriel

2017-01-01

Diabetes is a chronic disease characterized by high levels of blood glucose. Diabetic patients should normalize these levels in order to avoid short and long term clinical complications. Presently, blood glucose monitoring is dependent on frequent finger pricking and enzyme based systems that analyze the drawn blood. Continuous blood glucose monitors are already on market but suffer from technical problems, inaccuracy and short operation time. A novel approach for continuous glucose monitoring is the development of implantable cell-based biosensors that emit light signals corresponding to glucose concentrations. Such devices use genetically modified cells expressing chimeric genes with glucose binding properties. MSCs are good candidates as carrier cells, as they can be genetically engineered and expanded into large numbers. They also possess immunomodulatory properties that, by reducing local inflammation, may assist long operation time. Here, we generated a novel immortalized human MSC line co-expressing hTERT and a secreted glucose biosensor transgene using the Sleeping Beauty transposon technology. Genetically modified hMSCs retained their mesenchymal characteristics. Stable transgene expression was validated biochemically. Increased activity of hTERT was accompanied by elevated and constant level of stem cell pluripotency markers and subsequently, by MSC immortalization. Furthermore, these cells efficiently suppressed PBMC proliferation in MLR transwell assays, indicating that they possess immunomodulatory properties. Finally, biosensor protein produced by MSCs was used to quantify glucose in cell-free assays. Our results indicate that our immortalized MSCs are suitable for measuring glucose concentrations in a physiological range. Thus, they are appropriate for incorporation into a cell-based, immune-privileged, glucose-monitoring medical device. PMID:28949988

Generation of an immortalized mesenchymal stem cell line producing a secreted biosensor protein for glucose monitoring.

PubMed

Siska, Evangelia K; Weisman, Itamar; Romano, Jacob; Ivics, Zoltán; Izsvák, Zsuzsanna; Barkai, Uriel; Petrakis, Spyros; Koliakos, George

2017-01-01

Diabetes is a chronic disease characterized by high levels of blood glucose. Diabetic patients should normalize these levels in order to avoid short and long term clinical complications. Presently, blood glucose monitoring is dependent on frequent finger pricking and enzyme based systems that analyze the drawn blood. Continuous blood glucose monitors are already on market but suffer from technical problems, inaccuracy and short operation time. A novel approach for continuous glucose monitoring is the development of implantable cell-based biosensors that emit light signals corresponding to glucose concentrations. Such devices use genetically modified cells expressing chimeric genes with glucose binding properties. MSCs are good candidates as carrier cells, as they can be genetically engineered and expanded into large numbers. They also possess immunomodulatory properties that, by reducing local inflammation, may assist long operation time. Here, we generated a novel immortalized human MSC line co-expressing hTERT and a secreted glucose biosensor transgene using the Sleeping Beauty transposon technology. Genetically modified hMSCs retained their mesenchymal characteristics. Stable transgene expression was validated biochemically. Increased activity of hTERT was accompanied by elevated and constant level of stem cell pluripotency markers and subsequently, by MSC immortalization. Furthermore, these cells efficiently suppressed PBMC proliferation in MLR transwell assays, indicating that they possess immunomodulatory properties. Finally, biosensor protein produced by MSCs was used to quantify glucose in cell-free assays. Our results indicate that our immortalized MSCs are suitable for measuring glucose concentrations in a physiological range. Thus, they are appropriate for incorporation into a cell-based, immune-privileged, glucose-monitoring medical device.

α/β-Hydrolase domain-6 and saturated long chain monoacylglycerol regulate insulin secretion promoted by both fuel and non-fuel stimuli

PubMed Central

Zhao, Shangang; Poursharifi, Pegah; Mugabo, Yves; Levens, Emily J.; Vivot, Kevin; Attane, Camille; Iglesias, Jose; Peyot, Marie-line; Joly, Erik; Madiraju, S.R. Murthy; Prentki, Marc

2015-01-01

Objective α/β-Hydrolase domain-6 (ABHD6) is a newly identified monoacylglycerol (MAG) lipase. We recently reported that it negatively regulates glucose stimulated insulin secretion (GSIS) in the β cells by hydrolyzing lipolysis-derived MAG that acts as a metabolic coupling factor and signaling molecule via exocytotic regulator Munc13-1. Whether ABHD6 and MAG play a role in response to all classes of insulin secretagogues, in particular various fuel and non-fuel stimuli, is unknown. Methods Insulin secretion in response to various classes of secretagogues, exogenous MAG and pharmacological agents was measured in islets of mice deficient in ABHD6 specifically in the β cell (BKO). Islet perifusion experiments and determinations of glucose and fatty acid metabolism, cytosolic Ca2+ and MAG species levels were carried out. Results Deletion of ABHD6 potentiated insulin secretion in response to the fuels glutamine plus leucine and α-ketoisocaproate and to the non-fuel stimuli glucagon-like peptide 1, carbamylcholine and elevated KCl. Fatty acids amplified GSIS in control and BKO mice to the same extent. Exogenous 1-MAG amplified insulin secretion in response to fuel and non-fuel stimuli. MAG hydrolysis activity was greatly reduced in BKO islets without changes in total diacylglycerol and triacylglycerol lipase activity. ABHD6 deletion induced insulin secretion independently from KATP channels and did not alter the glucose induced rise in intracellular Ca2+. Perifusion studies showed elevated insulin secretion during second phase of GSIS in BKO islets that was not due to altered cytosolic Ca2+ signaling or because of changes in glucose and fatty acid metabolism. Glucose increased islet saturated long chain 1-MAG species and ABHD6 deletion caused accumulation of these 1-MAG species at both low and elevated glucose. Conclusion ABHD6 regulates insulin secretion in response to fuel stimuli at large and some non-fuel stimuli by controlling long chain saturated 1-MAG levels that synergize with other signaling pathways for secretion. PMID:26909310

Positive Allosteric Modulation of the Calcium-sensing Receptor by Physiological Concentrations of Glucose*

PubMed Central

Medina, Johan; Nakagawa, Yuko; Nagasawa, Masahiro; Fernandez, Anny; Sakaguchi, Kazushige; Kitaguchi, Tetsuya; Kojima, Itaru

2016-01-01

The calcium-sensing receptor (CaSR) is activated by various cations, cationic compounds, and amino acids. In the present study we investigated the effect of glucose on CaSR in HEK293 cells stably expressing human CaSR (HEK-CaSR cells). When glucose concentration in the buffer was raised from 3 to 25 mm, a rapid elevation of cytoplasmic Ca2+ concentration ([Ca2+]c) was observed. This elevation was immediate and transient and was followed by a sustained decrease in [Ca2+]c. The effect of glucose was detected at a concentration of 4 mm and reached its maximum at 5 mm. 3-O-Methylglucose, a non-metabolizable analogue of glucose, reproduced the effect of glucose. Sucrose also induced an elevation of [Ca2+]c in HEK-CaSR cells. Similarly, sucralose was nearly as effective as glucose in inducing elevation of [Ca2+]c. Glucose was not able to increase [Ca2+]c in the absence of extracellular Ca2+. The effect of glucose on [Ca2+]c was inhibited by NPS-2143, an allosteric inhibitor of CaSR. In addition, NPS-2143 also inhibited the [Ca2+]c responses to sucralose and sucrose. Glucose as well as sucralose decreased cytoplasmic cAMP concentration in HEK-CaSR cells. The reduction of cAMP induced by glucose was blocked by pertussis toxin. Likewise, sucralose reduced [cAMP]c. Finally, glucose increased [Ca2+]c in PT-r parathyroid cells and in Madin-Darby canine kidney cells, both of which express endogenous CaSR. These results indicate that glucose acts as a positive allosteric modulator of CaSR. PMID:27613866

Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

PubMed

Jensen, Majken K; Bartz, Traci M; Djoussé, Luc; Kizer, Jorge R; Zieman, Susan J; Rimm, Eric B; Siscovick, David S; Psaty, Bruce M; Ix, Joachim H; Mukamal, Kenneth J

2013-10-01

Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993. Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.

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.

A glucose-responsive insulin therapy protects animals against hypoglycemia

PubMed Central

Yang, Ruojing; Wu, Margaret; Lin, Songnian; Nargund, Ravi P.; Li, Xinghai; Kelly, Theresa; Yan, Lin; Dai, Ge; Qian, Ying; Dallas-yang, Qing; Fischer, Paul A.; Cui, Yan; Shen, Xiaolan; Huo, Pei; Feng, Danqing Dennis; Erion, Mark D.; Kelley, David E.

2018-01-01

Hypoglycemia is commonly associated with insulin therapy, limiting both its safety and efficacy. The concept of modifying insulin to render its glucose-responsive release from an injection depot (of an insulin complexed exogenously with a recombinant lectin) was proposed approximately 4 decades ago but has been challenging to achieve. Data presented here demonstrate that mannosylated insulin analogs can undergo an additional route of clearance as result of their interaction with endogenous mannose receptor (MR), and this can occur in a glucose-dependent fashion, with increased binding to MR at low glucose. Yet, these analogs retain capacity for binding to the insulin receptor (IR). When the blood glucose level is elevated, as in individuals with diabetes mellitus, MR binding diminishes due to glucose competition, leading to reduced MR-mediated clearance and increased partitioning for IR binding and consequent glucose lowering. These studies demonstrate that a glucose-dependent locus of insulin clearance and, hence, insulin action can be achieved by targeting MR and IR concurrently. PMID:29321379

Effects of organophosphorus anticholinesterase compounds on brain glucose and energy metabolism. Final summary report, 1 October 1981-29 February 1984

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

Medina, M.A.; Miller, A.L.

1984-09-01

The effects of Soman and paraoxon on cerebral metabolic rate (CMRg) and the levels of various metabolites in rate brain were investigated. In non-convulsing animals, 0.8 of the paraoxon LD50 and 0.5 of the Soman LD50 tended to lower CMRg. A higher dose of Soman, 0.8-0.95 of the LD50, resulted in convulsive seizures in some but not all of the animals. In convulsing rats the CMRg and lactate levels were elevated primarily in the cortex and thalamus/basal ganglia. Decreased ATP and glucose levels with an elevated CMRg and lactate concentration was observed in the cortex, suggesting that Soman may bemore » uncoupling oxidative phosphorylation. Pretreatment with atropine prevented the behavioral manifestations and the elevated CMRg but not the hyperglycemia produced by an 0.8 LD50 dose of Soman. These results suggest that Soman-induced convulsions are similar to those produced by other central nervous system (CNS) excitatory agents in that only certain brain regions are affected. The use of atropine to block the CNS disturbances produced by Soman appears to be effective also does not result in the extensive depression of CMRg observed with TAB, a mixture of trimedoxime, atropine and benactyzine.« less

Patient, Provider, and System Factors Associated With Failure to Follow-Up Elevated Glucose Results in Patients Without Diagnosed Diabetes.

PubMed

Bowen, Michael E; Merchant, Zahra; Abdullah, Kazeen; Bhat, Deepa; Fish, Jason; Halm, Ethan A

2017-01-01

Although elevated glucose values are strongly associated with undiagnosed diabetes, they are frequently overlooked. Patient, provider, and system factors associated with failure to follow-up elevated glucose values in electronic medical records (EMRs) are not well described. We conducted a chart review in a comprehensive EMR with a patient portal and results management features. Established primary care patients with no known diagnosis of diabetes and ≥ 1 glucose value >125 mg/dL were included. Follow-up failure was defined as (1) no documented comment on the glucose value or result communication to the patient within 30 days or (2) no hemoglobin A 1c (HbA 1c ) ordered within 30 days or resulted within 12 months. Associations were examined using Wilcoxon and χ 2 tests. Of 150 charts reviewed, 97 met inclusion criteria. The median glucose was 133 mg/dL, and 20% of patients had multiple values >125 mg/dL. Only 36% of elevated glucose values were followed up. No associations were observed between patient characteristics, diabetes risk factors, or provider characteristics and follow-up failures. Automated flagging of glucose values ≥140 mg/dL by highlighting them red in the EMR was not associated with improved follow-up (46% vs 32%; P = .19). Even when follow-up occurred (n = 35), only 31% completed gold standard diabetes testing (HbA 1c ) within 12 months. Of the resulted HbA 1c tests (n = 11), 55% were in the prediabetes range (5.7%-6.4%). Two-thirds of elevated glucose values were not followed up, despite EMR features facilitating results management. Greater understanding of the results management process and improved EMR functionalities to support results management are needed.

Effects of administration route, dietary condition, and blood glucose level on kinetics and uptake of 18F-FDG in mice.

PubMed

Wong, Koon-Pong; Sha, Wei; Zhang, Xiaoli; Huang, Sung-Cheng

2011-05-01

The effects of dietary condition and blood glucose level on the kinetics and uptake of (18)F-FDG in mice were systematically investigated using intraperitoneal and tail-vein injection. Dynamic PET was performed for 60 min on 23 isoflurane-anesthetized male C57BL/6 mice after intravenous (n = 11) or intraperitoneal (n = 12) injection of (18)F-FDG. Five and 6 mice in the intravenous and intraperitoneal groups, respectively, were kept fasting overnight (18 ± 2 h), and the others were fed ad libitum. Serial blood samples were collected from the femoral artery to measure (18)F-FDG and glucose concentrations. Image data were reconstructed using filtered backprojection with CT-based attenuation correction. The standardized uptake value (SUV) was estimated from the 45- to 60-min image. The metabolic rate of glucose (MRGlu) and (18)F-FDG uptake constant (K(i)) were derived by Patlak graphical analysis. In the brain, SUV and K(i) were significantly higher in fasting mice with intraperitoneal injection, but MRGlu did not differ significantly under different dietary states and administration routes. Cerebral K(i) was inversely related to elevated blood glucose levels, irrespective of administration route or dietary state. In myocardium, SUV, K(i), and MRGlu were significantly lower in fasting than in nonfasting mice for both routes of injection. Myocardial SUV and K(i) were strongly dependent on the dietary state, and K(i) did not correlate with the blood glucose level. Similar results were obtained for skeletal muscle, although the differences were not as pronounced. Intraperitoneal injection is a valid alternative route, providing pharmacokinetic data equivalent to data from tail-vein injection for small-animal (18)F-FDG PET. Cerebral K(i) varies inversely with blood glucose level, but the measured cerebral MRGlu does not correlate with blood glucose level or dietary condition. Conversely, the K(i) values of the myocardium and skeletal muscle are strongly dependent on dietary condition but not on blood glucose level. In tissue in which (18)F-FDG uptake declines with increasing blood glucose, correction for blood glucose level will make SUV a more robust outcome measure of MRGlu.

Prognostic implications of stress hyperglycemia in acute ST elevation myocardial infarction. Prospective observational study.

PubMed

Sanjuán, Rafael; Núñez, Julio; Blasco, M Luisa; Miñana, Gema; Martínez-Maicas, Helena; Carbonell, Nieves; Palau, Patricia; Bodí, Vicente; Sanchis, Juan

2011-03-01

In patients with acute myocardial infarction, elevation of plasma glucose levels is associated with worse outcomes. The aim of this study was to evaluate the association between stress hyperglycemia and in-hospital mortality in patients with acute myocardial infarction with ST-segment elevation (STEMI). We analyzed 834 consecutive patients admitted for STEMI to the Coronary Care Unit of our center. Association between admission glucose and mortality was assessed with Cox regression analysis. Discriminative accuracy of the multivariate model was assessed by Harrell's C statistic. Eighty-nine (10.7%) patients died during hospitalization. Optimal threshold glycemia level of 140mg/dl on admission to predict mortality was obtained by ROC curves. Those who presented glucose ≥140mg/dl showed higher rates of malignant ventricular tachyarrhythmias (28% vs. 18%, P=.001), complicative bundle branch block (5% vs. 2%, P=.005), new atrioventricular block (9% vs. 5%, P=.05) and in-hospital mortality (15% vs. 5%, P<.001). Multivariate analysis showed that those with glycemia ≥140mg/dl exhibited a 2-fold increase of in-hospital mortality risk (95% CI: 1.2-3.5, P=.008) irrespective of diabetes mellitus status (P-value for interaction=0.487 and 0.653, respectively). Stress hyperglycemia on admission is a predictor of mortality and arrhythmias in patients with STEMI and could be used in the stratification of risk in these patients. Copyright © 2010 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

Protection of vascular endothelial cells from high glucose-induced cytotoxicity by emodin.

PubMed

Gao, Yun; Zhang, Jun; Li, Guilin; Xu, Hong; Yi, Yun; Wu, Qin; Song, Miaomiao; Bee, Yong Mong; Huang, Liping; Tan, Mengxia; Liang, Shangdong; Li, GuoDong

2015-03-01

Induction of endothelial cytotoxicity by hyperglycemia in diabetes has been widely accepted. Emodin is a natural anthraquinone in rhubarb used for treatment of diabetes, but its mechanism of action is not fully understood. This study aimed to examine the potential beneficial effects of emodin on endothelial cytotoxicity caused by high glucose milieu. Culture of human umbilical vein endothelial cells (HUVECs) with high concentrations of glucose resulted in damage to the cells, leading to decreased formazan products by 14-27%, reduced DNA contents by 12-19%, and increased hypodiploid apoptosis by 40-109%. These adverse effects of high glucose could be prevented to a large extent by co-culture with 3 μM of emodin which per se did not affect HUVECs viability. In addition, CCL5 expression of HUVECs cultured in high glucose medium was significantly elevated at both mRNA and protein levels, an effect abolished after treatment with emodin. Moreover, the enhanced adhesion of monocytes to HUVECs (2.1-2.2 fold over control) and elevated chemotaxis activities (2.3-2.4 fold over control) in HUVECs cultured in high glucose medium were completely reversed by emodin. Emodin also suppressed activation of p38 MAPK and ERK1/2 due to high glucose. Our data demonstrated that endothelial cytotoxicity occurred clearly when HUVECs were exposed to high glucose milieu and emodin was able to alleviate the impairments. The protective effects of emodin might be related to the inhibition of CCL5 expression and subsequent cell stress/inflammatory events possibly mediated by activation of MAPK signaling pathways. Copyright © 2015 Elsevier Inc. All rights reserved.

Impaired fasting glucose and the metabolic syndrome in an indigenous Siberian population.

PubMed

Snodgrass, J Josh; Leonard, William R; Tarskaia, Larissa A; Egorova, Aitalina G; Maharova, Natalia V; Pinigina, Irina A; Halyev, Simeon D; Matveeva, Niurguyana P; Romanova, Anna N

2010-02-01

This study investigated the lifestyle and anthropometric correlates of impaired fasting glucose and the presence of metabolic syndrome (MetS) among an Indigenous high-latitude herding population from north-eastern Siberia. Cross-sectional study of Yakut (Sakha) adult volunteers. We collected health, lifestyle and anthropometric data among 166 Yakut adults (>or=18 years old; 101 females, 65 males) from the rural village of Tyungyulyu (62 degrees N, 130 degrees E; population 2,500), Sakha Republic (Yakutia), Russia. Measurements of fasting glucose, triglycerides, HDL cholesterol, blood pressure and waist circumference were used to document the presence of MetS based on the updated Adult Treatment Panel (ATP) III definition. Metabolic syndrome was relatively uncommon among study participants, with only 10% of participants classified as having MetS, including 8% of females and 12% of males. Elevated blood pressure and low HDL cholesterol were the most common features of MetS in Yakut men and women, while elevated fasting glucose and high triglycerides were uncommon in both sexes. Relatively low mean fasting glucose concentrations were documented among Yakut women (4.46+/-0.65 mmol/L) and men (4.41+/-0.76 mmol/L); no participants were classified as diabetic. Fasting glucose and MetS are at relatively low levels in this population; however, rising rates of obesity are likely to lead to future increases in MetS and impaired fasting glucose in this population. Further, increasing consumption of market foods, many high in refined sugars, is likely to contribute to an increased presence of impaired fasting glucose and MetS.

MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase-Mediated Gluconeogenesis.

PubMed

Zhuo, Shu; Yang, Mengmei; Zhao, Yanan; Chen, Xiaofang; Zhang, Feifei; Li, Na; Yao, Pengle; Zhu, Tengfei; Mei, Hong; Wang, Shanshan; Li, Yu; Chen, Shiting; Le, Yingying

2016-11-01

MicroRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes, which is characterized by insulin resistance and hepatic glucose overproduction. We show that miRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through an adenovirus-mediated gain- and loss-of-function study, we found that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice and identified glycerol kinase (Gyk) as a direct target of miR-451. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, the glycerol gluconeogenesis axis, and the AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibited hepatic gluconeogenesis, alleviated hyperglycemia, and improved glucose tolerance. Further studies showed that miR-451 is upregulated by glucose and insulin in hepatocytes; the elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. This study provides the first evidence that miR-451 and Gyk regulate the AKT-FOXO1-PEPCK/G6Pase pathway and play critical roles in hepatic gluconeogenesis and glucose homeostasis and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes. © 2016 by the American Diabetes Association.

Effects of the probiotic strain Lactobacillus johnsonii strain La1 on autonomic nerves and blood glucose in rats.

PubMed

Yamano, Toshihiko; Tanida, Mamoru; Niijima, Akira; Maeda, Keiko; Okumura, Nobuaki; Fukushima, Yoichi; Nagai, Katsuya

2006-10-12

Oral administration of Lactobacillus casei reportedly reduces blood glucose concentrations in a non-insulin-dependent diabetic KK-Ay mouse model. In order to determine if other lactobacillus strains affect glucose metabolism, we evaluated the effect of the probiotic strain Lactobacillus johnsonii La1 (LJLa1) strain on glucose metabolism in rats. Oral administration of LJLa1 via drinking water for 2 weeks inhibited the hyperglycemia induced by intracranial injection of 2-deoxy-D-glucose (2DG). We found that the hyperglucagonemic response induced by 2DG was also suppressed by LJLa1. Oral administration of LJLa1 for 2 weeks also reduced the elevation of blood glucose and glucagon levels after an oral glucose load in streptozotocin-diabetic rats. In addition, we recently observed that intraduodenal injection of LJLa1 reduced renal sympathetic nerve activity and enhanced gastric vagal nerve activity, suggesting that LJLa1 might affect glucose metabolism by changing autonomic nerve activity. Therefore, we evaluated the effect of intraduodenal administration of LJLa1 on adrenal sympathetic nerve activity (ASNA) in urethane-anesthetized rats, since the autonomic nervous system, including the adrenal sympathetic nerve, may be implicated in the control of the blood glucose levels. Indeed, we found that ASNA was suppressed by intraduodenal administration of LJLa1, suggesting that LJLa1 might improve glucose tolerance by reducing glucagon secretion via alteration of autonomic nerve activities.

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.

Immediate metabolic effects of different nutritional regimens in critically ill medical patients.

PubMed

Müller, T F; Müller, A; Bachem, M G; Lange, H

1995-07-01

Metabolic effects of different caloric regimens were investigated in nonsurgical, medical patients with multiple-organ failure (MOF). Seven total parenteral nutrition (TPN) regimens were administered, differing in amount (14, 28, and 56 kcal/kg per day, i.e., hypo-, iso-, and hypercaloric nutrition, respectively) and distribution [carbohydrates (COH), amino acids (AA), long-chain and medium-chain triglycerides (LCT/MCT)] of calories. Each regimen was administered over 12 h. Metabolism was monitored by energy expenditure (EE), body temperature (BT), protein breakdown (PB), and blood glucose and serum lactate levels. Measurements were started within 2 days of MOF onset. The study was conducted in a medical intensive care unit. Twenty patients with MOF on mechanical ventilation (mean Apache II score x = 26) were investigated. The mean values of the EE (x = 31 kcal/kg per day), BT (x = 38 degrees C), PB (x = 1.5 g/kg per day), and lactate (x = 2.0 mmol/l) and glucose level (x = 222 mg/dl) parameters were elevated. EE, BT, and lactate and glucose levels were significantly lower under hypocaloric nutrition than during iso- and hypercaloric nutrition (p < 0.01). Differences in the metabolic effects of LCT and MCT were not significant. PB was significantly elevated under hypercaloric nutrition (p < 0.01). Protein balance was positive under hypercaloric nutrition, and negative under iso- and hypocaloric nutrition. In nonsurgical, medical patients neither hypercaloric nor isocaloric nutritional support prevented protein catabolism; in contrast, they enhanced the metabolic burden measured by EE, thermogenesis, urea production rate, and glucose and lactate levels. A hypocaloric regimen is therefore recommended for these patients during the early phase of MOF.

Short term response of insulin, glucose, growth hormone and corticosterone to acute vibration in rats.

NASA Technical Reports Server (NTRS)

Dolkas, C. B.; Leon, H. A.; Chackerian, M.

1971-01-01

Study carried out to obtain some notion of the initial phasing and interactive effects among some hormones known to be responsive to vibration stress. Sprague-Dawley derived rats were exposed to the acute effects of confinement and confinement with lateral (plus or minus G sub y) vibration. The coincident monitoring of glucose, insulin, growth hormone, and corticosterone plasma levels, during and immediately subsequent to exposure to brief low level vibration, exhibits the effects of inhibition of insulin release by epinephrine. The ability of insulin (IRI) to return rapidly to basal levels, from appreciably depressed levels during vibration, in the face of elevated levels of glucose is also shown. Corticosterone responds with almost equal rapidity, but in opposite phase to the IRI. The immuno-assayable growth hormone (IGH) dropped from a basal level of 32 ng/ml to 7.3 ng/ml immediately subsequent to vibration and remained at essentially that level throughout the experiment (60 min). Whether these levels represent a real fall in the rat or whether they merely follow the immuno-logically deficient form is still in question.

RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose.

PubMed

Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P; Campanucci, Verónica A

2018-01-01

Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

PubMed Central

Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P.

2018-01-01

Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes. PMID:29474476

Fluctuations in nucleus accumbens extracellular glutamate and glucose during motivated glucose-drinking behavior: dissecting the neurochemistry of reward.

PubMed

Wakabayashi, Ken T; Myal, Stephanie E; Kiyatkin, Eugene A

2015-02-01

While motivated behavior involves multiple neurochemical systems, few studies have focused on the role of glutamate, the brain's excitatory neurotransmitter, and glucose, the energetic substrate of neural activity in reward-related neural processes. Here, we used high-speed amperometry with enzyme-based substrate-sensitive and control, enzyme-free biosensors to examine second-scale fluctuations in the extracellular levels of these substances in the nucleus accumbens shell during glucose-drinking behavior in trained rats. Glutamate rose rapidly after the presentation of a glucose-containing cup and before the initiation of drinking (reward seeking), decreased more slowly to levels below baseline during consumption (sensory reward), and returned to baseline when the ingested glucose reached the brain (metabolic reward). When water was substituted for glucose, glutamate rapidly increased with cup presentation and in contrast to glucose drinking, increased above baseline after rats tasted the water and refused to drink further. Therefore, extracellular glutamate show distinct changes associated with key events of motivated drinking behavior and opposite dynamics during sensory and metabolic components of reward. In contrast to glutamate, glucose increased at each stimulus and behavioral event, showing a sustained elevation during the entire behavior and a robust post-ingestion rise that correlated with the gradual return of glutamate levels to their baseline. By comparing active drinking with passive intra-gastric glucose delivery, we revealed that fluctuations in extracellular glucose are highly dynamic, reflecting a balance between rapid delivery because of neural activity, intense metabolism, and the influence of ingested glucose reaching the brain. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Continuous Glucose Monitoring in Female NOD Mice Reveals Daily Rhythms and a Negative Correlation With Body Temperature.

PubMed

Korstanje, Ron; Ryan, Jennifer L; Savage, Holly S; Lyons, Bonnie L; Kane, Kevin G; Sukoff Rizzo, Stacey J

2017-09-01

Previous studies with continuous glucose monitoring in mice have been limited to several days or weeks, with the mouse's physical attachment to the equipment affecting behavior and measurements. In the current study, we measured blood glucose and body temperature at 10-second intervals for 12 weeks in a cohort of NOD/ShiLtJ female mice using wireless telemetry. This allowed us to obtain a high-resolution profile of the circadian rhythm of these two parameters and the onset of hyperglycemic development in real time. The most striking observations were the elevated nocturnal concentrations of glucose into the diabetic range days before elevations in diurnal glucose (when glucose concentrations are historically measured) and the strong, negative correlation between elevated blood glucose concentrations and body temperature with a steady decline of the body temperature with diabetes development. Taken together, this technological advancement provides improved resolution in the study of the disease trajectory of diabetes in mouse models, including relevant translatability to the current technologies of continuous glucose monitoring now regularly used in patients. Copyright © 2017 Endocrine Society.

Behavior-associated and post-consumption glucose entry into the nucleus accumbens extracellular space during glucose free-drinking in trained rats

PubMed Central

Wakabayashi, Ken T.; Kiyatkin, Eugene A.

2015-01-01

Glucose is the primary energetic substrate for the metabolic activity of brain cells and its proper delivery from the arterial blood is essential for neural activity and normal brain functions. Glucose is also a unique natural reinforcer, supporting glucose-drinking behavior without food or water deprivation. While it is known that glucose enters brain tissue via gradient-dependent facilitated diffusion, it remains unclear how glucose levels are changed during natural behavior and whether the direct central action of ingested glucose can be involved in regulating glucose-drinking behavior. Here, we used glucose biosensors with high-speed amperometry to examine the pattern of phasic and tonic changes in extracellular glucose in the nucleus accumbens (NAc) during unrestricted glucose-drinking in well-trained rats. We found that the drinking behavior is highly cyclic and is associated with relatively large and prolonged increases in extracellular glucose levels. These increases had two distinct components: a highly phasic but relatively small behavior-related rise and a larger tonic elevation that results from the arrival of consumed glucose into the brain’s extracellular space. The large post-ingestion increases in NAc glucose began minutes after the cessation of drinking and were consistently associated with periods of non-drinking, suggesting that the central action of ingested glucose could inhibit drinking behavior by inducing a pause in activity between repeated drinking bouts. Finally, the difference in NAc glucose responses found between active, behavior-mediated and passive glucose delivery via an intra-gastric catheter confirms that motivated behavior is also associated with metabolic glucose use by brain cells. PMID:26190984

Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats

PubMed Central

Swithers, Susan E.; Laboy, Alycia F.; Clark, Kiely; Cooper, Stephanie; Davidson, T.L.

2012-01-01

Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety. PMID:22561130

Isolated diastolic hypertension associated risk factors among Chinese in Anhui Province, China.

PubMed

Wang, Yanchun; Xing, Fengjun; Liu, Rongjuan; Liu, Li; Zhu, Yu; Wen, Yufeng; Sun, Wenjie; Song, Ziwei

2015-04-22

To explore potential risk factors of isolated diastolic hypertension (IDH) among young and middle-aged Chinese. A community-based cross-sectional study was conducted among 338 subjects, aged 25 years and above, using random sampling technique. There were 68 cases of IDH, 46 cases of isolated systolic hypertension (ISH), 89 cases of systolic and diastolic hypertension (SDH), and 135 of subjects with normal blood pressure. Cases and controls were matched on sex by frequency matching. Demographic characteristics, blood pressure and other relevant information were collected. Compared with controls, patients with IDH and ISH had significant higher level of triglyceride, high density lipoprotein, blood glucose and body mass index (BMI) (p < 0.05); while patients with SDH had significantly higher level of total cholesterol, triglyceride, glucose and BMI (p < 0.05). Linear mixed effects model showed that drinking tea, family history of hypertension (FHH), higher blood glucose, triglyceride and low density lipoprotein were related with elevated diastolic blood pressure (DBP) (p < 0.01); HFH, blood glucose, creatinine and BMI have positive effect on systolic blood pressure (SBP) (p < 0.05). Drinking tea, FHH, high levels of triglyceride, high density lipoprotein, blood glucose and BMI are associated with IDH among young and middle-aged Chinese.

Effect of Pterocarpus santalinus bark, on blood glucose, serum lipids, plasma insulin and hepatic carbohydrate metabolic enzymes in streptozotocin-induced diabetic rats.

PubMed

Kondeti, Vinay Kumar; Badri, Kameswara Rao; Maddirala, Dilip Rajasekhar; Thur, Sampath Kumar Mekala; Fatima, Shaik Sameena; Kasetti, Ramesh Babu; Rao, Chippada Appa

2010-05-01

The present study was designed to investigate the effect of bark of Pterocarpus santalinus, an ethnomedicinal plant, on blood glucose, plasma insulin, serum lipids and the activities of hepatic glucose metabolizing enzymes in streptozotocin-induced diabetic rats. Streptozotocin-induced diabetic rats were treated (acute/short-term and long-term) with ethyl acetate:methanol fractions of ethanolic extract of the bark of P. santalinus. Fasting blood glucose, HbA(1C), plasma insulin and protein were estimated before and after the treatment, along with hepatic glycogen, and activities of hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and glucose-6-phosphate dehydrogenase. Further anti-hyperlipidemic activity was studied by measuring the levels of serum lipids and lipoproteins. Phytochemical analysis of active fraction showed the presence of flavonoids, glycosides and phenols. Biological testing of the active fraction demonstrated a significant antidiabetic activity by reducing the elevated blood glucose levels and glycosylated hemoglobin, improving hyperlipidemia and restoring the insulin levels in treated experimental induced diabetic rats. Further elucidation of mechanism of action showed improvement in the hepatic carbohydrate metabolizing enzymes after the treatment. Our present investigation suggests that active fraction of ethanolic extract of bark of P. santalinus decreases streptozotocin induced hyperglycemia by increasing glycolysis and decreasing gluconeogenesis. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Prader-Willi syndrome with elevated follicle stimulating hormone levels and diabetes mellitus.

PubMed

Nagai, T; Mimura, N; Tomizawa, T; Monden, T; Mori, M

1998-12-01

A 21 -year-old man with Prader-Willi syndrome (PWS) was hospitalized due to hyperglycemia. After diet therapy and transient insulin administration, his blood glucose levels improved. Based on the fact that his urinary C-peptide levels increased, the diabetes mellitus may have been due to insulin resistance with obesity. In addition, his testes had become atrophied. Testosterone levels remained low even after human chorionic gonadotropin (HCG) administration. Luteinizing hormone (LH) levels were also low after LH releasing hormone (LHRH) administration. The LH response increased slightly after daily LHRH administration, indicating hypothalamic hypogonadism. Follicle stimulating hormone (FSH) levels were, however, high and increased after LHRH administration. The selective FSH elevation may have been due to the accompanying idiopathic oligospermia.

DHEA-induced modulation of renal gluconeogenesis, insulin sensitivity and plasma lipid profile in the control- and dexamethasone-treated rabbits. Metabolic studies.

PubMed

Kiersztan, Anna; Nagalski, Andrzej; Nalepa, Paweł; Tempes, Aleksandra; Trojan, Nina; Usarek, Michał; Jagielski, Adam K

2016-02-01

In view of antidiabetic and antiglucocorticoid effects of dehydroepiandrosterone (DHEA) both in vitro and in vivo studies were undertaken: (i) to elucidate the mechanism of action of both dexamethasone phosphate (dexP) and DHEA on glucose synthesis in primary cultured rabbit kidney-cortex tubules and (ii) to investigate the influence of DHEA on glucose synthesis, insulin sensitivity and plasma lipid profile in the control- and dexP-treated rabbits. Data show, that in cultured kidney-cortex tubules dexP significantly stimulated gluconeogenesis by increasing flux through fructose-1,6-bisphosphatase (FBPase). DexP-induced effects were dependent only upon glucocorticoid receptor. DHEA decreased glucose synthesis via inhibition of glucose-6-phosphatase (G6Pase) and suppressed the dexP-induced stimulation of renal gluconeogenesis. Studies with the use of inhibitors of DHEA metabolism in cultured renal tubules showed for the first time that DHEA directly affects renal gluconeogenesis. However, in view of analysis of glucocorticoids and DHEA metabolites levels in urine, it seems likely, that testosterone may also contribute to DHEA-evoked effects. In dexP-treated rabbits, plasma glucose level was not altered despite increased renal and hepatic FBPase and G6Pase activities, while a significant elevation of both plasma insulin and HOMA-IR was accompanied by a decline of ISI index. It thus appears that increased insulin levels were required to maintain normoglycaemia and to compensate the insulin resistance. DHEA alone affected neither plasma glucose nor lipid levels, while it increased insulin sensitivity and diminished both renal and hepatic G6Pase activities. Surprisingly, DHEA co-administrated with dexP did not alter insulin sensitivity, while it partially suppressed the dexP-induced elevation of renal G6Pase activity and plasma cholesterol and triglyceride contents. As (i) gluconeogenic pathway in rabbit is similar to that in human, and (ii) DHEA counteracts several dexP-evoked effects, it seems likely, that its supplementation might be beneficial to patients treated with glucocorticoids. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Acute effects of feeding fructose, glucose and sucrose on blood lipid levels and systemic inflammation.

PubMed

Jameel, Faizan; Phang, Melinda; Wood, Lisa G; Garg, Manohar L

2014-12-16

Recent studies have demonstrated a relationship between fructose consumption and risk of developing metabolic syndrome. Mechanisms by which dietary fructose mediates metabolic changes are poorly understood. This study compared the effects of fructose, glucose and sucrose consumption on post-postprandial lipemia and low grade inflammation measured as hs-CRP. This was a randomized, single blinded, cross-over trial involving healthy subjects (n=14). After an overnight fast, participants were given one of 3 different isocaloric drinks, containing 50 g of either fructose or glucose or sucrose dissolved in water. Blood samples were collected at baseline, 30, 60 and 120 minutes post intervention for the analysis of blood lipids, glucose, insulin and high sensitivity C-reactive protein (hs-CRP). Glucose and sucrose supplementation initially resulted in a significant increase in glucose and insulin levels compared to fructose supplementation and returned to near baseline values within 2 hours. Change in plasma cholesterol, LDL and HDL-cholesterol (measured as area under curve, AUC) was significantly higher when participants consumed fructose compared with glucose or sucrose (P<0.05). AUC for plasma triglyceride levels however remained unchanged regardless of the dietary intervention. Change in AUC for hs-CRP was also significantly higher in subjects consuming fructose compared with those consuming glucose (P<0.05), but not sucrose (P=0.07). This study demonstrates that fructose as a sole source of energy modulates plasma lipids and hsCRP levels in healthy individuals. The significance of increase in HDL-cholesterol with a concurrent increase in LDL-cholesterol and elevated hs-CRP levels remains to be delineated when considering health effects of feeding fructose-rich diets. ACTRN12614000431628.

Up-regulation of aldolase A and methylglyoxal production in adipocytes.

PubMed

Liu, Jianghai; Desai, Kaushik; Wang, Rui; Wu, Lingyun

2013-04-01

We previously reported that up-regulation of aldolase B, a key enzyme in fructose metabolism, was mainly responsible for vascular methylglyoxal (MG) overproduction under different pathological conditions. Here we investigated whether aldolase A, an enzyme of the glycolytic pathway, also caused MG overproduction in insulin-sensitive adipocytes. The relative contributions of different metabolic pathways or enzymes to MG generation were evaluated in cultured 3T3-L1 adipocytes. Glucose (25 mM) had no effect on aldolase A gene expression, but insulin (100 nM) up-regulated aldolase A mRNA and protein levels in the absence or presence of 25 mM glucose in adipocytes. Treatment with insulin increased levels of basal or glucose (25 mM)-induced MG and glucose 6-phosphate. However, insulin, glucose (25 mM) or their combination had no effect on cellular levels of sorbitol and fructose, but down-regulated gene expression of aldolase B to a similar extent, when compared with the control group. Incubation of 3T3-L1 adipocytes with fructose, acetone, acetol, threonine or glycine (25 mM), with or without insulin did not alter cellular MG levels. The elevated MG levels induced by insulin, glucose (25 mM) or their combination in adipocytes was completely reduced by siRNA knock down of aldolase A or application of 2-deoxy-D-glucose (a non-specific inhibitor of glucose uptake and glycolysis), but not by knock down of aldolase B. Insulin enhanced MG overproduction in insulin-sensitive adipocytes by up-regulating aldolase A, a mechanism that could be involved in the development of insulin resistance and obesity. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

The Role of SGLT1 and GLUT2 in Intestinal Glucose Transport and Sensing

PubMed Central

Röder, Pia V.; Geillinger, Kerstin E.; Zietek, Tamara S.; Thorens, Bernard; Koepsell, Hermann; Daniel, Hannelore

2014-01-01

Intestinal glucose absorption is mediated by SGLT1 whereas GLUT2 is considered to provide basolateral exit. Recently, it was proposed that GLUT2 can be recruited into the apical membrane after a high luminal glucose bolus allowing bulk absorption of glucose by facilitated diffusion. Moreover, SGLT1 and GLUT2 are suggested to play an important role in intestinal glucose sensing and incretin secretion. In mice that lack either SGLT1 or GLUT2 we re-assessed the role of these transporters in intestinal glucose uptake after radiotracer glucose gavage and performed Western blot analysis for transporter abundance in apical membrane fractions in a comparative approach. Moreover, we examined the contribution of these transporters to glucose-induced changes in plasma GIP, GLP-1 and insulin levels. In mice lacking SGLT1, tissue retention of tracer glucose was drastically reduced throughout the entire small intestine whereas GLUT2-deficient animals exhibited higher tracer contents in tissue samples than wild type animals. Deletion of SGLT1 resulted also in reduced blood glucose elevations and abolished GIP and GLP-1 secretion in response to glucose. In mice lacking GLUT2, glucose-induced insulin but not incretin secretion was impaired. Western blot analysis revealed unchanged protein levels of SGLT1 after glucose gavage. GLUT2 detected in apical membrane fractions mainly resulted from contamination with basolateral membranes but did not change in density after glucose administration. SGLT1 is unequivocally the prime intestinal glucose transporter even at high luminal glucose concentrations. Moreover, SGLT1 mediates glucose-induced incretin secretion. Our studies do not provide evidence for GLUT2 playing any role in either apical glucose influx or incretin secretion. PMID:24587162

Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii

PubMed Central

Boychuk, Carie R.; Gyarmati, Peter; Xu, Hong

2015-01-01

Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated. PMID:26084907

Elevated concentrations of C-reactive protein in subjects with type 2 diabetes mellitus are moderately influenced by glycemic control.

PubMed

Rodríguez-Morán, M; Guerrero-Romero, F

2003-03-01

The aim of this study was to establish whether glycemic control results in decrease of C-reactive protein (CRP) in Type 2 diabetic subjects. Newly diagnosed Type 2 diabetic subjects were recruited and followed-up by 6-month intensive medical management. All the participants were carefully interviewed, clinically examined, and laboratory tested to exclude conditions likely to provoke an inflammatory response, which was an exclusion criterium. CRP was measured by automated microparticle enzyme immunoassay (IMx, Abbott Laboratories, USA). Two-hundred and forty-eight patients were included in the analysis of data. At baseline, average CRP levels were of 9.6 +/- 6.2 mg/l. Only 14 (5.7%) patients showed a fasting glucose equal or lower than 6.1 mmo/l (5.6 +/- 0.4 mmo/l); of them, 6 (42.8%) had elevated CRP levels (8.8 +/- 6.7 mg/l). The fasting glucose in the 234 (94.3%) non-controlled subjects was 13.1 +/- 4.8 mmol/l; of them 179 (76.5%) subjects showed elevated CRP levels (10.9 +/- 6.5 mg/I). At the end of the 6-month follow-up, the average fasting glucose and HbA1c in the overall group decreased from 12.5 +/- 5.0 to 9.0 +/- 1.6 mmol/l, p < 0.00001, and 13.0 +/- 4.9 to 8.9 +/- 2.9%, p < 0.00001, which resulted in a significant reduction of CRP levels (9.6 +/- 6.2 to 6.3 +/- 3.0 mg/l, p < 0.00001). Seventy-one (28.6%) patients reached glycemic control; however, only 29 (40.8%) of them reduced the CRP levels to 3 mg/l or less (1.3 +/- 1.9 mg/l), and the remaining 42 controlled patients maintained high CRP concentration (4.2 +/- 1.2 mg/I), p < 0.00001. Concentration of CRP is moderately influenced by glycemic control in the Type 2 diabetic subjects.

Obese First-Degree Relatives of Patients with Type 2 Diabetes with Elevated Triglyceride Levels Exhibit Increased β-Cell Function

PubMed Central

Torres-Rasgado, Enrique; Porchia, Leonardo M.; Ruiz-Vivanco, Guadalupe; Gonzalez-Mejia, M. Elba; Báez-Duarte, Blanca G.; Pulido-Pérez, Patricia; Rivera, Alicia; Romero, Jose R.

2015-01-01

Abstract Background: Type 2 diabetes mellitus (T2DM) is characterized as a disease continuum that is marked by metabolic changes that are present for several years, sometimes well before frank diagnosis of T2DM. Genetic predisposition, ethnicity, geography, alterations in BMI, and lipid profile are considered important markers for the pathogenesis of T2DM through mechanisms that remain unresolved and controversial. The aim of this study was to investigate the relationship between triglycerides (TGs) and β-cell function, insulin resistance (IR), and insulin sensitivity (IS) in obese first-degree relatives of patients with T2DM (FDR-T2DM) among subjects from central Mexico with normal glucose tolerance (NGT). Methods: We studied 372 FDR-T2DM subjects (ages,18–65) and determined body mass index (BMI), fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), insulin, and TGs levels. Subjects were categorized based on glycemic control [NGT, prediabetes (PT2DM), or T2DM]. NGT subjects were further categorized by BMI [normal weight (Ob−) or obese (Ob+)] and TGs levels (TG−, <150 mg/dL, or TG+, ≥150 mg/dL). β-cell function, IR, and IS were determined by the homeostasis model assessment of β-cell function (HOMA2-β), homeostasis model assessment of insulin resistance (HOMA2-IR), and Quantitative Insulin Sensitivity Check Index (QUICKI) indices, respectively. Results: The obese subjects with elevated TGs levels had 21%–60% increased β-cell function when compared to all groups (P<0.05). In addition, this group had insulin levels, IS, and IR similar to PT2DM. Furthermore, only in obese subjects did TGs correlate with β-cell function (ρ=0.502, P<0.001). Conclusion: We characterized FDR-T2DM subjects from central Mexico with NGT and revealed a class of obese subjects with elevated TGs and β-cell function, which may precede PT2DM. PMID:25423015

Overweight, high blood pressure and impaired fasting glucose in Uyghur, Han, and Kazakh Chinese children and adolescents.

PubMed

Yan, W L; Li, X S; Wang, Q; Huang, Y D; Zhang, W G; Zhai, X H; Wang, C C; Lee, J H

2015-01-01

To investigate whether the levels of blood pressure and fasting glucose differ among Chinese children of three different ethnicities (i.e., Uyghurs, Kazakhs, and Hans) and whether the differences are explained by childhood obesity. A school-based cross-sectional study was conducted in a large three ethnic pediatric population (n = 6633), whose ages ranged from 7 to 18 years. Anthropometrics and blood pressure were measured using standard protocols. Fasting glucose was measured in a subset of children (n = 2295) who were randomly selected based on ethnicity and age. The age-sex stratified Chinese national cut-offs were used to define obesity and high blood pressure (HBP). The prevalence of HBP, impaired fasting glucose (IFG), mean levels of blood pressure, and glucose were compared among three ethnic groups. 2142 Uyghurs, 2078 Han, and 1997 Kazakhs were analyzed. After adjusting for age and body mass index (BMI), the mean blood pressure for Uyghurs was on average, 2-4 mm Hg lower than those for Hans and Kazakhs. Kazakhs had the lowest mean fasting glucose compared with Hans and Uyghurs (4.5 vs. 5.0 vs. 4.8 mmol/L, respectively). The differences in blood pressure and fasting glucose persisted even after adjusting for age and BMI, and the differences among ethnic groups in blood pressure levels and fasting glucose levels were observed as early as 7-9 years of age. The prevalence of HBP and IFG differed significantly among Uyghurs, Hans, and Kazakhs, and the ethnic differences observed in childhood were consistent with those observed in adults from the same region. While childhood obesity is a significant risk factor for hypertension and elevated glucose, the differences among ethnic groups were not explained by obesity alone.

Fabrication of interdigitated high-performance zinc oxide nanowire modified electrodes for glucose sensing.

PubMed

Haarindraprasad, R; Hashim, Uda; Gopinath, Subash C B; Perumal, Veeradasan; Liu, Wei-Wen; Balakrishnan, S R

2016-06-21

Diabetes is a metabolic disease with a prolonged elevated level of glucose in the blood leads to long-term complications and increases the chances for cardiovascular diseases. The present study describes the fabrication of a ZnO nanowire (NW)-modified interdigitated electrode (IDE) to monitor the level of blood glucose. A silver IDE was generated by wet etching-assisted conventional lithography, with a gap between adjacent electrodes of 98.80 μm. The ZnO-based thin films and NWs were amended by sol-gel and hydrothermal routes. High-quality crystalline and c-axis orientated ZnO thin films were observed by XRD analyses. The ZnO thin film was annealed for 1, 3 and 5 h, yielding a good-quality crystallite with sizes of 50, 100 and 110 nm, and the band gaps were measured as 3.26, 3.20 and 3.17 eV, respectively. Furthermore, a flower-modeled NW was obtained with the lowest diameter of 21 nm. Our designed ZnO NW-modified IDE was shown to have a detection limit as low as 0.03 mg/dL (correlation coefficient = 0.98952) of glucose with a low response time of 3 s, perform better than commercial glucose meter, suitable to instantly monitor the glucose level of diabetes patients. This study demonstrated the high performance of NW-mediated IDEs for glucose sensing as alternative to current glucose sensors. Copyright © 2016 Elsevier B.V. All rights reserved.

Elevated Levels of Urinary Markers of Oxidative DNA and RNA Damage in Type 2 Diabetes with Complications.

PubMed

Liu, Xinle; Gan, Wei; Zou, Yuangao; Yang, Bin; Su, Zhenzhen; Deng, Jin; Wang, Lanlan; Cai, Jianping

2016-01-01

The mechanisms underlying progression of type 2 diabetes are complex and varied. Recent studies indicated that oxidative stress provided a new sight. To further assess the relationship between nucleic acid oxidation and complications in patients with type 2 diabetes and explore its possible molecular mechanisms, we studied 1316 subjects, including 633 type 2 diabetes patients and 683 age- and sex-matched healthy controls. Urinary levels of DNA oxidation marker 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and RNA oxidation marker 8-oxo-7,8-dihydroguanosine (8-oxoGuo) were measured by ultraperformance liquid chromatography and mass spectrometry (UPLC-MS/MS). Serum glucose, HbA1c, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides (TG) were also determined. The results showed significantly elevated levels of both the urinary 8-oxodGuo and 8-oxoGuo in diabetes patients with/without complications compared with age-matched healthy control subjects (p = 0.02 and p < 0.001, resp.). Patients with complications, especially macrovascular complications, exhibited higher levels of 8-oxoGuo than those without complications, while there was no difference in the concentrations of serum glucose and lipids. The finding indicates the role for oxidative damage to DNA and RNA, as a molecular mechanism contributing to the progression of type 2 diabetes. Elevated levels of 8-oxoGuo may be a risk factor for type 2 diabetes complications, especially in diabetic macrovascular complications.

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.

Fasting modifies Aroclor 1254 impact on plasma cortisol, glucose and lactate responses to a handling disturbance in Arctic charr

USGS Publications Warehouse

Jorgensen, E.H.; Vijayan, M.M.; Aluru, N.; Maule, A.G.

2002-01-01

Integrated effects of polychlorinated biphenyl (PCB) and nutritional status on responses to handling disturbance were investigated in the Arctic charr (Salvelinus alpinus). The fish were orally contaminated with Aroclor 1254 and held either with or without food for 5 months before they were subjected to a 10-min handling disturbance. Food-deprived fish were given 0, 1, 10 or 100 mg PCB kg−1 and the fed fish 0 or 100 mg PCB kg−1. Plasma cortisol, glucose and lactate levels were measured at 0 (pre-handling), 1, 3, 6 and 23 h after the handling disturbance. Food-deprived control fish had elevated plasma cortisol levels compared with fed fish before handling. These basal cortisol levels were suppressed by PCB in food-deprived fish, and elevated by PCB in fed fish. The immediate cortisol and glucose responses to handling disturbance were suppressed by PCB in a dose-dependent way in food-deprived fish. Although these responses were also lowered by PCB in the fed fish, the effect was much less pronounced than in food-deprived fish. There were only minor effects on plasma lactate responses. Our findings suggest that the stress responses of the Arctic charr are compromised by PCB and that the long-term fasting, typical of high-latitude fish, makes these species particularly sensitive to organochlorines such as PCB.

Characterization of the ZDSD Rat: A Translational Model for the Study of Metabolic Syndrome and Type 2 Diabetes

PubMed Central

Peterson, Richard G.; de Winter, Willem; Huebert, Norman; Hansen, Michael K.

2015-01-01

Metabolic syndrome and T2D produce significant health and economic issues. Many available animal models have monogenic leptin pathway mutations that are absent in the human population. Development of the ZDSD rat model was undertaken to produce a model that expresses polygenic obesity and diabetes with an intact leptin pathway. A lean ZDF rat with the propensity for beta-cell failure was crossed with a polygenetically obese Crl:CD (SD) rat. Offspring were selectively inbred for obesity and diabetes for >30 generations. In the current study, ZDSD rats were followed for 6 months; routine clinical metabolic endpoints were included throughout the study. In the prediabetic metabolic syndrome phase, ZDSD rats exhibited obesity with increased body fat, hyperglycemia, insulin resistance, dyslipidemia, glucose intolerance, and elevated HbA1c. As disease progressed to overt diabetes, ZDSD rats demonstrated elevated glucose levels, abnormal oral glucose tolerance, increases in HbA1c levels, reductions in body weight, increased insulin resistance with decreasing insulin levels, and dyslipidemia. The ZDSD rat develops prediabetic metabolic syndrome and T2D in a manner that mirrors the development of metabolic syndrome and T2D in humans. ZDSD rats will provide a novel, translational animal model for the study of human metabolic diseases and for the development of new therapies. PMID:25961053

FFA2 Contribution to Gestational Glucose Tolerance Is Not Disrupted by Antibiotics.

PubMed

Fuller, Miles; Li, Xiaoran; Fisch, Robert; Bughara, Moneb; Wicksteed, Barton; Kovatcheva-Datchary, Petia; Layden, Brian T

2016-01-01

During the insulin resistant phase of pregnancy, the mRNA expression of free fatty acid 2 receptor (Ffar2) is upregulated and as we recently reported, this receptor contributes to insulin secretion and pancreatic beta cell mass expansion in order to maintain normal glucose homeostasis during pregnancy. As impaired gestational glucose levels can affect metabolic health of offspring, we aimed to explore the role of maternal Ffar2 expression during pregnancy on the metabolic health of offspring and also the effects of antibiotics, which have been shown to disrupt gut microbiota fermentative activity (the source of the FFA2 ligands) on gestational glucose homeostasis. We found that maternal Ffar2 expression and impaired glucose tolerance during pregnancy had no effect on the growth rates, ad lib glucose and glucose tolerance in the offspring between 3 and 6 weeks of age. To disrupt short chain fatty acid production, we chronically treated WT mice and Ffar2-/- mice with broad range antibiotics and further compared their glucose tolerance prior to pregnancy and at gestational day 15, and also quantified cecum and plasma SCFAs. We found that during pregnancy antibiotic treatment reduced the levels of SCFAs in the cecum of the mice, but resulted in elevated levels of plasma SCFAs and altered concentrations of individual SCFAs. Along with these changes, gestational glucose tolerance in WT mice, but not Ffar2-/- mice improved while on antibiotics. Additional data showed that gestational glucose tolerance worsened in Ffar2-/- mice during a second pregnancy. Together, these results indicate that antibiotic treatment alone is inadequate to deplete plasma SCFA concentrations, and that modulation of gut microbiota by antibiotics does not disrupt the contribution of FFA2 to gestational glucose tolerance.

O-GlcNAc in cancer: An Oncometabolism-fueled vicious cycle.

PubMed

Hanover, John A; Chen, Weiping; Bond, Michelle R

2018-06-01

Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueled by oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glycosylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-GlcNAc modification of key targets in the cytoplasm, nucleus and mitochondrion. These targets include transcription factors, kinases, key cytoplasmic enzymes of intermediary metabolism, and electron transport chain complexes. O-GlcNAcylation can thereby alter epigenetics, transcription, signaling, proteostasis, and bioenergetics, key 'hallmarks of cancer'. In this review, we summarize accumulating evidence that many cancer hallmarks are linked to dysregulation of O-GlcNAc cycling on cancer-relevant targets. We argue that onconutrient and oncometabolite-fueled elevation increases HBP flux and triggers O-GlcNAcylation of key regulatory enzymes in glycolysis, Kreb's cycle, pentose-phosphate pathway, and the HBP itself. The resulting rerouting of glucose metabolites leads to elevated O-GlcNAcylation of oncogenes and tumor suppressors further escalating elevation in HBP flux creating a 'vicious cycle'. Downstream, elevated O-GlcNAcylation alters DNA repair and cellular stress pathways which influence oncogenesis. The elevated steady-state levels of O-GlcNAcylated targets found in many cancers may also provide these cells with a selective advantage for sustained growth, enhanced metastatic potential, and immune evasion in the tumor microenvironment.

Estimation of salivary glucose, salivary amylase, salivary total protein and salivary flow rate in diabetics in India.

PubMed

Panchbhai, Arati S; Degwekar, Shirish S; Bhowte, Rahul R

2010-09-01

Diabetes is known to influence salivary composition and function, eventually affecting the oral cavity. We thus evaluated saliva samples for levels of glucose, amylase and total protein, and assessed salivary flow rate in diabetics and healthy non-diabetics. We also analyzed these parameters with regard to duration and type of diabetes mellitus and gender, and aimed to assess the interrelationships among the variables included in the study. A total of 120 age- and sex-matched participants were divided into 3 groups of 40 each; the uncontrolled diabetic group, the controlled diabetic group and the healthy non-diabetic group. Salivary investigations were performed using unstimulated whole saliva. Mean salivary glucose levels were found to be significantly elevated in both uncontrolled and controlled diabetics, as compared to healthy non-diabetics. There were significant decreases in mean salivary amylase levels in controlled diabetics when compared to healthy non-diabetics. Other than salivary glucose, no other parameters were found to be markedly affected in diabetes mellitus. Further research is needed to explore the clinical implications of these study results.

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.

Fasting blood glucose level and prognosis in non-small cell lung cancer (NSCLC) patients.

PubMed

Luo, Juhua; Chen, Yea-Jyh; Chang, Li-Jung

2012-05-01

Diabetes has been consistently linked to many forms of cancers, such as liver, colorectal, pancreatic, and breast cancer, however, the role of diabetes in outcome among cancer patients remains unclear. In this study, we retrospectively reviewed electronic medical records of 342 inpatients newly diagnosed with NSCLC referred by a teaching hospital cancer center in southern Taiwan between 2005 and 2007 to examine the effects of fasting glucose levels at time of cancer diagnosis on overall survival in patients with non-small cell lung cancer (NSCLC). All patients were followed up until the end of 2010. The Kaplan-Meier method was used to compare survival curves for patients with and without diabetes. The Cox proportional hazards model was used to estimate hazard ratios for the association between diabetes, other prognostic factors and patient survival. We observed that significant prognostic factors for poor overall survival in patients with NSCLC included older age, smoking, poor performance status, advanced stage (stage IIIB or IV), and no cancer-directed surgery treatment. Particularly, we identified that diabetic state defined by fasting blood glucose level ≥126 mg/dl was another independent prognostic factor for these patients. Compared with those who had normal range of fasting glucose level (70-99 mg/dl), patients with high fasting glucose level (≥126 mg/dl) had 69% excess risk of all-cause mortality in patients with NSCLC. Diabetes as indicated by elevated fasting blood glucose was independently associated with a significantly higher risk of all-cause mortality in patients with NSCLC, indicating that diabetes or hyperglycemia effectively controlled may present an opportunity for improving prognosis in NSCLS patients with abnormal glucose level. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes.

PubMed

Jabbour, S A; Goldstein, B J

2008-08-01

The kidney plays a central role in the regulation of plasma glucose levels, although until recently this has not been widely appreciated or considered a target for therapeutic intervention. The sodium glucose co-transporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, which normally prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 that provoke the renal excretion of glucose have been discovered, thereby providing a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. To explore the physiology of SGLT2 action and discuss several SGLT2 inhibitors that have entered early clinical development. All publicly available data were identified by searching the internet for 'SGLT2' and 'SGLT2 inhibitor' through 1 November 2007. Published articles, press releases and abstracts presented at national and international meetings were considered. Sodium glucose co-transporter type 2 inhibition is a novel treatment option for diabetes, which has been studied in preclinical models and a few potent and selective SGLT2 inhibitors have been reported and are currently in clinical development. These agents appear to be safe and generally well tolerated, and will potentially be a beneficial addition to the growing battery of oral antihyperglycaemic agents.

Case 22:Type II diabetes

USDA-ARS?s Scientific Manuscript database

Diabetes mellitus is characterized by elevated blood glucose levels. It is composed of two types depending on the pathogenesis. Type I diabetes is characterized by insulin deficiency and usually has its onset during childhood or teenage years. This is also called ketosis-prone diabetes. Type II diab...

Comparison of vegetable shortening and cocoa butter as vehicles for cortisol manipulation in Salmo trutta.

PubMed

Birnie-Gauvin, K; Peiman, K S; Larsen, M H; Aarestrup, K; Gilmour, K M; Cooke, S J

2018-01-01

This study demonstrates that vegetable shortening and cocoa butter are two effective vehicles for intraperitoneal cortisol implants in juvenile teleosts, specifically brown trout Salmo trutta, residing in north temperate freshwater environments. Each vehicle showed a different pattern of cortisol elevation. Vegetable shortening was found to be a more suitable vehicle for long-term cortisol elevation [elevated at 3, 6 and 9 days post treatment (dpt)], while cocoa butter may be better suited for short-term cortisol elevation (only elevated at 3 dpt). Additionally, plasma cortisol levels were higher with cortisol-vegetable shortening than with cortisol-cocoa butter implants. Plasma glucose levels were elevated 6 and 9 dpt for fishes injected with cortisol-vegetable shortening, but did not change relative to controls and shams in cortisol-cocoa butter fishes. In conclusion, vegetable shortening and cocoa butter are both viable techniques for cortisol manipulation in fishes in temperate climates, providing researchers with different options depending on study objectives. © 2017 The Fisheries Society of the British Isles.

Higher hdl levels are a preventive factor for metabolic syndrome in obese Turkish children.

PubMed

Özer, Samet; Yılmaz, Resul; Özlem Kazanci, Nafia; Sönmezgöz, Ergün; Karaaslan, Erhan; Altuntaş, Buket; Emre Kuyucu, Yunus

2014-10-03

The definition of childhood metabolic syndrome has not been described clearly. Childhood obesity is increasing gradually, and the incidence of childhood metabolic syndrome is also rising. We aimed to show metabolic syndrome components and preventive factors for metabolic syndrome in obese children Methods: In the present study, 187 obese children and adolescents 5-18 years old were investigated retrospectively. Demographic data, anthropometric measurements, body mass index, blood pressure values, insulin levels, oral glucose tolerance test results, total cholesterol, high density lipoprotein, and triglyceride levels were obtained from hospital records. A body mass index > 95th percentile was considered obese. Insulin resistance was calculated according to the oral glucose tolerance test with 1.75 g/kg glucose maximum 75 g glucose. The insulin sensitivity index and homeostatic model assessment-insulin resistance (HOMA IR) were calculated and compared. Metabolic syndrome was diagnosed according to the modified WHO criteria adapted for metabolic syndrome in children. Abnormal glucose homeostasis was detected in 53% of subjects. Dyslipidaemia was present in 45.7% and hypertension in 16.6% of the patients. Metabolic syndrome was identified in 24.6% of obese children and adolescents. High HOMA-IR values and fasting glucose levels, elevated triglycerides and lower HDL levels were an indication of metabolic syndrome. Obesity and insulin resistance are significant factors for the development of metabolic syndrome in children and adolescents. In obese children higher HDL levels are preventive factor for metabolic syndrome. Preventing obesity and insulin resistance may decrease the prevalence of metabolic syndrome. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Isoproterenol exacerbates hyperglycemia and modulates chromium distribution in mice fed with a high fat diet.

PubMed

Chang, Geng-Ruei; Chen, Wen-Kai; Hou, Po-Hsun; Mao, Frank Chiahung

2017-12-01

Isoproterenol (ISO), a nonselective β-adrenoceptor agonist for treating bradycardia and asthma, has been proposed to raise blood glucose level. Little is known regarding the relationship between ISO treatment, the induced chromium (Cr) redistribution, and changes in glucose metabolism. We aimed to characterize the effects of a single dose of ISO on glucose homeostasis and Cr level changes in an obesity mouse model. Mice (C57BL6/j strain) were first fed for a continuous period of 12 weeks with either a high fat diet (HFD), to develop an obesity animal model, or a standard diet (SD), to develop a lean animal model as controls. These groups were each separated into two subgroups to receive either a single dose of ISO or saline (control). We measured in vivo their metabolic parameters, fasting glucose level, area under the curve (AUC) for glucose level time profile, insulin level time profile, insulin sensitivity index, and chromium distribution. After a single dose of ISO, the SD-fed mice had slightly higher blood glucose levels compared with the SD controls, when the level was measured 30 and 60min after injection. By contrast, the ISO-treated HFD-fed mice had significantly higher blood glucose levels and AUC during the entire 120min following one administration compared with the HFD control group. Additionally, they had a substantially lower HOMA-IR index, whereas insulin levels remained unchanged. The Cr level in their bones and liver was decreased, and loss of Cr through urinary excretion was elevated. The results demonstrated that ISO exacerbated hyperglycemic syndrome in the obesity animal model. ISO induced a net negative Cr balance as a result of increased urinary excretion, leading to Cr mobilization that was not desirable to overcome the hyperglycemia. Copyright © 2017 Elsevier GmbH. All rights reserved.

FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes.

PubMed

Laeger, Thomas; Baumeier, Christian; Wilhelmi, Ilka; Würfel, Josefine; Kamitz, Anne; Schürmann, Annette

2017-11-01

Fibroblast growth factor 21 (FGF21) is considered to be a promising therapeutic candidate for the treatment of type 2 diabetes. However, as FGF21 levels are elevated in obese and diabetic conditions we aimed to test if exogenous FGF21 is sufficient to prevent diabetes and beta cell loss in New Zealand obese (NZO) mice, a model for polygenetic obesity and type 2 diabetes. Male NZO mice were treated with a specific dietary regimen that leads to the onset of diabetes within 1 week. Mice were treated subcutaneously with PBS or FGF21 to assess changes in glucose homeostasis, energy expenditure, food intake and other metabolic endpoints. FGF21 treatment prevented islet destruction and the onset of hyperglycaemia, and improved glucose clearance. FGF21 increased energy expenditure by inducing browning in subcutaneous white adipose tissue. However, as a result of a compensatory increased food intake, body fat did not decrease in response to FGF21 treatment, but exhibited elevated Glut4 expression. FGF21 prevents the onset of diet-induced diabetes, without changing body fat mass. Beneficial effects are mediated via white adipose tissue browning and elevated thermogenesis. Furthermore, these data indicate that obesity does not induce FGF21 resistance in NZO mice.

The Impacts of Gastroileostomy Rat Model on Glucagon-like Peptide-1: a Promising Model to Control Type 2 Diabetes Mellitus.

PubMed

Keleidari, Behrouz; Mohammadi Mofrad, Rastin; Shahabi Shahmiri, Shahab; Sanei, Mohammad Hossein; Kolahdouzan, Mohsen; Sheikhbahaei, Erfan

2018-05-21

One of the new current treatment options for Diabetes Mellitus is about increasing glucagon-like peptide-1 (GLP-1) activity. GLP-1 with its incretin effect showed major role in glucose homeostasis. Gastroileostomy can increase GLP-1 secretion by rapid delivery of undigested food to the terminal ileum. We studied the early effects of a gastroileostomy on serum levels of GLP-1, glucose, and insulin in rats. Gastroileostomies with side-to-side anastomosis were performed on 15 male New Zealand rats. Blood samples were obtained before and 1 week after the gastroileostomy. Our results showed that the rats lost a lot of weight from start (330 ± 15 g) to the end (240 ± 25 g) of the experiment (p = 0.048). The data analysis showed that the gastroileostomy surgery elevates the level of GLP-1in plasma significantly (89.1852 vs. 177.440 respectively; p < 0.001) and caused a significant decrease in plasma glucose as well (92.00 and 66.29 mg/dL respectively; p < 0.001). However, the insulin state elevated after the surgery significantly (8.03 vs. 9.89; p < 0.001). In this study, we showed the effectiveness of gastroileostomy treatment to decrease body weight and plasma glucose with increased GLP-1 in rats. This small rat model suggests the potential of this surgery to treat type 2 diabetes mellitus.

Transgenic Wuzhishan minipigs designed to express a dominant-negative porcine growth hormone receptor display small stature and a perturbed insulin/IGF-1 pathway.

PubMed

Li, Feida; Li, Yong; Liu, Huan; Zhang, Xingju; Liu, Chuxin; Tian, Kai; Bolund, Lars; Dou, Hongwei; Yang, Wenxian; Yang, Huanming; Staunstrup, Nicklas Heine; Du, Yutao

2015-12-01

Growth hormone (GH) is an anabolic mitogen with widespread influence on cellular growth and differentiation as well as on glucose and lipid metabolism. GH binding to the growth hormone receptor (GHR) on hepatocytes prompts expression of insulin growth factor I (IGF-1) involved in nutritionally induced compensatory hyperplasia of pancreatic β-cell islets and insulin release. A prolonged hyperactivity of the IGF-1/insulin axis in the face of insulinotropic nutrition, on the other hand, can lead to collapse of the pancreatic islets and glucose intolerance. Individuals with Laron syndrome carry mutations in the GHR gene resulting in severe congenital IGF-1 deficiency and elevated GH serum levels leading to short stature as well as perturbed lipid and glucose metabolism. However, these individuals enjoy a reduced prevalence of acne, cancer and possibly diabetes. Minipigs have become important biomedical models for human conditions due to similarities in organ anatomy, physiology, and metabolism relative to humans. The purpose of this study was to generate transgenic Wuzhishan minipigs by handmade cloning with impaired systemic GHR activity and assess their growth profile and glucose metabolism. Transgenic minipigs featuring overexpression of a dominant-negative porcine GHR (GHR(dm)) presented postnatal growth retardation and proportionate dwarfism. Molecular changes included elevated GH serum levels and mild hyperglycemia. We believe that this model may prove valuable in the study of GH functions in relation to cancer, diabetes and longevity.

Chromium (d-Phenylalanine)3 Alleviates High Fat-Induced Insulin Resistance and Lipid Abnormalities

PubMed Central

Kandadi, Machender Reddy; Unnikrishnan, MK; Warrier, Ajaya Kumar Sankara; Du, Min; Ren, Jun; Sreejayan, Nair

2010-01-01

High-fat diet has been implicated as a major cause of insulin resistance and dyslipidemia. The objective of this study was to evaluate the impact of dietary-supplementation of chromium (d-phenylalanine)3 [Cr(d-Phe)3] on -glucose and -insulin tolerance in high-fat diet fed mice. C57BL/6-mice were randomly assigned to orally receive vehicle or Cr(d-Phe)3 (45 μg of elemental chromium/kg/day) for 8-weeks. High-fat-fed mice exhibited impaired whole-body -glucose and- insulin tolerance and elevated serum triglyceride levels compared to normal chow-fed mice. Insulin-stimulated glucose up- take in the gastrocnemius muscles, assessed as 2-[3H-deoxyglucose] incorporation was markedly diminished in high-fat fed mice compared to control mice. Treatment with chromium reconciled the high-fat diet-induced alterations in carbohydrate and lipid metabolism. Treatment of cultured, differentiated myotubes with palmitic acid evoked insulin resistance as evidenced by lower levels of insulin-stimulated Akt-phosphorylation, elevated JNK-phosphorylation, (assessed by Western blotting), attenuation of phosphoinositol-3-kinase activity (determined in the insulin-receptor substrate-1-immunoprecipitates by measuring the extent of phosphorylation of phosphatidylinositol by γ-32P-ATP), and impairment in cellular glucose up-take, all of which were inhibited by Cr(d-Phe)3. These results suggest a beneficial effect of chromium-supplementation in insulin resistant conditions. It is likely that these effects of chromium may be mediated by augmenting downstream insulin signaling. PMID:21134603

High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature.

PubMed

Li, Wei; Maloney, Ronald E; Aw, Tak Yee

2015-08-01

We previously demonstrated that in normal glucose (5mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG-occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG-occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Cardiac Expression of Human Type 2 Iodothyronine Deiodinase Increases Glucose Metabolism and Protects Against Doxorubicin-induced Cardiac Dysfunction in Male Mice

PubMed Central

Hong, Eun-Gyoung; Kim, Brian W.; Young Jung, Dae; Hun Kim, Jong; Yu, Tim; Seixas Da Silva, Wagner; Friedline, Randall H.; Bianco, Suzy D.; Seslar, Stephen P.; Wakimoto, Hiroko; Berul, Charles I.; Russell, Kerry S.; Won Lee, Ki; Larsen, P. Reed; Bianco, Antonio C.

2013-01-01

Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction in ventricular fractional shortening and resulted in more than 50% death in WT mice. In contrast, MHC-D2 mice showed increased survival rate after DOX treatment, and this was associated with a six-fold increase in myocardial glucose metabolism and improved cardiac function. Myocardial activity and expression of AMPK, GLUT1, and Akt were also elevated in MHC-D2 and WT mice following DOX treatment. Thus, our findings indicate an important role of thyroid hormone in cardiac metabolism and further suggest a protective role of glucose utilization in DOX-mediated cardiac dysfunction. PMID:23861374

High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature

PubMed Central

Li, Wei; Maloney, Ronald E.; Aw, Tak Yee

2015-01-01

We previously demonstrated that in normal glucose (5 mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6 h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG–occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG–occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes. PMID:25867911

Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model.

PubMed

Lamontagne, Julien; Al-Mass, Anfal; Nolan, Christopher J; Corkey, Barbara E; Madiraju, S R Murthy; Joly, Erik; Prentki, Marc

2017-11-24

Metabolic deceleration in pancreatic β-cells is associated with inhibition of glucose-induced insulin secretion (GIIS), but only in the presence of intermediate/submaximal glucose concentrations. Here, we used acute metformin treatment as a tool to induce metabolic deceleration in INS1 (832/13) β-cells, with the goal of identifying key pathways and metabolites involved in GIIS. Metabolites and pathways previously implicated as signals for GIIS were measured in the cells at 2-25 mm glucose, with or without 5 mm metformin. We defined three criteria to identify candidate signals: 1) glucose-responsiveness, 2) sensitivity to metformin-induced inhibition of the glucose effect at intermediate glucose concentrations, and 3) alleviation of metformin inhibition by elevated glucose concentrations. Despite the lack of recovery from metformin-induced impairment of mitochondrial energy metabolism (glucose oxidation, O 2 consumption, and ATP production), insulin secretion was almost completely restored at elevated glucose concentrations. Meeting the criteria for candidates involved in promoting GIIS were the following metabolic indicators and metabolites: cytosolic NAD + /NADH ratio (inferred from the dihydroxyacetone phosphate:glycerol-3-phosphate ratio), mitochondrial membrane potential, ADP, Ca 2+ , 1-monoacylglycerol, diacylglycerol, malonyl-CoA, and HMG-CoA. On the contrary, most of the purine and nicotinamide nucleotides, acetoacetyl-CoA, H 2 O 2 , reduced glutathione, and 2-monoacylglycerol were not glucose-responsive. Overall these results underscore the significance of mitochondrial energy metabolism-independent signals in GIIS regulation; in particular, the candidate lipid signaling molecules 1-monoacylglycerol, diacylglycerol, and malonyl-CoA; the predominance of K ATP /Ca 2+ signaling control by low ADP·Mg 2+ rather than by high ATP levels; and a role for a more oxidized state (NAD + /NADH) in the cytosol during GIIS that favors high glycolysis rates. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Type of supplemented simple sugar, not merely calorie intake, determines adverse effects on metabolism and aortic function in female rats

PubMed Central

Sangüesa, Gemma; Shaligram, Sonali; Akther, Farjana; Roglans, Núria; Laguna, Juan C.; Rahimian, Roshanak

2017-01-01

High consumption of simple sugars causes adverse cardiometabolic effects. We investigated the mechanisms underlying the metabolic and vascular effects of glucose or fructose intake and determined whether these effects are exclusively related to increased calorie consumption. Female Sprague-Dawley rats were supplemented with 20% wt/vol glucose or fructose for 2 mo, and plasma analytes and aortic response to vasodilator and vasoconstrictor agents were determined. Expression of molecules associated with lipid metabolism, insulin signaling, and vascular response were evaluated in hepatic and/or aortic tissues. Caloric intake was increased in both sugar-supplemented groups vs. control and in glucose- vs. fructose-supplemented rats. Hepatic lipogenesis was induced in both groups. Plasma triglycerides were increased only in the fructose group, together with decreased expression of carnitine palmitoyltransferase-1A and increased microsomal triglyceride transfer protein expression in the liver. Plasma adiponectin and peroxisome proliferator-activated receptor (PPAR)-α expression was increased only by glucose supplementation. Insulin signaling in liver and aorta was impaired in both sugar-supplemented groups, but the effect was more pronounced in the fructose group. Fructose supplementation attenuated aortic relaxation response to a nitric oxide (NO) donor, whereas glucose potentiated it. Phenylephrine-induced maximal contractions were reduced in the glucose group, which could be related to increased endothelial NO synthase (eNOS) phosphorylation and subsequent elevated basal NO in the glucose group. In conclusion, despite higher caloric intake in glucose-supplemented rats, fructose caused worse metabolic and vascular responses. This may be because of the elevated adiponectin level and the subsequent enhancement of PPARα and eNOS phosphorylation in glucose-supplemented rats. NEW & NOTEWORTHY This is the first study comparing the effects of glucose and fructose consumption on metabolic factors and aortic function in female rats. Our results show that, although total caloric consumption was higher in glucose-supplemented rats, fructose ingestion had a greater impact in inducing metabolic and aortic dysfunction. PMID:27923787

Glyoxylate, a New Marker Metabolite of Type 2 Diabetes

PubMed Central

Nikiforova, Victoria J.; Giesbertz, Pieter; Wiemer, Jan; Bethan, Bianca; Looser, Ralf; Liebenberg, Volker; Ruiz Noppinger, Patricia; Daniel, Hannelore; Rein, Dietrich

2014-01-01

Type 2 diabetes (T2D) is characterized by a variety of metabolic impairments that are closely linked to nonenzymatic glycation reactions of proteins and peptides resulting in advanced glycation end-products (AGEs). Reactive aldehydes derived from sugars play an important role in the generation of AGEs. Using metabolite profiling to characterize human plasma from diabetic versus nondiabetic subjects we observed in a recent study that the reactive aldehyde glyoxylate was increased before high levels of plasma glucose, typical for a diabetic condition, could be measured. Following this observation, we explored the relevance of increased glyoxylate in diabetic subjects and in diabetic C57BLKS/J-Leprdb/db−/− mice in the pathophysiology of diabetes. A retrospective study using samples of long-term blood donors revealed that glyoxylate levels unlike glucose levels became significantly elevated up to 3 years prior to diabetes diagnosis (difference to control P = 0.034). Elevated glyoxylate levels impact on newly identified mechanisms linking hyperglycemia and AGE production with diabetes-associated complications such as diabetic nephropathy. Glyoxylate in its metabolic network may serve as an early marker in diabetes diagnosis with predictive qualities for associated complications and as potential to guide the development of new antidiabetic therapies. PMID:25525609

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.

[Clinical value of insulin resistance in fasting normoglycemia].

PubMed

Perova, N V; Ozerova, I N; Aleksandrovich, O V; Metel'skaia, V A; Shal'nova, S A

2011-01-01

Aim of the study was to clarify the question of the presence of manifestations of insulin resistance (IR) in fasting normoglycemia and to assess their association with risk of development and presence of clinically overt cardiovascular diseases (CVD) caused by atherosclerosis. We included into this study 1127 men and women older than 55 years with normal blood serum level of glucose in fasting state (<6.1 mmol/l) without diabetes mellitus selected from a random sample of Moscow inhabitants (n=1186). In participants selected for this study we determined risk factors, calculated indexes of IR (HOMA-IR) and functional capacity of pancreatic -cells (HOMA-%B) using fasting levels of glucose and insulin. The examined subsample was divided into quartiles according to values of HOMA-IR. It was shown that in the 4-th quartile HOMA-%B was substantially higher than in other quartiles. With this values of body mass index and waist circumference were also highest in the 4-th quartile. Fasting insulin level compared with glucose level contributed more to determination of values of indexes of both IR and functional capacity of pancreatic -cells. In the upper 4-th quartile signs of atherogenic dyslipidemia appearing as higher concentration of triglycerides and lowered concentration of high density lipoprotein cholesterol manifested to the greatest degree. At statistical analysis of probability of CVD with clinical manifestations it was shown that in the 4-th quartile of distribution of HOMA-IR (>2.7) values of odds ratio (OR) of development of arterial hypertension (AH), total CVD, angina pectoris, history of brain stroke were elevated. With that in the 3-rd quartile of distribution i.e. at HOMA-IR >1.9 there were higher ORs of development of AH, CVD, angina pectoris. Thus even in the range of normal fasting glucose concentrations in subjects older than 55 years we detected IR associated with elevated risk of development of atherosclerosis related CVD. For detection of IR it is appropriate to measure in blood serum not only concentration of glucose but also fasting insulin level with subsequent calculation of HOMA-IR and HOMA-%B indexes.

Aqueous Fraction of Beta vulgaris Ameliorates Hyperglycemia in Diabetic Mice due to Enhanced Glucose Stimulated Insulin Secretion, Mediated by Acetylcholine and GLP-1, and Elevated Glucose Uptake via Increased Membrane Bound GLUT4 Transporters

PubMed Central

Kabir, Ashraf Ul; Samad, Mehdi Bin; Ahmed, Arif; Jahan, Mohammad Rajib; Akhter, Farjana; Tasnim, Jinat; Hasan, S. M. Nageeb; Sayfe, Sania Sarker; Hannan, J. M. A.

2015-01-01

Background The study was designed to investigate the probable mechanisms of anti-hyperglycemic activity of B. Vulgaris. Methodology/Principal Findings Aqueous fraction of B. Vulgaris extract was the only active fraction (50mg/kg). Plasma insulin level was found to be the highest at 30 mins after B. Vulgaris administration at a dose of 200mg/kg. B. Vulgaris treated mice were also assayed for plasma Acetylcholine, Glucagon Like Peptide-1 (GLP-1), Gastric Inhibitory Peptide (GIP), Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase-Activating Peptide (PACAP), Insulin Like Growth Factor-1 (IGF-1), Pancreatic Polypeptides (PP), and Somatostatin, along with the corresponding insulin levels. Plasma Acetylcholine and GLP-1 significantly increased in B. Vulgaris treated animals and were further studied. Pharmacological enhancers, inhibitors, and antagonists of Acetylcholine and GLP-1 were also administered to the test animals, and corresponding insulin levels were measured. These studies confirmed the role of acetylcholine and GLP-1 in enhanced insulin secretion (p<0.05). Principal signaling molecules were quantified in isolated mice islets for the respective pathways to elucidate their activities. Elevated concentrations of Acetylcholine and GLP-1 in B. Vulgaris treated mice were found to be sufficient to activate the respective pathways for insulin secretion (p<0.05). The amount of membrane bound GLUT1 and GLUT4 transporters were quantified and the subsequent glucose uptake and glycogen synthesis were assayed. We showed that levels of membrane bound GLUT4 transporters, glucose-6-phosphate in skeletal myocytes, activity of glycogen synthase, and level of glycogen deposited in the skeletal muscles all increased (p<0.05). Conclusion Findings of the present study clearly prove the role of Acetylcholine and GLP-1 in the Insulin secreting activity of B. Vulgaris. Increased glucose uptake in the skeletal muscles and subsequent glycogen synthesis may also play a part in the anti-hyperglycemic activity of B. Vulgaris. PMID:25647228

Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis

PubMed Central

Martin, Neil A.; McArthur, David L.; Hovda, David A.; Vespa, Paul; Johnson, Matthew L.; Horning, Michael A.; Brooks, George A.

2015-01-01

Abstract We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-2H2]glucose, i.e., D2-glucose, and [3-13C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2–10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain. PMID:25279664

Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis.

PubMed

Glenn, Thomas C; Martin, Neil A; McArthur, David L; Hovda, David A; Vespa, Paul; Johnson, Matthew L; Horning, Michael A; Brooks, George A

2015-06-01

We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-(2)H2]glucose, i.e., D2-glucose, and [3-(13)C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2-10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain.

Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism

PubMed Central

Cochran, Blake J.; Hou, Liming; Manavalan, Anil Paul Chirackal; Moore, Benjamin M.; Tabet, Fatiha; Sultana, Afroza; Cuesta Torres, Luisa; Tang, Shudi; Shrestha, Sudichhya; Senanayake, Praween; Patel, Mili; Ryder, William J.; Bongers, Andre; Maraninchi, Marie; Wasinger, Valerie C.; Westerterp, Marit; Tall, Alan R.; Barter, Philip J.

2016-01-01

Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes. PMID:27702832

Coadministration of alloxan and nicotinamide in rats produces biochemical changes in blood and pathological alterations comparable to the changes in type II diabetes mellitus.

PubMed

Vattam, K K; Raghavendran, Hrb; Murali, M R; Savatey, H; Kamarul, T

2016-08-01

In the present study, thirty six male Sprague Dawley rats were randomly divided into six groups and were injected with varying doses of alloxan (Ax) and nicotinamide (NA). The serum levels of glucose, insulin, and adiponectin were measured weekly up to 4 weeks. Elevated levels of glucose were observed in all groups on days 7, 14, 21, and 28, except in groups a and f (control). The serum insulin levels were significantly elevated in groups b and c on day 7, when compared with that in group f, whereas a decrease in the serum insulin levels was observed in groups d and e on days 21 and 28. The adiponectin levels showed inconsistencies on days 7 and 14. However, significant decrease in the adiponectin levels was observed on days 21 and 28. Histological section of the pancreas showed mild (group a), moderate (group b) to severe (groups c, d, and e) degenerative changes. Concomitant fatty changes in the liver and inflammatory infiltration of the kidney were markedly observed in all the treated groups, when compared to control. These results suggested that the use of selective combination of Ax120 + NA50 injection demonstrated type II diabetes mellitus in rats. © The Author(s) 2015.

Mapping glucose-mediated gut-to-brain signalling pathways in humans.

PubMed

Little, Tanya J; McKie, Shane; Jones, Richard B; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G; McLaughlin, John T

2014-08-01

Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. Copyright © 2014. Published by Elsevier Inc.

Protective effect of esculin on streptozotocin-induced diabetic renal damage in mice.

PubMed

Kang, Ki Sung; Lee, Woojung; Jung, Yujung; Lee, Ji Hwan; Lee, Seungyong; Eom, Dae-Woon; Jeon, Youngsic; Yoo, Hye Hyun; Jin, Ming Ji; Song, Kyung Il; Kim, Won Jun; Ham, Jungyeob; Kim, Hyoung Ja; Kim, Su-Nam

2014-03-05

The present study investigated the presence and mechanism of esculin-mediated renoprotection to assess its therapeutic potential. Esculin was orally administered at 20 mg/kg/day for 2 weeks to streptozotocin-induced diabetic mice, and its effects were compared with those of the vehicle in normal and diabetic mice. After oral administration of esculin to mice, the concentrations of esculin and esculetin in blood were 159.5 ± 29.8 and 9.7 ± 4.9 ng/mL at 30 min, respectively. Food and water intake were significantly increased in the diabetic mice compared to normal mice but attenuated in mice receiving esculin. The elevated blood glucose level and hepatic glucose-6-phosphatase expression were significantly reduced in esculin-treated diabetic mice, supporting the antidiabetic effect of esculin. Esculin also increased the uptake of glucose and induced the insulin-evoked phosphorylation of insulin receptor, Akt, and glycogen synthase kinase 3β in C2C12 myotubes, indicating a potential for improvement of insulin sensitivity. In addition, esculin lessened the elevated blood creatinine levels in diabetic mice and ameliorated diabetes-induced renal dysfunction by reducing caspase-3 activation in the kidney. Data support the beneficial effect of esculin against diabetes and oxidative stress-related inflammatory processes in the kidney.

Thioredoxin-interacting protein (Txnip) is a critical regulator of hepatic glucose production.

PubMed

Chutkow, William A; Patwari, Parth; Yoshioka, Jun; Lee, Richard T

2008-01-25

Thioredoxin-interacting protein (Txnip) has been recently described as a possible link between cellular redox state and metabolism; Txnip binds thioredoxin and inhibits its disulfide reductase activity in vitro, while a naturally occurring strain of Txnip-deficient mice has hyperlipidemia, hypoglycemia, and ketosis exacerbated by fasting. We generated Txnip-null mice to investigate the role of Txnip in glucose homeostasis. Txnip-null mice were hypoglycemic, hypoinsulinemic, and had blunted glucose production following a glucagon challenge, consistent with a central liver glucose-handling defect. Glucose release from isolated Txnip-null hepatocytes was 2-fold lower than wild-type hepatocytes, whereas beta-hydroxybutyrate release was increased 2-fold, supporting an intrinsic defect in hepatocyte glucose metabolism. While hepatocyte-specific gene deletion of Txnip did not alter glucose clearance compared with littermate controls, Txnip expression in the liver was required for maintaining normal fasting glycemia and glucose production. In addition, hepatic overexpression of a Txnip transgene in wild-type mice resulted in elevated serum glucose levels and decreased ketone levels. Liver homogenates from Txnip-null mice had no significant differences in the glutathione oxidation state or in the amount of available thioredoxin. However, overexpression of wild-type Txnip in Txnip-null hepatocytes rescued cellular glucose production, whereas overexpression of a C247S mutant Txnip, which does not bind thioredoxin, had no effect. These data demonstrate that Txnip is required for normal glucose homeostasis in the liver. While available thioredoxin is not changed in Txnip-null mice, the effects of Txnip on glucose homeostasis are abolished by a single cysteine mutation that inhibits binding to thioredoxin.

Targeting hepatic glutaminase activity to ameliorate hyperglycemia.

PubMed

Miller, Russell A; Shi, Yuji; Lu, Wenyun; Pirman, David A; Jatkar, Aditi; Blatnik, Matthew; Wu, Hong; Cárdenas, César; Wan, Min; Foskett, J Kevin; Park, Junyoung O; Zhang, Yiyi; Holland, William L; Rabinowitz, Joshua D; Birnbaum, Morris J

2018-05-01

Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids. In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition. Yet, the mechanism by which glucagon stimulates gluconeogenesis remains incompletely understood. Contrary to the prevailing belief that glucagon acts primarily on cytoplasmic and nuclear targets, we find glucagon-dependent stimulation of mitochondrial anaplerotic flux from glutamine that increases the contribution of this amino acid to the carbons of glucose generated during gluconeogenesis. This enhanced glucose production is dependent on protein kinase A (PKA) and is associated with glucagon-stimulated calcium release from the endoplasmic reticulum, activation of mitochondrial α-ketoglutarate dehydrogenase, and increased glutaminolysis. Mice with reduced levels of hepatic glutaminase 2 (GLS2), the enzyme that catalyzes the first step in glutamine metabolism, show lower glucagon-stimulated glutamine-to-glucose flux in vivo, and GLS2 knockout results in higher fasting plasma glucagon and glutamine levels with lower fasting blood glucose levels in insulin-resistant conditions. As found in genome-wide association studies (GWAS), human genetic variation in the region of GLS2 is associated with higher fasting plasma glucose; here we show in human cryopreserved primary hepatocytes in vitro that these natural gain-of-function missense mutations in GLS2 result in higher glutaminolysis and glucose production. These data emphasize the importance of gluconeogenesis from glutamine, particularly in pathological states of increased glucagon signaling, while suggesting a possible new therapeutic avenue to treat hyperglycemia.

Characterization of beta-cell function of pancreatic islets isolated from bank voles developing glucose intolerance/diabetes: an animal model showing features of both type 1 and type 2 diabetes mellitus, and a possible role of the Ljungan virus.

PubMed

Blixt, Martin; Niklasson, Bo; Sandler, Stellan

2007-01-01

Bank voles (Clethrionomys glareolus) kept in captivity develop diabetes mellitus to a significant extent. Also in wild bank voles, elevated blood glucose has been observed. A newly isolated picornavirus named Ljungan virus (LV) has been found in the pancreas of these bank voles. Moreover, LV infection in combination with environmental factors may cause glucose intolerance/diabetes (GINT/D) in normal mice. The aim of the present study was to investigate the functional characteristics of pancreatic islets, isolated from bank voles, bred in the laboratory but considered LV infected. About 20% of all males and females were classified as GINT/D following a glucose tolerance test. Of these animals the majority had become diabetic by 20 weeks of age, with a tendency towards an earlier onset in the males. GINT/D animals had increased serum insulin levels. Islets were tested on the day of isolation (day 0) and after 1 week of culture for their insulin content and their capacity to synthesize (pro)insulin, secrete insulin and metabolize glucose. Functional differences could be observed between normal and GINT/D animals as well as between genders. An elevated basal insulin secretion was observed on day 0 indicating beta-cell dysfunction among islets isolated from diabetic males. In vitro culture could reverse some functional changes. The increased serum insulin level and the increased basal islet insulin secretion may suggest that the animals had developed a type 2 diabetes-like condition. It is likely that the putative stress imposed in the laboratory, maybe in combination with LV infection, can lead to an increased functional demand on the beta-cells.

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.

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance.

PubMed

Palanivel, R; Fullerton, M D; Galic, S; Honeyman, J; Hewitt, K A; Jorgensen, S B; Steinberg, G R

2012-11-01

Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic-euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity.

Hyperglycemia and advanced glycation end products (AGEs) suppress the differentiation of 3T3-L1 preadipocytes.

PubMed

Chang, Chia-Chu; Chen, Chen-Yu; Chang, Geen-Dong; Chen, Ting-Huan; Chen, Woan-Ling; Wen, Hui-Chin; Huang, Chih-Yang; Chang, Chung-Ho

2017-08-15

Aging is characterized by mild hyperglycemia and accumulation of advanced glycation end products (AGEs). Effects of chronic exposure to hyperglycemia or AGEs on the adipogenic differentiation of 3T3-L1 preadipocytes remain unclear. We examined the chronic effect of AGEs and high glucose on the differentiation of 3T3-L1 cells by culturing 3T3-L1 cells in the presence of AGEs or 25 mM glucose for 1 month. Chronic incubation of 3T3-L1 cells with AGEs or high glucose blocked their differentiation into mature adipocytes as evidenced by reduced levels of adipocyte markers such as accumulated oil droplets, GPDH, aP2, adiponectin and of adipogenesis regulators PPARγ and C/EBPα. Levels or activities of Src, PDK1, Akt, and NF-κB were higher in AGEs- and high glucose-treated cells than those in 3T3-L1 cells. Levels of Bcl-2 were elevated in AGEs- and high glucose-treated cells, and were attenuated by inhibitors of PI3-kinase, Akt and NF-κB. Moreover, adipogenesis was attenuated in 3T3-L1 cells stably expressing Bcl-2 or YAP. These results suggest that chronic AGEs and high glucose treatments up-regulate Bcl-2 and YAP via the Akt-NF-κB pathway and impair adipogenesis.

Hyperglycemia and advanced glycation end products (AGEs) suppress the differentiation of 3T3-L1 preadipocytes

PubMed Central

Chang, Geen-Dong; Chen, Ting-Huan; Chen, Woan-Ling; Wen, Hui-Chin; Huang, Chih-Yang; Chang, Chung-Ho

2017-01-01

Aging is characterized by mild hyperglycemia and accumulation of advanced glycation end products (AGEs). Effects of chronic exposure to hyperglycemia or AGEs on the adipogenic differentiation of 3T3-L1 preadipocytes remain unclear. We examined the chronic effect of AGEs and high glucose on the differentiation of 3T3-L1 cells by culturing 3T3-L1 cells in the presence of AGEs or 25 mM glucose for 1 month. Chronic incubation of 3T3-L1 cells with AGEs or high glucose blocked their differentiation into mature adipocytes as evidenced by reduced levels of adipocyte markers such as accumulated oil droplets, GPDH, aP2, adiponectin and of adipogenesis regulators PPARγ and C/EBPα. Levels or activities of Src, PDK1, Akt, and NF-κB were higher in AGEs- and high glucose-treated cells than those in 3T3-L1 cells. Levels of Bcl-2 were elevated in AGEs- and high glucose-treated cells, and were attenuated by inhibitors of PI3-kinase, Akt and NF-κB. Moreover, adipogenesis was attenuated in 3T3-L1 cells stably expressing Bcl-2 or YAP. These results suggest that chronic AGEs and high glucose treatments up-regulate Bcl-2 and YAP via the Akt-NF-κB pathway and impair adipogenesis. PMID:28903400

Monitoring blood glucose levels in female mink during the reproductive cycle: 2. Effects of short-term fish oil, chromium picolinate, and acetylsalicylic acid supplementation during late lactation

PubMed Central

Hynes, Amber M.J.; Rouvinen-Watt, Kirsti

2007-01-01

Mink nursing sickness is a metabolic disorder characterized by hyperglycemia that is similar to the metabolic syndrome associated with type 2, or non-insulin-dependent, diabetes mellitus. This research studied the effects of short-term administration of antidiabetic supplements on the blood glucose concentration in female mink during late lactation. Female mink that had blood glucose levels < 5.5 mmol/L (normoglycemic [NG]) or ≥ 5.5 mmol/L (hyperglycemic [HG]) early in lactation were given daily supplements of various combinations of herring oil (HerO, 3% in diet), chromium picolinate (CrPic, 200 μg), and acetylsalicylic acid (ASA, 100 mg) for 1 wk starting at day 21 post partum. In the NG mink, most of the treatments did not significantly change the blood glucose concentration from day 28 to 42 post partum. However, treatment with ASA alone and treatment with the combination HerO-CrPic-ASA elevated the blood glucose levels when compared with those of the control group, which had received just the basal diet. In the HG mink, all treatment combinations except CrPic alone and ASA alone, reduced the blood glucose concentration. Thus, in lactating mink with hyperglycemia, the blood glucose concentration may be effectively lowered by dietary antidiabetic supplementation; however, because hyperglycemia also occurs before nursing, preventive measures are recommended throughout the year. PMID:17955898

Impact of hyperglycemia in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention: the HORIZONS-AMI trial.

PubMed

Planer, David; Witzenbichler, Bernhard; Guagliumi, Giulio; Peruga, Jan Z; Brodie, Bruce R; Xu, Ke; Fahy, Martin; Mehran, Roxana; Stone, Gregg W

2013-09-10

Few studies have examined the association between hyperglycemia and adverse outcomes in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). We therefore evaluated the prognostic utility of admission hyperglycemia in the HORIZONS-AMI trial. Admission glucose levels were available in 3405 of 3602 (94.5%) enrolled patients, of which 566 patients (16.6%) were known to have diabetes. Outcomes were assessed at 30 days and 3 years, stratified by baseline glucose level and diabetes status. Median [IQR] admission glucose level in the entire study cohort was 138.0 [115.4, 171.0] mg/dl. Multivariable adjusted 30-day mortality was significantly increased in all patients with admission glucose in the highest glucose tertile vs. the lower two-thirds (HR [95%CI]=3.53 [1.89, 6.60], p<0.0001); in patients with diabetes (4.40 [2.04, 9.50], p=0.0002); and in patients without diabetes (3.33 [1.16, 9.55], p=0.03). By ROC analysis, the best cut-off values for 30-day mortality were 169 mg/dl for all patients (AUC=0.76), 149 mg/dl for patients without diabetes (AUC=0.77), and 231 mg/dl for patients with diabetes (AUC=0.69). Baseline hyperglycemia was also an independent predictor of 3-year mortality in all patients (HR [95%CI]=1.93 [1.35, 2.76], P=0.0003), patients with diabetes (2.65 [1.28, 5.47], P=0.008), and patients without diabetes (1.58 [1.05, 2.36], P=0.03). In patients with STEMI undergoing primary PCI, admission hyperglycemia is an independent predictor of early and late mortality in both patients with and without known diabetes. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells

PubMed Central

Mugabo, Yves; Zhao, Shangang; Lamontagne, Julien; Al-Mass, Anfal; Peyot, Marie-Line; Corkey, Barbara E.; Joly, Erik; Madiraju, S. R. Murthy; Prentki, Marc

2017-01-01

Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters. PMID:28280244

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

PubMed Central

Lanaspa, Miguel A; Ishimoto, Takuji; Li, Nanxing; Cicerchi, Christina; Orlicky, David J.; Ruzicky, Philip; Rivard, Christopher; Inaba, Shinichiro; Roncal-Jimenez, Carlos A.; Bales, Elise S.; Diggle, Christine P.; Asipu, Aruna; Petrash, J. Mark; Kosugi, Tomoki; Maruyama, Shoichi; Sanchez-Lozada, Laura G.; McManaman, James L.; Bonthron, David T; Sautin, Yuri Y.; Johnson, Richard J.

2013-01-01

Carbohydrates with high glycemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations glucose are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously-produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase deficient mice were protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism whereby glucose promotes the development of metabolic syndrome. PMID:24022321

Artemisia princeps extract promoted glucose uptake in cultured L6 muscle cells via glucose transporter 4 translocation.

PubMed

Yamamoto, Norio; Ueda, Manabu; Kawabata, Kyuichi; Sato, Takuya; Kawasaki, Kengo; Hashimoto, Takashi; Ashida, Hitoshi

2010-01-01

Artemisia princeps is a familiar plant as a food substance and medicinal herb. In this study, we evaluated the effects of an ethanol extract of A. princeps (APE) on glucose uptake in differentiated L6 muscle cells. Treatment with APE elevated deoxyglucose uptake, and translocation of the insulin-responsive glucose transporter (GLUT4) to the plasma membrane in L6 myotubes occurred. The PI3K inhibitor LY294002 attenuated glucose uptake induced by APE. Phosphorylation of the Ser(473) residue of Akt was not observed, but phosphorylation of PI3K, Akt (Thr(308)), and atypical PKC was. In addition, APE stimulated phosphorylation of AMP-activated protein kinase (AMPK) at a level similar to 5'-amino-5-imidazolecarboxamide-riboside (AICAR). These results indicate that APE stimulates glucose uptake by inducing GLUT4 translocation, which is in part mediated by combination of the PI3K-dependent atypical PKC pathway and AMPK pathways.

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.

A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.

PubMed

Gautam, Dinesh; Han, Sung-Jun; Hamdan, Fadi F; Jeon, Jongrye; Li, Bo; Li, Jian Hua; Cui, Yinghong; Mears, David; Lu, Huiyan; Deng, Chuxia; Heard, Thomas; Wess, Jürgen

2006-06-01

One of the hallmarks of type 2 diabetes is that pancreatic beta cells fail to release sufficient amounts of insulin in the presence of elevated blood glucose levels. Insulin secretion is modulated by many hormones and neurotransmitters including acetylcholine, the major neurotransmitter of the peripheral parasympathetic nervous system. The physiological role of muscarinic acetylcholine receptors expressed by pancreatic beta cells remains unclear at present. Here, we demonstrate that mutant mice selectively lacking the M3 muscarinic acetylcholine receptor subtype in pancreatic beta cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, transgenic mice selectively overexpressing M3 receptors in pancreatic beta cells show a profound increase in glucose tolerance and insulin release. Moreover, these mutant mice are resistant to diet-induced glucose intolerance and hyperglycemia. These findings indicate that beta cell M3 muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis.

Low glucose availability stimulates progesterone production by mouse ovaries in vitro.

PubMed

Wilsterman, Kathryn; Pepper, Aimee; Bentley, George E

2017-12-15

Steroid production by the ovary is primarily stimulated by gonadotropins but can also be affected by biological cues that provide information about energy status and environmental stress. To further understand which metabolic cues the ovary can respond to, we exposed gonadotropin-stimulated mouse ovaries in vitro to glucose metabolism inhibitors and measured steroid accumulation in media. Gonadotropin-stimulated ovaries exposed to 2-deoxy-d-glucose increased progesterone production and steroidogenic acute regulatory protein mRNA levels. However, oocytes and granulosa cells in antral follicles do not independently mediate this response because targeted treatment of these cell types with a different inhibitor of glucose metabolism (bromopyruvic acid) did not affect progesterone production. Elevated progesterone production is consistent with the homeostatic role of progesterone in glucose regulation in mammals. It also may regulate follicle growth and/or atresia within the ovary. These results suggest that ovaries can regulate glucose homeostasis in addition to their primary role in reproductive activity. © 2017. Published by The Company of Biologists Ltd.

Impact of stress-induced diabetes on outcomes in severely burned children.

PubMed

Finnerty, Celeste C; Ali, Arham; McLean, Josef; Benjamin, Nicole; Clayton, Robert P; Andersen, Clark R; Mlcak, Ronald P; Suman, Oscar E; Meyer, Walter; Herndon, David N

2014-04-01

Post-burn hyperglycemia leads to graft failure, multiple organ failure, and death. A hyperinsulinemic-euglycemic clamp is used to keep serum glucose between 60 and 110 mg/dL. Because of frequent hypoglycemic episodes, a less-stringent sliding scale insulin protocol is used to maintain serum glucose levels between 80 and 160 mg/dL after elevations >180 mg/dL. We randomized pediatric patients with massive burns into 2 groups, patients receiving sliding scale insulin to lower blood glucose levels (n = 145) and those receiving no insulin (n = 98), to determine the differences in morbidity and mortality. Patients 0 to 18 years old with burns covering ≥ 30% of the total body surface area and not randomized to receive anabolic agents were included in this study. End points included glucose levels, infections, resting energy expenditure, lean body mass, bone mineral content, fat mass, muscle strength, and serum inflammatory cytokines, hormones, and liver enzymes. Maximal glucose levels occurred within 6 days of burn injury. Blood glucose levels were age dependent, with older children requiring more insulin (p < 0.05). Daily maximum and daily minimum, but not 6 am, glucose levels were significantly different based on treatment group (p < 0.05). Insulin significantly increased resting energy expenditure and improved bone mineral content (p < 0.05). Each additional wound infection increased incidence of hyperglycemia (p = 0.004). There was no mortality in patients not receiving insulin, only in patients who received insulin (p < 0.004). Muscle strength was increased in patients receiving insulin (p < 0.05). Burn-induced hyperglycemia develops in a subset of severely burned children. Length of stay was reduced in the no insulin group, and there were no deaths in this group. Administration of insulin positively impacted bone mineral content and muscle strength, but increased resting energy expenditure, hypoglycemic episodes, and mortality. New glucose-lowering strategies might be needed. Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Effect of an aqueous extract of Scoparia dulcis on plasma and tissue glycoproteins in streptozotocin induced diabetic rats.

PubMed

Latha, M; Pari, L

2005-02-01

The influence of Scoparia dulcis, a traditionally used plant for the treatment of diabetes mellitus, was examined in streptozotocin diabetic rats on dearrangement in glycoprotein levels. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin. An aqueous extract of Scoparia dulcis plant was administered orally for 6 weeks. The effect of the Scoparia dulcis extract on blood glucose, plasma insulin, plasma and tissue glycoproteins studied was in comparison to glibenclamide. The levels of blood glucose and plasma glycoproteins were increased significantly whereas the level of plasma insulin was significantly decreased in diabetic rats. There was a significant decrease in the level of sialic acid and elevated levels of hexose, hexosamine and fucose in the liver and kidney of streptozotocin diabetic rats. Oral administration of Scoparia dulcis plant extract (SPEt) to diabetic rats led to decreased levels of blood glucose and plasma glycoproteins. The levels of plasma insulin and tissue sialic acid were increased whereas the levels of tissue hexose, hexosamine and fucose were near normal. The present study indicates that Scoparia dulcis possesses a significant beneficial effect on glycoproteins in addition to its antidiabetic effect.

Isolated Diastolic Hypertension Associated Risk Factors among Chinese in Anhui Province, China

PubMed Central

Wang, Yanchun; Xing, Fengjun; Liu, Rongjuan; Liu, Li; Zhu, Yu; Wen, Yufeng; Sun, Wenjie; Song, Ziwei

2015-01-01

Objective: To explore potential risk factors of isolated diastolic hypertension (IDH) among young and middle-aged Chinese. Methods: A community-based cross-sectional study was conducted among 338 subjects, aged 25 years and above, using random sampling technique. There were 68 cases of IDH, 46 cases of isolated systolic hypertension (ISH), 89 cases of systolic and diastolic hypertension (SDH), and 135 of subjects with normal blood pressure. Cases and controls were matched on sex by frequency matching. Demographic characteristics, blood pressure and other relevant information were collected.Results: Compared with controls, patients with IDH and ISH had significant higher level of triglyceride, high density lipoprotein, blood glucose and body mass index (BMI) (p < 0.05); while patients with SDH had significantly higher level of total cholesterol, triglyceride, glucose and BMI (p < 0.05). Linear mixed effects model showed that drinking tea, family history of hypertension (FHH), higher blood glucose, triglyceride and low density lipoprotein were related with elevated diastolic blood pressure (DBP) (p < 0.01); HFH, blood glucose, creatinine and BMI have positive effect on systolic blood pressure (SBP) (p < 0.05). Conclusions: Drinking tea, FHH, high levels of triglyceride, high density lipoprotein, blood glucose and BMI are associated with IDH among young and middle-aged Chinese. PMID:25913184

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

Determination of reference values for elevated fasting and random insulin levels and their associations with metabolic risk factors among rural Pakistanis from Sindh Province.

PubMed

Ahmadani, Muhammad Yakoob; Hakeem, Rubina; Fawwad, Asher; Basit, Abdul; Shera, A Samad

2008-06-01

To assess insulin levels and their association with metabolic risk factors (family history of diabetes, abnormal glucose tolerance, hypertension, overweight and android obesity) among a representative group of Pakistan. The study data was taken from the database of a population-based survey conducted in Sindh Province, Pakistan, in 1994 to assess the prevalence of diabetes mellitus and impaired glucose tolerance (IGT). Through stratified random sampling; oral glucose tolerance tests were performed in 967 adults; every fifth sample was estimated for fasting and random (2-hour post-75 gm glucose load) insulin levels. The total number of metabolic risk factors was counted for each subject, and their association with insulin levels studied. Of the 130 subjects, 56.1% were females and 95.4% were Sindhi. The mean age of males and females was 43.84 and 40.61 years, respectively. Family history for diabetes and frequency of overweight had significant positive associations with both fasting and random insulin levels (P < 0.05). Association between hypertension and insulin levels was significant only for random insulin levels, and between android obesity, abnormal glucose tolerance, or male gender and insulin levels only for fasting insulin levels (P < 0.05). Metabolic risk factors had significant positive associations with both fasting (r = 0.351 P = 0.000) as well as random insulin levels (r = 0.364 P = 0.000). This paper provides baseline pioneering information applicable to the Pakistani population. Furthermore, the observations made in this study about differences in association of fasting or random insulin levels with various metabolic risk factors highlight the possibility of using either of them for risk assessment. This finding needs to be assessed in a larger and nationally representative sample.

Glucose deprivation elicits phenotypic plasticity via ZEB1-mediated expression of NNMT

PubMed Central

Kanska, Justyna; Aspuria, Paul-Joseph P.; Taylor-Harding, Barbie; Spurka, Lindsay; Funari, Vincent; Orsulic, Sandra; Karlan, Beth Y.; Wiedemeyer, W. Ruprecht

2017-01-01

Glucose is considered the primary energy source for all cells, and some cancers are addicted to glucose. Here, we investigated the functional consequences of chronic glucose deprivation in serous ovarian cancer cells. We found that cells resistant to glucose starvation (glucose-restricted cells) demonstrated increased metabolic plasticity that was dependent on NNMT (Nicotinamide N-methyltransferase) expression. We further show that ZEB1 induced NNMT, rendered cells resistant to glucose deprivation and recapitulated metabolic adaptations and mesenchymal gene expression observed in glucose-restricted cells. NNMT depletion reversed metabolic plasticity in glucose-restricted cells and prevented de novo formation of glucose-restricted colonies. In addition to its role in glucose independence, we found that NNMT was required for other ZEB1-induced phenotypes, such as increased migration. NNMT protein levels were also elevated in metastatic and recurrent tumors compared to matched primary carcinomas, while normal ovary and fallopian tube tissue had no detectable NNMT expression. Our studies define a novel ZEB1/NNMT signaling axis, which elicits mesenchymal gene expression, as well as phenotypic and metabolic plasticity in ovarian cancer cells upon chronic glucose starvation. Understanding the causes of cancer cell plasticity is crucial for the development of therapeutic strategies to counter intratumoral heterogeneity, acquired drug resistance and recurrence in high-grade serous ovarian cancer (HGSC). PMID:28412735

Dysglycemia and long-term mortality: observations from the Israel study of glucose intolerance, obesity and hypertension.

PubMed

Bergman, Michael; Chetrit, Angela; Roth, Jesse; Dankner, Rachel

2015-05-01

We describe the relationship between dysglycemia and long-term mortality and elucidate the relationship between blood glucose levels during an oral glucose tolerance test (OGTT) and haemoglobin A1 (HbA1) and mortality. A cohort of 1410 individuals was followed for 33 years since 1980. Fasting and post-OGTT glucose parameters were used to categorize the cohort according to baseline glycemic status. The mortality rate increased from 43% in normoglycemic individuals to 53.3, 61.7, 72.9 and 88.0% in those with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG/IGT and diabetes, respectively. The highest mortality rate, compared with the normoglycemic category, was observed in individuals with IFG/IGT and diabetes according to a Cox proportional hazard model (HR = 1.38, 95%CI 1.10-1.74 and HR = 2.14, 95%CI 1.70-2.70, respectively), followed by individuals with IGT and IFG, but this did not reach statistical significance. We speculate that the IFG group may represent a mixture of individuals en route from normal to the next two categories as well as another cohort whose glucose levels are stably set at the upper reaches of the normal distribution. Significant differences were found between 1 and 2 h glucose values (p < 0.001). Fasting, 60 and 120 min glucose values were positively associated with increasing HbA1 quintiles (p < 0.05). The mean HbA1 was significantly higher in those who died (p = 0.01). The highest mortality (58.8%) was observed in the upper HbA1 quintile that was also associated with the highest prevalence of the metabolic syndrome (17.2%). This study shows a continuous relationship between the severity of dysglycemia and long-term mortality and should promote the early recognition of prediabetes. The 1 h post-load glucose level was continuously associated with increasing HbA1 concentrations and may therefore serve as an early marker for abnormalities in glucose tolerance. An elevated 1 h post-load glucose level may potentially identify at-risk individuals well before the traditional 2 h glucose value. Copyright © 2014 John Wiley & Sons, Ltd.

Biometric Screening and Future Employer Medical Costs: Is It Worth It to Know?

PubMed

Vanichkachorn, Greg; Marchese, Maya; Roy, Brad; Opel, Gordon

2017-12-01

To study the relationship between a biometric wellness data and future/actual medical costs. A relationship between total cholesterol to high density lipoprotein ratio, blood pressure, and blood glucose and medical costs, based on analysis of claims data, was explored in 1834 employees that had both wellness program biometric and claims data in 2016. Increased total cholesterol to HDL ratio is strongly associated with increased average costs (P < 0.01). Similarly, an increased glucose level is strongly associated with increased average costs (P = 0.001). There was no evidence of a relationship between elevated blood pressure and higher costs. By investing in an employer-sponsored biometric screening of full cholesterol and glucose profiles, medium-sized employers can identify high-risk employees who are expected to incur significantly higher healthcare costs, as compared with low-risk level employees, and improve treatment outcomes.

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

Unraveling the concentration-dependent metabolic response of Pseudomonas sp. HF-1 to nicotine stress by ¹H NMR-based metabolomics.

PubMed

Ye, Yangfang; Wang, Xin; Zhang, Limin; Lu, Zhenmei; Yan, Xiaojun

2012-07-01

Nicotine can cause oxidative damage to organisms; however, some bacteria, for example Pseudomonas sp. HF-1, are resistant to such oxidative stress. In the present study, we analyzed the concentration-dependent metabolic response of Pseudomonas sp. HF-1 to nicotine stress using ¹H NMR spectroscopy coupled with multivariate data analysis. We found that the dominant metabolites in Pseudomonas sp. HF-1 were eight aliphatic organic acids, six amino acids, three sugars and 11 nucleotides. After 18 h of cultivation, 1 g/L nicotine caused significant elevation of sugar (glucose, trehalose and maltose), succinate and nucleic acid metabolites (cytidine, 5'-CMP, guanine 2',3'-cyclic phosphate and adenosine 2',3'-cyclic phosphate), but decrease of glutamate, putrescine, pyrimidine, 2-propanol, diethyl ether and acetamide levels. Similar metabolomic changes were induced by 2 g/L nicotine, except that no significant change in trehalose, 5'-UMP levels and diethyl ether were found. However, 3 g/L nicotine led to a significant elevation in the two sugars (trehalose and maltose) levels and decrease in the levels of glutamate, putrescine, pyrimidine and 2-propanol. Our findings indicated that nicotine resulted in the enhanced nucleotide biosynthesis, decreased glucose catabolism, elevated succinate accumulation, severe disturbance in osmoregulation and complex antioxidant strategy. And a further increase of nicotine level was a critical threshold value that triggered the change of metabolic flow in Pseudomonas sp. HF-1. These findings revealed the comprehensive insights into the metabolic response of nicotine-degrading bacteria to nicotine-induced oxidative toxicity.

[Impact of streptozotocininduced hyperglycemia on anxiety level and physical fatigue of Wistar rats].

PubMed

Sidorova, Yu S; Shipelin, V A; Zorin, S N; Mazo, V K; Petrov, N A; Kochetkova, A A

2015-01-01

The aim of the study was to evaluate type 2 diabetes medicamental biomodel in 70-days experiment. Control group animals were provided with water ad libitum throughout the experiment, experimental group animals for the first two weeks were provided with 20% solution of fructose ad libitum instead of water. On the 15th day, experimental group animals (average body weight 257±8 g) were injected abdominally with streptozotocin (STZ) in dosage 40 mg/kg of body weight. For the next three weeks on the 22nd, 28th and 36th days, glucose level in blood taken from the tail vein was measured using portable electrochemical glucometer. On the 37th day animals with blood glucose level 11.0 mmol/L or higher were included in experimental group for further research. On the 44th and 60th day control measurements of glucose level were conducted. On the 70th day animals were taken out of experiment by decapitation under ether anesthesia. The concentration of glucose, glycosylated hemoglobin, triglycerides, cholesterine, HLD and LDL were measured in blood serum. Additionally anxiety level of animals was evaluated before and after STZ injection using Elevated plusmaze. The comparison of physical fatigue of control and experimental groups was performed using treadmill. On the 37th day blood glucose concentration of control group animals was 6.6±0.4 mmol/L. 33% of animals (13 of 40) with glucose level 11.0 mmol/L or higher formed the experimental group (average glucose level 16.2±1.3 mmol/L), other 27 rats had normal glucose level. The anxiety level of diabetic rats was higher than in control group. Diabetic rats showed significantly lower physical fatigue than control rats. On the 44th and 60th day of experiment glucose level in experimental rats from group 2 (15.5±1.4 и 14.8±1.2 mmol/L) was significantly higher than of control animals (7.0±0.5 и 6.8±0.3 mmol/L). Glycated hemoglobin level in blood serum of diabetic group (7.2±0.7%) was significantly higher than of control group (3.3±0.2%). This proves the progression of stable long-term hyperglycemia. According to results represented model can be used for initial experimental evaluation of tested antidiabetic biologically active substances.

Thiamine and its phosphate esters in relation to cardiometabolic risk factors in Saudi Arabs

PubMed Central

2013-01-01

Background 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. Methods 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. Results 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. Conclusions 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. PMID:24059534

Increased ophthalmic acid production is supported by amino acid catabolism under fasting conditions in mice.

PubMed

Kobayashi, Sho; Lee, Jaeyong; Takao, Toshifumi; Fujii, Junichi

2017-09-23

Glutathione (GSH) plays pivotal roles in antioxidation and detoxification. The transsulfuration pathway, in conjunction with methionine metabolism, produces equimolar amounts of cysteine (Cys) and 2-oxobutyric acid (2OB). The resulting 2OB is then converted into 2-aminobutyric acid (2AB) by a transaminase and is utilized as a substitute for Cys by the GSH-synthesizing machinery to produce ophthalmic acid (OPT). By establishing a method for simultaneously measuring Cys, GSH, and OPT by liquid chromatography-mass spectrometry, we found that fasting causes an elevation in OPT levels in the liver and blood plasma, even though the levels of Cys and GSH are decreased. Autophagy was activated, but the levels of GSH/OPT-synthesizing enzymes remained unchanged. After 6 h of fasting, the mice were given 1% 2AB and/or 5% glucose in the drinking water for an additional 24 h and the above metabolites analyzed. 2AB administration caused an increase in OPT levels, and, when glucose was co-administered with 2AB, the levels of OPT were elevated further but GSH levels were decreased somewhat. These results suggest that, while Cys is utilized for glyconeogenesis under fasting conditions, reaching levels that were insufficient for the synthesis of GSH, 2OB was preferentially converted to 2AB via amino acid catabolism and was utilized as a building block for OPT. Thus the consumption of Cys and the parallel elevation of 2AB under fasting conditions appeared to force γ-glutamylcysteine synthetase to form γ-glutamyl-2AB, despite the fact that the enzyme has a higher Km value for 2AB than Cys. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of simvastatin on CAT-1-mediated arginine transport and NO level under high glucose conditions in conditionally immortalized rat inner blood-retinal barrier cell lines (TR-iBRB).

PubMed

Tun, Temdara; Kang, Young-Sook

2017-05-01

Hyperglycemia causes the breakdown of the blood-retinal barrier by impairing endothelial nitric oxide synthase (eNOS) function. Statins have many pleiotropic effects such as improving endothelial barrier permeability and increasing eNOS mRNA stability. The objective of this study was to determine effect of simvastatin on l-arginine transport and NO production under high-glucose conditions in conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB). Changes in l-arginine transport uptake and, expression levels of cationic amino acid transporter 1 (CAT-1) and eNOS mRNA were investigated after pre-treatment with simvastatin and NOS inhibitors (l-NMMA and l-NAME) under high-glucose conditions using TR-iBRB, an in vitro model of iBRB. The NO level released from TR-iBRB cells was examined using Griess reagents. Under high glucose conditions, [ 3 H]l-arginine uptake was decreased in TR-iBRB cells. Simvastatin pretreatment elevated [ 3 H]l-arginine uptake, the expression levels of CAT-1 and eNOS mRNA, and NO production under high-glucose conditions. Moreover, the co-treatment with simvastatin and NOS inhibitors reduced [ 3 H]l-arginine uptake compared to pretreatment with simvastatin alone. Our results suggest that, in the presence of high-glucose levels, increased l-arginine uptake due to simvastatin treatment was associated with increased CAT-1 and eNOS mRNA levels, leading to higher NO production in TR-iBRB cells. Thus, simvastatin might be a good modulator for diabetic retinopathy therapy by increasing of the l-arginine uptake and improving endothelial function in retinal capillary endothelial cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Serum glycerophosphate levels are increased in Japanese men with type 2 diabetes.

PubMed

Daimon, Makoto; Soga, Tomoyoshi; Hozawa, Atsushi; Oizumi, Toshihide; Kaino, Wataru; Takase, Kaoru; Karasawa, Shigeru; Jimbu, Yumi; Wada, Kiriko; Kameda, Wataru; Susa, Shinji; Kayama, Takamasa; Saito, Kaori; Tomita, Masaru; Kato, Takeo

2012-01-01

To identify metabolites showing changes in serum levels among Japanese male with diabetes. We performed metabolite profiling by coupling capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry using fasting serum samples from Japanese male subjects with diabetes (n=17), impaired glucose tolerance (IGT; n=5) and normal glucose tolerance (NGT; n=14). Other than the expected differences in characteristics related to abnormal glucose metabolism, the percent body fat was significantly different among subjects with diabetes, IGT and NGT (27.3±6.2, 22.2±4.5 and 19.2±6.0%, respectively, p=0.0022). Therefore, percent body fat was considered as a possible confounding factor in subsequent analyses. Of 560 metabolites detected using our platform, the levels of 74 metabolites were quantified in all of the serum samples. Significant differences between diabetes and NGT were observed for 24 metabolites. The top-ranked metabolite was glycerol-3-phophate (glycerophosphate), which was significantly higher in subjects with diabetes than in those with NGT, even after Bonferroni correction for multiple testing (11.7±3.6 vs. 6.4±1.9 µM, respectively; corrected p=0.0222). Stepwise multiple regression analyses revealed that serum glycerophosphate levels were significantly correlated with 2-h plasma glucose after a 75-g oral glucose tolerance test (r=0.553, p=0.0005), independently of other characteristics, including FPG and HbA1c. Serum glycerophosphate levels were found to be elevated in Japanese men with diabetes, and correlated with 2-h PG, independent of FPG and HbA1c. Namely, serum glycerophosphate level at fasting condition can be a marker for predicting glucose intolerance. These results warrant further studies to evaluate the relevance of glycerophosphate in the pathophysiology of diabetes.

[LED LIGHTING AS A FACTOR FOR THE STIMULATION OF THE HORMONE SYSTEM].

PubMed

Deynego, V N; Kaptsov, V A

2015-01-01

There are considered questions of non-visual effects of blue LED light sources on hormonal systems (cortisol, glucose, insulin) providing the high human performance. In modern conditions hygiene strategy for child and adolescent health strategy was shown to be replaced by a strategy of light stimulation of the hormonal profile. There was performed a systematic analysis of the axis "light stimulus-hypothalamus-pituitary-adrenals-cortisol-glucose-insulin". The elevation of the content of cortisol leads to the increase of the glucose level in the blood and the stimulation of the production of insulin, which can, like excessive consumption of food, give rise to irreversible decline in the number of insulin receptors on the cell surface, and thus--to a steady reduction in the ability of cells to utilize glucose, i.e. to type 2 diabetes or its aggravation.

[Prevalence of Risk Factors of Non-Communicable Disease in Kyrgyzstan: Assessment using WHO STEPS Approach].

PubMed

A, T A; Makhmutkhodzhaev, S A; Kydyralieva, R B; Altymysheva, A T; Dzhakipova, R S; Zhorupbekova, K S; Ryskulova, S T; Knyazeva, V G; Kaliev, M T; Dzhumagulova, A S

2016-12-01

Assessment of prevalence of risk factors for non-communicable diseases (NCD) based on WHO "STEPS" approach was conducted in Kyrgyzstan. Results of this study demonstrated high prevalence of NCD risk factors: 94.2% of subjects aged 24-64 years had risk factors. Prevalence of elevated blood pressure was 48.7, smoking - 25.7, hypercholesterolemia - 23.6, excessive alcohol consumption - 31.4, physical inactivity 11.4, obesity - 23.1, elevated glucose level - 4.5, diabetes - 8.8, inadequate intake of fruits and vegetables - 74%. The data obtained would allow to draft effective preventive measures to combat NCD risk factors at the national level.

CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion.

PubMed

Zheng, Hongzhi; Fu, Jingqi; Xue, Peng; Zhao, Rui; Dong, Jian; Liu, Dianxin; Yamamoto, Masayuki; Tong, Qingchun; Teng, Weiping; Qu, Weidong; Zhang, Qiang; Andersen, Melvin E; Pi, Jingbo

2015-04-01

The inability of pancreatic β-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in β-cells on β-cell function and glucose homeostasis. Silencing of Nrf1 in β-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 β-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from β-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase. Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in β-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS. Nrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting β-cells.

Oxidative stress and antioxidant biomarker responses after a moderate-intensity soccer training session.

PubMed

Mello, Rodrigo; Mello, Ricardo; Gomes, Diego; Paz, Gabriel Andrade; Nasser, Igor; Miranda, Humberto; Salerno, Verônica P

2017-01-01

The present study investigated the effects of a moderate-intensity soccer training session on the production of reactive oxygen species (ROS) and the antioxidant capacity in athletes along with the biomarkers creatine kinase and transaminases for lesions in muscle and liver cells. Twenty-two male soccer players participated in this study. Blood samples were collected 5 min before and after a moderate-intensity game simulation. The results showed a decrease in the concentration of reduced glutathione (GSH) from an elevation in the production of ROS that maintained the redox homeostasis. Although the session promoted an elevated energy demand, observed by an increase in lactate and glucose levels, damage to muscle and/or liver cells was only suggested by a significant elevation in the levels of alanine transaminase (ALT). Of the two biomarkers analysed, the results suggest that measurements of the ALT levels could be adopted as a method to monitor recovery in athletes.

Postnatal Ablation of POMC Neurons Induces an Obese Phenotype Characterized by Decreased Food Intake and Enhanced Anxiety-Like Behavior

PubMed Central

Greenman, Yona; Drori, Yonat; Asa, Sylvia L.; Navon, Inbal; Forkosh, Oren; Gil, Shosh; Stern, Naftali

2013-01-01

Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus are central components of systems regulating appetite and energy homeostasis. Here we report on the establishment of a mouse model in which the ribonuclease III ribonuclease Dicer-1 has been specifically deleted from POMC-expressing neurons (POMCΔDCR), leading to postnatal cell death. Mice are born phenotypically normal, at the expected genetic ratio and with normal hypothalamic POMC-mRNA levels. At 6 weeks of age, no POMC neurons/cells could be detected either in the arcuate nucleus or in the pituitary of POMCΔDCR mice. POMCΔDCR develop progressive obesity secondary to decreased energy expenditure but unrelated to food intake, which was surprisingly lower than in control mice. Reduced expression of AgRP and ghrelin receptor in the hypothalamus and reduced uncoupling protein 1 expression in brown adipose tissue can potentially explain the decreased food intake and decreased heat production, respectively, in these mice. Fasting glucose levels were dramatically elevated in POMCΔDCR mice and the glucose tolerance test revealed marked glucose intolerance in these mice. Secondary to corticotrope ablation, basal and stress-induced corticosterone levels were undetectable in POMCΔDCR mice. Despite this lack of activation of the neuroendocrine stress response, POMCΔDCR mice exhibited an anxiogenic phenotype, which was accompanied with elevated levels of hypothalamic corticotropin-releasing factor and arginine-vasopressin transcripts. In conclusion, postnatal ablation of POMC neurons leads to enhanced anxiety and the development of obesity despite decreased food intake and glucocorticoid deficiency. PMID:23676213

Serum FGF21 in girls with anorexia nervosa - comparison to normal weight and obese female adolescents.

PubMed

Mikolajczak, Agata; Oswiecimska, Joanna M; Swietochowska, Elzbieta; Roczniak, Wojciech; Ziora, Katarzyna T

2017-07-01

Fibroblast growth factor 21 (FGF21) is a hepatokine, myokine and adipokine of a potent influence to energy homeostasis. Data according its serum concentrations in AN are contradictory. Analysis of serum FGF21 in girls with acute anorexia nervosa and comparison the results with normal weight and obese female adolescents considering their nutritional status, carbohydrate and lipid metabolism. Serum FGF21 concentrations were evaluated using commercially available ELISA kit in 32 Polish girls with restrictive AN (AN), 29 girls with obesity (O) and 21 healthy controls (C). Anthropometric measurements (weight, height, BMI) and laboratory assays (serum fasting glucose, insulin, HOMA-IR, total cholesterol, HDL, LDL, triglycerides, C-reactive protein) were performed. Mean serum FGF-21 in the AN group was significantly lower, whereas in the O group it was significantly higher than in healthy controls. In all examined girls significant positive correlations between FGF21 and BMI were noted. We also observed significant positive relationships between serum FGF21 levels and fasting glucose, triglycerides, CRP, insulin and HOMA-IR. In all examined girls serum concentrations of this hormone correlated negatively with age and HDL-cholesterol levels. 1) Serum FGF21 concentrations are decreased in AN and elevated in obesity. They are independently and positively related to BMI and insulin resistance; 2) Decreased serum FGF21 in AN may support the maintenance of normal blood glucose through adjustment the insulin levels and insulin sensitivity; 3) Elevated FGF21 levels in obesity may be considered adaptive mechanism preventing insulin resistance and its metabolic consequences.

Elevation of Glucose 6-Phosphate Dehydrogenase Activity Induced by Amplified Insulin Response in Low Glutathione Levels in Rat Liver

PubMed Central

Taniguchi, Misako; Mori, Nobuko; Iramina, Chizuru

2016-01-01

Weanling male Wistar rats were fed on a 10% soybean protein isolate (SPI) diet for 3 weeks with or without supplementing 0.3% sulfur-containing amino acids (SAA; methionine or cystine) to examine relationship between glutathione (GSH) levels and activities of NADPH-producing enzymes, glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME), in the liver. Of rats on the 10% SPI diet, GSH levels were lower and the enzyme activities were higher than of those fed on an SAA-supplemented diet. Despite the lower GSH level, γ-glutamylcysteine synthetase (γ-GCS) activity was higher in the 10% SPI group than other groups. Examination of mRNAs of G6PD and ME suggested that the GSH-suppressing effect on enzyme induction occurred prior to and/or at transcriptional levels. Gel electrophoresis of G6PD indicated that low GSH status caused a decrease in reduced form and an increase in oxidized form of the enzyme, suggesting an accelerated turnover rate of the enzyme. In primary cultured hepatocytes, insulin response to induce G6PD activity was augmented in low GSH levels manipulated in the presence of buthionine sulfoximine. These findings indicated that elevation of the G6PD activity in low GSH levels was caused by amplified insulin response for expression of the enzyme and accelerated turnover rate of the enzyme molecule. PMID:27597985

Role of various indices derived from an oral glucose tolerance test in the prediction of conversion from prediabetes to type 2 diabetes.

PubMed

Kim, Ye An; Ku, Eu Jeong; Khang, Ah Reum; Hong, Eun Shil; Kim, Kyoung Min; Moon, Jae Hoon; Choi, Sung Hee; Park, Kyong Soo; Jang, Hak Chul; Lim, Soo

2014-11-01

The clinical implications of prediabetes for development of type 2 diabetes may differ for Asian ethnicity. We investigated various indices derived from a 2-h oral glucose tolerance test (OGTT) in people with prediabetes to predict their future risk of diabetes. We recruited 406 consecutive subjects with prediabetes from 2005 to 2006 and followed them up every 3-6 months for up to 9 years. Prediabetes was defined as isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), combined glucose intolerance (CGI), or isolated elevated HbA1c (5.7-6.4%, 39-46 mmol/mol) without IFG or IGT. The rate of diabetes conversion was compared between prediabetes categories. The association of glycemic indices with development of diabetes was also investigated. Eighty-one patients were diagnosed with diabetes during the 9-year follow-up (median 46.0 months). The rate of diabetes conversion was higher in subjects with CGI (31.9%), or isolated IGT (18.5%) than in those with isolated IFG (15.2%) or isolated elevated HbA1c (10.9%). Surrogate markers reflecting β-cell dysfunction were more closely associated with diabetes conversion than insulin resistance indices. Subjects with a 30-min postload glucose ≥ 165 mg/dL and a 30-min C-peptide < 5 ng/mL had 8.83 times greater risk (95% confidence interval 2.98-26.16) of developing diabetes than other prediabetic subjects. In Asians, at least Koreans, β-cell dysfunction seems to be the major determinant for diabetes conversion. A combination of high glucose and low C-peptide levels at 30 min after OGTT may be a good predictor for diabetes conversion in this population. Copyright © 2014. Published by Elsevier Ireland Ltd.

Impact of differing glucose-lowering regimens on the pattern of association between glucose control and survival.

PubMed

Currie, Craig J; Holden, Sarah E; Jenkins-Jones, Sara; Morgan, Christopher Ll; Voss, Bernd; Rajpathak, Swapnil N; Alemayehu, Berhanu; Peters, John R; Engel, Samuel S

2018-04-01

To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose-lowering regimens with differing risks of hypoglycaemia. Data were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose-lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all-cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time-dependent covariable. There were 6646 deaths in a total follow-up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95-1.12); sulphonylurea, aHR 1.11 (95% CI 0.99-1.25); insulin, aHR 1.47 (95% CI 1.25-1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94-1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13-1.35) and including insulin, aHR 1.28 (95% CI 1.18-1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all-cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia. The pattern of mortality risk across the range of HbA1c differed by glucose-lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.

PubMed

Liu, Laura X; Rowe, Glenn C; Yang, Steven; Li, Jian; Damilano, Federico; Chan, Mun Chun; Lu, Wenyun; Jang, Cholsoon; Wada, Shogo; Morley, Michael; Hesse, Michael; Fleischmann, Bernd K; Rabinowitz, Joshua D; Das, Saumya; Rosenzweig, Anthony; Arany, Zoltan

2017-12-08

Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations, are not well understood. To determine the mechanisms underlying cardiac substrate use during pregnancy. We use here 13 C glucose, 13 C lactate, and 13 C fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not seem altered. Insulin signaling seems intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 (cluster of differentiation 36) and GLUT4 (glucose transporter type 4), are also unchanged. Rather, we find that the pregnancy hormone progesterone induces PDK4 (pyruvate dehydrogenase kinase 4) in cardiomyocytes and that elevated PDK4 levels in late pregnancy lead to inhibition of PDH (pyruvate dehydrogenase) and pyruvate flux into the tricarboxylic acid cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy. Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling. © 2017 American Heart Association, Inc.

Thyroid stimulating hormone increases hepatic gluconeogenesis via CRTC2.

PubMed

Li, Yujie; Wang, Laicheng; Zhou, Lingyan; Song, Yongfeng; Ma, Shizhan; Yu, Chunxiao; Zhao, Jiajun; Xu, Chao; Gao, Ling

2017-05-05

Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with abnormal glucose levels. We previously reported that TSH has direct effects on gluconeogenesis. However, the underlying molecular mechanism remains unclear. In this study, we observed increased fasting blood glucose and glucose production in a mouse model of subclinical hypothyroidism (only elevated TSH levels). TSH acts via the classical cAMP/PKA pathway and CRTC2 regulates glucose homeostasis. Thus, we explore whether CRTC2 is involved in the process of TSH-induced gluconeogenesis. We show that TSH increases CRTC2 expression via the TSHR/cAMP/PKA pathway, which in turn upregulates hepatic gluconeogenic genes. Furthermore, TSH stimulates CRTC2 dephosphorylation and upregulates p-CREB (Ser133) in HepG2 cells. Silencing CRTC2 and CREB decreases the effect of TSH on PEPCK-luciferase, the rate-limiting enzyme of gluconeogenesis. Finally, the deletion of TSHR reduces the levels of the CRTC2:CREB complex in mouse livers. This study demonstrates that TSH activates CRTC2 via the TSHR/cAMP/PKA pathway, leading to the formation of a CRTC2:CREB complex and increases hepatic gluconeogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Beneficial Effects of Pentanema vestitum Linn. Whole Plant on the Glucose and Other Biochemical Parameters of Alloxan Induced Diabetic Rabbits

PubMed Central

Ilahi, Ikram; Asghar, Ali; Ali, Shujat; Khan, Murad; Khan, Nasrullah

2012-01-01

The residents of Lower Dir and Malakand agency, Khyber Pakhtunkhwa, Pakistan, use the dry powder of whole plant of Pentanema vestitum for the treatment of asthma and diabetes. No documented reports are available about the therapeutic action of Pentanema vestitum. The present study was aimed to explore the antihyperglycemic effect of 70% methanol extract of Pentanema vestitum whole plant in glucose-induced nondiabetic hyperglycemic and alloxan-induced diabetic rabbits. During this study, the effects of plant extract on the serum lipid profile, GPT, ALP, bilirubin and creatinine of diabetic rabbits were also studied. The extract of Pentanema vestitum whole plant exhibited significant (P < 0.05) antihyperglycemic activity in glucose-induced hyperglycemic rabbits. Treatment of alloxan-induced diabetic rabbits with extract significantly (P < 0.05) reduced the elevated levels of serum glucose, GPT, ALP, bilirubin and creatinine. During the study of lipid profile, the extract proved to be antihyperlipidemic and HDL boosting in diabetic rabbit models. From the finding of the present research, it was concluded that the 70% methanol extract of Pentanema vestitum whole plant has beneficial effects on serum levels of glucose, lipid profile, GPT, ALP, bilirubin, and creatinine of diabetic rabbits. PMID:23316385

Redirection of the Respiro-Fermentative Flux Distribution in Saccharomyces cerevisiae by Overexpression of the Transcription Factor Hap4p

PubMed Central

Blom, Jolanda; De Mattos, M. Joost Teixeira; Grivell, Leslie A.

2000-01-01

Reduction of aerobic fermentation on sugars by altering the fermentative/oxidative balance is of significant interest for optimization of industrial production of Saccharomyces cerevisiae. Glucose control of oxidative metabolism in baker's yeast is partly mediated through transcriptional regulation of the Hap4p subunit of the Hap2/3/4/5p transcriptional activator complex. To alleviate glucose repression of oxidative metabolism, we constructed a yeast strain with constitutively elevated levels of Hap4p. Genetic analysis of expression levels of glucose-repressed genes and analysis of respiratory capacity showed that Hap4p overexpression (partly) relieves glucose repression of respiration. Analysis of the physiological properties of the Hap4p overproducer in batch cultures in fermentors (aerobic, glucose excess) has shown that the metabolism of this strain is more oxidative than in the wild-type strain, resulting in a significant reduced ethanol production and improvement of growth rate and a 40% gain in biomass yield. Our results show that modification of one or more transcriptional regulators can be a powerful and a widely applicable tool for redirection of metabolic fluxes in microorganisms. PMID:10788368

Vitamin D status and metabolic syndrome in the elderly: the Rotterdam Study.

PubMed

Vitezova, A; Zillikens, M C; van Herpt, T T W; Sijbrands, E J G; Hofman, A; Uitterlinden, A G; Franco, O H; Kiefte-de Jong, J C

2015-03-01

The effects of vitamin D in the elderly are inconsistent. The aim of this study was to evaluate the association between vitamin D status and the metabolic syndrome (MetS) in the elderly, as well as between vitamin D status and the components of MetS (i.e. serum glucose, triglycerides (TG), HDL cholesterol (HDL-C), waist circumference (WC), and blood pressure (BP)). The study was embedded in the Rotterdam Study, a population-based cohort of middle-aged and elderly adults. We analyzed data from 3240 people (median age 71.2 years) who did not have type 2 diabetes mellitus at baseline. We found higher 25-hydroxyvitamin D (25(OH)D) concentrations associated with lower prevalence of MetS (odds ratio (OR); 95% CI: 0.61; 0.49, 0.77 for adequate levels (≥75  nmol/l) vs deficiency (<50  nmol/l). In addition, in analysis of the individual components, the ORs for adequate vs deficient vitamin D levels were: 0.66 (95% CI 0.53, 0.83) for elevated WC, 0.67 (95% CI 0.52, 0.86) for reduced HDL-C, 0.69 (95% CI 0.54, 0.88) for elevated TG, and 0.80 (95% CI 0.65, 0.99) for elevated fasting glucose. Vitamin D was not associated with elevated blood pressure, and ORs for adequacy vs deficiency were 0.82 (95% CI 0.65, 1.03). Higher 25(OH)D concentrations in the elderly are associated with lower prevalence of MetS and, in particular, with more beneficial HDL-C, TG, WC, and serum glucose. Since the prevalence of vitamin D deficiency is common worldwide and its risk increases with age, if causality is proven, benefits of improving vitamin D status among the elderly may be great. © 2015 European Society of Endocrinology.

Association between impaired fasting glycaemia in pediatric obesity and type 2 diabetes in young adulthood.

PubMed

Hagman, E; Danielsson, P; Brandt, L; Ekbom, A; Marcus, C

2016-08-22

In adults, impaired fasting glycemia (IFG) increases the risk for type 2 diabetes mellitus (T2DM). This study aimed to investigate to which extent children with obesity develop T2DM during early adulthood, and to determine whether IFG and elevated hemoglobin A1c (HbA1c) in obese children are risk markers for early development of T2DM. In this prospective cohort study, 1620 subjects from the Swedish Childhood Obesity Treatment Registry - BORIS who were ⩾18 years at follow-up and 8046 individuals in a population-based comparison group, matched on gender age and living area, were included. IFG was defined according to both ADA (cut-off 5.6 mmol l(-1)) and WHO (6.1 mmol l(-1)). Elevated HbA1c was defined according to ADA (cut-off 39 mmol l(-1)). Main outcome was T2DM medication, as a proxy for T2DM. Data on medications were retrieved from a national registry. The childhood obesity cohort were 24 times more likely to receive T2DM medications in early adulthood compared with the comparison group (95% confidence interval (CI): 12.52-46). WHO-defined IFG predicted future use of T2DM medication with an adjusted hazard ratio (HR) of 3.73 (95% CI: 1.87-7.45) compared with those who had fasting glucose levels <5.6 mmol l(-1). A fasting glucose level of 5.6-6.0 mmol l(-1), that is, the IFG-interval added by American Diabetes Association (ADA), did not increase the use of T2DM medication more than pediatric obesity itself, adjusted HR=1.72 (0.84-3.52). Elevated levels of HbA1c resulted in an adjusted HR=3.12 (1.50-6.52). More severe degree of obesity also increased the future T2DM risk. IFG according to WHO and elevated HbA1c (39-48 mmol l(-1)), but not the additional fasting glucose interval added by ADA (5.6-6.0 mmol l(-1)), can be considered as prediabetes in the obese pediatric population in Sweden.

Antidiabetic Activity of Aqueous Leaves Extract of Sesbania sesban (L) Merr. in Streptozotocin Induced Diabetic Rats

PubMed Central

Pandhare, Ramdas B.; Sangameswaran, B.; Mohite, Popat B.; Khanage, Shantaram G.

2011-01-01

The aqueous leaves extract of Sesbania sesban (L) Merr. (Family: Fabaceae) was evaluated for its antidiabetic potential on normal and streptozotocin (STZ)-induced diabetic rats. In the chronic model, the aqueous extract was administered to normal and STZ- induced diabetic rats at the doses of 250 and 500 mg/kg body weight (b.w.) p.o. per day for 30 days. The fasting Blood Glucose Levels (BGL), serum insulin level and biochemical data such as glycosylated hemoglobin, Total Cholesterol (TC), Triglycerides (TG), High Density Lipoproteins (HDL) and Low Density Lipoproteins (LDL) were evaluated and all were compared to that of the known anti-diabetic drug glibenclamide (0.25 mg/kg b.w.). The statistical data indicated significant increase in the body weight, liver glycogen, serum insulin and HDL levels and decrease in blood glucose, glycosylated hemoglobin, total cholesterol and serum triglycerides when compared with glibenclamide. Thus the aqueous leaves extract of Sesbania sesban had beneficial effects in reducing the elevated blood glucose level and lipid profile of STZ-induced diabetic rats. PMID:23407749

Application of Raman spectroscopy in type 2 diabetes screening in blood using leucine and isoleucine amino-acids as biomarkers and in comparative anti-diabetic drugs efficacy studies.

PubMed

Birech, Zephania; Mwangi, Peter Waweru; Bukachi, Fredrick; Mandela, Keith Makori

2017-01-01

Diabetes is an irreversible condition characterized by elevated blood glucose levels. Currently, there are no predictive biomarkers for this disease and the existing ones such as hemoglobin A1c and fasting blood glucose are used only when diabetes symptoms are noticed. The objective of this work was first to explore the potential of leucine and isoleucine amino acids as diabetes type 2 biomarkers using their Raman spectroscopic signatures. Secondly, we wanted to explore whether Raman spectroscopy can be applied in comparative efficacy studies between commercially available anti-diabetic drug pioglitazone and the locally used anti-diabetic herbal extract Momordica spinosa (Gilg.)Chiov. Sprague Dawley (SD) rat's blood was used and were pipetted onto Raman substrates prepared from conductive silver paste smeared glass slides. Prominent Raman bands associated with glucose (926, 1302, 1125 cm-1), leucine (1106, 1248, 1302, 1395 cm-1) and isolecucine (1108, 1248, 1437 and 1585 cm-1) were observed. The Raman bands centered at 1125 cm-1, 1395 cm-1 and 1437 cm-1 associated respectively to glucose, leucine and isoleucine were chosen as biomarker Raman peaks for diabetes type 2. These Raman bands displayed decreased intensities in blood from diabetic SD rats administered antidiabetic drugs pioglitazone and herbal extract Momordica spinosa (Gilg.)Chiov. The intensity decrease indicated reduced concentration levels of the respective biomarker molecules: glucose (1125 cm-1), leucine (1395 cm-1) and isoleucine (1437 cm-1) in blood. The results displayed the power and potential of Raman spectroscopy in rapid (10 seconds) diabetes and pre-diabetes screening in blood (human or rat's) with not only glucose acting as a biomarker but also leucine and isoleucine amino-acids where intensities of respectively assigned bands act as references. It also showed that using Raman spectroscopic signatures of the chosen biomarkers, the method can be an alternative for performing comparative efficacy studies between known and new anti-diabetic drugs. Reports on use of Raman spectroscopy in type 2 diabetes mellitus screening with Raman bands associated with leucine and isoleucine molecules acting as reference is rare in literature. The use of Raman spectroscopy in pre-diabetes screening of blood for changes in levels of leucine and isoleucine amino acids is particularly interesting as once elevated levels are noticed, necessary interventions to prevent diabetes development can be initiated.

A Randomized Cross-Over Trial of the Postprandial Effects of Three Different Diets in Patients with Type 2 Diabetes

PubMed Central

Bunjaku, Bekim; Rosenqvist, Ulf; Nystrom, Fredrik H.; Guldbrand, Hans

2013-01-01

Background In the clinic setting both fasting levels of glucose and the area under the curve (AUC) of glucose, by determination of HbA1c levels, are used for risk assessments, in type 2 diabetes (NIDDM). However little is known about postprandial levels, and hence AUC, regarding other traditional risk factors such as insulin and blood-lipids and how this is affected by different diets. Objective To study postprandial effects of three diets, during a single day, in NIDDM. Methods A low-fat diet (45–56 energy-% from carbohydrates), and a low-carbohydrate diet (16–24 energy-% from carbohydrates) was compared with a Mediterranean-style diet (black coffee for breakfast and the same total-caloric intake as the other two diets for lunch with red wine, 32–35 energy−% from carbohydrates) in a randomized cross-over design. Total-caloric intake/test-day at the clinic from food was 1025–1080 kCal in men and 905–984 kCal in women. The test meals were consumed at a diabetes ward under supervision. Results Twenty-one participants were recruited and 19 completed the studies. The low-carbohydrate diet induced lower insulin and glucose excursions compared with the low-fat diet (p<0.0005 for both AUC). The insulin-response following the single Mediterranean-style lunch-meal was more pronounced than during the low-fat diet lunch (insulin increase-ratio of the low-fat diet: 4.35±2.2, of Mediterranean-style diet: 8.12±5.2, p = 0.001) while postprandial glucose levels were similar. The increase-ratio of insulin correlated with the elevation of the incretin glucose-dependent insulinotropic-polypeptide following the Mediterranean-style diet lunch (Spearman, r = 0.64, p = 0.003). Conclusions The large Mediterranean-style lunch-meal induced similar postprandial glucose-elevations as the low-fat meal despite almost double amount of calories due to a pronounced insulin-increase. This suggests that accumulation of caloric intake from breakfast and lunch to a single large Mediterranean style lunch-meal in NIDDM might be advantageous from a metabolic perspective. Trial Registration ClinicalTrials.gov NCT01522157 NCT01522157 PMID:24312178

Cardiovascular risk factors in pre-pubertal schoolchildren in Angola

PubMed Central

Silva, Amílcar BT; Rodrigues, Sérgio L; Baldo, Marcelo P; Mill, José Geraldo; Silva, Amílcar BT; Capingana, Daniel P; Magalhães, Pedro; Gonçalves, Mauer AA; Mateus, Miguel SB; Molina, Maria del Carmen B

2016-01-01

Summary Methods The incidence of obesity is increasing worldwide, especially in countries with accelerated economic growth. We determined the prevalence of and associations between overweight/ obesity and cardiovascular risk factors in pre-pubertal (seven- to 11-year-old) schoolchildren (both genders, n = 198) in Luanda, Angola. Biochemical (fasting blood) and clinical examinations were obtained in a single visit. Data are reported as prevalence (95% confidence intervals) and association (r, Pearson). Results Prevalence of overweight/obesity was 17.7% (12.4–23.0%), high blood pressure (BP < 90% percentile) was 14.6% (9.7–19.5%), elevated glucose level was 16.7% (11.5–21.9%) and total cholesterol level < 170 mg/dl (4.4 mmol/l) was 69.2% (62.8–75.6%). Significant associations between body mass index (BMI) and systolic and diastolic BP (r = 0.46 and 0.40, respectively; p < 0.05) were found. No association between BMI and elevated glucose or cholesterol levels was found. Conclusion The prevalence of cardiovascular risk factors was high in pre-pubertal schoolchildren in Angola and fat accumulation was directly associated with blood pressure increase but not with other cardiovascular risk factors. PMID:27805243

Blood glucose control for patients with acute coronary syndromes in Qatar.

PubMed

Wilby, Kyle John; Elmekaty, Eman; Abdallah, Ibtihal; Habra, Masa; Al-Siyabi, Khalid

2016-01-01

Blood glucose is known to be elevated in patients presenting with acute coronary syndromes. However a gap in knowledge exists regarding effective management strategies once admitted to acute care units. It is also unknown what factors (if any) predict elevated glucose values during initial presentation. OBJECTIVES of the study were to characterize blood glucose control in patients admitted to the cardiac care unit (CCU) in Qatar and to determine predictive factors associated with high glucose levels (>10 mmol/l) on admission to the CCU. All data for this study were obtained from the CCU at Heart Hospital in Doha, Qatar. A retrospective chart review was completed for patients admitted to the CCU in Qatar from October 1st, 2012 to March 31st, 2013, of which 283 were included. Baseline characteristics (age, gender, nationality, medical history, smoking status, type of acute coronary syndrome), capillary and lab blood glucose measurements, and use of insulin were extracted. Time spent in glucose ranges of <4, 4 to <8, 8 to <10, and >10 mmol/1 was calculated manually. Univariate and multivariate logistic regression were performed to assess factors associated with high glucose on admission. The primary analysis was completed with capillary data and a sensitivity analysis was completed using laboratory data. Blood glucose values measured on admission and throughout length of stay in the CCU. Capillary blood glucose data showed majority of time was spent in the range of >10 mmol/l (41.95%), followed by 4-8 mmol/l (35.44%), then 8-10 mmol/l (21.45%), and finally <4 mmol/l (1.16%). As a sensitivity analysis, laboratory data showed very similar findings. Diabetes, hypertension, and non-smoker status predicted glucose values >10 mmol/l on admission (p < 0.05) in a univariate analysis but only diabetes remained significant in a multivariate model (OR 23.3; 95% CI, 11.5-47.3). Diabetes predicts high glucose values on hospital admission for patients with ACS and patients are not being adequately controlled throughout CCU stay.

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

Heart, Emma; Palo, Meridith; Womack, Trayce

Pancreatic β-cells release insulin in response to elevation of glucose from basal (4–7 mM) to stimulatory (8–16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H{sub 2}O{sub 2}), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H{sub 2}O{sub 2} inhibit insulin secretion. Menadione, which produces H{sub 2}O{sub 2} via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cellmore » line, and primary rodent islets. Menadione-dependent redox cycling and resulting H{sub 2}O{sub 2} production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1–10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H{sub 2}O{sub 2} formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H{sub 2}O{sub 2} and menadione on insulin secretion. -- Highlights: ► Menadione stimulation or inhibition of insulin secretion is dependent upon applied glucose levels. ► Menadione-dependent H{sub 2}O{sub 2} production is proportional to applied glucose levels. ► Quinone-mediated redox cycling is dependent on glycolysis.« less

Elevated O-GlcNAcylation stabilizes FOXM1 by its reduced degradation through GSK-3β inactivation in a human gastric carcinoma cell line, MKN45 cells.

PubMed

Inoue, Yosuke; Moriwaki, Kazumasa; Ueda, Yasuhiro; Takeuchi, Toshihisa; Higuchi, Kazuhide; Asahi, Michio

2018-01-08

O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for intracellular signaling. Elevated O-GlcNAcylation is a general feature of cancer and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor progression is not fully elucidated. Forkhead box M1 (FOXM1), a master mitotic transcription factor, has been implicated in all major hallmarks of cancer, and is wildly expressed in solid tumors. Given that FOXM1 expression was reported to be elevated in gastric cancer, we examined the effect of high glucose or an inhibitor of O-GlcNAc hydrolase, Thiamet G (TMG), on FOXM1 protein expression in a human gastric cancer cell line, MKN45 cells, and confirmed that FOXM1 protein level and the cell proliferation were upregulated. To investigate the molecular mechanisms by which FOXM1 protein expression is regulated by O-GlcNAcylation, the effect of high glucose and TMG on FOXM1 ubiquitination was examined in MKN45 cells. As a result, the ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3β. High glucose and TMG treatment increased phospho-serine 9 GSK-3β, an inactive form, and the degradation of FOXM1 protein was suppressed by treatment of GSK-3β inhibitors in MKN45 cells. Taken together, we suggest that high glucose and elevated O-GlcNAcylation stabilize FOXM1 protein by its reduced degradation via GSK-3β inactivation in MKN45 cells, suggesting that the higher risk of gastric cancer in diabetic patients could be partially due to O-GlcNAcylation-mediated FOXM1 stabilization. Copyright © 2017 Elsevier Inc. All rights reserved.

Chromium (D-phenylalanine)3 alleviates high fat-induced insulin resistance and lipid abnormalities.

PubMed

Kandadi, Machender Reddy; Unnikrishnan, M K; Warrier, Ajaya Kumar Sankara; Du, Min; Ren, Jun; Sreejayan, Nair

2011-01-01

High-fat diet has been implicated as a major cause of insulin resistance and dyslipidemia. The objective of this study was to evaluate the impact of dietary-supplementation of chromium (D-phenylalanine)(3) [Cr(D-Phe)(3)] on glucose and insulin tolerance in high-fat diet fed mice. C57BL/6-mice were randomly assigned to orally receive vehicle or Cr(D-Phe)(3) (45 μg of elemental chromium/kg/day) for 8-weeks. High-fat-fed mice exhibited impaired whole-body-glucose and -insulin tolerance and elevated serum triglyceride levels compared to normal chow-fed mice. Insulin-stimulated glucose up-take in the gastrocnemius muscles, assessed as 2-[(3)H-deoxyglucose] incorporation was markedly diminished in high-fat fed mice compared to control mice. Treatment with chromium reconciled the high-fat diet-induced alterations in carbohydrate and lipid metabolism. Treatment of cultured, differentiated myotubes with palmitic acid evoked insulin resistance as evidenced by lower levels of insulin-stimulated Akt-phosphorylation, elevated JNK-phosphorylation, (assessed by Western blotting), attenuation of phosphoinositol-3-kinase activity (determined in the insulin-receptor substrate-1-immunoprecipitates by measuring the extent of phosphorylation of phosphatidylinositol by γ-(32)P-ATP), and impairment in cellular glucose up-take, all of which were inhibited by Cr(d-Phe)(3). These results suggest a beneficial effect of chromium-supplementation in insulin resistant conditions. It is likely that these effects of chromium may be mediated by augmenting downstream insulin signaling. Copyright © 2010 Elsevier Inc. All rights reserved.

Methylglyoxal and carboxyethyllysine reduce glutamate uptake and S100B secretion in the hippocampus independently of RAGE activation.

PubMed

Hansen, Fernanda; Battú, Cíntia Eickhoff; Dutra, Márcio Ferreira; Galland, Fabiana; Lirio, Franciane; Broetto, Núbia; Nardin, Patrícia; Gonçalves, Carlos-Alberto

2016-02-01

Diabetes is a metabolic disease characterized by high fasting-glucose levels. Diabetic complications have been associated with hyperglycemia and high levels of reactive compounds, such as methylglyoxal (MG) and advanced glycation endproducts (AGEs) formation derived from glucose. Diabetic patients have a higher risk of developing neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. Herein, we examined the effect of high glucose, MG and carboxyethyllysine (CEL), a MG-derived AGE of lysine, on oxidative, metabolic and astrocyte-specific parameters in acute hippocampal slices, and investigated some of the mechanisms that could mediate these effects. Glucose, MG and CEL did not alter reactive oxygen species (ROS) formation, glucose uptake or glutamine synthetase activity. However, glutamate uptake and S100B secretion were decreased after MG and CEL exposure. RAGE activation and glycation reactions, examined by aminoguanidine and L-lysine co-incubation, did not mediate these changes. Acute MG and CEL exposure, but not glucose, were able to induce similar effects on hippocampal slices, suggesting that conditions of high glucose concentrations are primarily toxic by elevating the rates of these glycation compounds, such as MG, and by generation of protein cross-links. Alterations in the secretion of S100B and the glutamatergic activity mediated by MG and AGEs can contribute to the brain dysfunction observed in diabetic patients.

Caffeine can decrease subjective energy depending on the vehicle with which it is consumed and when it is measured.

PubMed

Young, H A; Benton, D

2013-07-01

Energy drinks contain glucose and caffeine, although in the longer term both adversely influence blood glucose homeostasis, with the unconsidered potential to have adverse consequences for cognition and mood. The objective of this study was to consider the influence on interstitial glucose levels, mood and cognition of drinks differing in their caffeine content and glycaemic load. Ninety minutes after a standard breakfast, a yoghurt-, glucose- or water-based drink, with or without 80 mg of caffeine, was consumed. The consumption of caffeine negatively influenced glucose homeostasis: that is, irrespective of the vehicle, caffeine consumption resulted in elevated levels of blood glucose throughout the study. Thirty minutes after consuming caffeine and water, rather than water alone, greater subjective energy was reported. However, after 90 and 150 min, caffeine administered in water increased tiredness, hostility and confusion. In contrast, combining caffeine with a yoghurt-based drink increased energy, agreeableness and clearheadedness later in the morning. There were no effects of caffeine on ratings of mood when it was taken with glucose. Caffeine, irrespective of vehicle, resulted in better memory, quicker reaction times in the choice reaction time test and the working memory task, and better and quicker responses with the vigilance task. Further research should consider how caffeine interacts with macronutrients and the timescale over which such effects occur.

Evidence against impaired brain microtubule protein polymerization at high glucose concentrations or during diabetes mellitus.

PubMed

Eaker, E Y; Angelastro, J M; Purich, D L; Sninsky, C A

1991-06-01

Previous studies suggest that brain microtubule protein exposed to high glucose levels or isolated from diabetic rats can become glucosylated and that this impairs GTP-induced microtubule polymerization. We set out to extend that investigation to define the mechanistic basis for inhibition of microtubule assembly during diabetes or on incubation at high glucose levels. Rat and bovine brain microtubule protein was purified by cycles of polymerization/depolymerization. When microtubules were incubated for 1 h in either buffer or buffer containing glucose (up to 165 mM), there was no difference in polymerization, a finding contrary to the earlier study. Other rats were injected with vehicle or streptozotocin (90 mg/kg) to induce diabetes as evidenced by serum glucose in excess of 300 mg%, and at 4 weeks, brain microtubule protein was isolated by the polymerization cycling method. Again, there was no difference in the amount or purity of isolated microtubule protein between control or diabetic rats. We also observed no increase in microtubule glucosylation, and GTP-induced polymerization in vitro was indistinguishable for protein derived from brains of normal rats and rats with diabetes as measured by turbidity or electron microscopy. Our results suggest that in vitro incubation with glucose or in vivo elevation of glucose during diabetes fails to impair microtubule polymerization, pointing to other mechanisms for the neuropathy associated with diabetes.

Growth and ethanol fermentation ability on hexose and pentose sugars and glucose effect under various conditions in thermotolerant yeast Kluyveromyces marxianus.

PubMed

Rodrussamee, Nadchanok; Lertwattanasakul, Noppon; Hirata, Katsushi; Suprayogi; Limtong, Savitree; Kosaka, Tomoyuki; Yamada, Mamoru

2011-05-01

Ethanol fermentation ability of the thermotolerant yeast Kluyveromyces marxianus, which is able to utilize various sugars including glucose, mannose, galactose, xylose, and arabinose, was examined under shaking and static conditions at high temperatures. The yeast was found to produce ethanol from all of these sugars except for arabinose under a shaking condition but only from hexose sugars under a static condition. Growth and sugar utilization rate under a static condition were slower than those under a shaking condition, but maximum ethanol yield was slightly higher. Even at 40°C, a level of ethanol production similar to that at 30°C was observed except for galactose under a static condition. Glucose repression on utilization of other sugars was observed, and it was more evident at elevated temperatures. Consistent results were obtained by the addition of 2-deoxyglucose. The glucose effect was further examined at a transcription level, and it was found that KmGAL1 for galactokinase and KmXYL1 for xylose reductase for galactose and xylose/arabinose utilization, respectively, were repressed by glucose at low and high temperatures, but KmHXK2 for hexokinase was not repressed. We discuss the possible mechanism of glucose repression and the potential for utilization of K. marxianus in high-temperature fermentation with mixed sugars containing glucose.

The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion

PubMed Central

Heart, Emma; Palo, Meridith; Womack, Trayce; Smith, Peter J. S.; Gray, Joshua P.

2011-01-01

Pancreatic β-cells release insulin in response to elevation of glucose from basal (4-7 mM) to stimulatory (8-16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H2O2), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H2O2 inhibit insulin secretion. Menadione, which produces H2O2 via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H2O2 production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H2O2 formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H2O2 and menadione on insulin secretion. PMID:22115979

The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion.

PubMed

Heart, Emma; Palo, Meridith; Womack, Trayce; Smith, Peter J S; Gray, Joshua P

2012-01-15

Pancreatic β-cells release insulin in response to elevation of glucose from basal (4-7mM) to stimulatory (8-16mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H(2)O(2)), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H(2)O(2) inhibit insulin secretion. Menadione, which produces H(2)O(2) via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H(2)O(2) production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H(2)O(2) formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H(2)O(2) and menadione on insulin secretion. Published by Elsevier Inc.

Effects of Topical Anesthetics on Behavior, Plasma Corticosterone, and Blood Glucose Levels after Tail Biopsy of C57BL/6NHSD Mice (Mus musculus)

PubMed Central

Dudley, Emily S; Johnson, Robert A; French, DeAnne C; Boivin, Gregory P

2016-01-01

Tail biopsy is a common procedure that is performed to obtain genetic material for determining genotype of transgenic mice. The use of anesthetics or analgesics is recommended, although identifying safe and effective drugs for this purpose has been challenging. We evaluated the effects of topical 2.5% lidocaine–2.5% prilocaine cream applied to the distal tail tip at 5 or 60 min before biopsy, immersion of the tail tip for 10 seconds in ice-cold 70% ethanol just prior to biopsy, and immersion of the tail tip in 0.5% bupivacaine for 30 s after biopsy. Mice were 7, 11, or 15 d old at the time of tail biopsy. Acute behavioral responses, plasma corticosterone, and blood glucose were measured after biopsy, and body weight and performance in elevated plus maze and open-field tests after weaning. Ice-cold ethanol prior to biopsy prevented acute behavioral responses to biopsy, and both ice-cold ethanol and bupivacaine prevented elevations in corticosterone and blood glucose after biopsy. Tail biopsy with or without anesthesia did not affect body weight or performance on elevated plus maze or open-field tests. We recommend the use of ice-cold ethanol for topical anesthesia prior to tail biopsy in mice 7 to 15 d old. PMID:27423152

Effects of Topical Anesthetics on Behavior, Plasma Corticosterone, and Blood Glucose Levels after Tail Biopsy of C57BL/6NHSD Mice (Mus musculus).

PubMed

Dudley, Emily S; Johnson, Robert A; French, DeAnne C; Boivin, Gregory P

2016-01-01

Tail biopsy is a common procedure that is performed to obtain genetic material for determining genotype of transgenic mice. The use of anesthetics or analgesics is recommended, although identifying safe and effective drugs for this purpose has been challenging. We evaluated the effects of topical 2.5% lidocaine-2.5% prilocaine cream applied to the distal tail tip at 5 or 60 min before biopsy, immersion of the tail tip for 10 seconds in ice-cold 70% ethanol just prior to biopsy, and immersion of the tail tip in 0.5% bupivacaine for 30 s after biopsy. Mice were 7, 11, or 15 d old at the time of tail biopsy. Acute behavioral responses, plasma corticosterone, and blood glucose were measured after biopsy, and body weight and performance in elevated plus maze and open-field tests after weaning. Ice-cold ethanol prior to biopsy prevented acute behavioral responses to biopsy, and both ice-cold ethanol and bupivacaine prevented elevations in corticosterone and blood glucose after biopsy. Tail biopsy with or without anesthesia did not affect body weight or performance on elevated plus maze or open-field tests. We recommend the use of ice-cold ethanol for topical anesthesia prior to tail biopsy in mice 7 to 15 d old.

The influence of elevated CO2 on non-structural carbohydrate distribution and fructan accumulation in wheat canopies

NASA Technical Reports Server (NTRS)

Smart, D. R.; Chatterton, N. J.; Bugbee, B.

1994-01-01

We grew 2.4 m2 wheat canopies in a large growth chamber under high photosynthetic photon flux (1000 micromoles m-2 s-1) and using two CO2 concentrations, 360 and 1200 micromoles mol-1. Photosynthetically active radiation (400-700 nm) was attenuated slightly faster through canopies grown in 360 micromoles mol-1 than through canopies grown in 1200 micromoles mol-1, even though high-CO2 canopies attained larger leaf area indices. Tissue fractions were sampled from each 5-cm layer of the canopies. Leaf tissue sampled from the tops of canopies grown in 1200 micromoles mol-1 accumulated significantly more total non-structural carbohydrate, starch, fructan, sucrose, and glucose (p < 0.05) than for canopies grown in 360 micromoles mol-1. Non-structural carbohydrate did not significantly increase in the lower canopy layers of the elevated CO2 treatment. Elevated CO2 induced fructan synthesis in all leaf tissue fractions, but fructan formation was greatest in the uppermost leaf area. A moderate temperature reduction of 10 degrees C over 5 d increased starch, fructan and glucose levels in canopies grown in 1200 micromoles mol-1, but concentrations of sucrose and fructose decreased slightly or remained unchanged. Those results may correspond with the use of fructosyl-residues and release of glucose when sucrose is consumed in fructan synthesis.

Association of the hypertriglyceridemic waist phenotype and type 2 diabetes mellitus among adults in China.

PubMed

Ren, Yongcheng; Zhang, Ming; Zhao, Jingzhi; Wang, Chongjian; Luo, Xinping; Zhang, Jiatong; Zhu, Tian; Li, Xi; Yin, Lei; Pang, Chao; Feng, Tianping; Wang, Bingyuan; Zhang, Lu; Li, Linlin; Yang, Xiangyu; Zhang, Hongyan; Hu, Dongsheng

2016-09-01

To clarify the association of the hypertriglyceridemic waist phenotype and type 2 diabetes mellitus among adults in China. In the present case-control study, we included 1,685 patients with type 2 diabetes mellitus and 7,141 normal glucose-tolerant controls from the Henan Province of China in 2011. Elevated waist circumference (GW) was defined as ≥90 cm for men and ≥80 cm for women. Hypertriglyceridemia (HT) was defined as >1.7 m mol/L triglycerides (TG) level. The association of hypertriglyceridemic waist phenotype and type 2 diabetes mellitus was investigated by sex, body mass index, physical activity, and family history of diabetes. Cases and controls differed in age, waist circumference (WC), weight, TG level, fasting glucose, body mass index, smoking status, diabetic family history, physical activity and hypertriglyceridemic waist phenotype (P < 0.05), but not alcohol drinking (P = 0.63). In the overall sample, as compared with the phenotype of normal TG level and normal WC (NTNW), normal TG level/enlarged WC (NTGW), elevated TG level/normal WC (HTNW) and elevated TG level/enlarged WC (HTGW) were associated with type 2 diabetes mellitus (odds ratio 4.14, 2.42 and 6.23, respectively). Only HTGW was consistently associated with risk of type 2 diabetes mellitus, with or without adjustment. The strongest relationship between HTGW and type 2 diabetes mellitus was for subjects with body mass index <24.0 kg/m(2) (odds ratio 6.54, 95% confidence interval 4.22-10.14) after adjustment for cofounding variables. HTGW was stably and significantly associated with risk of type 2 diabetes mellitus in adult Chinese. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

PubMed Central

Palanivel, R.; Fullerton, M. D.; Galic, S.; Honeyman, J.; Hewitt, K. A.; Jorgensen, S. B.; Steinberg, G. R.

2017-01-01

Aims/hypothesis Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. Methods We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. Results The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic–euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). Conclusions/interpretation These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity. PMID:22872213

Elevated 1-h post-challenge plasma glucose levels in subjects with normal glucose tolerance or impaired glucose tolerance are associated with whole blood viscosity.

PubMed

Marini, Maria Adelaide; Fiorentino, Teresa Vanessa; Andreozzi, Francesco; Mannino, Gaia Chiara; Perticone, Maria; Sciacqua, Angela; Perticone, Francesco; Sesti, Giorgio

2017-08-01

It has been suggested that glucose levels ≥155 mg/dl at 1-h during an oral glucose tolerance test (OGTT) may predict development of type 2 diabetes and cardiovascular events among adults with normal glucose tolerance (NGT 1 h-high). Studies showed a link between increased blood viscosity and type 2 diabetes. However, whether blood viscosity is associated with dysglycemic conditions such as NGT 1 h-high, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) is unsettled. 1723 non-diabetic adults underwent biochemical evaluation and OGTT. A validated formula based on hematocrit and total plasma proteins was employed to estimate whole blood viscosity. Subjects were categorized into NGT with 1 h glucose <155 mg/dL (NGT-1 h-low), NGT-1 h-high, IFG and/or IGT. Hematocrit and blood viscosity values appeared significantly higher in individuals with NGT 1 h-high, IFG and/or IGT as compared to NGT 1 h-low subjects. Blood viscosity was significantly correlated with age, waist circumference, blood pressure, HbA1c, fasting, 1- and 2-h post-challenge insulin levels, total cholesterol and low-density lipoprotein, triglycerides, fibrinogen, white blood cell, and inversely correlated with high-density lipoprotein and insulin sensitivity. Of the four glycemic parameters, 1-h post-challenge glucose showed the strongest correlation with blood viscosity (β = 0.158, P < 0.0001) in a multivariate regression analysis model including several atherosclerosis risk factors. Our results demonstrate a positive relationship between blood viscosity and 1-h post-challenge plasma glucose. They also suggest that a subgroup of NGT individuals with 1-h post-challenge plasma >155 mg/dl have increased blood viscosity comparable to that observed in subjects with IFG and/or IGT.

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.

Diagnostic Challenges of Central Nervous System Tuberculosis

PubMed Central

Loeffler, Ann M.; Honarmand, Somayeh; Flood, Jennifer M.; Baxter, Roger; Jacobson, Susan; Alexander, Rick; Glaser, Carol A.

2008-01-01

Central nervous system tuberculosis (TB) was identified in 20 cases of unexplained encephalitis referred to the California Encephalitis Project. Atypical features (encephalitic symptoms, rapid onset, age) and diagnostic challenges (insensitive cerebrospinal fluid [CSF] TB PCR result, elevated CSF glucose levels in patients with diabetes, negative result for tuberculin skin test) complicated diagnosis. PMID:18760024

Comparative effectiveness of carvedilol and propranolol on glycemic control and insulin resistance associated with L-thyroxin-induced hyperthyroidism--an experimental study.

PubMed

Bhatt, Parloop; Makwana, Dharmesh; Santani, Devdas; Goyal, Ramesh

2007-05-01

The present study was undertaken to investigate the effectiveness of adrenergic antagonists carvedilol and propranolol on L-thyroxin-induced cardiovascular and metabolic disturbances in rats. Treatment with L-thyroxin sodium (75 mg/kg body mass, s.c., every alternate day for 3 weeks), produced a significant increase in food and water intake, body temperature, heart rate, systolic blood pressure, along with an increase in serum T3, T4, and triglyceride levels. Besides a significant reduction in body mass, serum levels of TSH and cholesterol were also reduced following L-thyroxin treatment. Carvedilol (10 mg/kg body mass, orally) and propranolol (10 mg/kg body mass, i.p.) administered daily in the third week to 2 separate groups of L-thyroxin-treated animals reversed thyroxin-induced loss in body mass and rise in body temperature, blood pressure, and heart rate. Propranolol treatment increased TSH levels and decreased T3 and T4 levels in hyperthyroid animals, whereas carvedilol did not produce any effect on thyroid hormones. Carvedilol treatment reversed thyroxin induced hypertriglyceridemia, whereas propranolol treatment had no effect. Both carvedilol and propranolol prevented decrease in cholesterol levels induced by thyroxine. Compared with normal animals, L-thyroxin-treated animals showed a state of hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, and insulin resistance, as inferred from elevated fasting serum glucose and insulin levels, higher area under the curve over 120 min for glucose, and decreased insulin sensitivity index (KITT). Propranolol and carvedilol treatment significantly decreased fasting serum glucose levels. Treatment with propranolol did not alter serum insulin levels, area-under-the-curve glucose, or KITT values. However, treatment with carvedilol significantly reduced area-under-the-curve glucose, decreased fasting serum insulin levels and significantly increased KITT values. In conclusion, carvedilol appears to produce favorable effects on insulin sensitivity and glycemic control and can therefore be considered as more efficacious adjunctive treatment than propranolol in hyperthyroidism.

Attenuation of insulin resistance in rats by agmatine: role of SREBP-1c, mTOR and GLUT-2.

PubMed

Sharawy, Maha H; El-Awady, Mohammed S; Megahed, Nirmeen; Gameil, Nariman M

2016-01-01

Insulin resistance is a serious health condition worldwide; however, its exact mechanisms are still unclear. This study investigates agmatine (AGM; an endogenous metabolite of L-arginine) effects on insulin resistance induced by high fructose diet (HFD) in rats and the possible involved mechanisms. Sprague Dawley rats were fed 60% HFD for 12 weeks, and AGM (10 mg/kg/day, orally) was given from week 9 to 12. AGM significantly reduced HFD-induced elevation in fasting insulin level, homeostasis model assessment of insulin resistance (HOMA-IR) index and liver glycogen content from 3.44-, 3.62- and 2.07- to 2.59-, 2.78- and 1.3-fold, respectively, compared to the control group, while it increased HFD-induced reduction in glucose tolerance. Additionally, AGM significantly decreased HFD-induced elevation in serum triglycerides, low density lipoprotein cholesterol and very low density lipoprotein cholesterol levels from 3.18-, 2.97- and 4.75- to 1.25-, 1.25- and 1.07-fold, respectively, compared to control group. Conversely, AGM had no significant effect on HFD-induced changes in fasting glucose, glycosylated hemoglobin, insulin tolerance and high density lipoprotein cholesterol. Furthermore, AGM significantly reduced HFD-induced elevation in mRNA expression of glucose transporter type-2 (GLUT-2), mammalian target of rapamycin (mTOR) and sterol regulatory element-binding protein-1c (SREBP-1c) without affecting that of peroxisome proliferator-activated receptor-alpha (PPAR-α) in the liver. Additionally, AGM enhanced ACh-induced aortic relaxation and attenuated liver steatosis induced by HFD. In conclusion, AGM may have a therapeutic potential in insulin resistance through suppressing SREBP-1c, mTOR and GLUT-2 in liver.

Polycystic ovary disease. A risk factor for gestational diabetes?

PubMed

Lanzone, A; Caruso, A; Di Simone, N; De Carolis, S; Fulghesu, A M; Mancuso, S

1995-04-01

We investigated the impact of pregestationally elevated insulin plasma levels on glycemic control in pregnant women with polycystic ovary disease (PCOD). Twelve patients with PCOD who became pregnant within six months following evaluation of their metabolic status were the study subjects. Four were obese and six (two obese) had a hyperinsulinemic response to the oral glucose tolerance test (OGTT). They were tested with the OGTT at 28-30 weeks of gestation. We also tested 12 normal patients and 10 consecutive patients with gestational diabetes; all were at the same gestational age. Plasma levels of insulin and glucose were determined in the samples collected for a period of four hours after glucose load (100 g). All PCOD patients significantly increased their insulin secretion in pregnancy. The hyperinsulinemic PCOD patients developed gestational diabetes (two patients) and impaired gestational glucose tolerance (three patients). The area under the insulin curve was greater in PCOD patients than in control and gestational diabetes patients (P < .01). In spite of their large increase in insulin secretion observed during pregnancy, patients with PCOD may develop a derangement of glycemic control, probably related to their pregestational insulinemic status.

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes.

PubMed

Jung, Jong Gab; Choi, Sung-E; Hwang, Yoon-Jung; Lee, Sang-A; Kim, Eun Kyoung; Lee, Min-Seok; Han, Seung Jin; Kim, Hae Jin; Kim, Dae Jung; Kang, Yup; Lee, Kwan-Woo

2011-10-15

Elevated fatty acid levels have been thought to contribute to insulin resistance. Repression of the glucose transporter 4 (GLUT4) gene as well as impaired GLUT4 translocation may be a mediator for fatty acid-induced insulin resistance. This study was initiated to determine whether palmitate treatment repressed GLUT4 expression, whether glucose/fatty acid metabolism influenced palmitate-induced GLUT4 gene repression (PIGR), and whether attempts to prevent PIGR restored palmitate-induced impairment of glucose uptake (PIIGU) in C2 myotubes. Not only stimulators of fatty acid oxidation, such as bezafibrate, AICAR, and TOFA, but also TCA cycle substrates, such as pyruvate, leucine/glutamine, and α-ketoisocaproate/monomethyl succinate, significantly prevented PIGR. In particular, supplementing with pyruvate through methyl pyruvate resulted in nearly complete prevention of PIIGU, whereas palmitate treatment reduced the intracellular pyruvate level. These results suggest that pyruvate depletion plays a critical role in PIGR and PIIGU; thus, pyruvate supplementation may help prevent obesity-induced insulin resistance in muscle cells. Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.

Current concepts about chromium supplementation in type 2 diabetes and insulin resistance.

PubMed

Wang, Zhong Q; Cefalu, William T

2010-04-01

Chromium has been established to be an essential trace element in mammals in regard to maintenance of normal carbohydrate metabolism. Studies that provided chromium to human subjects in documented deficiency states noted improved glucose levels. However, controversy exists as to whether dietary supplementation with chromium should be routinely recommended in subjects without documented deficiencies. Over the recent past, several well-designed clinical trials have provided evidence in favor of and against a beneficial effect of chromium. It appears that across all subject phenotypes (eg, lean and obese, insulin sensitive and insulin resistant), a consistent significant and beneficial effect of chromium may not be observed. Specifically, recent data fail to demonstrate significant improvement in carbohydrate metabolism in individuals with metabolic syndrome, impaired glucose tolerance, or consistently in individuals with type 2 diabetes. However, patient selection may be an important factor in determining clinical response, as it was concluded that a clinical response to chromium (ie, decreased glucose and improved insulin sensitivity) may be more likely in insulin-resistant individuals with type 2 diabetes who have more elevated fasting glucose and hemoglobin A(1c) levels.

Physiological effects of potassium chloride, formalin and handling stress on bonytail

USGS Publications Warehouse

Sykes, Catherine L.; Caldwell, Colleen A.; Gould, William R.

2011-01-01

We characterized the sublethal physiological changes in bonytail Gila elegans subjected to consecutive 750-mg/L potassium chloride (KCl) and 25-mg/L formalin treatments for the removal of zebra mussel Dreissena polymorpha and quagga mussel D. bugensis veligers. Plasma cortisol, glucose, and osmolality were measured over 24 h and at 14 d posthandling after exposing bonytail to KCl and one net stressor (capture with a net), KCl plus formalin and two net stressors, and one or two net stressors without chemicals. Elevated plasma cortisol (322–440 ng/mL) and glucose (254–399 mg/dL) concentrations were observed in all treatments compared with the concentrations in control fish (plasma cortisol, 56 ng/mL; glucose, 43 mg/dL). While there were no detectable differences in plasma osmolality among the treatment and control fish, a difference was observed between fish that were handled once versus twice. Chemical effects of stress were not observed in any of the physiological responses when the KCl treatment was compared with the one-net stressor treatment or when the KCl plus formalin treatment was compared with the two-net stressor treatment. Cumulative responses, however, were observed between one net stressor and two net stressors for plasma glucose and osmolality but not for plasma cortisol. Plasma cortisol and glucose levels remained elevated at 24 h posthandling, indicating that bonytail had not completely recovered from the handling stressors and would benefit from a recovery period in protected refugia before being released.

Hyperosmolarity induced by high glucose promotes senescence in human glomerular mesangial cells.

PubMed

del Nogal, Maria; Troyano, Nuria; Calleros, Laura; Griera, Mercedes; Rodriguez-Puyol, Manuel; Rodriguez-Puyol, Diego; Ruiz-Torres, María P

2014-09-01

Hyperglycemia is involved in the diabetic complication of different organs and can elevate serum osmolarity. Here, we tested whether hyperosmolarity promoted by high glucose levels induces cellular senescence in renal cells. We treated Wistar rats with streptozotocin to induce diabetes or with consecutive daily injections of mannitol to increase serum osmolarity and analyzed p53 and p16 genes in renal cortex by immunohistochemistry. Both diabetic and mannitol treated rats showed a significant increase in serum osmolarity, without significant signs of renal dysfunction, but associated with increased staining for p53 and p16 in the renal cortex. An increase in p53 and p16 expression was also found in renal cortex slices and glomeruli isolated from healthy rats, which were later treated with 30 mM glucose or mannitol. Intracellular mechanisms involved were analyzed in cultured human glomerular mesangial cells treated with 30 mM glucose or mannitol. After treatments, cells showed increased p53, p21 and p16 expression and elevated senescence-associated β-galactosidase activity. Senescence was prevented when myo-inositol was added before treatment. High glucose or mannitol induced constitutive activation of Ras and ERK pathways which, in turn, were activated by oxidative stress. In summary, hyperosmolarity induced renal senescence, particularly in glomerular mesangial cells, increasing oxidative stress, which constitutively activated Ras-ERK 1/2 pathway. Cellular senescence could contribute to the organ dysfunction associated with diabetes. Copyright © 2014 Elsevier Ltd. All rights reserved.

MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells.

PubMed

Richards, Paul; Rachdi, Latif; Oshima, Masaya; Marchetti, Piero; Bugliani, Marco; Armanet, Mathieu; Postic, Catherine; Guilmeau, Sandra; Scharfmann, Raphael

2018-03-01

Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels. © 2017 by the American Diabetes Association.

Glucose intolerance, insulin resistance and cardiovascular risk factors in first degree relatives of women with polycystic ovary syndrome.

PubMed

Yilmaz, Murat; Bukan, Neslihan; Ersoy, Reyhan; Karakoç, Ayhan; Yetkin, Ilhan; Ayvaz, Göksun; Cakir, Nuri; Arslan, Metin

2005-09-01

The aim of the present study was to evaluate insulin resistance (IR), glucose tolerance status and cardiovascular risk factors in first degree relatives of patients with polycystic ovary syndrome (PCOS). A total of 120 family members [Mothers(PCOS) (n = 40), Fathers(PCOS) (n = 38), Sisters(PCOS) (n = 25) and Brothers(PCOS) (n = 17)] of 55 patients with PCOS and 75 unrelated healthy control subjects without a family history of diabetes or PCOS (four age- and weight-matched subgroups, i.e. Control(Mothers), Control(Fathers), Control(Sisters) and Control(Brothers)) were studied. IR was assessed by homeostatic model assessment (HOMA IR), log HOMA, insulin sensivity index (ISI), the quantitative insulin sensitivity check index (QUICKI) and area under the curve for insulin during the oral glucose tolerance test (AUCI, AUCG) in with normal glucose tolerance (NGT) subjects and controls. Serum adiponectin, resistin, homocysteine and lipid levels were measured. The prevalence of any degree of glucose intolerance was 40% in Mothers(PCOS) and 52% in Fathers(PCOS). In total, six (15%) glucose tolerance disorders were identified in the Control(Mothers) and Control(Fathers) in first degree relatives of control subjects. The first degree relatives of PCOS patients had significantly higher serum fasting insulin, HOMA-IR, Log HOMA and AUCI levels in all subgroups than the control subjects. The control subjects had significantly elevated QUCKI, ISI levels and serum adiponectin levels compared to the first degree relatives of PCOS subjects in all subgroups. The serum Hcy and resistin levels increased significantly in both Fathers(PCOS) and Mothers(PCOS) groups but not Brothers(PCOS) and Sister(PCOS). The results of the present study support the finding that the first degree relatives of PCOS patients carry an increased risk of cardiovascular disease, as do PCOS patients.

Pseudohyperglycemia: Effects of Unwashed Hand after Fruit Peeling or Handling on Fingertips Blood Glucose Monitoring Results.

PubMed

Olamoyegun, M A; Oloyede, T; Adewoye, O G; Abdulkarim, S O; Adeleke, A A

2016-01-01

Self-monitoring of blood glucose (SMBG) is an important component of management for diabetes mellitus (DM), especially in T1DM and T2DM patients who are on insulin therapy. Adequate blood glucose monitoring and prompt intervention are necessary to prevent blood glucose (BG) fluctuation and delay long-term diabetes complications. People with DM are advised to clean their hands before SMBG to remove any dirt or food residue that might affect the reading. The study tested the hypothesis that falsely elevated BG levels from fingertip occur after peeling or handling fruits in an unwashed hand. Fifty apparently healthy nondiabetes volunteers were enrolled. Capillary BG samples were collected from the fingertips after peeling or handling apple, orange, banana, watermelon, and pawpaw, followed by no hand washing for 1 h, cleaning the fingertip with alcohol swab once, five times, and washing hand thoroughly with tap water and drying. These samples were then analyzed with two different glucose meters. The mean BG values, measured from fingertip blood samples after peeling, and handling any of the fruits followed by no hand washing were significantly high, even after cleaning fingertip with a swab of alcohol once. However, there were no significant difference in BG levels measured after peeling and handling fruits followed by hand washing and the level of BG before peeling and handling fruits. Handling of peeled fruits with no hand washing with tap water is associated with overestimation of capillary BG (Pseudohyperglycemia) monitored with glucose meters.

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.

Single-cell imaging of bioenergetic responses to neuronal excitotoxicity and oxygen and glucose deprivation.

PubMed

Connolly, Niamh M C; Düssmann, Heiko; Anilkumar, Ujval; Huber, Heinrich J; Prehn, Jochen H M

2014-07-30

Excitotoxicity is a condition occurring during cerebral ischemia, seizures, and chronic neurodegeneration. It is characterized by overactivation of glutamate receptors, leading to excessive Ca(2+)/Na(+) influx into neurons, energetic stress, and subsequent neuronal injury. We and others have previously investigated neuronal populations to study how bioenergetic parameters determine neuronal injury; however, such experiments are often confounded by population-based heterogeneity and the contribution of effects of non-neuronal cells. Hence, we here characterized bioenergetics during transient excitotoxicity in rat and mouse primary neurons at the single-cell level using fluorescent sensors for intracellular glucose, ATP, and activation of the energy sensor AMP-activated protein kinase (AMPK). We identified ATP depletion and recovery to energetic homeostasis, along with AMPK activation, as surprisingly rapid and plastic responses in two excitotoxic injury paradigms. We observed rapid recovery of neuronal ATP levels also in the absence of extracellular glucose, or when glycolytic ATP production was inhibited, but found mitochondria to be critical for fast and complete energetic recovery. Using an injury model of oxygen and glucose deprivation, we identified a similarly rapid bioenergetics response, yet with incomplete ATP recovery and decreased AMPK activity. Interestingly, excitotoxicity also induced an accumulation of intracellular glucose, providing an additional source of energy during and after excitotoxicity-induced energy depletion. We identified this to originate from extracellular, AMPK-dependent glucose uptake and from intracellular glucose mobilization. Surprisingly, cells recovering their elevated glucose levels faster to baseline survived longer, indicating that the plasticity of neurons to adapt to bioenergetic challenges is a key indicator of neuronal viability. Copyright © 2014 the authors 0270-6474/14/3410192-14$15.00/0.

Glucose-dependent downregulation of glucagon gene expression mediated by selective interactions between ALX3 and PAX6 in mouse alpha cells.

PubMed

Mirasierra, Mercedes; Vallejo, Mario

2016-04-01

The stimulation of glucagon secretion in response to decreased glucose levels has been studied extensively. In contrast, little is known about the regulation of glucagon gene expression in response to fluctuations in glucose concentration. Paired box 6 (PAX6) is a key transcription factor that regulates the glucagon promoter by binding to the G1 and G3 elements. Here, we investigated the role of the transcription factor aristaless-like homeobox 3 (ALX3) as a glucose-dependent modulator of PAX6 activity in alpha cells. Experiments were performed in wild-type or Alx3-deficient islets and alphaTC1 cells. We used chromatin immunoprecipitations and electrophoretic mobility shift assays for DNA binding, immunoprecipitations and pull-down assays for protein interactions, transfected cells for promoter activity, and small interfering RNA and quantitative RT-PCR for gene expression. Elevated glucose concentration resulted in stimulated expression of Alx3 and decreased glucagon gene expression in wild-type islets. In ALX3-deficient islets, basal glucagon levels were non-responsive to changes in glucose concentration. In basal conditions ALX3 bound to the glucagon promoter at G3, but not at G1. ALX3 could form heterodimers with PAX6 that were permissive for binding to G3 but not to G1. Thus, increasing the levels of ALX3 in response to glucose resulted in the sequestration of PAX6 by ALX3 for binding to G1, thus reducing glucagon promoter activation and glucagon gene expression. Glucose-stimulated expression of ALX3 in alpha cells provides a regulatory mechanism for the downregulation of glucagon gene expression by interfering with PAX6-mediated transactivation on the glucagon G1 promoter element.

Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice.

PubMed

Jia, Yingli; He, Jinzhao; Wang, Liang; Su, Limin; Lei, Lei; Huang, Wei; Geng, Xiaoqiang; Zhang, Shun; Meng, Xiaolu; Zhou, Hong; Yang, Baoxue

2018-01-01

A sodium-glucose co-transporter-2 inhibitor dapagliflozin is widely used for lowering blood glucose and its usage is limited in type 2 diabetes mellitus patients with moderate renal impairment. As its effect on kidney function is discrepant and complicated, the aim of this study is to determine the effect of dapagliflozin on the progression of diabetic nephropathy and related mechanisms. Twelve-week-old male C57BL/6 wild-type and db/db mice were treated with vehicle or 1 mg/kg dapagliflozin for 12 weeks. Body weight, blood glucose, insulin tolerance, glucose tolerance, pyruvate tolerance and 24-hour urine were measured every 4 weeks. At 24 weeks of age, renal function was evaluated by blood urea nitrogen level, creatinine clearance, urine output, urinary albumin excretion, Periodic Acid-Schiff staining, Masson's trichrome staining and electron microscopy. Changes in insulin signaling and gluconeogenic key regulatory enzymes were detected using Western blot analysis. Dapagliflozin did not alleviate but instead aggravated diabetic nephropathy manifesting as increased levels of microalbuminuria, blood urea nitrogen, and glomerular and tubular damage in db/db mice. Despite adequate glycemic control by dapagliflozin, urinary glucose excretion increased after administration before 24 weeks of age and was likely associated with renal impairment. Increased urinary glucose excretion was mainly derived from the disturbance of glucose homeostasis with elevated hepatic and renal gluconeogenesis induced by dapagliflozin. Although it had no effect on insulin sensitivity and glucose tolerance, dapagliflozin further induced the expression of gluconeogenic key rate-limiting enzymes through increasing the expression levels of FoxO1 in the kidney and liver. These experimental results indicate that dapagliflozin aggravates diabetes mellitus-induced kidney injury, mostly through increasing gluconeogenesis. © 2018 The Author(s). Published by S. Karger AG, Basel.

Mangiferin Upregulates Glyoxalase 1 Through Activation of Nrf2/ARE Signaling in Central Neurons Cultured with High Glucose.

PubMed

Liu, Yao-Wu; Cheng, Ya-Qin; Liu, Xiao-Li; Hao, Yun-Chao; Li, Yu; Zhu, Xia; Zhang, Fan; Yin, Xiao-Xing

2017-08-01

Mangiferin, a natural C-glucoside xanthone, has anti-inflammatory, anti-oxidative, neuroprotective actions. Our previous study showed that mangiferin could attenuate diabetes-associated cognitive impairment of rats by enhancing the function of glyoxalase 1 (Glo-1) in brain. The aim of this study was to investigate whether Glo-1 upregulation by mangiferin in central neurons exposed to chronic high glucose may be related to activation of Nrf2/ARE pathway. Compared with normal glucose (25 mmol/L) culture, Glo-1 protein, mRNA, and activity levels were markedly decreased in primary hippocampal and cerebral cortical neurons cultured with high glucose (50 mmol/L) for 72 h, accompanied by the declined Nrf2 nuclear translocation and protein expression of Nrf2 in cell nucleus, as well as protein expression and mRNA level of γ-glutamylcysteine synthetase (γ-GCS) and superoxide dismutase activity, target genes of Nrf2/ARE signaling. Nonetheless, high glucose cotreating with mangiferin or sulforaphane, a typical inducer of Nrf2 activation, attenuated the above changes in both central neurons. In addition, mangiferin and sulforaphane significantly prevented the formation of advanced glycation end-products (AGEs) reflecting Glo-1 activity, while elevated the level of glutathione, a cofactor of Glo-1 activity and production of γ-GCS, in high glucose cultured central neurons. These findings demonstrated that Glo-1 was greatly downregulated in central neurons exposed to chronic high glucose, which is expected to lead the formation of AGEs and oxidative stress damages. We also proved that mangiferin enhanced the function of Glo-1 under high glucose condition by inducing activation of Nrf2/ARE signaling pathway.

Short-term fasting, seizure control and brain amino acid metabolism.

PubMed

Yudkoff, Marc; Daikhin, Yevgeny; Nissim, Ilana; Horyn, Oksana; Luhovyy, Bogdan; Lazarow, Adam; Nissim, Itzhak

2006-01-01

The ketogenic diet is an effective treatment for seizures, but the mechanism of action is unknown. It is uncertain whether the anti-epileptic effect presupposes ketosis, or whether the restriction of calories and/or carbohydrate might be sufficient. We found that a relatively brief (24 h) period of low glucose and low calorie intake significantly attenuated the severity of seizures in young Sprague-Dawley rats (50-70 gms) in whom convulsions were induced by administration of pentylenetetrazole (PTZ). The blood glucose concentration was lower in animals that received less dietary glucose, but the brain glucose level did not differ from control blood [3-OH-butyrate] tended to be higher in blood, but not in brain, of animals on a low-glucose intake. The concentration in brain of glutamine increased and that of alanine declined significantly with low-glucose intake. The blood alanine level fell more than that of brain alanine, resulting in a marked increase ( approximately 50%) in the brain:blood ratio for alanine. In contrast, the brain:blood ratio for leucine declined by about 35% in the low-glucose group. When animals received [1-(13)C]glucose, a metabolic precursor of alanine, the appearance of (13)C in alanine and glutamine increased significantly relative to control. The brain:blood ratio for [(13)C]alanine exceeded 1, indicating that the alanine must have been formed in brain and not transported from blood. The elevated brain(alanine):blood(alanine) could mean that a component of the anti-epileptic effect of low carbohydrate intake is release of alanine from brain-to-blood, in the process abetting the disposal of glutamate, excess levels of which in the synaptic cleft would contribute to the development of seizures.

Gut microbiota composition is correlated to grid floor induced stress and behavior in the BALB/c mouse.

PubMed

Bangsgaard Bendtsen, Katja Maria; Krych, Lukasz; Sørensen, Dorte Bratbo; Pang, Wanyong; Nielsen, Dennis Sandris; Josefsen, Knud; Hansen, Lars H; Sørensen, Søren J; Hansen, Axel Kornerup

2012-01-01

Stress has profound influence on the gastro-intestinal tract, the immune system and the behavior of the animal. In this study, the correlation between gut microbiota composition determined by Denaturing Grade Gel Electrophoresis (DGGE) and tag-encoded 16S rRNA gene amplicon pyrosequencing (454/FLX) and behavior in the Tripletest (Elevated Plus Maze, Light/Dark Box, and Open Field combined), the Tail Suspension Test, and Burrowing in 28 female BALB/c mice exposed to two weeks of grid floor induced stress was investigated. Cytokine and glucose levels were measured at baseline, during and after exposure to grid floor. Stressing the mice clearly changed the cecal microbiota as determined by both DGGE and pyrosequencing. Odoribacter, Alistipes and an unclassified genus from the Coriobacteriaceae family increased significantly in the grid floor housed mice. Compared to baseline, the mice exposed to grid floor housing changed the amount of time spent in the Elevated Plus Maze, in the Light/Dark Box, and burrowing behavior. The grid floor housed mice had significantly longer immobility duration in the Tail Suspension Test and increased their number of immobility episodes from baseline. Significant correlations were found between GM composition and IL-1α, IFN-γ, closed arm entries of Elevated Plus Maze, total time in Elevated Plus Maze, time spent in Light/Dark Box, and time spent in the inner zone of the Open Field as well as total time in the Open Field. Significant correlations were found to the levels of Firmicutes, e.g. various species of Ruminococccaceae and Lachnospiraceae. No significant difference was found for the evaluated cytokines, except an overall decrease in levels from baseline to end. A significant lower level of blood glucose was found in the grid floor housed mice, whereas the HbA1c level was significantly higher. It is concluded that grid floor housing changes the GM composition, which seems to influence certain anxiety-related parameters.

Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea.

PubMed

Norman, Daniel; Bardwell, Wayne A; Arosemena, Farah; Nelesen, Richard; Mills, Paul J; Loredo, Jose S; Lavine, Joel E; Dimsdale, Joel E

2008-01-01

Nonalcoholic fatty liver disease (NAFLD) is a disorder that often presents with elevated serum aminotransferase levels. Although it has classically been linked with the metabolic syndrome, recent studies suggest NAFLD may also be associated with obstructive sleep apnea (OSA). This study evaluates the association between serum aminotransferase levels and factors connected with: either the metabolic syndrome (elevated body mass index [BMI], lipid profile, blood pressure, fasting glucose), or with OSA severity (apnea hypopnea index, lowest oxygen saturation level, oxygen desaturation index, percent of time below 90% saturation [%T<90]). Retrospective case series. 109 adult patients with OSA at a university hospital general clinical research center. Markers of hypoxia (lowest oxygen saturation level and %T<90), correlated significantly with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (Pearson's r = -0.31 to -0.38, P <0.003), while apnea hypopnea index, body mass index, blood pressure, fasting glucose, triglyceride, and cholesterol levels did not. Hierarchical linear regression was then done to determine the best predictors of aminotransferase levels. Markers of metabolic syndrome were entered as one block and markers of sleep apnea as another. Regression analyses explained 16.3% of the variance in AST and 18.9% of the variance in ALT, with %T<90 playing the largest role. In patients with obstructive sleep apnea, serum aminotransferase levels are better predicted by markers of oxygen desaturation than by factors traditionally associated with the metabolic syndrome.

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.

Serum C-reactive protein and white blood cell count in morbidly obese surgical patients.

PubMed

Chen, Sheng-Bin; Lee, Yi-Chih; Ser, Kong-Han; Chen, Jung-Chien; Chen, Shu Chung; Hsieh, Hsing-Fang; Lee, Wei-Jei

2009-04-01

Obesity has been widely recognized as a chronic inflammatory condition and associated with elevated inflammatory indicators including C-reactive protein (CRP) and white blood cell count (WBC). Recent studies have shown elevated CRP or WBC is a significant risk factor for cardiac events and stroke but the clinical significance of CRP and WBC has not been clearly studied in morbidly obese patients. This study is aimed at the clinical significance of WBC and CRP in morbidly obese patients and the change after bariatric surgery. The study was a prospectively controlled clinical study. From December 1, 2001 to January 31, 2006, of 640 (442 females and 198 males) consecutive morbid obese patients enrolled in a surgically supervised weight loss program with at least 1 year's follow-up were examined. Of the patients, 476 (74.4%) had elevated CRP and 100 (15.6%) had elevated WBC at preoperative study. CRP and WBC were significantly related and both increased with increasing body mass index (BMI). CRP is also increased with increasing waist, glucose level, hemoglobin, albumin, Ca, insulin, C-peptide, and metabolic syndrome while WBC is increased with metabolic syndrome but decreased with increasing age. Multivariate analysis confirmed fasting glucose level and hemoglobin are independent predictors of the elevation of CRP while age is the only independent predictor for elevated WBC. Both WBC and CRP levels decreased rapidly after obesity surgery. These improvements resulted in a 69.8% reduction of CRP and 26.4% reduction of WBC 1 year after surgery. Although individuals who underwent laparoscopic gastric bypass lost significantly more weight (36.8 +/- 11.7 kg vs. 17.3 +/- 10.8 kg; p = 0.000) and achieved a lower BMI (27.8 +/- 4.6 vs. 35.0 +/- 5.5; p = 0.000) than individuals who underwent laparoscopic gastric banding, there was no difference in the resolution of elevated CRP 1 year after surgery (95.9% vs. 84.5%; p = 0.169) and WBC (99.4% vs. 98.3%; p = 0.323). Both baseline WBC and CRP are elevated in morbid obese patients but CRP has a better clinical significance. Significant weight reduction 1 year after surgery markedly reduced CRP and WBC with a resolution rate of 93.9% and 98.2% separately. Obesity surgery performed by laparoscopic surgery is recommended for obese patients with elevated CRP or WBC.

Characteristic hydrolyzing of megalosaccharide by human salivary α-amylase and small intestinal enzymes, and its bioavailability in healthy subjects.

PubMed

Nakamura, Sadako; Takami, Masayuki; Tanabe, Kenichi; Oku, Tsuneyuki

2014-09-01

The digestibility of Megalosaccharide® (newly developed carbohydrate comprising α-1,4-glucosaccharide) was investigated in vitro and in vivo. Isomaltosyl-megalosaccharide® (IMS) and nigerosyl-megalosaccharide® (NMS) contain 20% and 50% of the megalosaccharide fraction (degree of polymerization (DP) 10-35), respectively. IMS was hydrolyzed readily by α-amylase to oligosaccharides (DP ≤ 7), and a small amount of glucose was produced from oligosaccharides by small intestinal enzymes (SIEs). NMS was partially hydrolyzed by α-amylase to oligosaccharides, and a small amount of glucose produced by SIEs. When IMS and NMS were treated by SIEs after treatment with human saliva α-amylase for a few minutes, IMS and NMS were hydrolyzed readily to glucose. Plasma levels of glucose and insulin upon ingestion of 50 g of IMS or NMS were elevated the same as those for 50 g of glucose, and breath hydrogen was not excreted. These results suggest that IMS and NMS are digestible carbohydrates.

Blood glucose concentration and risk of liver cancer: systematic review and meta-analysis of prospective studies.

PubMed

Han, Hedong; Zhang, Tianyi; Jin, Zhichao; Guo, Honglei; Wei, Xin; Liu, Yuzhou; Chen, Qi; He, Jia

2017-07-25

The question of whether elevated blood glucose is a risk factor for liver cancer has been intensively studied, yet with inconsistent results. To explore the relationship between blood glucose concentration and risk of liver cancer, we conduct a meta-analysis of prospective studies. Literature search was comprehensively performed using database of PubMed, EMBASE and the Cochrane Library through October 2016. Random-effect models were used to combine the effect estimations. Eight articles containing ten studies with a total of 1975 liver cancer cases were included. The pooled RRs demonstrated that elevated fasting blood glucose was associated with increased risk of liver cancer (combined RRs: 1.77; 95% CI: 1.46, 2.13) with mild heterogeneity (I2 = 30.40%, P = 0.17). In sensitivity analysis, the pooled result remained significant (combined RRs: 1.33; 95% CI: 1.12, 1.59; I2 = 33.90%, P = 0.16) when we restricted blood glucose categories in the range of nondiabetic subjects. We also detected a J-shaped non-linear dose-response relationship between blood glucose concentration and risk of liver cancer. There is evidence that elevated blood glucose increases risk of liver cancer across the range of prediabetes and diabetes. Considering the rapidly increasing prevalence of prediabetes and diabetes, controlling blood glucose may lower the risk of liver cancer.

Fever is not responsible for the elevated glucose kinetics in sepsis

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

Lang, C.H.; Bagby, G.J.; Blakesley, H.L.

Previous studies have suggested that alterations in the classical neuroendocrine system may not be responsible for the increased glucose metabolism observed during hypermetabolic sepsis. The purpose of the present study was to determine whether inhibition of the cyclooxygenase pathway with indomethacin, which prevents the production of arachidonic acid metabolites by this pathway and the sepsis-induced increase in body temperature, would abolish the increases in glucose appearance (Ra), recycling, and hyperlactacidemia. Sepsis was induced in chronically catheterized conscious rats by multiple injections of live Escherichia coli via a subcutaneous catheter. Septic animals received iv injections of indomethacin every 6-8 hr tomore » block the cyclooxygenase pathway. Glucose kinetics were assessed in 24-hr fasted rats using a constant iv infusion of (6-/sup 3/H)- and (U-/sup 14/C) glucose. Treatment with indomethacin prevented the 1-2/sup 0/C increase in body temperature observed in septic animals. Septic rats exhibited an elevated plasma lactate concentration and increased rates of glucose appearance and recycling. The sepsis-induced alterations in these variables were not attenuated by indomethacin. These results suggest that neither elevated body temperature nor the generation of arachidonic acid metabolites of the cyclooxygenase pathway is responsible for increasing glucose production in hypermetabolic septic rats.« less

Effects of small interfering RNA-mediated hepatic glucagon receptor inhibition on lipid metabolism in db/db mice.

PubMed

Han, Seongah; Akiyama, Taro E; Previs, Stephen F; Herath, Kithsiri; Roddy, Thomas P; Jensen, Kristian K; Guan, Hong-Ping; Murphy, Beth A; McNamara, Lesley A; Shen, Xun; Strapps, Walter; Hubbard, Brian K; Pinto, Shirly; Li, Cai; Li, Jing

2013-10-01

Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is a key regulator for glucose homeostasis, antagonizing the glucagon receptor (GCGR) is a possible therapeutic strategy for the treatment of diabetes mellitus. To study the effect of hepatic GCGR inhibition on the regulation of lipid metabolism, we generated siRNA-mediated GCGR knockdown (si-GCGR) in the db/db mouse. The hepatic knockdown of GCGR markedly reduced plasma glucose levels; however, total plasma cholesterol was increased. The detailed lipid analysis showed an increase in the LDL fraction, and no change in VLDL HDL fractions. Further studies showed that the increase in LDL was the result of over-expression of hepatic lipogenic genes and elevated de novo lipid synthesis. Inhibition of hepatic glucagon signaling via siRNA-mediated GCGR knockdown had an effect on both glucose and lipid metabolism in db/db mice.

Hypometabolism as a therapeutic target in Alzheimer's disease.

PubMed

Costantini, Lauren C; Barr, Linda J; Vogel, Janet L; Henderson, Samuel T

2008-12-03

The pathology of Alzheimer's disease (AD) is characterized by cerebral atrophy in frontal, temporal, and parietal regions, with senile plaques, dystrophic neurites, and neurofibrillar tangles within defined areas of the brain. Another characteristic of AD is regional hypometabolism in the brain. This decline in cerebral glucose metabolism occurs before pathology and symptoms manifest, continues as symptoms progress, and is more severe than that of normal aging. Ketone bodies are an efficient alternative fuel for cells that are unable to metabolize glucose or are 'starved' of glucose. AC-1202 is designed to elevate serum ketone levels safely. We previously showed that treatment with AC-1202 in patients with mild-to-moderate AD improves memory and cognition. Treatment outcomes were influenced by apolipoprotein E genotype status. These data suggest that AC-1202 may be an effective treatment for cognitive dysfunction by providing an alternative substrate for use by glucose-compromised neurons.

Metabolic changes in rat striatum following convulsive seizures.

PubMed

Darbin, Olivier; Risso, Jean Jacque; Carre, Emily; Lonjon, Michel; Naritoku, Dean K

2005-07-19

Generalized convulsive seizures increase glucose utilization within the brain but their impact on metabolism is not well known. The striatum receives excitatory input from widespread sources in the brain and could potentially reflect energy depletion in the brain resulting from generalized seizures. We utilized multiprobe microdialysis in freely moving rats subjected to maximal electroshock to simultaneously measure glucose, lactate, and pyruvate levels in the interstitial space within striatum and in peripheral subcutaneous tissue. A brief convulsive seizure was associated with marked changes in striatal and peripheral metabolism during the post-ictal state that lasted up to 1 h. There were significant central and peripheral elevations of glucose, pyruvate, and lactate, reflecting increased glucose metabolism. Interestingly, the lactate-to-pyruvate ratio increased significantly in the periphery but remained unchanged in the striatum. Thus, there appears to be brain mechanisms that maintain adequate energy sources and prevent anaerobic shift during the post-ictal state.

The Association of Arsenic Exposure and Arsenic Metabolism with the Metabolic Syndrome and its Individual Components: Prospective Evidence from the Strong Heart Family Study.

PubMed

Spratlen, Miranda J; Grau-Perez, Maria; Best, Lyle G; Yracheta, Joseph; Lazo, Mariana; Vaidya, Dhananjay; Balakrishnan, Poojitha; Gamble, Mary V; Francesconi, Kevin A; Goessler, Walter; Cole, Shelley A; Umans, Jason G; Howard, Barbara V; Navas-Acien, Ana

2018-03-15

Inorganic arsenic exposure is ubiquitous and both exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. The association between arsenic exposure and arsenic metabolism with metabolic syndrome and its individual components, however, is relatively unknown. We used poisson regression with robust variance to evaluate the association between baseline arsenic exposure (urine arsenic levels) and metabolism (relative percentage of arsenic species over their sum) with incident metabolic syndrome and its individual components (elevated waist circumference, elevated triglycerides, reduced HDL, hypertension, elevated fasting plasma glucose) in 1,047 participants from the Strong Heart Family Study, a prospective family-based cohort in American Indian communities (baseline visits in 1998-1999 and 2001-2003, follow-up visits in 2001-2003 and 2006-2009). 32% of participants developed metabolic syndrome over follow-up. An IQR increase in arsenic exposure was associated with 1.19 (95% CI: 1.01, 1.41) greater risk for elevated fasting plasma glucose but not with other individual components or overall metabolic syndrome. Arsenic metabolism, specifically lower MMA% and higher DMA% was associated with higher risk of overall metabolic syndrome and elevated waist circumference, but not with any other component. These findings support there is a contrasting and independent association between arsenic exposure and arsenic metabolism with metabolic outcomes which may contribute to overall diabetes risk.

[The effects of the combined use of mineral water with ascorbic acid and rutin experimentally and clinically].

PubMed

Polushina, N D; Kartazaeva, V A; Botvineva, L A; Kozhevnikov, S A

2000-01-01

Effects of a single and course intake of glucose, ascorbic acid and rutin in combination with mineral water Essentuki N17 on blood levels of glucose, hydrocortisone, ACTH, insulin were studied in 336 Wistar male rats. 80 patients with diabetes mellitus type I and II received a course of ascorutin and mineral water. Mineral water proved able to reduce a hyperglycemic effect of vitamins. A course of mineral water and ascorutin promotes improvement of carbohydrate, lipid metabolism, elevates plasma content of ascorbic acid, diminishes the need in sugar-reducing drugs.

The Glucotoxicity Protecting Effect of Ezetimibe in Pancreatic Beta Cells via Inhibition of CD36.

PubMed

Yoon, Ji Sung; Moon, Jun Sung; Kim, Yong-Woon; Won, Kyu Chang; Lee, Hyoung Woo

2016-04-01

Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 μM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic β-cells through a decrease in fatty acid influx via inhibition of CD36.

The Glucotoxicity Protecting Effect of Ezetimibe in Pancreatic Beta Cells via Inhibition of CD36

PubMed Central

2016-01-01

Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 μM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic β-cells through a decrease in fatty acid influx via inhibition of CD36. PMID:27051238

Efficacy and safety of teneligliptin in addition to insulin therapy in type 2 diabetes mellitus patients on hemodialysis evaluated by continuous glucose monitoring.

PubMed

Yajima, Takahiro; Yajima, Kumiko; Hayashi, Makoto; Takahashi, Hiroshi; Yasuda, Keigo

2016-12-01

Appropriate glycemic control without hypoglycemia is important in patients with type 2 diabetes on hemodialysis. Teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, can be used without dose adjustment for these patients. Using continuous glucose monitoring (CGM), we evaluated the efficacy and safety of adding teneligliptin to insulin therapy. Twenty-one type 2 diabetes mellitus patients on hemodialysis treated with insulin were enrolled. After the adjustment of insulin dose, their blood glucose level was monitored by CGM. Insulin dose was reduced after teneligliptin administration. The median total daily insulin dose significantly reduced from 18 (9-24)U to 6 (0-14)U (p<0.0001). Maximum, mean, and standard deviation of blood glucose level on the hemodialysis and non-hemodialysis days did not change after teneligliptin administration. However, minimum blood glucose level was significantly elevated on the hemodialysis day after teneligliptin administration (from 3.9±1.0mmol/L to 4.4±0.9mmol/L, p=0.040). The incidence of asymptomatic hypoglycemia on the hemodialysis day detected by CGM significantly decreased from 38.1% to 19.0% (p=0.049). Teneligliptin may contribute toward reducing the total daily insulin dose and preventing hypoglycemic events on the hemodialysis day in type 2 diabetes mellitus patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mapping glucose-mediated gut-to-brain signalling pathways in humans☆

PubMed Central

Little, Tanya J.; McKie, Shane; Jones, Richard B.; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G.; McLaughlin, John T.

2014-01-01

Objectives Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Experimental design Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250 ml) of: 1 M glucose + predosing with dexloxiglumide (CCK1 receptor antagonist), 1 M glucose + placebo, or 0.9% saline (control) + placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Principal observations Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose + dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Conclusions Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. PMID:24685436

The effects of the aqueous extract and residue of Matcha on the antioxidant status and lipid and glucose levels in mice fed a high-fat diet.

PubMed

Xu, Ping; Ying, Le; Hong, Gaojie; Wang, Yuefei

2016-01-01

Matcha is a kind of powdered green tea produced by grinding with a stone mill. In the present study, the preventive effects of the aqueous extract (water-soluble) and residue (water-insoluble) of Matcha on the antioxidant status and lipid and glucose levels in mice fed a high-fat diet were investigated. Mice were fed seven different experimental diets for 4 weeks: a normal diet control (NC), a high-fat diet (HF), a high-fat diet with 0.025% Matcha (MLD), a high-fat diet with 0.05% Matcha (MMD), a high-fat diet with 0.075% Matcha (MHD), a high-fat diet with 0.05% Matcha aqueous extracts (ME), and a high-fat diet with 0.05% Matcha residues (MR). It was found that serum total cholesterol (TC) and triglyceride (TG) levels of the MHD group were significantly decreased compared to those of the HF group. Furthermore, in the MHD group, the level of high-density lipoprotein-cholesterol (HDL-C) was elevated, on the contrary the level of low-density lipoprotein-cholesterol (LDL-C) was suppressed. Moreover, Matcha could significantly lower the blood glucose levels, and improve the superoxide dismutase (SOD) activity and malondialdehyde (MAD) contents both in serum and liver; besides, the serum GSH-Px activity indicated that the oxidative stress caused by HF could be reversed by administration of Matcha. These findings suggest that Matcha has beneficial effects through the suppression of the blood glucose (BG) accumulation and promotion of the lipid metabolism and antioxidant activities. Moreover, the water-insoluble part of Matcha is suggested to play an important role in the suppression of diet-induced high levels of lipid and glucose.

Prevalence of traditional and novel markers of cardiovascular disease risk in Scottish adolescents: socioeconomic effects.

PubMed

Buchan, Duncan S; Ollis, Stewart; Thomas, Non-Eleri; Simpson, Alan; Young, John D; Cooper, Stephen-Mark; Malina, Robert M; Cockcroft, John R; Baker, Julien S

2012-10-01

Information on the health status and physical activity of Scottish adolescents is limited. This study examines the prevalence of cardiovascular disease (CVD) risk in Scottish adolescents by socioeconomic status (SES). Participants were recruited from two high schools that differed in the SES of the students in attendance. The sample included 73 boys and 34 girls (16.4 ± 0.6 years). Variables included anthropometry, physical activity, physical fitness, blood pressure, diet, and 11 metabolic markers of CVD risk. Significant sex differences (P ≤ 0.01) were noted for stature, waist circumference, waist-hip ratio, physical activity, cardiorespiratory fitness, muscular power, sprint speed, and several CVD risk factors: high-density lipoprotein (HDL), low-density lipoprotein (LDL), interleukin-6 (IL-6), and C-reactive protein (CRP) levels. Boys from a lower SES had significantly higher levels of glucose and plasminogen activator inhibitor-1 (PAI-1) but lower levels of adiponectin compared with boys from a higher SES. Girls from a lower SES had significantly (P ≤ 0.01) higher glucose and PAI-1 levels but lower levels of insulin and adiponectin than girls from a higher SES. High fat diets, low physical activity levels, and elevated CRP and total cholesterol levels were the CVD risk factors most commonly identified as being at-risk levels in this cohort, regardless of sex or SES. SES differences were not consistently apparent, but several CVD risk factors were identified as elevated in this sample of adolescents, regardless of sex or SES.

The protective role of low-concentration alcohol in high-fructose induced adverse cardiovascular events in mice.

PubMed

Wu, Xiaoqi; Pan, Bo; Wang, Ying; Liu, Lingjuan; Huang, Xupei; Tian, Jie

2018-01-01

Cardiovascular disease remains a worldwide public health issue. As fructose consumption is dramatically increasing, it has been demonstrated that a fructose-rich intake would increase the risk of cardiovascular disease. In addition, emerging evidences suggest that low concentration alcohol intake may exert a protective effect on cardiovascular system. This study aimed to investigate whether low-concentration alcohol consumption would prevent the adverse effects on cardiovascular events induced by high fructose in mice. From the results of hematoxylin-eosin staining, echocardiography, heart weight/body weight ratio and the expression of hypertrophic marker ANP, we found high-fructose result in myocardial hypertrophy and the low-concentration alcohol consumption would prevent the cardiomyocyte hypertrophy from happening. In addition, we observed low-concentration alcohol consumption could inhibit mitochondria swollen induced by high-fructose. The elevated levels of glucose, triglyceride, total cholesterol in high-fructose group were reduced by low concentration alcohol. Low expression levels of SIRT1 and PPAR-γ induced by high-fructose were significantly elevated when fed with low-concentration alcohol. The histone lysine 9 acetylation (acH3K9) level was decreased in PPAR-γ promoter in high-fructose group but elevated when intake with low concentration alcohol. The binding levels of histone deacetylase SIRT1 were increased in the same region in high-fructose group, while the low concentration alcohol can prevent the increased binding levels. Overall, our study indicates that low-concentration alcohol consumption could inhibit high-fructose related myocardial hypertrophy, cardiac mitochondria damaged and disorders of glucose-lipid metabolism. Furthermore, these findings also provide new insights into histone acetylation-deacetylation mechanisms of low-concentration alcohol treatment that may contribute to the prevention of cardiovascular disease induced by high-fructose intake. Copyright © 2017 Elsevier Inc. All rights reserved.

A Candida guilliermondii lysine hyperproducer capable of elevated citric acid production.

PubMed

West, Thomas P

2016-05-01

A mutant of the yeast Candida guilliermondii ATCC 9058 exhibiting elevated citric acid production was isolated based upon its ability to overproduce lysine. This method involved the use of a solid medium containing a combination of lysine analogues to identify a mutant that produced a several-fold higher lysine level compared to its parent strain using glucose or glycerol as a carbon source. The mutant strain was also capable of producing more than a fivefold higher citric acid level on glycerol as a carbon source compared to its parent strain. It was concluded that the screening of yeast lysine hyperproducer strains could provide a rapid approach to isolate yeast citric acid hyperproducer strains.

Serum chemerin level during the first trimester of pregnancy and the risk of gestational diabetes mellitus.

PubMed

Yang, Xuezhou; Quan, Xiaozhen; Lan, Yanli; Ye, Jinhai; Wei, Qipeng; Yin, Xiaofang; Fan, Fangfang; Xing, Hui

2017-10-01

To investigate the association between chemerin level in the first trimester of pregnancy and the risk of gestational diabetes mellitus. The blood samples of 212 women at 8-12 weeks of gestation were collected. After screening for gestational diabetes mellitus (GDM), 19 women with GDM and 20 women randomly selected from 144 women with normal glucose tolerance (NGT) were included in the study. Blood samples were collected from these women. Triglycerides, glucose, total cholesterol, and HDL cholesterol, LDL cholesterol, insulin and chemerin were measured. Gestational weight gain and body mass index was assessed. Serum levels of chemerin were significantly elevated during late gestation, and the risk of GDM was positively associated with maternal serum chemerin in the first trimester. Serum chemerin level during the first trimester of pregnancy has the potential to predict risk of GDM.

Glucose intolerance develops prior to increased adiposity and accelerated cessation of estrous cyclicity in female growth-restricted rats

PubMed Central

Intapad, Suttira; Dasinger, John Henry; Brown, Andrew D.; Fahling, Joel M.; Esters, Joyee; Alexander, Barbara T.

2015-01-01

Background The incidence of metabolic disease increases in early menopause. Low birth weight influences the age at menopause. Thus, this study tested the hypothesis that intrauterine growth restriction programs early reproductive aging and impaired glucose homeostasis in female rats. Methods Estrous cyclicity, body composition, and glucose homeostasis were determined in female control and growth-restricted rats at 6 and 12 months of age; sex steroids at 12 months. Results Glucose intolerance was present at 6 months of age prior to cessation of estrous cyclicity and increased adiposity in female growth-restricted rats. However, female growth-restricted rats exhibited persistent estrus and a significant increase in adiposity, fasting glucose and testosterone at 12 months of age (P<0.05). Insulin release in response to a glucose challenge was blunted in conjunction with a reduction in protein expression of pancreatic glucose transporter type 2 and estrogen receptor alpha at 12 months of age in female growth-restricted rats (P<0.05). Conclusion This study demonstrated that slow fetal growth programmed glucose intolerance that developed prior to early estrous acyclicity; yet, fasting glucose levels were elevated in conjunction with increased adiposity, accelerated cessation of estrous cyclicity and a shift towards testosterone excess at 12 months of age in female growth-restricted rats. PMID:26854801

Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis.

PubMed

Gautam, D; Han, S-J; Duttaroy, A; Mears, D; Hamdan, F F; Li, J H; Cui, Y; Jeon, J; Wess, J

2007-11-01

The release of insufficient amounts of insulin in the presence of elevated blood glucose levels is one of the key features of type 2 diabetes. Various lines of evidence indicate that acetylcholine (ACh), the major neurotransmitter of the parasympathetic nervous system, can enhance glucose-stimulated insulin secretion from pancreatic beta-cells. Studies with isolated islets prepared from whole body M(3) muscarinic ACh receptor knockout mice showed that cholinergic amplification of glucose-dependent insulin secretion is exclusively mediated by the M(3) muscarinic receptor subtype. To investigate the physiological relevance of this muscarinic pathway, we used Cre/loxP technology to generate mutant mice that lack M(3) receptors only in pancreatic beta-cells. These mutant mice displayed impaired glucose tolerance and significantly reduced insulin secretion. In contrast, transgenic mice overexpressing M(3) receptors in pancreatic beta-cells showed a pronounced increase in glucose tolerance and insulin secretion and were resistant to diet-induced glucose intolerance and hyperglycaemia. These findings indicate that beta-cell M(3) muscarinic receptors are essential for maintaining proper insulin secretion and glucose homeostasis. Moreover, our data suggest that enhancing signalling through beta-cell M(3) muscarinic receptors may represent a new avenue in the treatment of glucose intolerance and type 2 diabetes.

Ameliorative effect of hydro-methanolic extract from roots of Rauwolfia serpentina on some biochemical parameters of type 1 diabetic mice.

PubMed

Azmi, Muhammad Bilal; Qureshi, Shamim A; Ahmed, Syed Danish Haseen; Mudassir, Hina Akram; Imtiaz, Fauzia; Rais, Sumera; Khan, Auwais Ahmed; Ahsan, Muhammad

2018-03-01

Present work seeks to investigate the biochemical parameters in terms of hypoglycemic and hypolipidemic effects of hydro-methanolic roots extract (HyMREt) of Rauwolfia serpentina in type 1 (alloxan induced) diabetic mice. Animals were divided into seven groups, four control groups, and three were test groups (HyMREt at 50, 100, & 150mg/kg). Each treatment was repeated for 14 days regularly in all seven respective groups and afterwards the body weights, fasting blood glucose (FBG), insulin, and serum lipid levels were determined. Total body weights of diabetic mice treated with HyMREt extract were dose dependently (p<0.05) improved. FBG of test groups were significantly (p<0.0001) reduced in comparison with diabetic controls which displayed elevated fasting blood glucose level. The insulin levels of HyMREt treated groups were significantly (p<0.0001) higher than those of diabetic controls. Lower triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-c) and very low density lipoprotein cholesterol (VLDL-c) whereas elevated level of high density lipoprotein cholesterol (HDL-c) were observed in test dose treated groups. In comparison with diabetic controls, the converse levels of serum lipid were observed. Significant improvement in cardio-protective indices and coronary risk index was also observed. Findings of present study support the hypoglycemic and hypolipidemic potential of HyMREt of R. serpentina.

Evaluation of serum lipid profile, body mass index, and waistline in Chinese patients with type 2 diabetes mellitus.

PubMed

Cui, Rongtao; Qi, Zhiming; Zhou, Lin; Li, Zuohong; Li, Qing; Zhang, Junyong

2016-01-01

People with type 2 diabetes are at an increased risk of hypertension, arteriosclerosis, heart disease, and stroke. Glucose intolerance (insulin resistance) is the main feature of type 2 diabetes. Obesity leads to insulin resistance, dyslipidemia, etc. The aim of this study was to assess the biochemical parameters and measures of obesity in type 2 diabetes mellitus (T2DM). A total of 2,273 males and 6,547 females previously healthy volunteers (aged 41-95 years old) were recruited by open invitation. The basic information, including age, sex, height, weight, body mass index (BMI), waistline, hipline, menstrual cycle, and medical history, was collected by questionnaire survey and physical examination. Serum lipid profile, liver transaminase, blood glucose, postprandial blood glucose, and hemoglobin A1c were obtained after 12 hours of fasting. According to our results, diabetic patients presented serum lipid abnormality. Elevated triglyceride (TG) levels (≥1.7 mmol/L) were noted in 19.69% of males and 20.40% of females, and reduced high-density lipoprotein cholesterol (HDL-C) levels (≤1.15 mmol/L) were noted in 21.96% of males and 15.74% of females. The combination of elevated TG and reduced HDL-C was the most prevalent of the combined lipid abnormalities. In contrast, no differences were observed in the levels of low-density lipoprotein cholesterol and total cholesterol. Moreover, there were statistically significant differences in the levels of BMI and waistline between T2DM and non-T2DM participants. After adjustment for BMI, logistic regression analysis revealed that the subjects with BMI ≤20 kg/m(2) and >30 kg/m(2) had a significantly elevated hazard ratio of T2DM compared with participants having a BMI range of 20-30 kg/m(2) in both males and females. However, there was a significant difference between T2DM patients and non-T2DM patients in waistline (χ (2)=8.57, P<0.001) than in BMI parameter (χ (2)=6.29, P<0.001). The present study shows for the first time that low levels of HDL-C, high levels of TG, and abnormal levels in BMI and waistline increase the risk of type 2 T2DM in Chinese people.

Ferulic acid lowers body weight and visceral fat accumulation via modulation of enzymatic, hormonal and inflammatory changes in a mouse model of high-fat diet-induced obesity.

PubMed

de Melo, T S; Lima, P R; Carvalho, K M M B; Fontenele, T M; Solon, F R N; Tomé, A R; de Lemos, T L G; da Cruz Fonseca, S G; Santos, F A; Rao, V S; de Queiroz, M G R

2017-01-05

Previous studies have reported on the glucose and lipid-lowering effects of ferulic acid (FA) but its anti-obesity potential has not yet been firmly established. This study investigated the possible anti-obesitogenic effects of FA in mice fed a high-fat diet (HFD) for 15 weeks. To assess the antiobesity potential of FA, 32 male Swiss mice, weighing 20-25 g (n=6-8 per group) were fed a normal diet (ND) or HFD, treated orally or not with either FA (10 mg/kg) or sibutramine (10 mg/kg) for 15 weeks and at the end of this period, the body weights of animals, visceral fat accumulation, plasma levels of glucose and insulin hormone, amylase and lipase activities, the satiety hormones ghrelin and leptin, and tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCH-1) were analyzed. Results revealed that FA could effectively suppress the HFD-associated increase in visceral fat accumulation, adipocyte size and body weight gain, similar to sibutramine, the positive control. FA also significantly (P<0.05) decreased the HFD-induced elevations in serum lipid profiles, amylase and lipase activities, and the levels of blood glucose and insulin hormone. The markedly elevated leptin and decreased ghrelin levels seen in HFD-fed control mice were significantly (P<0.05) reversed by FA treatment, almost reaching the values seen in ND-fed mice. Furthermore, FA demonstrated significant (P<0.05) inhibition of serum levels of inflammatory mediators TNF-α, and MCH-1. These results suggest that FA could be beneficial in lowering the risk of HFD-induced obesity via modulation of enzymatic, hormonal and inflammatory responses.

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

Ferulic acid lowers body weight and visceral fat accumulation via modulation of enzymatic, hormonal and inflammatory changes in a mouse model of high-fat diet-induced obesity

PubMed Central

de Melo, T.S.; Lima, P.R.; Carvalho, K.M.M.B.; Fontenele, T.M.; Solon, F.R.N.; Tomé, A.R.; de Lemos, T.L.G.; da Cruz Fonseca, S.G.; Santos, F.A.; Rao, V.S.; de Queiroz, M.G.R.

2017-01-01

Previous studies have reported on the glucose and lipid-lowering effects of ferulic acid (FA) but its anti-obesity potential has not yet been firmly established. This study investigated the possible anti-obesitogenic effects of FA in mice fed a high-fat diet (HFD) for 15 weeks. To assess the antiobesity potential of FA, 32 male Swiss mice, weighing 20–25 g (n=6–8 per group) were fed a normal diet (ND) or HFD, treated orally or not with either FA (10 mg/kg) or sibutramine (10 mg/kg) for 15 weeks and at the end of this period, the body weights of animals, visceral fat accumulation, plasma levels of glucose and insulin hormone, amylase and lipase activities, the satiety hormones ghrelin and leptin, and tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCH-1) were analyzed. Results revealed that FA could effectively suppress the HFD-associated increase in visceral fat accumulation, adipocyte size and body weight gain, similar to sibutramine, the positive control. FA also significantly (P<0.05) decreased the HFD-induced elevations in serum lipid profiles, amylase and lipase activities, and the levels of blood glucose and insulin hormone. The markedly elevated leptin and decreased ghrelin levels seen in HFD-fed control mice were significantly (P<0.05) reversed by FA treatment, almost reaching the values seen in ND-fed mice. Furthermore, FA demonstrated significant (P<0.05) inhibition of serum levels of inflammatory mediators TNF-α, and MCH-1. These results suggest that FA could be beneficial in lowering the risk of HFD-induced obesity via modulation of enzymatic, hormonal and inflammatory responses. PMID:28076453

Hyperuricemia Causes Pancreatic β-Cell Death and Dysfunction through NF-κB Signaling Pathway

PubMed Central

Jia, Lu; Xing, Jing; Ding, Ying; Shen, Yachen; Shi, Xuhui; Ren, Wei; Wan, Meng; Guo, Jianjin; Zheng, Shujing; Liu, Yun; Liang, Xiubin; Su, Dongming

2013-01-01

Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid–treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid–treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11–7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis. PMID:24205181

Identification and prediction of group-based glycemic control trajectories during the transition to adolescence.

PubMed

Rohan, Jennifer M; Rausch, Joseph R; Pendley, Jennifer Shroff; Delamater, Alan M; Dolan, Lawrence; Reeves, Grafton; Drotar, Dennis

2014-10-01

To identify trajectories of glycemic control over a period of 3 years in a pediatric sample of youth diagnosed with Type 1 diabetes transitioning to adolescence. A second aim was to examine a set of modifiable individual and family level baseline predictors of glycemic control group membership. This multisite, prospective study included 239 children and adolescents (ages 9-11 years at baseline) diagnosed with Type 1 diabetes and their caregivers. Glycemic control was based on hemoglobin A1c (HbA1c) collected at 6-month intervals over a period of 3 years. Predictors of glycemic control membership included baseline global executive functioning, diabetes self-management, diabetes-specific family conflict, blood glucose monitoring frequency, and relevant individual and family level covariates. Group-based trajectory analyses were used to describe patterns of glycemic control from baseline to 36 months and 3 trajectories were identified: low risk (42.9%), elevated risk (44.6%), and high risk (12.1%) subgroups. Baseline maternal-reported family conflict, blood glucose monitoring frequency, and gender were significant predictors of glycemic control group membership. Higher levels of baseline family conflict, lower frequency of blood glucose monitoring, and female gender were associated with elevated and high-risk group membership. These findings underscore the importance of examining trajectories of HbA1c across time. These results suggest that problematic trajectories of glycemic control are evident during the transition to adolescence. Furthermore, there are modifiable individual and family level characteristics that predict group membership and hence could be targeted in interventions to ensure adequate glycemic control is maintained over time and that risks for diabetes-related complications are reduced.

Identification and Prediction of Group-Based Glycemic Control Trajectories during the Transition to Adolescence

PubMed Central

Rohan, Jennifer M.; Rausch, Joseph R.; Pendley, Jennifer Shroff; Delamater, Alan M.; Dolan, Lawrence; Reeves, Grafton; Drotar, Dennis

2014-01-01

Objective To identify trajectories of glycemic control over a period of three years in a pediatric sample of youth diagnosed with type 1 diabetes transitioning to adolescence. A second aim was to examine a set of modifiable individual and family-level baseline predictors of glycemic control group membership. Methods This multisite, prospective study included 239 children and adolescents (ages 9–11 years at baseline) diagnosed with type 1 diabetes and their caregivers. Glycemic control was based on hemoglobin A1c (HbA1c) collected at six month intervals over a period of three years. Predictors of glycemic control membership included baseline global executive functioning, diabetes self-management, diabetes-specific family conflict, blood glucose monitoring frequency, and relevant individual and family level covariates. Results Group-based trajectory analyses were used to describe patterns of glycemic control from baseline to 36 months and three trajectories were identified: low risk (42.9%), elevated risk (44.6%), and high risk (12.1%) subgroups. Baseline maternal-reported family conflict, blood glucose monitoring frequency, and gender were significant predictors of glycemic control group membership. Higher levels of baseline family conflict, lower frequency of blood glucose monitoring, and female gender were associated with elevated and high risk group membership. Conclusions These findings underscore the importance of examining trajectories of HbA1c across time. These results suggest that problematic trajectories of glycemic control are evident during the transition to adolescence. Furthermore, there are modifiable individual and family-level characteristics that predict group membership and hence could be targeted in interventions to ensure adequate glycemic control is maintained over time and that risks for diabetes-related complications are reduced. PMID:24274797

Elevation of blood β-hydroxybutyrate concentration affects glucose metabolism in dairy cows before and after parturition.

PubMed

Zarrin, M; Grossen-Rösti, L; Bruckmaier, R M; Gross, J J

2017-03-01

Recent studies in mid- and late-lactation dairy cows showed that β-hydroxybutyrate (BHB) infusion had a considerable effect on glucose metabolism and immune response during intramammary lipopolysaccharide challenge. The objective of the present study was to infuse BHB during the dry period and after parturition to investigate the effects of elevated plasma BHB concentrations on metabolism and endocrine changes in transition dairy cows. The hypothesis tested was that regulation of glucose metabolism would change at different physiological stages and an additional elevation of BHB concentration would alter glucose concentration. Multiparous Holstein cows in wk -2 (antepartum, a.p.; n = 6) and wk +2 (postpartum, p.p.; n = 8) relative to calving were infused (4 h from 0800 to 1200 h) with a BHB solution to increase plasma BHB concentration to 1.5 to 2.0 mmol/L (HyperB). The same period the next day without any infusion was considered the control period (CON). Blood samples were taken 1 h before the start of infusion as reference samples and every 30 min during the following 6 h (4 h of infusion and 2 h after infusion) in the HyperB and CON periods, and analyzed for glucose, BHB, insulin, and glucagon concentrations. During the steady state period (the latter 2 h of the 4-h infusion), plasma BHB concentration reached 1.87 ± 0.05 mmol/L (a.p.) and 1.93 ± 0.05 mmol/L (p.p.) in HyperB compared with 0.55 ± 0.06 mmol/L (a.p.) and 0.64 ± 0.04 mmol/L (p.p.) in CON, respectively. The 4-h average BHB infusion rate was 12.4 ± 1.0 and 13.3 ± 0.9 μmol/kg of BW per minute in wk -2 and +2, respectively. Infusion of BHB caused a decrease of plasma glucose concentrations relative to preinfusion levels both before and after parturition, although basal glucose concentrations were different before and after calving. Infusion of BHB increased plasma insulin concentrations a.p. but not p.p., despite a higher basal insulin concentration before than after parturition. These findings show that effects of hyperketonemia on plasma glucose concentrations are similar before and after calving but that endocrine adaptation to hyperketonemia differs before and after parturition. We assume that BHB is a metabolic key regulator in early lactating dairy cows and may affect glucose concentration by further pathways such as gluconeogenesis and altered lipolysis. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells.

PubMed

Mugabo, Yves; Zhao, Shangang; Lamontagne, Julien; Al-Mass, Anfal; Peyot, Marie-Line; Corkey, Barbara E; Joly, Erik; Madiraju, S R Murthy; Prentki, Marc

2017-05-05

Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Metabolism and acetylation contribute to leucine-mediated inhibition of cardiac glucose uptake.

PubMed

Renguet, Edith; Ginion, Audrey; Gélinas, Roselle; Bultot, Laurent; Auquier, Julien; Robillard Frayne, Isabelle; Daneault, Caroline; Vanoverschelde, Jean-Louis; Des Rosiers, Christine; Hue, Louis; Horman, Sandrine; Beauloye, Christophe; Bertrand, Luc

2017-08-01

High plasma leucine levels strongly correlate with type 2 diabetes. Studies of muscle cells have suggested that leucine alters the insulin response for glucose transport by activating an insulin-negative feedback loop driven by the mammalian target of rapamycin/p70 ribosomal S6 kinase (mTOR/p70S6K) pathway. Here, we examined the molecular mechanism involved in leucine's action on cardiac glucose uptake. Leucine was indeed able to curb glucose uptake after insulin stimulation in both cultured cardiomyocytes and perfused hearts. Although leucine activated mTOR/p70S6K, the mTOR inhibitor rapamycin did not prevent leucine's inhibitory action on glucose uptake, ruling out the contribution of the insulin-negative feedback loop. α-Ketoisocaproate, the first metabolite of leucine catabolism, mimicked leucine's effect on glucose uptake. Incubation of cardiomyocytes with [ 13 C]leucine ascertained its metabolism to ketone bodies (KBs), which had a similar negative impact on insulin-stimulated glucose transport. Both leucine and KBs reduced glucose uptake by affecting translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Finally, we found that leucine elevated the global protein acetylation level. Pharmacological inhibition of lysine acetyltransferases counteracted this increase in protein acetylation and prevented leucine's inhibitory action on both glucose uptake and GLUT4 translocation. Taken together, these results indicate that leucine metabolism into KBs contributes to inhibition of cardiac glucose uptake by hampering the translocation of GLUT4-containing vesicles via acetylation. They offer new insights into the establishment of insulin resistance in the heart. NEW & NOTEWORTHY Catabolism of the branched-chain amino acid leucine into ketone bodies efficiently inhibits cardiac glucose uptake through decreased translocation of glucose transporter 4 to the plasma membrane. Leucine increases protein acetylation. Pharmacological inhibition of acetylation reverses leucine's action, suggesting acetylation involvement in this phenomenon.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/leucine-metabolism-inhibits-cardiac-glucose-uptake/. Copyright © 2017 the American Physiological Society.

Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.

PubMed

Czupryniak, Leszek; Loba, Jerzy; Pawlowski, Maciej; Nowak, Dariusz; Bialasiewicz, Piotr

2005-05-01

Obstructive sleep apnea syndrome (OSAS) is often associated with impaired glucose metabolism. Data on the effects of OSAS treatment with continuous positive airway pressure (CPAP) on blood glucose and insulin resistance are conflicting. The study aimed at assessing the immediate effect of CPAP on glucose control measured with a continuous glucose monitoring system (CGMS). Nine non-diabetes subjects with OSAS (mean age 53.0 +/- 8.0 years; body mass index 34.8 +/- 5.3 kg/m2) underwent 2 overnight polysomnographic examinations: a diagnostic study and one with CPAP treatment. Continuous glucose monitoring system (CGMS) was applied overnight on both occasions. Glucose metabolism was assessed with a 75-g oral glucose tolerance test, plasma insulin and homeostatic model assessment of insulin resistance (HOMA-IR) index. The mean (+/- SD) apnoea-hypopnea index (AHI) at diagnostic polysomnography was 54.3 +/- 29.3 (range 16-81). Fasting plasma insulin levels in patients with OSAS was 84.3 +/- 43.4 pM at baseline, and the HOMA-IR was 3.6 +/- 2.2. CPAP treatment in the subjects with OSAS resulted in a significant reduction in the AHI to 4.5 +/- 7.1. All of the major saturation parameters improved significantly on CPAP. CGMS showed mean glucose values significantly higher during the CPAP night than during the diagnostic night: 80 +/- 11 mg/dL versus 63 +/- 7 mg/dL (P < .01). Fasting insulin and HOMA-IR measured after the CPAP night tended to be higher than at baseline (98.4 +/- 51.0 pmol vs 84.3 +/- 43.4 pmol and 3.9 pmol +/- 2.6 vs 3.6 +/- 2.2 pmol, respectively, P > .05). CPAP treatment in nondiabetic obese patients with OSAS may have an immediate elevating effect on blood glucose.

Postprandial and basal hyperglycaemia in type 2 diabetes: Contributions to overall glucose exposure and diabetic complications.

PubMed

Monnier, L; Colette, C

2015-12-01

Both postprandial and fasting (basal) hyperglycaemia contribute to overall hyperglycaemia (ambient hyperglycaemia) in type 2 diabetes (T2D). Postprandial glucose is the main contributor in fairly well controlled individuals, whereas basal hyperglycaemia becomes the preponderant contributor in poorly controlled patients. A more generally acceptable description of the contribution of postprandial glucose is to simply say that the absolute impact of postprandial glucose to HbA1c remains constant at approximately 1% across the entire HbA1c spectrum of non-insulin-treated patients with T2D. While epidemiological and pathophysiological studies seem to indicate that excessive postprandial glucose excursions play a role in or are predictors of cardiovascular diseases, there is still currently a lack of clinical evidence that correcting post-meal hyperglycaemia can improve clinical outcomes. However, even in the absence of consensus, there are many reasons for thinking that excessive postprandial glucose might be an independent risk factor for diabetic complications as it contributes to both overall glucose exposure and glycaemic variability, especially in those who have HbA1c levels < 7.5-8%. Given that excessive glucose fluctuations from peaks to nadirs activate oxidative stress, it seems reasonable to consider that a key player in the pathogenesis of diabetic complications, according to the latest IDF guidelines, is post-meal glucose, thereby warranting its assessment and treatment when found at abnormally elevated levels. Nevertheless, healthcare professionals should bear in mind that targeting both post-meal and basal plasma glucose, giving equal consideration to both of them, is probably the best strategy for achieving optimal glycaemic control and thus preventing or reducing the risk of diabetic complications. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Effect of Global ATGL Knockout on Murine Fasting Glucose Kinetics.

PubMed

Coelho, Margarida; Nunes, Patricia; Mendes, Vera M; Manadas, Bruno; Heerschap, Arend; Jones, John G

2015-01-01

Mice deficient in adipose triglyceride lipase (ATGL(-/-)) present elevated ectopic lipid levels but are paradoxically glucose-tolerant. Measurement of endogenous glucose production (EGP) and Cori cycle activity provide insights into the maintenance of glycemic control in these animals. These parameters were determined in 7 wild-type (ATGL(+/-)) and 6 ATGL(-/-) mice by a primed-infusion of [U-(13)C6]glucose followed by LC-MS/MS targeted mass-isotopomer analysis of blood glucose. EGP was quantified by isotope dilution of [U-(13)C6]glucose while Cori cycling was estimated by analysis of glucose triose (13)C-isotopomers. Fasting plasma free fatty-acids were significantly lower in ATGL(-/-) versus control mice (0.43 ± 0.05 mM versus 0.73 ± 0.11 mM, P < 0.05). Six-hour fasting EGP rates were identical for both ATGL(-/-) and control mice (79 ± 11 versus 71 ± 7 μmol/kg/min, resp.). Peripheral glucose metabolism was dominated by Cori cycling (80 ± 2% and 82 ± 7% of glucose disposal for ATGL(-/-) and control mice, resp.) indicating that peripheral glucose oxidation was not significantly upregulated in ATGL(-/-) mice under these conditions. The glucose (13)C-isotopomer distributions in both ATGL(-/-) and control mice were consistent with extensive hepatic pyruvate recycling. This suggests that gluconeogenic outflow from the Krebs cycle was also well compensated in ATGL(-/-) mice.

[Changes of serum aminotransferase in children with obstructive sleep apnea hypopnea syndrome].

PubMed

Chen, Zhenjiang; Duo, Likun

2013-08-01

Obstructive sleep apnea hypopnea syndrome (OSAHS) and non-alcoholic fatty liver disease (NAFLD) are both strongly associated with obesity. Whether OSAHS is an independent risk factor for liver injury or not is uncertain. To assess the hypothesis that OSAHS is associated with liver injury independent of obesity. One hundred and thirty children with OSAHS and 77 children with primary snoring(PS) were enrolled. Polysomnography was performed. Body mass index (BMI), liver function tests, serum lipids, fasting plasma glucose (FPG), and insulin (INS) were measured. Seventeen children of OSAHS had elevated serum aminotransferase levels,while only 2 children of non-OSAHS had elevated serum aminotransferase in healthy control group (chi2 = 5.18, P < 0.05; OR = 5.64 CI 1.27-24.97). Fifteen children of obese had elevated serum aminotransferase levels, while only 4 children had elevated serum aminotransferase in non-obese group (chi2 = 4.58, P < 0.05; (OR = 1.97 CI 1.06-3.67). Seventy cases of obese children, 15 cases of elevated aminotransferase levels (21.4%), namely fatty liver patients, of these children, 14 had OSAHS (93.3%). In contrast, OSAHS was present in only 67.3% of obese children without elevated aminotransferase. OSAHS may be a risk factor for liver injury independent of obesity; Increased liver enzyme levels are frequently found in obese snoring children, particularly among those with OSAHS.

The Role of Incretins in Glucose Homeostasis and Diabetes Treatment

PubMed Central

Kim, Wook; Egan, Josephine M.

2009-01-01

Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d’être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to β-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects. PMID:19074620

Comparison of sitagliptin with nateglinide on postprandial glucose and related hormones in drug-naïve Japanese patients with type 2 diabetes mellitus: A pilot study

PubMed Central

Tanimoto, Masumi; Kanazawa, Akio; Hirose, Takahisa; Yoshihara, Tomoaki; Kobayashi-Kimura, Saeko; Nakanishi, Risa; Tosaka, Yuka; Sasaki-Omote, Ruri; Kudo-Fujimaki, Kyoko; Komiya, Koji; Ikeda, Fuki; Someya, Yuki; Mita, Tomoya; Fujitani, Yoshio; Watada, Hirotaka

2015-01-01

Aims/Introduction Dipeptidyl peptidase-4 inhibitors and glinides are effective in reducing postprandial hyperglycemia. However, little information is available on the comparative effects of the two drugs on the levels of postprandial glucose. The aim of the present study was to compare the effects of sitagliptin and nateglinide on meal tolerance tests in drug-naïve patients with type 2 diabetes mellitus. Materials and Methods The study participants were 19 patients with type 2 diabetes mellitus, which was inadequately controlled by diet and exercise. An open-label, prospective, cross-over trial was carried out to compare the effects of single-dose sitagliptin and nateglinide on the postprandial glucose level and its related hormones during meal tests. Results The change in area under the curve (AUC) of glucose from 0 to 180 min (AUC0–180 min) during the meal test by nateglinide was similar to that by sitagliptin. As expected, the change in active glucagon like peptide-1 was significantly higher after a single-dose of sitagliptin than nateglinide. Then, insulin secretion relative to glucose elevation (ISG) (ΔISG0–180 min: ΔAUC0–180 min insulin/AUC0–180 min glucose) was significantly enhanced by nateglinide compared with sitagliptin. Conversely, glucagon level (ΔAUC0–180 min glucagon) was increased by administration of nateglinide, whereas the glucagon level was reduced by administration of sitagliptin. Conclusions The effects of sitagliptin on postprandial glucose levels were similar to those of nateglinide in drug-naïve type 2 diabetes patients. However, the induced changes in insulin, active glucagon-like peptide-1 and glucagon during meal loading suggest that reduction of postprandial hyperglycemia was achieved by the unique effect of each drug. PMID:26417414

Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome*

PubMed Central

Liaset, Bjørn; Hao, Qin; Jørgensen, Henry; Hallenborg, Philip; Du, Zhen-Yu; Ma, Tao; Marschall, Hanns-Ulrich; Kruhøffer, Mogens; Li, Ruiqiang; Li, Qibin; Yde, Christian Clement; Criales, Gabriel; Bertram, Hanne C.; Mellgren, Gunnar; Øfjord, Erik Snorre; Lock, Erik-Jan; Espe, Marit; Frøyland, Livar; Madsen, Lise; Kristiansen, Karsten

2011-01-01

Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1α, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferator-activated receptor β/δ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome. PMID:21680746

In vitro glucose uptake activity of Aegles marmelos and Syzygium cumini by activation of Glut-4, PI3 kinase and PPARgamma in L6 myotubes.

PubMed

Anandharajan, R; Jaiganesh, S; Shankernarayanan, N P; Viswakarma, R A; Balakrishnan, A

2006-06-01

The purpose of the present study is to investigate the effect of methanolic extracts of Aegles marmelos and Syzygium cumini on a battery of targets glucose transporter (Glut-4), peroxisome proliferator activator receptor gamma (PPARgamma) and phosphatidylinositol 3' kinase (PI3 kinase) involved in glucose transport. A. marmelos and S. cumini are anti-diabetic medicinal plants being used in Indian traditional medicine. Different solvent extracts extracted sequentially were analysed for glucose uptake activity at each step and methanol extracts were found to be significantly active at 100ng/ml dose comparable with insulin and rosiglitazone. Elevation of Glut-4, PPARgamma and PI3 kinase by A. marmelos and S. cumini in association with glucose transport supported the up-regulation of glucose uptake. The inhibitory effect of cycloheximide on A. marmelos- and S. cumini-mediated glucose uptake suggested that new protein synthesis is required for the elevated glucose transport. Current observation concludes that methanolic extracts of A. marmelos and S. cumini activate glucose transport in a PI3 kinase-dependent fashion.

Underlying pathways for interferon risk to type II diabetes mellitus.

PubMed

Abdel-Hamid, Nabil; Jubori, Taghreed Al; Farhan, Amaal; Mahrous, Mariam; Gouri, Adel; Awad, Ezzat; Breuss, Johannes

2013-11-01

It has been known that chronic liver treatments interfere with blood glucose metabolism. It was recognized that diabetes mellitus among chronic hepatitis C was greater in other types of chronic liver diseases. Hepatitis C directly promotes insulin resistance through the proteosomal degradation of insulin resistance substrate. It suppressed hepatocyte glucose uptake through down-regulation of surface expression of glucose transporter. Long-term exposure to cytokine over expression seems to be cytotoxic to both beta cells of the pancreas and to hepatocytes. Elevated tumor necrosis factor-a, or its neutralization, increased insulin sensitivity. Interferon-a may also elevate the serum level of interleukin-1 which is cytotoxic to pancreatic islet cells. Both diabetes mellitus and resistance to interferon-a therapy are abnormally mediated by over-expression of suppressor of cytokine signaling-1 in hepatocytes of chronic hepatitis C patients. These data suggest that interferon-a therapy should be administered with caution in patients showing any predisposition to Diabetes mellitus. Anti inflammatory therapy is critically recommended as a protector against disease development due to cytokine mediated Diabetes mellitus during hepatitis C therapy, since inflammation seems to be a main candidate to interferon suspected diabetogenesis.

Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/−-IRS-1+/− Double Heterozygous (IR-IRS1dh) Mice

PubMed Central

Franko, Andras; Kunze, Alexander; Böse, Marlen; von Kleist-Retzow, Jürgen-Christoph; Paulsson, Mats; Hartmann, Ursula; Wiesner, Rudolf J.

2017-01-01

Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR)+/−-insulin receptor substrate-1 (IRS-1)+/− double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver. PMID:28556799

The metabolism of carbohydrates and lipid peroxidation in lead-exposed workers.

PubMed

Kasperczyk, Aleksandra; Dobrakowski, Michal; Ostałowska, Alina; Zalejska-Fiolka, Jolanta; Birkner, Ewa

2015-12-01

The present study was undertaken to estimate the effect of occupational exposure to lead on the blood concentration of glucose and several enzymes involved in glycolysis, the citric acid cycle, and the pentose phosphate pathway. To estimate the degree of lipid peroxidation, the concentrations of conjugated dienes were determined. The examined group included 145 healthy male employees of lead-zinc works. Taking into account the mean blood lead levels, the examined group was divided into two subgroups. The control group was composed of 36 healthy male administrative workers. The markers of lead exposure were significantly elevated in both subgroups when compared with the controls. There were no significant changes in fasting glucose concentration and fructose-1,6-bisphosphate aldolase activity in the study population. The concentration of conjugated dienes was significantly higher in both subgroups, whereas the activity of malate dehydrogenase was significantly higher only in the group with higher exposure. The activities of lactate dehydrogenase and sorbitol dehydrogenase were significantly decreased in the examined subgroups. The activity of glucose-6-phosphate dehydrogenase decreased significantly in the group with higher exposure and could be the cause of the elevated concentrations of conjugated dienes. It is possible to conclude that lead interferes with carbohydrate metabolism, but compensatory mechanisms seem to be efficient, as glucose homeostasis in lead-exposed workers was not disturbed. © The Author(s) 2013.

Products based on a high fiber barley genotype, but not on common barley or oats, lower postprandial glucose and insulin responses in healthy humans.

PubMed

Liljeberg, H G; Granfeldt, Y E; Björck, I M

1996-02-01

Postprandial blood glucose and insulin responses to cereal products made from common barley, oats or a barley genotype containing elevated levels of beta-glucans were evaluated in nine healthy subjects. Porridges were made from commercial Swedish whole-meal barley or oat flours, and a mixed whole-meal porridge using the high fiber barley genotype and commercial Swedish common barley (50:50). Also studied were two types of flour-based bread products composed of high fiber barley and common barley in ratios of 50:50 or 80:20, respectively. The common oat and barley porridges produced postprandial glucose and insulin responses similar to the white wheat bread reference, suggesting that the naturally occurring dietary fiber in these whole-meal flours has no impact on the glucose tolerance. In contrast, all high fiber barley products induced significantly lower responses than did the reference product, with the glycemic and insulin indices ranging from 57 to 72 or 42 to 72%, respectively. It is concluded that "lente" products of high sensory quality can be prepared from a barley genotype with an elevated content of soluble dietary fiber. The glycemic index of these products compares favorably with that of products made from common cereals, suggesting their use as a potential component of diets for patients with diabetes and hyperlipidemia, and for individuals predisposed to metabolic disease.

Pancreatic Fat Is Associated With Metabolic Syndrome and Visceral Fat but Not Beta-Cell Function or Body Mass Index in Pediatric Obesity.

PubMed

Staaf, Johan; Labmayr, Viktor; Paulmichl, Katharina; Manell, Hannes; Cen, Jing; Ciba, Iris; Dahlbom, Marie; Roomp, Kirsten; Anderwald, Christian-Heinz; Meissnitzer, Matthias; Schneider, Reinhard; Forslund, Anders; Widhalm, Kurt; Bergquist, Jonas; Ahlström, Håkan; Bergsten, Peter; Weghuber, Daniel; Kullberg, Joel

2017-03-01

Adolescents with obesity have increased risk of type 2 diabetes and metabolic syndrome (MetS). Pancreatic fat has been related to these conditions; however, little is known about associations in pediatric obesity. The present study was designed to explore these associations further. We examined 116 subjects, 90 with obesity. Anthropometry, MetS, blood samples, and oral glucose tolerance tests were assessed using standard techniques. Pancreatic fat fraction (PFF) and other fat depots were quantified using magnetic resonance imaging. The PFF was elevated in subjects with obesity. No association between PFF and body mass index-standard deviation score (BMI-SDS) was found in the obesity subcohort. Pancreatic fat fraction correlated to Insulin Secretion Sensitivity Index-2 and Homeostatic Model Assessment of Insulin Resistance in simple regression; however, when using adjusted regression and correcting for BMI-SDS and other fat compartments, PFF correlated only to visceral adipose tissue and fasting glucose. Highest levels of PFF were found in subjects with obesity and MetS. In adolescents with obesity, PFF is elevated and associated to MetS, fasting glucose, and visceral adipose tissue but not to beta-cell function, glucose tolerance, or BMI-SDS. This study demonstrates that conclusions regarding PFF and its associations depend on the body mass features of the cohort.

Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/--IRS-1+/- Double Heterozygous (IR-IRS1dh) Mice.

PubMed

Franko, Andras; Kunze, Alexander; Böse, Marlen; von Kleist-Retzow, Jürgen-Christoph; Paulsson, Mats; Hartmann, Ursula; Wiesner, Rudolf J

2017-05-30

Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR) +/- -insulin receptor substrate-1 (IRS-1) +/- double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver.

Contribution of nonesterified fatty acids to insulin resistance in the elderly with normal fasting but diabetic 2-hour postchallenge plasma glucose levels: the Baltimore Longitudinal Study of Aging.

PubMed

Carlson, Olga D; David, Jehan D; Schrieder, Jessica M; Muller, Dennis C; Jang, Hyeung-Jin; Kim, Byung-Joon; Egan, Josephine M

2007-10-01

Isolated postchallenge hyperglycemia (IPH) with normal fasting plasma glucose <100 mg/dL and plasma glucose with diabetic 2-hour plasma glucose >or=200 mg/dL after an oral glucose tolerance test (OGTT) is a common occurrence in the elderly. We sought to understand what unique characteristics this population might have that puts it at risk for this particular metabolic finding. We therefore conducted a longitudinal study of volunteers in the Baltimore Longitudinal Study of Aging (BLSA). All volunteers had an OGTT performed (75 g) on 2 or more occasions. We measured plasma levels of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), ghrelin, leptin, adiponectin, resistin, C-reactive protein, cytokines, and their soluble receptors, as well as nonesterified free fatty acids (NEFAs). We determined that 22 subjects in BLSA had IPH, accounting for 2.1% of the BLSA population. All 22 were older than 65 years. They were then matched by age, sex, and body mass index to 12 subjects who had isolated impaired glucose tolerance (IGT) and 15 subjects with normal glucose tolerance (NGT). All subjects had normal fasting glucose levels <100 mg/dL in accordance with the American Diabetes Association Expert Committee on the Classification and Diagnosis of Diabetes Mellitus criteria (2003). We found that subjects with IPH had similar plasma insulin levels to the other 2 groups, except at the 2-hour time when their insulin levels were higher than NGT (P < .05). Although there was a clear trend for differences in the insulinogenic index, the areas under the curves for insulin, systolic blood pressure, adiponectin, and C-reactive protein across the glucose tolerance categories revealed no statistical significance. Cytokines and their soluble receptors, gut hormones, and adipokines were similar in all 3 groups. The NEFA levels were significantly elevated in the fasting state (P < .05) in the IPH compared with NGT, with IGT intermediate between the other 2 groups. The rate of clearance of NEFAs after the OGTT decreased progressively from the NGT to the IPH group (in micromoles per liter per minute: NGT, 11.9 vs IGT, 7.6 vs IPH, 3.0). We conclude that the rate of suppression of lipolysis in the elderly determines the sensitivity of glucose uptake to insulin after OGTT.

Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors.

PubMed

Boidot, Romain; Végran, Frédérique; Meulle, Aline; Le Breton, Aude; Dessy, Chantal; Sonveaux, Pierre; Lizard-Nacol, Sarab; Feron, Olivier

2012-02-15

The monocarboxylate transporter (MCT) family member MCT1 can transport lactate into and out of tumor cells. Whereas most oxidative cancer cells import lactate through MCT1 to fuel mitochondrial respiration, the role of MCT1 in glycolysis-derived lactate efflux remains less clear. In this study, we identified a direct link between p53 function and MCT1 expression. Under hypoxic conditions, p53 loss promoted MCT1 expression and lactate export produced by elevated glycolytic flux, both in vitro and in vivo. p53 interacted directly with the MCT1 gene promoter and altered MCT1 mRNA stabilization. In hypoxic p53(-/-) tumor cells, NF-κB further supported expression of MCT1 to elevate its levels. Following glucose deprivation, upregulated MCT1 in p53(-/-) cells promoted lactate import and favored cell proliferation by fuelling mitochondrial respiration. We also found that MCT1 expression was increased in human breast tumors harboring p53 mutations and coincident features of hypoxia, with higher MCT1 levels associated with poorer clinical outcomes. Together, our findings identify MCT1 as a target for p53 repression and they suggest that MCT1 elevation in p53-deficient tumors allows them to adapt to metabolic needs by facilitating lactate export or import depending on the glucose availability.

Ionoregulatory and endocrine responses to disturbed salt and water balance in Mozambique tilapia exposed to confinement and handling stress.

PubMed

Breves, Jason P; Hirano, Tetsuya; Grau, E Gordon

2010-03-01

This study assessed the endocrine and ionoregulatory responses by tilapia (Oreochromis mossambicus) to disturbances of hydromineral balance during confinement and handling. In fresh water (FW), confinement and handling for 0.5, 1, 2 and 6h produced elevations in plasma cortisol and glucose; a reduction in plasma osmolality was observed at 6h. Elevations in plasma prolactins (PRL(177) and PRL(188)) accompanied this fall in osmolality while no effect upon growth hormone (GH) was evident; an increase in insulin-like growth-factor I (IGF-I) occurred at 0.5h. In seawater (SW), confinement and handling increased plasma osmolality and glucose between 0.5 and 6h; no effect on plasma cortisol was seen due to variable control levels. Concurrently, both PRLs were reduced in stressed fish with only transient changes in the GH/IGF-I axis. Next, the branchial expression of Na(+)/K(+)/2Cl(-) cotransporter (NKCC) and Na(+)/Cl(-) cotransporter (NCC) was characterized following confinement and handling for 6h. In SW, NKCC mRNA levels increased in stressed fish concurrently with elevated plasma osmolality and diminished gill Na(+), K(+)-ATPase activity; NCC was unchanged in stressed fish irrespective of salinity. Taken together, PRL and NKCC participate in restoring osmotic balance during acute stress while the GH/IGF-I axis displays only modest responses. Copyright 2009 Elsevier Inc. All rights reserved.

Fiber type- and fatty acid composition-dependent effects of high-fat diets on rat muscle triacylglyceride and fatty acid transporter protein-1 content.

PubMed

Marotta, Mario; Ferrer-Martnez, Andreu; Parnau, Josep; Turini, Marco; Macé, Katherine; Gómez Foix, Anna M

2004-08-01

Intramuscular triacylglyceride (TAG) is considered an independent marker of insulin resistance in humans. Here, we examined the effect of high-fat diets, based on distinct fatty acid compositions (saturated, monounsaturated or n-6 polyunsaturated), on TAG levels and fatty acid transporter protein (FATP-1) expression in 2 rat muscles that differ in their fiber type, soleus, and gastrocnemius; the relationship to whole body glucose intolerance was also studied. Compared with carbohydrate-fed rats, the groups subjected to any one of the high-fat diets consistently exhibited enhanced body weight gain and adiposity, elevated plasma free fatty acids and TAG in the fed condition, hyperinsulinemia, and glucose intolerance. TAG content was consistently higher in soleus than in gastrocnemius, but was only significantly elevated by the n-6 polyunsaturated-based diet. FATP-1 levels in soleus were double those in gastrocnemius muscle in carbohydrate-fed animals. High-fat diets caused an elevation in FATP-1 protein content in soleus, but a reduction in gastrocnemius. In conclusion, the hyperinsulinemic hyperlipidemic condition upregulates FATP-1 expression in soleus and downregulates that of gastrocnemius. Hypercaloric saturated, monounsaturated, or n-6 polyunsaturated lipid diets cause equivalent whole body insulin resistance in rats, but only an n-6 polyunsaturated acid-based diet triggers intramuscular TAG accumulation. Copyright 2004 Elsevier Inc.

The importance of waist circumference and body mass index in cross-sectional relationships with risk of cardiovascular disease in Vietnam.

PubMed

Tran, Nga Thi Thu; Blizzard, Christopher Leigh; Luong, Khue Ngoc; Truong, Ngoc Le Van; Tran, Bao Quoc; Otahal, Petr; Nelson, Mark; Magnussen, Costan; Gall, Seana; Bui, Tan Van; Srikanth, Velandai; Au, Thuy Bich; Ha, Son Thai; Phung, Hai Ngoc; Tran, Mai Hoang; Callisaya, Michele

2018-01-01

Waist circumference (WC) is an indicator of intra-abdominal adipose tissue, high levels of which confer an increased risk of cardiometabolic disease. Population data on WC should be more informative than data on body mass index (BMI), which is a general indicator of body size. This study aimed to evaluate the importance of WC relative to BMI in cross-sectional relationships with blood pressure (BP), glucose, and total cholesterol (TC) in the adult population of Vietnam. The data were collected in a population-based survey conducted during 2009-10 using the "WHO STEPwise approach to surveillance of risk factors for non-communicable disease" (STEPS) methodology. The survey participants (n = 14 706 aged 25 to 64 years) were selected by multi-stage stratified cluster sampling from eight provinces representative of the eight geographical regions of Vietnam. All measurements were performed in accordance with the STEPS protocols. All analyses were performed using complex survey methods. The measurements of WC and BMI were highly correlated (men r = 0.80, women r = 0.77). For men, the strongest and predominant associations with BP, glucose, and TC were for WC or an index based on WC. For women, this was true for glucose but BMI was more important for BP and TC. WC or an index based on WC provided better discrimination than BMI of hypertension and elevated glucose, and of raised TC for men. Information on four new anthropometric indices did not improve model fit or subject discrimination. For BP/hypertension, glucose/elevated glucose, and TC/raised TC, WC was more informative than BMI for Vietnamese men, but both WC and BMI were important for Vietnamese women. Both WC and BMI need to be assessed for estimation of CVD risk in Vietnam.

Why control blood glucose levels?

PubMed

Rossini, A A

1976-03-01

The controversy as to the relationship between the degree of control of diabetes and the progression of the complications of the disease has not been solved. However, in this review, various studies suggesting a relationship between the metabolic abnormality and the diabetic complications are examined. The disadvantages of the uncontrolled diabetes mellitus can be divided into two major categories-short-term and long-term. The short-term disadvantages of controlled diabetes mellitus include the following: (1) ketoacidosis and hyperosmolar coma; (2) intracellular dehydration; (3) electrolyte imbalance; (4) decreased phagocytosis; (5) immunologic and lymphocyte activity; (6) impairment of wound healing; and (7) abnormality of lipids. The long-term disadvantages of uncontrolled diabetes melitus include the following: (1) nephropathy; (2) neuropathy; (3) retinopathy; (4) cataract formation; (5) effect on perinatal mortality; (6) complications of vascular disease; and (7) the evaluation of various clinical studies suggesting the relationship of elevated blood glucose levels and complications of diabetes mellitus. It is suggested that until the question of control can absolutely be resolved, the recommendation is that the blood glucose levels should be controlled as close to the normal as possible.

Caudal hindbrain lactate infusion alters glucokinase, SUR1, and neuronal substrate fuel transporter gene expression in the dorsal vagal complex, lateral hypothalamic area, and ventromedial nucleus hypothalamus of hypoglycemic male rats.

PubMed

Vavaiya, Kamlesh V; Briski, Karen P

2007-10-24

While in vitro studies show that the oxidizable energy substrate, lactate, is a preferred fuel for CNS neurons during states of energy crisis, and that lactate may regulate neuronal glucose uptake under those conditions, its role in neuronal function in vivo remains controversial. Glucose-excited neurons in hindbrain dorsal vagal complex (DVC) monitor both glucose and lactate, and express both the glucose sensor, glucokinase (GK), and the SUR1 subunit of the plasma membrane energy transducer, K(ATP). Fourth ventricular lactate infusion exacerbates insulin-induced hypoglycemia (IIH) and IIH-associated patterns of DVC neuronal activation. We investigated the hypothesis that during glucoprivation, lactate regulates neuronal monocarboxylate and glucose transporter gene transcription in the DVC, and adjustments in these gene profiles are correlated with altered GK and SUR1 mRNA expression. We also examined whether caudal hindbrain lactate repletion alters the impact of hypoglycemia on substrate fuel uptake and metabolic sensing functions in other characterized metabolic monitoring sites, e.g., the ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic area (LHA). qPCR was used to measure MCT2, GLUT3, GLUT4, GK, and SUR1 transcripts in the microdissected DVC, VMH, and LHA from groups of male rats treated by continuous infusion of aCSF or lactate into the caudal fourth ventricle (CV4), initiated prior to injection of Humulin R or saline. Blood glucose was decreased in response to insulin, a response that was significantly augmented by CV4 lactate infusion. IIH alone did not alter mean DVC MCT2, GLUT3, GLUT4, GK, or SUR1 mRNA levels, but these transcripts were increased in the lactate plus insulin group, relative to both euglycemic and aCSF-infused hypoglycemic rats. IIH decreased MCT2, GLUT3, and SUR1 gene profiles in the VMH; CV4 lactate infusion during IIH further diminished these transcripts, and suppressed GLUT4 and GK mRNA levels in this site. In LHA, IIH increased GLUT3 and SUR1 gene expression to an equal extent, with or without lactate, while GLUT4, MCT2, and GK mRNA levels were elevated only in response to lactate plus insulin. These studies show that caudal hindbrain-targeted delivery of exogenous lactate during IIH upregulates neuronal monocarboxylate and glucose transporter, GK, and SUR1 gene profiles in the DVC, and results in increased or decreased GLUT4 and GK mRNA in LHA and VMH, respectively. These data suggest that lactate and glucose utilization by DVC neurons may be enhanced in response to local lactate surfeit, alone or relative to glucose deficiency, and that increases in intracellular glucose and net energy yield may be correlated with elevated GK and SUR1 gene transcription, respectively, in local glucose sensing neurons. The results also imply that GLUT4- and GK-mediated glucose uptake and glucose sensing functions in the VMH and LHA may be reactive to DVC signaling of relative lactate abundance within the caudal hindbrain, and/or to physiological sequelae of this fuel augmentation, including amplified hypoglycemia.

The effect of endurance training and subsequent physical inactivity on glycaemic control after oral glucose load and physical exercise in healthy men

NASA Astrophysics Data System (ADS)

Radikova, Zofia; Ksinantova, Lucia; Kaciuba-Uscilko, Hanna; Nazar, Krystyna; Vigas, Milan; Koska, Juraj

2007-02-01

Physical inactivity during space flight has a profound effect on glucose metabolism. The aim of this study was to test whether endurance training (ET) may improve a negative effect of subsequent -6∘ head-down bed rest (HDBR) on glucose metabolism. Fourteen healthy males completed the study consisting of 6 weeks lasting ET followed by 6 days HDBR. Treadmill exercise at 80% of pre-training VO2max and 75 g oral glucose tolerance test (OGTT) were performed before and after ET as well as after HDBR. ET increased VO2max by 11%. ET significantly lowered while HDBR had no effect on fasting and OGTT plasma glucose levels. ET had no effect while HDBR was followed by an augmentation of insulin and C-peptide response to OGTT. Insulin sensitivity tended to increase after ET and to decrease during HDBR, however, mostly without statistical significance. Plasma glucose, insulin and C-peptide response to exercise were elevated after HDBR only. Our study shows that antecedent physical training could ameliorate a negative effect of simulated microgravity on insulin-mediated glucose metabolism.

Relationship between reported carbohydrate intake and fasting blood sugar

USDA-ARS?s Scientific Manuscript database

Background: Elevated fasting blood glucose ranges from normal glucose tolerance (under 100 mg/dL) to impaired glucose tolerance (100-125 mg/dL) to diabetes mellitus (above 126 mg/dL). Dietary intake may have a direct influence on glucose metabolism. Objective: We hypothesized that dietary carbohydra...

Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea.

PubMed

Kheirandish-Gozal, Leila; Sans Capdevila, Oscar; Kheirandish, Ebrahim; Gozal, David

2008-01-01

Fatty liver disease (FLD) is a highly prevalent condition in obese (Ob) children, who are at increased risk for obstructive sleep apnea (OSA). However, the contribution of OSA to FLD remains unknown. Prospective study. Polysomnographic evaluation and assessment of plasma levels of insulin, glucose, and lipids, and liver function tests. A total of 518 consecutive snoring children 4 to 17 years of age who were being evaluated for habitual snoring and suspected OSA. A total of 376 children had body mass index z score of < 1.20 (non-Ob children), 3 children (<1%) had elevated serum aminotransferase (LFT) levels, and 248 had OSA (65.9%). Among the 142 overweight/Ob children, 46 had elevated LFT levels (32.4%); of these children, 42 had OSA (91.3%). In contrast, OSA was present in only 71.8% of Ob children without elevated LFT level (p < 0.01). Insulin resistance and hyperlipidemia were more likely to occur in children with FLD. Furthermore, FLD was improved after treatment of OSA in 32 of 42 Ob children (p < 0.0001). Increased liver enzyme levels are frequently found in Ob snoring children, particularly among those with OSA and/or metabolic dysfunction. Effective treatment of OSA results in improved liver function test results in the vast majority of these patients.

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.

Glucometabolic effects of single and repeated exposure to forced-swimming stressor in Sprague-Dawley rats.

PubMed

Morakinyo, Ayodele Olufemi; Iranloye, Bolanle Olubusola; Ogunsola, Oluseyi Abimbola

2018-04-01

We aimed to evaluate the effects of a single (acute) and repeated (chronic) exposure to forced-swimming stressor on glucose tolerance, insulin sensitivity, lipid profile and glycogen content in male rats. Thirty adult male Sprague-Dawley rats (12 weeks old) were divided randomly into five groups: control group, single exposure (SE) to forced-swim stressor, repeated exposure to forced-swim stressor for 7 days (RE7), 14 days (RE14) and 28 days (RE28). Glucose tolerance test and Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) were undertaken on fasting rats to obtain glucose and insulin profiles. ELISA was performed to assess plasma insulin and corticosterone levels. Total cholesterol, triglyceride, high- and low-density lipoproteins, hepatic and skeletal glycogen content were also determined. Repeated exposure to stressor induced glucose intolerance and insulin resistance in the experimental rats. Results showed that all RE groups exhibited a significantly higher area under the curve compared with others (p=0.0001); similarly, HOMA-IR increased (p=0.0001) in all RE groups compared with control. Prolonged exposure to stressor significantly increased the plasma insulin and corticosterone levels but decreased the glycogen content in the liver and skeletal muscle when compared with the control group. Additionally, chronic stressor significantly increased the total cholesterol and triglyceride levels, however, acute stressor produced significantly elevated high-density lipoproteins level. In conclusion, repeated exposure to forced-swimming stressor induced glucose intolerance and insulin resistance in rats by disrupting the insulin sensitivity as well as heightening the glycogenolysis in the liver and skeletal muscle. Acute stressor was unable to cause glucose intolerance and insulin resistance but it appears that may have a positive effect on the lipid metabolism.

Mondo/ChREBP-Mlx-Regulated Transcriptional Network Is Essential for Dietary Sugar Tolerance in Drosophila

PubMed Central

Havula, Essi; Teesalu, Mari; Hyötyläinen, Tuulia; Seppälä, Heini; Hasygar, Kiran; Auvinen, Petri; Orešič, Matej; Sandmann, Thomas; Hietakangas, Ville

2013-01-01

Sugars are important nutrients for many animals, but are also proposed to contribute to overnutrition-derived metabolic diseases in humans. Understanding the genetic factors governing dietary sugar tolerance therefore has profound biological and medical significance. Paralogous Mondo transcription factors ChREBP and MondoA, with their common binding partner Mlx, are key sensors of intracellular glucose flux in mammals. Here we report analysis of the in vivo function of Drosophila melanogaster Mlx and its binding partner Mondo (ChREBP) in respect to tolerance to dietary sugars. Larvae lacking mlx or having reduced mondo expression show strikingly reduced survival on a diet with moderate or high levels of sucrose, glucose, and fructose. mlx null mutants display widespread changes in lipid and phospholipid profiles, signs of amino acid catabolism, as well as strongly elevated circulating glucose levels. Systematic loss-of-function analysis of Mlx target genes reveals that circulating glucose levels and dietary sugar tolerance can be genetically uncoupled: Krüppel-like transcription factor Cabut and carbonyl detoxifying enzyme Aldehyde dehydrogenase type III are essential for dietary sugar tolerance, but display no influence on circulating glucose levels. On the other hand, Phosphofructokinase 2, a regulator of the glycolysis pathway, is needed for both dietary sugar tolerance and maintenance of circulating glucose homeostasis. Furthermore, we show evidence that fatty acid synthesis, which is a highly conserved Mondo-Mlx-regulated process, does not promote dietary sugar tolerance. In contrast, survival of larvae with reduced fatty acid synthase expression is sugar-dependent. Our data demonstrate that the transcriptional network regulated by Mondo-Mlx is a critical determinant of the healthful dietary spectrum allowing Drosophila to exploit sugar-rich nutrient sources. PMID:23593032

Conjoint regulation of glucagon concentrations via plasma insulin and glucose in dairy cows.

PubMed

Zarrin, M; Wellnitz, O; Bruckmaier, R M

2015-04-01

Insulin and glucagon are glucoregulatory hormones that contribute to glucose homeostasis. Plasma insulin is elevated during normoglycemia or hyperglycemia and acts as a suppressor of glucagon secretion. We have investigated if and how insulin and glucose contribute to the regulation of glucagon secretion through long term (48 h) elevated insulin concentrations during simultaneous hypoglycemia or euglycemia in mid-lactating dairy cows. Nineteen Holstein dairy cows were randomly assigned to 3 treatment groups: an intravenous insulin infusion (HypoG, n = 5) to decrease plasma glucose concentrations (2.5 mmol/L), a hyperinsulinemic-euglycemic clamp to study effects of insulin at simultaneously normal glucose concentrations (EuG, n = 6) and a 0.9% saline infusion (NaCl, n = 8). Plasma glucose was measured at 5-min intervals, and insulin and glucose infusion rates were adjusted accordingly. Area under the curve of hourly glucose, insulin, and glucagon concentrations on day 2 of infusion was evaluated by analysis of variance with treatments as fixed effect. Insulin infusion caused an increase of plasma insulin area under the curve (AUC)/h in HypoG (41.9 ± 8.1 mU/L) and EuG (57.8 ± 7.8 mU/L) compared with NaCl (13.9 ± 1.1 mU/L; P < 0.01). Induced hyperinsulinemia caused a decline of plasma glucose AUC/h to 2.3 ± 0.1 mmol/L in HypoG (P < 0.01), whereas plasma glucose AUC/h remained unchanged in EuG (3.8 ± 0.2 mmol/L) and NaCl (4.1 ± 0.1 mmol/L). Plasma glucagon AUC/h was lower in EuG (84.0 ± 6.3 pg/mL; P < 0.05) and elevated in HypoG (129.0 ± 7.0 pg/mL; P < 0.01) as compared with NaCl (106.1 ± 5.4 pg/mL). The results show that intravenous insulin infusion induces elevated glucagon concentrations during hypoglycemia, although the same insulin infusion reduces glucagon concentrations at simultaneously normal glucose concentrations. Thus, insulin does not generally have an inhibitory effect on glucagon concentrations. If simultaneously glucose is low and insulin is high, glucagon is upregulated to increase glucose availability. Therefore, insulin and glucose are conjoint regulatory factors of glucagon concentrations in dairy cows, and the plasma glucose status is the key factor to decide if its concentrations are increased or decreased. This regulatory effect can be important for the maintenance of glucose homeostasis if insulin secretion is upregulated by other factors than high glucose such as high plasma lipid and protein concentrations at simultaneously low glucose. Copyright © 2015 Elsevier Inc. All rights reserved.

Dietary intake, glucose metabolism and sex hormones in women with polycystic ovary syndrome (PCOS) compared with women with non-PCOS-related infertility.

PubMed

Tsai, Ya-Hui; Wang, Ting-Wen; Wei, Hsiao-Jui; Hsu, Chien-Yeh; Ho, Hsin-Jung; Chen, Wen-Hua; Young, Robert; Liaw, Chian-Mey; Chao, Jane C-J

2013-06-28

The present study investigated dietary intake, glucose metabolism and sex hormones in women with polycystic ovary syndrome (PCOS). A total of forty-five women (aged 25–40 years) with PCOS and 161 control women (aged 25–43 years) with non-PCOS-related infertility were recruited. Anthropometry, glucose tolerance and sex hormones were determined and dietary intake was assessed. Women with PCOS had lower serum sex hormone-binding globulin and increased BMI, waist:hip ratio, luteinising hormone, ratio of luteinising hormone: follicle-stimulating hormone, testosterone and free androgen index (FAI). Postprandial glucose, fasting insulin and insulin resistance were elevated in women with PCOS. Women with PCOS had reduced energy and carbohydrate intake but higher fat intake. Serum sex hormone-binding globulin level was negatively associated with BMI in both groups and negatively correlated with macronutrient intake in the PCOS group with hyperandrogenism. However, FAI was positively correlated with BMI, waist circumference and glucose metabolic parameters in both groups. Therefore, women with PCOS consume lower energy and carbohydrate compared with those with non-PCOS-related infertility and macronutrient intake is only negatively associated with serum sex hormone-binding globulin level in the PCOS group with hyperandrogenism.

Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

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

Sekiya, Motohiro; Yahagi, Naoya, E-mail: nyahagi-tky@umin.ac.jp; Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655

2009-09-25

It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets,more » leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.« less

NMDAR antagonists for the treatment of diabetes mellitus-Current status and future directions.

PubMed

Welters, Alena; Klüppel, Carina; Mrugala, Jessica; Wörmeyer, Laura; Meissner, Thomas; Mayatepek, Ertan; Heiss, Christian; Eberhard, Daniel; Lammert, Eckhard

2017-09-01

Diabetes mellitus is characterized by chronically elevated blood glucose levels accelerated by a progressive decline of insulin-producing β-cells in the pancreatic islets. Although medications are available to transiently adjust blood glucose to normal levels, the effects of current drugs are limited when it comes to preservation of a critical mass of functional β-cells to sustainably maintain normoglycemia. In this review, we recapitulate recent evidence on the role of pancreatic N-methyl-D-aspartate receptors (NMDARs) in β-cell physiology, and summarize effects of morphinan-based NMDAR antagonists that are beneficial for insulin secretion, glucose tolerance and islet cell survival. We further discuss NMDAR-mediated molecular pathways relevant for neuronal cell survival, which may also be important for the preservation of β-cell function and mass. Finally, we summarize the literature for evidence on the role of NMDARs in the development of diabetic long-term complications, and highlight beneficial pharmacologic aspects of NMDAR antagonists in diabetic nephropathy, retinopathy as well as neuropathy. © 2017 John Wiley & Sons Ltd.

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.

Targeted Disruption of Pancreatic-Derived Factor (PANDER, FAM3B) Impairs Pancreatic β-Cell Function

PubMed Central

Robert-Cooperman, Claudia E.; Carnegie, Jason R.; Wilson, Camella G.; Yang, Jichun; Cook, Joshua R.; Wu, Jianmei; Young, Robert A.; Wolf, Bryan A.; Burkhardt, Brant R.

2010-01-01

OBJECTIVE Pancreatic-derived factor (PANDER, FAM3B) is a pancreatic islet-specific cytokine-like protein that is secreted from β-cells upon glucose stimulation. The biological function of PANDER is unknown, and to address this we generated and characterized a PANDER knockout mouse. RESEARCH DESIGN AND METHODS To generate the PANDER knockout mouse, the PANDER gene was disrupted and its expression was inhibited by homologous recombination via replacement of the first two exons, secretion signal peptide and transcriptional start site, with the neomycin gene. PANDER−/− mice were then phenotyped by a number of in vitro and in vivo tests to evaluate potential effects on glucose regulation, insulin sensitivity, and β-cell morphology and function. RESULTS Glucose tolerance tests demonstrated significantly higher blood glucose levels in PANDER−/− versus wild-type male mice. To identify the mechanism of the glucose intolerance, insulin sensitivity and pancreatic β-cell function were examined. Hyperinsulinemic-euglycemic clamps and insulin tolerance testing showed similar insulin sensitivity for both the PANDER−/− and wild-type mice. The in vivo insulin response following intraperitoneal glucose injection surprisingly produced significantly higher insulin levels in the PANDER−/− mice, whereas insulin release was blunted with arginine administration. Islet perifusion and calcium imaging studies showed abnormal responses of the PANDER−/− islets to glucose stimulation. In contrast, neither islet architecture nor insulin content was impacted by the loss of PANDER. Interestingly, the elevated insulin levels identified in vivo were attributed to decreased hepatic insulin clearance in the PANDER−/− islets. Taken together, these results demonstrated decreased pancreatic β-cell function in the PANDER−/− mouse. CONCLUSIONS These results support a potential role of PANDER in the pancreatic β-cell for regulation or facilitation of insulin secretion. PMID:20566664

Glucose rapidly decreases plasma membrane GLUT4 content in rat skeletal muscle.

PubMed

Marette, A; Dimitrakoudis, D; Shi, Q; Rodgers, C D; Klip, A; Vranic, M

1999-02-01

We have previously demonstrated that chronic hyperglycemia per se decreases GLUT4 glucose transporter expression and plasma membrane content in mildly streptozotocin- (STZ) diabetic rats (Biochem. J. 284, 341-348, 1992). In the present study, we investigated the effect of an acute rise in glycemia on muscle GLUT4 and GLUT1 protein contents in the plasma membrane, in the absence of insulin elevation. Four experimental groups of rats were analyzed in the postabsorptive state: 1. Control rats. 2. Hyperglycemic STZ-diabetic rats with moderately reduced fasting insulin levels. 3. STZ-diabetic rats made normoglycemic with phlorizin treatment. 4. Phlorizin-treated (normoglycemic) STZ-diabetic rats infused with glucose for 40 min. The uniqueness of the latter model is that glycemia can be rapidly raised without any concomitant increase in plasma insulin levels. Plasma membranes were isolated from hindlimb muscle and GLUT1 and GLUT4 proteins amounts determined by Western blot analysis. As predicted, STZ-diabetes caused a significant decrease in the abundance of GLUT4 in the isolated plasma membranes. Normalization of glycemia for 3 d with phlorizin treatment restored plasma membrane GLUT4 content in muscle of STZ-diabetic rats. A sudden rise in glycemia over a period of 40 min caused the GLUT4 levels in the plasma membrane fraction to decrease to those of nontreated STZ-diabetic rats. In contrast to the GLUT4 transporter, plasma membrane GLUT1 abundance was not changed by the acute glucose challenge. It is concluded that glucose can have regulatory effect by acutely reducing plasma membrane GLUT4 protein contents in rat skeletal muscle. We hypothesize that this glucose-induced downregulation of plasma membrane GLUT4 could represent a protective mechanism against excessive glucose uptake under hyperglycemic conditions accompanied by insulin resistance.

Oral administration of soybean peptide Vglycin normalizes fasting glucose and restores impaired pancreatic function in Type 2 diabetic Wistar rats.

PubMed

Jiang, Hua; Feng, Jueping; Du, Zhongxia; Zhen, Hui; Lin, Mei; Jia, Shaohui; Li, Tao; Huang, Xinyuan; Ostenson, Claes-Goran; Chen, Zhengwang

2014-09-01

Vglycin, a natural 37-residue polypeptide isolated from pea seeds in which six half-cysteine residues are embedded in three pairs of disulfide bonds, is resistant to digestive enzymes and has antidiabetic potential. To investigate the pharmacological activity of Vglycin in vivo and to examine the mechanisms involved, the therapeutic effect of Vglycin in diabetic rats was examined. Diabetes was induced in Wistar rats by high-fat diet and multiple streptozotocin intraperitoneal injections. Diabetic rats were treated daily with Vglycin for 4 weeks. Body weight, food intake, fasting plasma glucose and insulin levels were assayed weekly. Glucose and insulin tolerance tests were conducted on Day 29. Subsequently, levels of p-Akt in the liver and pancreas and cleaved PARP, Pdx-1 and insulin in the pancreas were detected by immunoblotting. The morphology of the pancreas and the insulin expression in the pancreas were analyzed by hematoxylin-eosin staining and immunohistochemistry, respectively. Furthermore, human liver-derived cell lines were used to explore the in vitro effects of Vglycin on insulin sensitivity and glucose uptake. Chronic treatment with Vglycin normalized fasting glucose levels in diabetic rats. The improvement in glucose homeostasis and the increased insulin sensitivity mediated by restored insulin signaling likely contributed to decreased food intake and reduced body weight. Vglycin protected pancreatic cells from damage by streptozotocin. Although insulin synthesis and secretion in impaired β-cell were not significantly elevated, islets morphology was improved in the Vglycin-treated groups. These results suggest that Vglycin could be useful in Type 2 diabetes for restoring impaired insulin signaling, glucose tolerance and pancreatic function. Copyright © 2014 Elsevier Inc. All rights reserved.

Type I neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice

PubMed Central

Arai, Takatomo; Ono, Yumika; Arimura, Yujiro; Sayama, Keimon; Suzuki, Tomohiro; Shinjo, Satoko; Kanai, Mai; Abe, Shin-ichi; Semba, Kentaro; Goda, Nobuhito

2017-01-01

Neuregulin1 is an epidermal growth factor (EGF)-like domain-containing protein that has multiple isoforms and functions as a local mediator in the control of various cellular functions. Here we show that type I isoform of neuregulin1 with an α-type EGF-like domain (Nrg1α) is the major isoform in mouse liver and regulates hepatic glucose production. Forced expression of Nrg1α in mouse liver enhanced systemic glucose disposal and decreased hepatic glucose production with reduced fasting blood glucose levels. Nuclear forkhead box protein O1 (FoxO1) and its downstream targets, PEPCK and G6Pase, were suppressed in liver and isolated hepatocytes by Nrg1α overexpression. In contrast, silencing of Nrg1α enhanced glucose production with increased PEPCK and G6Pase expressions in cAMP/dexamethasone-stimulated hepatocytes. Mechanistically, the recombinant α-type EGF-like domain of NRG1α (rNRG1α) stimulated the ERBB3 signalling pathway in hepatocytes, resulting in decreased nuclear FoxO1 accumulation via activation of both the AKT and ERK pathways. In addition, acute treatment with rNRG1α also suppressed elevation of blood glucose levels after both glucose and pyruvate challenge. Although a liver-specific deletion of Nrg1 gene in mice showed little effect on systemic glucose metabolism, these results suggest that NRG1α have a novel regulatory function in hepatic gluconeogenesis by regulating the ERBB3-AKT/ERK-FoxO1 cascade. PMID:28218289

Metabolic effects of antipsychotics in prepubertal children: a retrospective chart review.

PubMed

Ebert, Tanya; Midbari, Yael; Shmilovitz, Ronen; Kosov, Ira; Kotler, Moshe; Weizman, Abraham; Ram, Anca

2014-05-01

Antipsychotics, especially atypical ones, are in common use in children and adolescents with psychotic or affective spectrum disorders, as well as in various other psychopathologies. The adverse effects of atypical antipsychotics in children and adolescents are similar to those seen in adults, and include weight gain, elevated blood glucose levels, and hyperlipidemia. In this retrospective chart review, we compared these adverse events in children who were treated with typical, atypical, or no antipsychotic treatment. The medical charts of 72 children, 65 boys and 7 girls, were reviewed. All children were 6-13 years old (mean age 9.5±1.7 years). In total, 48 children received antipsychotic treatment, and 24 children were in the control group. Data were extracted from the medical charts, including weight, height, body mass index (BMI), blood pressure, aspartate transaminase (AST), alanine transaminase (ALT), triglycerides, total cholesterol, and glucose blood levels. We examined the values in the beginning of the antipsychotic treatment and at release from the hospital in the study group, and at admission and in the end of the drug-free period or at release from the hospital (a duration of at least 4 weeks) in the control group. The average weight gain was 3.9±3.8 kg in the atypical antipsychotic treatment (AAT) group, 1.1±4.4 kg in the typical antipsychotic treatment (TAT) group, and 0.23±2.9 kg in the control group. The average increase in BMI was 15.1±22.0 percentiles in the AAT group, 6.4±14.2 percentiles in the TAT group, and 1.6±12.5 percentiles in the control group. No statistically significant difference was found in the increase in height percentile. There were no significant differences in the rates of elevated values of serum triglycerides, cholesterol, AST, ALT, or fasting blood glucose. We found a significant increase in both absolute weight gain and BMI percentile following atypical antipsychotic treatment. In contrast, typical antipsychotic treatment did not affect weight gain significantly, and the same was true for the control group. In addition, the rates of elevated values of biochemical parameters (AST, ALT, total cholesterol, triglycerides, and fasting blood glucose levels) were very low at the beginning of the study, and were not significantly altered by the various treatments.

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.

Effects of prandial challenge on triglyceridemia, glycemia, and pro-inflammatory activity in persons with chronic paraplegia

PubMed Central

Ellenbroek, Dennis; Kressler, Jochen; Cowan, Rachel E.; Burns, Patricia A.; Mendez, Armando J.; Nash, Mark S.

2015-01-01

Context/Objective Exaggerated postprandial lipemia has been reported after spinal cord injury (SCI). We examined metabolite and accompanying pro-inflammatory biomarker responses to repeat feeding of typical high-fat meals in individuals with chronic paraplegia. Design Descriptive trial. Methods Metabolites (triglycerides, glucose, and insulin) and inflammatory biomarkers (interleukin-6 and high-sensitivity C-reactive protein (hsCRP)) were measured under fasting conditions in 11 recreationally active individuals with chronic (>1 year) paraplegia. Subjects received high-fat meals at time point 0 and again at minute 240. Antecubital venous blood was obtained at time points −30 (fasting), 0 (first meal), 30, 60, 90, 120, 240 (second meal), 360, and 480 minutes. Correlations were examined among the study variables. Exploratory subgroup analysis was performed for subjects with levels of postprandial glucose greater than >200 mg/dl. Results Triglycerides showed a significant rise 4 hours after eating. Basal inflammatory markers were elevated, and did not undergo additional change during the testing. Additionally, subjects with excessive postprandial glucose responses showed higher hsCRP levels than those having typical glucose responses both for fasting (11.8 ± 6.5 vs. 2.9 ± 2.7 mg/l, P = 0.064) and postprandial (11.1 ± 4.9 vs. 3.7 ± 3.8 mg/l, P = 0.018) values. Conclusions Despite elevations in metabolic response markers, inflammatory markers did not change significantly after consumption of population-representative (i.e. hypercaloric) mixed-nutrient meals. Levels of fasting CRP in the high-risk range are consistent with other reports in persons with SCI and continue to pose concern for their cardiovascular disease risk. The possible association between postprandial metabolic responses and inflammatory states warrants further investigation to identify individual component risks for this secondary health hazard. PMID:24617559

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.

Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men.

PubMed

Brøns, Charlotte; Jensen, Christine B; Storgaard, Heidi; Hiscock, Natalie J; White, Andrew; Appel, Julie S; Jacobsen, Stine; Nilsson, Emma; Larsen, Claus M; Astrup, Arne; Quistorff, Bjørn; Vaag, Allan

2009-05-15

A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by (31)P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.

Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels

PubMed Central

Liu, Jinfeng; Dong, Huansheng; Zhang, Yong; Cao, Mingjun; Song, Lili; Pan, Qingjie; Bulmer, Andrew; Adams, David B.; Dong, Xiao; Wang, Hongjun

2015-01-01

Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. PMID:26017184

Lipoprotein(a) is not related to markers of insulin resistance in pregnancy.

PubMed

Todoric, Jelena; Handisurya, Ammon; Leitner, Karoline; Harreiter, Juergen; Hoermann, Gregor; Kautzky-Willer, Alexandra

2013-10-01

Dyslipidemia, a major risk factor for cardiovascular disease is a common finding in patients with type 2 diabetes and among women with gestational diabetes. Elevated levels of lipoprotein(a) [Lp(a)] are linked to increased risk of cardiovascular disease. However, its relationship with insulin resistance, type 2 diabetes and gestational diabetes is controversial and unproven. Here we aimed to clarify whether Lp(a) levels are associated with insulin sensitivity in pregnancy. Sixty-four women with gestational diabetes and 165 with normal glucose tolerance were enrolled in the study. Fasting Lp(a) serum levels were measured in all women at 24-28 weeks of gestation. In pregnancy, there was no significant difference in serum Lp(a) concentrations between the two groups. Its level did not correlate with markers of insulin resistance (HOMA-IR), insulin sensitivity (HOMA-S%), pancreatic beta-cell function (HOMA-B%) and insulin sensitivity in dynamic conditions (OGIS). In addition, fasting glucose and insulin levels and those throughout an oral glucose tolerance test were independent of Lp(a) concentrations in our study group. Lp(a) levels in pregnant women do not differ with respect to the presence or absence of gestational diabetes. Although influenced by some components of the lipid profile, such as triglycerides and HDL-C, insulin resistance in pregnancy is not affected by Lp(a).

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.

Type 2 diabetes mellitus in children and adolescents.

PubMed

Dileepan, Kavitha; Feldt, M Max

2013-12-01

On the basis of strong research evidence and consensus, type 1 diabetes mellitus (DM) remains the most common form of DM in children and adolescents. The incidence of type 2 DM in the pediatric population is rapidly increasing because of the obesity epidemic, and minority groups are disproportionately affected. (2) (10) (19) On the basis of some research evidence and consensus, it can be challenging to initially differentiate between type 2 DM and type 1 DM clinically because of the increased prevalence of obesity, the complex interplay of autoimmunity and obesity, and common symptoms at presentation. (1) (10) (19) Significant evidence and consensus support a genetic basis for the development of type 2 DM in children. Physicians should routinely screen at risk children older than age 10 years for DM. Screening criteria include obesity, a family history of type 2 DM, a minority racial or ethnic background, acanthosis nigricans, or other diseases associated with insulin resistance, including polycystic ovary syndrome, hypertension, or dyslipidemia. (1) (10) (18) (19) On the basis of consensus, diagnosis of type 2 DM can be confirmed by an elevated fasting blood glucose level greater than 126 mg/dl (7.0 mmol/L), an elevated 2-hour plasma glucose greater than 200 mg/dL (11.1 mmol/L) on an oral glucose tolerance test, an elevated random blood glucose greater than 200 mg/dL (11.1 mmol/L), or a hemoglobin A1c level greater than 6.5% with suggestive symptoms. (10) According to strong research evidence and consensus, once the diagnosis has been made, treatment should be based on the acuity of presentation and should focus on lifestyle modification and on normalizing hyperglycemia to minimize complications. Metformin is currently first-line treatment for type 2 DM in children and adolescents older than age 10 years who present nonacutely. (18) (19) Strong research evidence and consensus demonstrate that because type 2 DM has an insidious onset, microvascular and macrovascular complications can be present at the time of diagnosis. Patients should be screened for the presence of complications when the diagnosis of type 2 DM is made and in follow-up. (6) (10).

Apolipoprotein A-I interactions with insulin secretion and production.

PubMed

Rye, Kerry-Anne; Barter, Philip J; Cochran, Blake J

2016-02-01

Human population studies have established that an elevated plasma high-density lipoprotein cholesterol (HDL-C) level is associated with a decreased risk of developing cardiovascular disease. In addition to having several potentially cardioprotective functions, HDLs and apolipoprotein (apo)A-I, the main HDL apolipoprotein, also have antidiabetic properties. Interventions that elevate plasma HDL-C and apoA-I levels improve glycemic control in people with type 2 diabetes mellitus by enhancing pancreatic β-cell function and increasing insulin sensitivity. This review is concerned with recent advances in understanding the mechanisms by which HDLs and apoA-I improve pancreatic β-cell function. HDLs and apoA-I increase insulin synthesis and secretion in pancreatic β cells. The underlying mechanism of this effect is similar to what has been reported for intestinally derived incretins, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, which both increase β-cell insulin secretion under high glucose conditions. This involves the activation of a heterotrimeric G protein Gαs subunit on the β-cell surface that leads to induction of a transmembrane adenylyl cyclase, increased intracellular cyclic adenosine monophosphate and Ca levels, and activation of protein kinase A. Protein kinase A increases insulin synthesis by excluding FoxO1 from the β-cell nucleus and derepressing transcription of the insulin gene.

Glucometabolic hormones and cardiovascular risk markers in antipsychotic-treated patients.

PubMed

Ebdrup, Bjørn H; Knop, Filip K; Madsen, Anna; Mortensen, Henrik B; Søgaard, Birgitte; Holst, Jens J; Szecsi, Pal B; Lublin, Henrik

2014-09-01

Treatment with antipsychotic drugs is widely associated with metabolic side effects such as weight gain and disturbed glucose metabolism, but the pathophysiologic mechanisms are unclear. Fifty nondiabetic (fasting plasma glucose ≤ 7.0 mmol/L), antipsychotic-treated male patients (ICD-10 diagnosis code F20, F21, F22, F25, F28, or F60; mean ± SD age = 33.0 ± 6.7 years; body mass index [BMI; kg/m²] = 26.0 ± 4.7; waist circumference = 95.9 ± 13.3 cm; glycated hemoglobin A1c [HbA1c] = 5.7% ± 0.3%) and 93 age- and waist circumference-matched healthy male controls (age = 33 ± 7.3 years; BMI = 26.1 ± 3.9; waist circumference = 94.6 ± 11.9 cm; HbA1c = 5.7% ± 0.3%) participated in this cross-sectional study. Blood was sampled in the fasting state and 90 minutes after ingestion of a standardized liquid meal (2,268 kJ). The primary outcomes were glucometabolic hormones and cardiovascular risk markers. Data were collected between March 2008 and February 2010. Compared to healthy controls, patients were characterized by elevated fasting levels of proinsulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) (P < .05) and higher postprandial levels of insulin, proinsulin, C-peptide, and GIP (P ≤ .02). Also, patients exhibited elevated plasma levels of C-reactive protein and signs of dyslipidemia. Fasting plasma levels of insulin, glucagon, glucagon-like peptide-1 (GLP-1), ghrelin, leptin, adiponectin, tumor necrosis factor-α, plasminogen activator inhibitor-1, and interleukin-6 and postprandial levels of glucagon, GLP-1, ghrelin, leptin, and adiponectin did not differ between groups. Presenting with an insulin resistant-like pattern, including beta cell hypersecretion and elevated GIP levels, nondiabetic antipsychotic-treated patients display emerging signs of dysmetabolism and a compromised cardiovascular risk profile. The appetite-regulating hormones GLP-1 and ghrelin appear not to be influenced by antipsychotic treatment. Our findings provide new clinical insight into the pathophysiology associated with metabolic side effects of antipsychotic treatment and put emphasis on the importance of implementing metabolic screening into psychiatric practice. ClinicalTrials.gov identifier NCT00627757. © Copyright 2014 Physicians Postgraduate Press, Inc.

Elevated extracellular glucose and uncontrolled type 1 diabetes enhance NFAT5 signaling and disrupt the transverse tubular network in mouse skeletal muscle

PubMed Central

Hernández-Ochoa, Erick O; Robison, Patrick; Contreras, Minerva; Shen, Tiansheng; Zhao, Zhiyong; Schneider, Martin F

2012-01-01

The transcription factor nuclear factor of activated T-cells 5 (NFAT5) is a key protector from hypertonic stress in the kidney, but its role in skeletal muscle is unexamined. Here, we evaluate the effects of glucose hypertonicity and hyperglycemia on endogenous NFAT5 activity, transverse tubular system morphology and Ca2+ signaling in adult murine skeletal muscle fibers. We found that exposure to elevated glucose (25–50 mmol/L) increased NFAT5 expression and nuclear translocation, and NFAT-driven transcriptional activity. These effects were insensitive to the inhibition of calcineurin A, but sensitive to both p38a mitogen-activated protein kinases and phosphoinositide 3-kinase-related kinase inhibition. Fibers exposed to elevated glucose exhibited disrupted transverse tubular morphology, characterized by swollen transverse tubules and an increase in longitudinal connections between adjacent transverse tubules. Ca2+ transients elicited by a single, brief electric field stimuli were increased in amplitude in fibers challenged by elevated glucose. Muscle fibers from type 1 diabetic mice exhibited increased NFAT5 expression and transverse tubule disruptions, but no differences in electrically evoked Ca2+ transients. Our results suggest the hypothesis that these changes in skeletal muscle could play a role in the pathophysiology of acute and severe hyperglycemic episodes commonly observed in uncontrolled diabetes. PMID:22966145

Evidence for the absence of cerebral glucose-6-phosphatase activity in glycogen storage disease type I (Von Gierke's disease)

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

Phelps, M.E.; Mazziotta, J.C.; Hawkins, R.A.

1981-01-01

Glycogen storage disease type I (GSD-I) is characterized by a functional deficit in glucose-6-phosphatase that normally hydrolyzes glucose-6-PO/sub 4/ to glucose. This enzyme is primarily found in liver, kidney, and muscle but it is also present in brain, where it appears to participate in the regulation of cerebral tissue glucose. Since most neurological symptoms in GSD-I patients involve systemic hypoglycemia, previous reports have not examined possible deficiencies in phosphatase activity in the brain. Positron computed tomography, F-18-labeled 2-fluorodeoxyglucose (FDG) and a tracer kinetic model for FDG were used to measure the cortical plasma/tissue forward and reverse transport, phosphorylation and dephosphorylationmore » rate constants, tissue/plasma concentration gradient, tissue concentration turnover rate for this competitive analog of glucose, and the cortical metabolic rates for glucose. Studies were carried out in age-matched normals (N = 13) and a single GSD-I patient. The dephosphorylation rate constant in the GSD-I patient was about one tenth the normal value indicating a low level of cerebral phosphatase activity. The other measured parameters were within normal limits except for the rate of glucose phosphorylation which reflected a cortical glucose metabolic rate one half the normal value. Since glucose transport and tissue glucose concentration was normal, the reduced cortical glucose metabolism probably results from the use of alternative substrates (..beta..-hydroxybutyrate and acetoacetate) which are consistently elevated in the plasma of GSD-I patients.« less

Kinetic Modeling of Human Hepatic Glucose Metabolism in Type 2 Diabetes Mellitus Predicts Higher Risk of Hypoglycemic Events in Rigorous Insulin Therapy*

PubMed Central

König, Matthias; Holzhütter, Hermann-Georg

2012-01-01

A major problem in the insulin therapy of patients with diabetes type 2 (T2DM) is the increased occurrence of hypoglycemic events which, if left untreated, may cause confusion or fainting and in severe cases seizures, coma, and even death. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. Our simulations reveal in line with experimental and clinical data from a multitude of studies in T2DM, (i) significant changes in the relative contribution of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization; (ii) decreased postprandial glycogen storage as well as increased glycogen depletion in overnight fasting and short term fasting; and (iii) a shift of the set point defining the switch between hepatic glucose production and hepatic glucose utilization to elevated plasma glucose levels, respectively, in T2DM relative to normal, healthy subjects. Intriguingly, our model simulations predict a restricted gluconeogenic response of the liver under impaired hormonal signals observed in T2DM, resulting in an increased risk of hypoglycemia. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounced in case of tightly controlled insulin treatment. Given this Janus face mode of action of insulin, our model simulations underline the great potential that normalization of the plasma glucagon profile may have for the treatment of T2DM. PMID:22977253

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.

Studying neuroprotective effect of Atorvastatin as a small molecule drug on high glucose-induced neurotoxicity in undifferentiated PC12 cells: role of NADPH oxidase.

PubMed

Rayegan, Samira; Dehpour, Ahmad Reza; Sharifi, Ali Mohammad

2017-02-01

Overproduction of reactive oxygen species (ROS) by NADPH oxidase (NOX) activation has been considered the essential mechanism induced by hyperglycemia in various tissues. However, there is no comprehensive study on the role of NOXs in high glucose (HG)-induced toxic effect in neural tissues. Recently, a therapeutic strategy in oxidative related pathologies has been introduced by blocking the undesirable actions of NOX enzymes by small molecules. The protective roles of Statins in ameliorating oxidative stress by NOX inhibition have been shown in some tissues except neural. We hypothesized then, that different NOXs may have role in HG-induced neural cell injury. Furthermore, we postulate that Atorvastatin as a small molecule may modulate this NOXs activity to protect neural cells. Undifferentiated PC12 cells were treated with HG (140 mM/24 h) in the presence and absence of Atorvastatin (1 μM/96 h). The cell viability was measured by MTT assay and the gene and protein expressions profile of NOX (1-4) were determined by RT-PCR and western blotting, respectively. Levels of ROS and malondialdehyde (MDA) were also evaluated. Gene and protein expression levels of NOX (1-4) and consequently ROS and MDA levels were elevated in HG-treated PC12 cells. Atorvastatin could significantly decrease HG-induced NOXs, ROS and MDA elevation and improve impaired cell viability. It can be concluded that HG could elevate NOXs activity, ROS and MDA levels in neural tissues and Atorvastatin as a small molecule NOX inhibitor drug may prevent and delay diabetic complications, particularly neuropathy.

Elevated levels of branched-chain amino acids have little effect on pancreatic islet cells, but L-arginine impairs function through activation of the endoplasmic reticulum stress response.

PubMed

Mullooly, Niamh; Vernon, Wendy; Smith, David M; Newsholme, Philip

2014-03-01

Recent metabolic profiling studies have identified a correlation between branched-chain amino acid levels, insulin resistance associated with prediabetes and susceptibility to type 2 diabetes. Glucose and lipids in chronic excess have been reported to induce toxic effects in pancreatic β-cells, but the effect of elevated amino acid concentrations on primary islet cell function has not been investigated to date. The aim of this study was to investigate the effect of chronic exposure to various amino acids on islet cell function in vitro. Isolated rat islets were incubated over periods of 48 h with a range of concentrations of individual amino acids (0.1 μm to 10 mm). After 48 h, islets were assessed for glucose-dependent insulin secretion capacity, proliferation or islet cell apoptosis. We report that elevated levels of branched-chain amino acids have little effect on pancreatic islet cell function or viability; however, increased levels of the amino acid l-arginine were found to be β-cell toxic, causing a dose-dependent decrease in insulin secretion accompanied by a decrease in islet cell proliferation and an increase in islet cell apoptosis. These effects were not due to l-arginine-dependent increases in production of nitric oxide but arose through elicitation of the islet cell endoplasmic reticulum stress response. This novel finding indicates, for the first time, that the l-arginine concentration in vitro may impact negatively on islet cell function, thus indicating further complexity in relationship to in vivo susceptibility of β-cells to nutrient-induced dysfunction.

The effects of copper on blood and biochemical parameters of rainbow trout (Oncorhynchus mykiss)

USGS Publications Warehouse

Dethloff, G.M.; Schlenk, D.; Khan, S.; Bailey, H.C.

1999-01-01

Metals are released into aquatic systems from many sources, often at sublethal concentrations. The effects of sublethal concentrations of metals on fish are not entirely understood. The objective of this study was to determine the hematological and biochemical effects of a range of copper concentrations (6.4, 16.0, 26.9 ??g Cu/L) on rainbow trout (Oncorhynchus mykiss) over a prolonged period of time. Trout were exposed to copper, and, at intervals of 3, 7, 14, and 21 days, selected parameters were evaluated. Hemoglobin, hematocrit, plasma glucose, and plasma cortisol levels were elevated in trout exposed to 26.9 ??g Cu/L at day 3 and then returned to levels comparable to control fish. Plasma protein and lactate levels were not significantly altered in trout from any copper treatment. Hepatic copper concentration and hepatic metallothionein mRNA expression were consistently elevated in trout exposed to 26.9 ??g Cu/L. Both of these parameters stabilized by day 3, with only hepatic copper concentration showing a further increase at day 21. Hepatic copper concentration and hepatic metallothionein mRNA expression appear to be robust indicators of copper exposure. Most blood-based parameters evaluated appear to be associated with a transitory, nonspecific stress response. The return of elevated hematological and biochemical parameters to control levels after 3 days and thestabilization of hepatic metallothionein mRNA expression and copper concentration over a similar time period suggested acclimation to dissolved copper at 26.9 ??g/L. Further analysis of the data on blood-based parameters indicated that certain parameters (hemoglobin, hematocrit, plasma glucose, plasma cortisol) may be useful in field monitoring.

Application of Raman spectroscopy in type 2 diabetes screening in blood using leucine and isoleucine amino-acids as biomarkers and in comparative anti-diabetic drugs efficacy studies

PubMed Central

Mwangi, Peter Waweru; Bukachi, Fredrick; Mandela, Keith Makori

2017-01-01

Diabetes is an irreversible condition characterized by elevated blood glucose levels. Currently, there are no predictive biomarkers for this disease and the existing ones such as hemoglobin A1c and fasting blood glucose are used only when diabetes symptoms are noticed. The objective of this work was first to explore the potential of leucine and isoleucine amino acids as diabetes type 2 biomarkers using their Raman spectroscopic signatures. Secondly, we wanted to explore whether Raman spectroscopy can be applied in comparative efficacy studies between commercially available anti-diabetic drug pioglitazone and the locally used anti-diabetic herbal extract Momordica spinosa (Gilg.)Chiov. Sprague Dawley (SD) rat’s blood was used and were pipetted onto Raman substrates prepared from conductive silver paste smeared glass slides. Prominent Raman bands associated with glucose (926, 1302, 1125 cm−1), leucine (1106, 1248, 1302, 1395 cm−1) and isolecucine (1108, 1248, 1437 and 1585 cm−1) were observed. The Raman bands centered at 1125 cm−1, 1395 cm−1 and 1437 cm−1 associated respectively to glucose, leucine and isoleucine were chosen as biomarker Raman peaks for diabetes type 2. These Raman bands displayed decreased intensities in blood from diabetic SD rats administered antidiabetic drugs pioglitazone and herbal extract Momordica spinosa (Gilg.)Chiov. The intensity decrease indicated reduced concentration levels of the respective biomarker molecules: glucose (1125 cm−1), leucine (1395 cm−1) and isoleucine (1437 cm−1) in blood. The results displayed the power and potential of Raman spectroscopy in rapid (10 seconds) diabetes and pre-diabetes screening in blood (human or rat’s) with not only glucose acting as a biomarker but also leucine and isoleucine amino-acids where intensities of respectively assigned bands act as references. It also showed that using Raman spectroscopic signatures of the chosen biomarkers, the method can be an alternative for performing comparative efficacy studies between known and new anti-diabetic drugs. Reports on use of Raman spectroscopy in type 2 diabetes mellitus screening with Raman bands associated with leucine and isoleucine molecules acting as reference is rare in literature. The use of Raman spectroscopy in pre-diabetes screening of blood for changes in levels of leucine and isoleucine amino acids is particularly interesting as once elevated levels are noticed, necessary interventions to prevent diabetes development can be initiated. PMID:28926628

Semipurified fractions from the submerged-culture broth of Agaricus blazei Murill reduce blood glucose levels in streptozotocin-induced diabetic rats.

PubMed

Oh, Tae W; Kim, Yun A; Jang, Wook J; Byeon, Jae I; Ryu, Chung H; Kim, Jeong O; Ha, Yeong L

2010-04-14

Hypoglycemic action of semipurified fractions from hot-water extracts of the submerged-culture broth of Agaricus blazei Murill was examined in streptozotocin (60 mg/kg, intraperitoneal)-induced diabetic male Sprague-Dawley rats, relative to the diabetes drug metformin. The hot-water extract, treated with ethanol to remove beta-glucans and glycoproteins, was freeze-dried, and fractionated into hexane, chloroform, ethyl acetate (EA), and butanol fractions. The EA fraction (EAF; 200 mg/kg body weight) reduced (p < 0.05) the blood glucose level in the oral glucose tolerance test, relative to the other fractions and control. In a 14 day-treatment study, diabetic rats treated with the EAF displayed a suppressed blood glucose level and elevated plasma insulin and glucose transport-4 proteins; the reactions occurred in a dose-dependent manner (200 and 400 mg/kg body weight) compared to those in control animals. The EAF reduced the levels of triglyceride and cholesterol in plasma, the activity of glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase in blood, and the content of thiobarbituric acid reactive substance in the liver and kidney. The hypoglycemic efficacy of the EAF (400 mg/kg body weight) was similar to that of metformin (500 mg/kg body weight). The EAF contained substantial amounts of isoflavonoids including genistein, genistin, daidzein, and daidzin, which could have contributed to the fraction's hypoglycemic action. These results indicate that the hot-water extract of the submerged-culture broth of Agaricus blazei contains an EAF having potent hypoglycemic action, which could be useful in the treatment of diabetes mellitus.

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.

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.

Advanced glycation end product (AGE) modified proteins in tears of diabetic patients.

PubMed

Zhao, Zhenjun; Liu, Jingfang; Shi, Bingyin; He, Shuixiang; Yao, Xiaoli; Willcox, Mark D P

2010-08-11

High glucose level in diabetic patients may lead to advanced glycation end product (AGE) modified proteins. This study investigated AGE modified proteins in tears and compared their levels in diabetic patients (DM) with non-diabetic controls (CTL). Basal tears were collected from DM with (DR) or without (DNR) retinopathy and CTL. Total AGE modified proteins were detected quantitatively by a dot immunobinding assay. The AGE modified proteins were separated in 1D- and 2D-SDS gels and detected by western-blotting. The individual AGE modified proteins were also compared between groups using densitometry. Compared with the CTL group, tear concentrations of AGE modified proteins were significantly elevated in DR and DNR groups. The concentration of AGE modified proteins in diabetic tears were positively correlated with AGE modified hemoglobin (HbA1c) and postprandial blood glucose level (PBG). Western blotting of AGE modified proteins from 1D-SDS gels showed several bands, the major one at around 60 kDa. The intensities of AGE modified protein bands were higher in DM tears than in CTL tears. Western blotting from 2D-SDS gels showed a strongly stained horizontal strip, which corresponded to the major band in 1D-SDS gels. Most of the other AGE modified protein species were within molecular weight of 30-60 kDa, PI 5.2-7.0. Densitometry analysis demonstrated several AGE modified proteins were elevated in DR or DNR tears. Total and some individual AGE modified proteins were elevated in DM tears. AGE modified proteins in tears may be used as biomarkers to diagnose diabetes and/or diabetic retinopathy.

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

Marked over expression of uncoupling protein-2 in beta cells exerts minor effects on mitochondrial metabolism

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

Hals, Ingrid K., E-mail: ingrid.hals@ntnu.no; Ogata, Hirotaka; Pettersen, Elin

2012-06-29

Highlights: Black-Right-Pointing-Pointer The impact of UCP-2 over expression on mitochondrial function is controversial. Black-Right-Pointing-Pointer We tested mitochondrial functions at defined levels of overexpression. Black-Right-Pointing-Pointer We find minor increases of fatty acid oxidation and uncoupling. Black-Right-Pointing-Pointer Effects were seen only at high level (fourfold) of over expression. Black-Right-Pointing-Pointer Hence it is doubtful whether these effects are of importance in diabetes. -- Abstract: Evidence is conflicting as to the impact of elevated levels of uncoupling protein-2 (UCP-2) on insulin-producing beta cells. Here we investigated effects of a fourfold induction of UCP-2 protein primarily on mitochondrial parameters and tested for replication of positivemore » findings at a lower level of induction. We transfected INS-1 cells to obtain a tet-on inducible cell line. A 48 h exposure to 1 {mu}g/ml of doxycycline (dox) induced UCP-2 fourfold (424 {+-} 113%, mean {+-} SEM) and 0.1 {mu}g/ml twofold (178 {+-} 29%, n = 3). Fourfold induced cells displayed normal viability (MTT, apoptosis), normal cellular insulin contents and, glucose-induced insulin secretion (+27 {+-} 11%) as well as D-[U-{sup 14}C]-glucose oxidation (+5 {+-} 9% at 11 mM glucose). Oxidation of [1-{sup 14}C]-oleate was increased from 4088 to 5797 fmol/{mu}g prot/2 h at 3.3 mM glucose, p < 0.03. Oxidation of L-[{sup 14}C(U)]-glutamine was unaffected. Induction of UCP-2 did not significantly affect measures of mitochondrial membrane potential (Rhodamine 123) or mitochondrial mass (Mitotracker Green) and did not affect ATP levels. Oligomycin-inhibited oxygen consumption (a measure of mitochondrial uncoupling) was marginally increased, the effect being significant in comparison with dox-only treated cells, p < 0.05. Oxygen radicals, assessed by dichlorofluorescin diacetate, were decreased by 30%, p < 0.025. Testing for the lower level of UCP-2 induction did not reproduce any of the positive findings. A fourfold induction of UCP-2 was required to exert minor metabolic effects. These findings question an impact of moderately elevated UCP-2 levels in beta cells as seen in diabetes.« less

[Piperine regulates glucose metabolism disorder in HepG2 cells of insulin resistance models via targeting upstream target of AMPK signaling pathway].

PubMed

Wan, Chun-Ping; Wei, Ya-Gai; Li, Xiao-Xue; Zhang, Li-Jun; Yang, Rui; Bao, Zhao-Ri-Ge-Tu

2017-02-01

To investigate the effect of piperine on the disorder of glucose metabolism in the cell model with insulin resistance (IR) and explore the molecules mechanism on intervening the upstream target of AMPK signaling pathway. The insulin resistance models in HepG2 cells were established by fat emulsion stimulation. Then glucose consumption in culture supernatant was detected by GOD-POD method. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of leptin(LEP) and adiponectin(APN) in culture supernatant; Real-time quantitative PCR was used to assess the mRNA expression of APN and LEP; and the protein expression levels of LepR, AdipoR1, AdipoR2 and the activation of AMPK signaling pathway were detected by Western blot analysis. The results showed that piperine, rosiglitazone and AMPK agonist AICAR could significantly elevate the glucose consumption in insulin resistance cell models, enhance the level of APN, promote APN mRNA transcripts and increase the protein expression of Adipo receptor. Meanwhile,AMPKα mRNA and р-AMPKα protein expressions were also increased in piperine treated cells, but both LEP mRNA expression and LepR protein expressions were decreased in piperine treated group. The results indicated that piperine could significantly ameliorate the glucose metabolism disorder in insulin resistance cell models through regulating upstream molecules (APN and LEP) of AMPK signaling pathway, and thus activate the AMPK signaling pathway. Copyright© by the Chinese Pharmaceutical Association.

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.

Volunteering and Cardiovascular Disease Risk: Does Helping Others Get "Under the Skin?".

PubMed

Burr, Jeffrey A; Han, Sae Hwang; Tavares, Jane L

2016-10-01

This study investigated whether volunteering was related to 5 risk factors for cardiovascular disease (CVD) and the metabolic syndrome (MetS) among middle-aged and older adults. Data from the 2004 and 2006 waves of the Health and Retirement Study (N = 7,803) were examined. Logistic regression was used to describe the relationships among volunteering and central adiposity, hypertension, lipid dysregulation, elevated blood glucose levels, and high inflammation, along with 2 indexes of the MetS. Among middle-aged adults, results showed that volunteers were less likely to have high central adiposity, lipid dysregulation, elevated blood glucose levels, and MetS compared with non-volunteers. For older adults, results showed volunteers were less likely to be hypertensive and more likely to have lipid dysregulation than their non-volunteer counterparts. These results supported findings from other studies that formal volunteering is beneficial for middle-aged adults, and to a lesser degree, older adults. Further research is required to determine what factors may mediate the volunteer-CVD risk relationships. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Maternal lipopolysaccharide exposure results in glucose metabolism disorders and sex hormone imbalance in male offspring.

PubMed

Zhao, Mei; Yuan, Li; Yuan, Man-Man; Huang, Li-Li; Su, Chang; Chen, Yuan-Hua; Yang, Yu-Ying; Hu, Yan; Xu, De-Xiang

2018-04-01

An adverse intrauterine environment may be an important factor contributing to the development of type 2 diabetes in later life. The present study investigated the longitudinal effects of maternal lipopolysaccharide (LPS) exposure during the third trimester on glucose metabolism and sex hormone balance in the offspring. Pregnant mice were intraperitoneally injected with LPS (50 μg/kg) daily from gestational day (GD) 15 to GD17. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were assessed at postnatal day (PND) 60 and PND120. Sex hormones, their receptors, and metabolic enzymes (aromatase) were measured in male offspring at different phases of development (PND14: juvenile; PND35: adolescence; PND60: adulthood; and PND120: middle age). LPS-exposed male offspring exhibited glucose intolerance and insulin resistance by GTT and ITT at middle age, accompanied by an increase in fasting blood glucose and reductions in serum insulin levels and hepatic phosphorylated (p) -AKT/AKT ratio. However, glucose intolerance and insulin resistance were not observed in LPS-exposed female offspring. Maternal LPS exposure upregulated hepatic aromatase proteins and mRNA levels in male offspring at all time points. At adolescence, the testosterone/estradiol ratio (T/E2) was markedly reduced in LPS-exposed male offspring. Moreover, maternal LPS exposure significantly increased hepatic estrogen receptor (ER) α expressions and decreased hepatic androgen receptor (AR) expressions in male offspring. At adulthood, maternal LPS exposure increased serum estradiol levels, decreased serum testosterone levels and elevated hepatic ERβ expressions in male offspring. In conclusion, maternal LPS exposure upregulated aromatase expressions, followed by a reduction in the T/E2 ratio and an alteration in sex hormone receptor activity, which might be involved in the development of glucose metabolism disorders in middle-aged male offspring. This study provides a novel clue and direction to clarify the pathogenesis of maternal infection-related diabetes in male offspring. Copyright © 2018 Elsevier B.V. All rights reserved.

Regulation of blood glucose level by kainic acid in mice: involvement of glucocorticoid system and non-NMDA receptors.

PubMed

Kim, Chea-Ha; Park, Soo-Hyun; Sim, Yun-Beom; Kim, Sung-Su; Jung, Jun-Sub; Sharma, Naveen; Suh, Hong-Won

2017-02-28

Kainic acid (KA) is a well-known excitatory neurotoxic substance. In the present study, effects of KA-injected intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the blood glucose level were investigated in ICR mice. We found that KA administered intraperitoneally (i.p.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) increased the blood glucose and corticosterone levels, suggesting that KA-induced hyperglycemia appeared to be due to increased blood corticosterone level. In support of this finding, adrenalectomy causes a reduction of KA-induced hyperglycemia and neuronal cell death in CA3 regions of the hippocampus. In addition, pretreatment with i.c.v. or i.t. injection of CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione; a non-NMDA receptor blocker) attenuated the i.p. and i.c.v. administered KA-induced hyperglycemia. KA administered i.c.v. caused an elevation of the blood corticosterone level whereas the plasma insulin level was reduced. Moreover, i.c.v. pretreatment with CNQX inhibited the decrease of plasma insulin level induced by KA i.c.v. injection, whereas the KA-induced plasma corticosterone level was further enhanced by CNQX pretreatment. Our results suggest that KA administered systemically or centrally produces hyperglycemia. A glucocorticoid system appears to be involved in KA-induced hyperglycemia. Furthermore, central non-N-methyl-D-aspartate receptors may be responsible for KA-induced hyperglycemia.

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

Step On It! - Workplace cardiovascular risk assessment of New York City yellow taxi drivers

PubMed Central

Gany, Francesca; Bari, Sehrish; Gill, Pavan; Ramirez, Julia; Ayash, Claudia; Loeb, Rebecca; Aragones, Abraham; Leng, Jennifer

2015-01-01

Background Multiple factors associated with taxi driving can increase the risk of cardiovascular disease (CVD) in taxi drivers. Methods This paper describes the results of Step On It!, which assessed CVD risk factors among New York City taxi drivers at John F. Kennedy International Airport. Drivers completed an intake questionnaire and free screenings for blood pressure, glucose and body mass index (BMI). Results 466 drivers participated. 9% had random plasma glucose values >200 mg/dl. 77% had elevated BMIs. Immigrants who lived in the U.S. for >10 years had 2.5 times the odds (CI: 1.1–5.9) of having high blood pressure compared to newer immigrants. Discussion Abnormalities documented in this study were significant, especially for immigrants with greater duration of residence in the U.S., and underscore the potential for elevated CVD risk in this vulnerable population, and the need to address this risk through frameworks that utilize multiple levels of intervention. PMID:25680879

Metabolic engineering for improved production of ethanol by Corynebacterium glutamicum.

PubMed

Jojima, Toru; Noburyu, Ryoji; Sasaki, Miho; Tajima, Takahisa; Suda, Masako; Yukawa, Hideaki; Inui, Masayuki

2015-02-01

Recombinant Corynebacterium glutamicum harboring genes for pyruvate decarboxylase (pdc) and alcohol dehydrogenase (adhB) can produce ethanol under oxygen deprivation. We investigated the effects of elevating the expression levels of glycolytic genes, as well as pdc and adhB, on ethanol production. Overexpression of four glycolytic genes (pgi, pfkA, gapA, and pyk) in C. glutamicum significantly increased the rate of ethanol production. Overexpression of tpi, encoding triosephosphate isomerase, further enhanced productivity. Elevated expression of pdc and adhB increased ethanol yield, but not the rate of production. Fed-batch fermentation using an optimized strain resulted in ethanol production of 119 g/L from 245 g/L glucose with a yield of 95% of the theoretical maximum. Further metabolic engineering, including integration of the genes for xylose and arabinose metabolism, enabled consumption of glucose, xylose, and arabinose, and ethanol production (83 g/L) at a yield of 90 %. This study demonstrated that C. glutamicum has significant potential for the production of cellulosic ethanol.

Glucose Administration Enhances fMRI Brain Activation and Connectivity Related to Episodic Memory Encoding for Neutral and Emotional Stimuli

ERIC Educational Resources Information Center

Parent, Marise B.; Krebs-Kraft, Desiree L.; Ryan, John P.; Wilson, Jennifer S.; Harenski, Carla; Hamann, Stephan

2011-01-01

Glucose enhances memory in a variety of species. In humans, glucose administration enhances episodic memory encoding, although little is known regarding the neural mechanisms underlying these effects. Here we examined whether elevating blood glucose would enhance functional MRI (fMRI) activation and connectivity in brain regions associated with…

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.

Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.

PubMed Central

Boden, G; Chen, X

1995-01-01

It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus. PMID:7657800

Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.

PubMed

Boden, G; Chen, X

1995-09-01

It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus.

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.

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

PubMed Central

Petrie, John L.; Al-Oanzi, Ziad H.; Arden, Catherine; Tudhope, Susan J.; Mann, Jelena; Kieswich, Julius; Yaqoob, Muhammad M.; Towle, Howard C.

2013-01-01

In the liver, a high glucose concentration activates transcription of genes encoding glucose 6-phosphatase and enzymes for glycolysis and lipogenesis by elevation in phosphorylated intermediates and recruitment of the transcription factor ChREBP (carbohydrate response element binding protein) and its partner, Mlx, to gene promoters. A proposed function for this mechanism is intracellular phosphate homeostasis. In extrahepatic tissues, MondoA, the paralog of ChREBP, partners with Mlx in transcriptional induction by glucose. We tested for glucose induction of regulatory proteins of the glycogenic pathway in hepatocytes and identified the glycogen-targeting proteins, GL and PTG (protein targeting to glycogen), as being encoded by Mlx-dependent glucose-inducible genes. PTG induction by glucose was MondoA dependent but ChREBP independent and was enhanced by forced elevation of fructose 2,6-bisphosphate and by additional xylitol-derived metabolites. It was counteracted by selective depletion of fructose 2,6-bisphosphate with a bisphosphatase-active kinase-deficient variant of phosphofructokinase 2/fructosebisphosphatase 2, which prevented translocation of MondoA to the nucleus and recruitment to the PTG promoter. We identify a novel role for MondoA in the liver and demonstrate that elevated fructose 2,6-bisphosphate is essential for recruitment of MondoA to the PTG promoter. Phosphometabolite activation of MondoA and ChREBP and their recruitment to target genes is consistent with a mechanism for gene regulation to maintain intracellular phosphate homeostasis. PMID:23207906

Plasma apelin levels in obstructive sleep apnea and the effect of continuous positive airway pressure therapy.

PubMed

Henley, David E; Buchanan, Fiona; Gibson, Rosemary; Douthwaite, Jennie A; Wood, Susan A; Woltersdorf, Wolfram W; Catterall, James R; Lightman, Stafford L

2009-10-01

Apelin is a peptide hormone with cardiovascular and glucose homeostasis properties, and obstructive sleep apnea (OSA) is complicated by cardiovascular and metabolic comorbidities. Plasma apelin has not been previously assessed in OSA. We investigated the response of plasma apelin to a 2-h 75 g oral glucose tolerance test (OGTT) and the effect of 3 months compliant continuous positive airway pressure (CPAP) therapy in 15 obese males with newly diagnosed OSA. Plasma apelin and serum cortisol were recorded 10 minutely, while serum insulin and glucose were measured 30 minutely. Ten subjects had plasma apelin measured at intervals across a 24-h period to investigate for circadian variation in apelin levels, and this was repeated following 3 months compliant CPAP therapy. Fasting (0.342+/-0.038 vs 0.288+/-0.024 ng/ml, P=0.04), 30 min (0.399+/-0.035 vs 0.312+/-0.036 ng/ml, P=0.007) and 120 min (0.402+/-0.030 vs 0.259+/-0.024 ng/ml, P<0.001) apelin levels were reduced following CPAP. The area under curve for apelin OGTT response was lower post-CPAP (44.1+/-3.3 vs 35.8+/-2.3 ng/ml per min, P<0.001). Mean OGTT apelin levels showed a significant treatment effect (P=0.006) and a time effect (P<0.001), and the effect of time was different pre- versus post-CPAP (P=0.005). No significant variability in apelin levels existed across the 24-h period at diagnosis. Lower levels were evident overnight following treatment (P=0.004). Improvements in insulin and glucose parameters and reduced cortisol levels were found post-CPAP. In summary, untreated OSA was associated with elevated plasma apelin levels, altered apelin secretory dynamics in response to oral glucose and lack of an apparent circadian variability, which was restored following CPAP.

Branched-chain amino acids supplementation protects streptozotocin-induced insulin secretion and the correlated mechanism.

PubMed

Lu, Ming; Zhang, Xiujuan; Zheng, Dongmei; Jiang, Xiuyun; Chen, Qing

2015-01-01

Significant evidence demonstrates that oxidative stress can impair insulin secretion and contribute to the development of type 2 diabetes. Branched-chain amino acids (BCAAs) are reported to be positively related to insulin secretion. This study aimed to determine how oxidative stress affects the function of islets and whether BCAAs can ameliorate the oxidative stress, and accompanying c-jun N-terminal kinase (JNK), protein kinase D1 (PKD1), and pancreatic/duodenal homeobox-1 (PDX-1) changes induced by streptozotocin (STZ). Plasma glucose, plasma insulin, and JNK, PKD1 and PDX-1 mRNA and protein expression were measured in rats treated with STZ and BCAAs. The glucose level in STZ-induced diabetic rats was much higher than that in control animals, and the elevated plasma glucose level in diabetic rats could be significantly inhibited by BCAAs treatment. Consistent with the change in glucose levels, the levels of insulin were also affected by BCAAs treatment. The mRNA and protein expression of JNK, PDX-1, and PKD1 were significantly altered in diabetic rats compared with the control group (P<0.01) and treatment with a low dose of BCAA reversed these changes in those above markers significantly (P<0.01). The present study demonstrated that STZ-induced oxidative stress could reduce serum insulin levels and alter the JNK, PDX-1, and PKD1 expression. BCAAs restored the levels of serum insulin reversed changes in JNK, PDX-1, and PKD1 expression. © 2014 International Union of Biochemistry and Molecular Biology.

Everolimus induces rapid plasma glucose normalization in insulinoma patients by effects on tumor as well as normal tissues.

PubMed

Fiebrich, Helle-Brit; Siemerink, Ester J M; Brouwers, Adrienne H; Links, Thera P; Remkes, Wouter S; Hospers, Geke A P; de Vries, Elisabeth G E

2011-01-01

Mammalian target of rapamycin inhibitor everolimus administered to four insulinoma patients rapidly controlled hypoglycemia (Kulke et al., N Engl J Med 2009;360:195-197). We wanted to identify the kinetics of everolimus effects on controlling hypoglycemia and understand underlying mechanisms. Three consecutive patients with a metastasized symptomatic insulinoma were started on 100 μg of octreotide subcutaneously three times daily. Because of persisting hypoglycemias, treatment with daily 10 mg of oral everolimus was initiated. Serial plasma glucose levels and serum insulin levels were measured. Computer tomography (CT) scans were performed before and after 2 and 5 months of treatment. [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) scans, to visualize glucose metabolism, were made before and after 2 weeks, 5 weeks, and 5 months of treatment. The ¹⁸F-FDG uptake was quantified as the maximum standardized uptake value. All patients achieved control of hypoglycemia on everolimus within 14 days. Insulin levels were 2.5- to 6.3-fold elevated before start of treatment and declined 14%-64% after 4 weeks of treatment. CT scans showed stable disease at 2 months in all patients, with progressive disease after 5 months in one. Before treatment, both the tumor lesions and the muscles and myocardium showed high ¹⁸F-FDG uptake. Everolimus reduced tumor and muscle ¹⁸F-FDG uptake after 2 weeks by 26% ± 14% and 19% ± 41%, and after 5 months by 31% ± 13% and 27% ± 41%. Everolimus normalizes plasma glucose levels in metastatic insulinoma within 14 days, coinciding with a lower glucose uptake in tumor and muscles and declining (pro)insulin levels. This effect on tumor as well as normal tissues explains the rapid controlling of hypoglycemia.

The effect of midday moderate-intensity exercise on postexercise hypoglycemia risk in individuals with type 1 diabetes.

PubMed

Davey, Raymond J; Howe, Warwick; Paramalingam, Nirubasini; Ferreira, Luis D; Davis, Elizabeth A; Fournier, Paul A; Jones, Timothy W

2013-07-01

Exercise increases the risk of hypoglycemia in type 1 diabetes. Recently we reported a biphasic increase in glucose requirements to maintain euglycemia after late-afternoon exercise, suggesting a unique pattern of delayed risk for nocturnal hypoglycemia. This study examined whether this pattern of glucose requirements occurs if exercise is performed earlier in the day. Ten adolescents with type 1 diabetes underwent a hyperinsulinemic euglycemic glucose clamp on 2 different occasions during which they either rested or performed 45 minutes of moderate-intensity exercise at midday. Glucose was infused to maintain euglycemia for 17 hours after exercise. The glucose infusion rate (GIR) to maintain euglycemia, glucose rates of appearance and disappearance, and levels of counterregulatory hormones were compared between conditions. GIRs to maintain euglycemia were not significantly different between groups at baseline (9.8 ± 1.4 and 9.5 ± 1.6 g/h before the exercise and rest conditions, respectively) and did not change in the rest condition throughout the study. In contrast, GIR increased more than 3-fold during exercise (from 9.8 ± 1.4 to 30.6 ± 4.7 g/h), fell within the first hour of recovery, but remained elevated until 11 hours after exercise before returning to baseline levels. The pattern of glucose requirements to maintain euglycemia in response to moderate-intensity exercise performed at midday suggests that the risk of exercise-mediated hypoglycemia increases during and for several hours after moderate-intensity exercise, with no evidence of a biphasic pattern of postexercise risk of hypoglycemia.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.

PubMed

Tyrrell, Jessica; Richmond, Rebecca C; Palmer, Tom M; Feenstra, Bjarke; Rangarajan, Janani; Metrustry, Sarah; Cavadino, Alana; Paternoster, Lavinia; Armstrong, Loren L; De Silva, N Maneka G; Wood, Andrew R; Horikoshi, Momoko; Geller, Frank; Myhre, Ronny; Bradfield, Jonathan P; Kreiner-Møller, Eskil; Huikari, Ville; Painter, Jodie N; Hottenga, Jouke-Jan; Allard, Catherine; Berry, Diane J; Bouchard, Luigi; Das, Shikta; Evans, David M; Hakonarson, Hakon; Hayes, M Geoffrey; Heikkinen, Jani; Hofman, Albert; Knight, Bridget; Lind, Penelope A; McCarthy, Mark I; McMahon, George; Medland, Sarah E; Melbye, Mads; Morris, Andrew P; Nodzenski, Michael; Reichetzeder, Christoph; Ring, Susan M; Sebert, Sylvain; Sengpiel, Verena; Sørensen, Thorkild I A; Willemsen, Gonneke; de Geus, Eco J C; Martin, Nicholas G; Spector, Tim D; Power, Christine; Järvelin, Marjo-Riitta; Bisgaard, Hans; Grant, Struan F A; Nohr, Ellen A; Jaddoe, Vincent W; Jacobsson, Bo; Murray, Jeffrey C; Hocher, Berthold; Hattersley, Andrew T; Scholtens, Denise M; Davey Smith, George; Hivert, Marie-France; Felix, Janine F; Hyppönen, Elina; Lowe, William L; Frayling, Timothy M; Lawlor, Debbie A; Freathy, Rachel M

2016-03-15

Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. Offspring birth weight from 18 studies. Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Cerebrospinal Fluid Glucose and Lactate: Age-Specific Reference Values and Implications for Clinical Practice

PubMed Central

Leen, Wilhelmina G.; Willemsen, Michèl A.; Wevers, Ron A.; Verbeek, Marcel M.

2012-01-01

Cerebrospinal fluid (CSF) analysis is an important tool in the diagnostic work-up of many neurological disorders, but reference ranges for CSF glucose, CSF/plasma glucose ratio and CSF lactate based on studies with large numbers of CSF samples are not available. Our aim was to define age-specific reference values. In 1993 The Nijmegen Observational CSF Study was started. Results of all CSF samples that were analyzed between 1993 and 2008 at our laboratory were systematically collected and stored in our computerized database. After exclusion of CSF samples with an unknown or elevated erythrocyte count, an elevated leucocyte count, elevated concentrations of bilirubin, free hemoglobin, or total protein 9,036 CSF samples were further studied for CSF glucose (n = 8,871), CSF/plasma glucose ratio (n = 4,516) and CSF lactate values (n = 7,614). CSF glucose, CSF/plasma glucose ratio and CSF lactate were age-, but not sex dependent. Age-specific reference ranges were defined as 5–95th percentile ranges. CSF glucose 5th percentile values ranged from 1.8 to 2.9 mmol/L and 95th percentile values from 3.8 to 5.6 mmol/L. CSF/plasma glucose ratio 5th percentile values ranged from 0.41 to 0.53 and 95th percentile values from 0.82 to 1.19. CSF lactate 5th percentile values ranged from 0.88 to 1.41 mmol/L and 95th percentile values from 2.00 to 2.71 mmol/L. Reference ranges for all three parameters were widest in neonates and narrowest in toddlers, with lower and upper limits increasing with age. These reference values allow a reliable interpretation of CSF results in everyday clinical practice. Furthermore, hypoglycemia was associated with an increased CSF/plasma glucose ratio, whereas hyperglycemia did not affect the CSF/plasma glucose ratio. PMID:22880096

Energy metabolism in astrocytes and neurons treated with manganese: relation among cell-specific energy failure, glucose metabolism, and intercellular trafficking using multinuclear NMR-spectroscopic analysis.

PubMed

Zwingmann, Claudia; Leibfritz, Dieter; Hazell, Alan S

2003-06-01

A central question in manganese neurotoxicity concerns mitochondrial dysfunction leading to cerebral energy failure. To obtain insight into the underlying mechanism(s), the authors investigated cell-specific pathways of [1-13C]glucose metabolism by high-resolution multinuclear NMR-spectroscopy. Five-day treatment of neurons with 100-micro mol/L MnCl(2) led to 50% and 70% decreases of ATP/ADP and phosphocreatine-creatine ratios, respectively. An impaired flux of [1-13C]glucose through pyruvate dehydrogenase, which was associated with Krebs cycle inhibition and hence depletion of [4-13C]glutamate, [2-13C]GABA, and [13C]glutathione, hindered the ability of neurons to compensate for mitochondrial dysfunction by oxidative glucose metabolism and further aggravated neuronal energy failure. Stimulated glycolysis and oxidative glucose metabolism protected astrocytes against energy failure and oxidative stress, leading to twofold increased de novo synthesis of [3-13C]lactate and fourfold elevated [4-13C]glutamate and [13C]glutathione levels. Manganese, however, inhibited the synthesis and release of glutamine. Comparative NMR data obtained from cocultures showed disturbed astrocytic function and a failure of astrocytes to provide neurons with substrates for energy and neurotransmitter metabolism, leading to deterioration of neuronal antioxidant capacity (decreased glutathione levels) and energy metabolism. The results suggest that, concomitant to impaired neuronal glucose oxidation, changes in astrocytic metabolism may cause a loss of intercellular homeostatic equilibrium, contributing to neuronal dysfunction in manganese neurotoxicity.

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.

Basal levels of metabolic activity are elevated in Genetic Absence Epilepsy Rats from Strasbourg (GAERS): measurement of regional activity of cytochrome oxidase and lactate dehydrogenase by histochemistry.

PubMed

Dufour, Franck; Koning, Estelle; Nehlig, Astrid

2003-08-01

The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are considered an isomorphic, predictive, and homologous model of human generalized absence epilepsy. It is characterized by the expression of spike-and-wave discharges in the thalamus and cortex. In this strain, basal regional rates of cerebral glucose utilization measured by the quantitative autoradiographic [(14)C]2-deoxyglucose technique display a widespread consistent increase compared to a selected strain of genetically nonepileptic rats (NE). In order to verify whether these high rates of glucose metabolism are paralleled by elevated activities of the enzymes of the glycolytic and tricarboxylic acid cycle pathways, we measured by histochemistry the regional activity of the two key enzymes of glucose metabolism, lactate dehydrogenase (LDH) for the anaerobic pathway and cytochrome oxidase (CO) for the aerobic pathway coupled to oxidative phosphorylation. CO and LDH activities were significantly higher in GAERS than in NE rats in 24 and 28 of the 30 brain regions studied, respectively. The differences in CO and LDH activity between both strains were widespread, affected all brain systems studied, and ranged from 12 to 63%. The data of the present study confirm the generalized increase in cerebral glucose metabolism in GAERS, occurring both at the glycolytic and at the oxidative step. However, they still do not allow us to understand why the ubiquitous mutation(s) generates spike-and-wave discharges only in the thalamocortical circuit.

Dapagliflozin in patients with type II diabetes mellitus, with and without elevated triglyceride and reduced high-density lipoprotein cholesterol levels.

PubMed

Bays, Harold E; Sartipy, Peter; Xu, John; Sjöström, Carl David; Underberg, James A

Dapagliflozin is a selective sodium-glucose cotransporter 2 inhibitor that improves glycemic control in patients with type II diabetes mellitus (T2DM) by reducing renal glucose reabsorption. The aim was to evaluate the lipid effects of dapagliflozin 10 mg or placebo in patients with T2DM with/without baseline elevated triglyceride and reduced high-density lipoprotein (HDL) cholesterol levels. This was a post hoc analysis of 10 phase 3, placebo-controlled studies of dapagliflozin 10 mg (N = 2237) or placebo (N = 2164) administered for 24 weeks in patients with T2DM. Patients with elevated triglyceride (≥150 mg/dL [1.69 mmol/L]) and reduced HDL cholesterol levels (<40 mg/dL [1.04 mmol/L] in men; <50 mg/dL [1.29 mmol/L] in women) were included (group A). The reference group (group B) included patients who did not meet the defined lipid criteria. The effects of dapagliflozin on fasting lipid profiles were generally similar in the 2 lipid groups (ie, groups A and B) and, compared with placebo, were associated with minor increases in non-HDL cholesterol, low-density lipoprotein, and HDL cholesterol levels. The effects on triglyceride levels were inconsistent. The incidence of adverse events (AEs)/serious AEs, and AEs of genital infection, urinary tract infection, volume reduction, renal function, and hypoglycemia were similar in the 2 lipid groups. Patients with T2DM treated with dapagliflozin experienced minor changes in lipid levels; the changes were generally similar in the 2 lipid groups. The clinical significance of these changes in lipids is unclear, especially in view of the positive effects of dapagliflozin on other cardiovascular disease risk factors. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Dual effect of cell-cell contact disruption on cytosolic calcium and insulin secretion.

PubMed

Jaques, Fabienne; Jousset, Hélène; Tomas, Alejandra; Prost, Anne-Lise; Wollheim, Claes B; Irminger, Jean-Claude; Demaurex, Nicolas; Halban, Philippe A

2008-05-01

Cell-to-cell interactions play an important role in insulin secretion. Compared with intact islets, dispersed pancreatic beta-cells show increased basal and decreased glucose-stimulated insulin secretion. In this study, we used mouse MIN6B1 cells to investigate the mechanisms that control insulin secretion when cells are in contact with each other or not. RNAi-mediated silencing of the adhesion molecule E-cadherin in confluent cells reduced glucose-stimulated secretion to the levels observed in isolated cells but had no impact on basal secretion. Dispersed cells presented high cytosolic Ca(2+) activity, depolymerized cytoskeleton and ERK1/2 activation in low glucose conditions. Both the increased basal secretion and the spontaneous Ca(2+) activity were corrected by transient removal of Ca(2+) or prolonged incubation of cells in low glucose, a procedure that restored the ability of dispersed cells to respond to glucose (11-fold stimulation). In conclusion, we show that dispersed pancreatic beta-cells can respond robustly to glucose once their elevated basal secretion has been corrected. The increased basal insulin secretion of dispersed cells is due to spontaneous Ca(2+) transients that activate downstream Ca(2+) effectors, whereas engagement of cell adhesion molecules including E-cadherin contributes to the greater secretory response to glucose seen in cells with normal intercellular contacts.

Mouse handling limits the impact of stress on metabolic endpoints.

PubMed

Ghosal, Sriparna; Nunley, Amanda; Mahbod, Parinaz; Lewis, Alfor G; Smith, Eric P; Tong, Jenny; D'Alessio, David A; Herman, James P

2015-10-15

Studies focused on end-points that are confounded by stress are best performed under minimally stressful conditions. The objective of this study was to demonstrate the impact of handling designed to reduce animal stress on measurements of glucose tolerance. A cohort of mice (CD1.C57BL/6) naïve to any specific handling was subjected to either a previously described "cup" handling method, or a "tail-picked" method in which the animals were picked up by the tail (as is common for metabolic studies). Following training, an elevated plus maze (EPM) test was performed followed by measurement of blood glucose and plasma corticosterone. A second cohort (CD1.C57BL/6) was rendered obese by exposure to a high fat diet, handled with either the tail-picked or cup method and subjected to an intraperitoneal glucose tolerance test. A third cohort of C57BL/6 mice was exposed to a cup regimen that included a component of massage and was subjected to tests of anxiety-like behavior, glucose homeostasis, and corticosterone secretion. We found that the cup mice showed reduced anxiety-like behaviors in the EPM coupled with a reduction in blood glucose levels compared to mice handled by the tail-picked method. Additionally, cup mice on the high fat diet exhibited improved glucose tolerance compared to tail-picked controls. Finally, we found that the cup/massage group showed lower glucose levels following an overnight fast, and decreased anxiety-like behaviors associated with lower stress-induced plasma corticosterone concentration compared to tail-picked controls. These data demonstrate that application of handling methods that reduce anxiety-like behaviors in mice mitigates the confounding contribution of stress to interpretation of metabolic endpoints (such as glucose tolerance). Copyright © 2015 Elsevier Inc. All rights reserved.

Mouse Handling Limits the Impact of Stress on Metabolic Endpoints

PubMed Central

Ghosal, Sriparna; Nunley, Amanda; Mahbod, Parinaz; Lewis, Alfor G.; Smith, Eric P.; Tong, Jenny; D’Alessio, David A.; Herman, James P.

2015-01-01

Studies focused on end-points that are confounded by stress are best performed under minimally stressful conditions. The objective of this study was to demonstrate the impact of handling designed to reduce animal stress on measurements of glucose tolerance. A cohort of mice (CD1.C57BL/6) naïve to any specific handling were subjected to either a previously described “cup” handling method, or a “tail-picked” method in which the animals were picked up by the tail (as is common for metabolic studies). Following training, an elevated plus maze (EPM) test was performed followed by measurement of blood glucose and plasma corticosterone. A second cohort (CD1.C57BL/6) was rendered obese by exposure to a high fat diet, handled with either the tail-picked or cup method and subjected to an intraperitoneal glucose tolerance test. A third cohort of C57BL/6 mice was exposed to a cup regimen that included a component of massage and was subjected to tests of anxiety-like behavior, glucose homeostasis, and corticosterone secretion. We found that the cup mice showed reduced anxiety-like behaviors in the EPM coupled with a reduction in blood glucose levels compared to mice handled by the tail-picked method. Additionally, cup mice on the high fat diet exhibited improved glucose tolerance compared to tail-picked controls. Finally, we found that the cup/massage group showed lower glucose levels following an overnight fast, and decreased anxiety-like behaviors associated with lower stress-induced plasma corticosterone concentration compared to tail-picked controls. These data demonstrate that application of handling methods that reduce anxiety-like behaviors in mice mitigates the confounding contribution of stress to interpretation of metabolic endpoints (such as glucose tolerance). PMID:26079207

Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey

PubMed Central

Wu, Ying; Zou, Meng; Raulerson, Chelsea K.; Jackson, Kayla; Yuan, Wentao; Wang, Haifeng; Shou, Weihua; Wang, Ying; Luo, Jingchun; Lange, Leslie A.; Lange, Ethan M.; Gordon-Larsen, Penny; Du, Shufa; Huang, Wei; Mohlke, Karen L.

2018-01-01

To identify genetic contributions to type 2 diabetes (T2D) and related glycemic traits (fasting glucose, fasting insulin, and HbA1c), we conducted genome-wide association analyses (GWAS) in up to 7,178 Chinese subjects from nine provinces in the China Health and Nutrition Survey (CHNS). We examined patterns of population structure within CHNS and found that allele frequencies differed across provinces, consistent with genetic drift and population substructure. We further validated 32 previously described T2D- and glycemic trait-loci, including G6PC2 and SIX3-SIX2 associated with fasting glucose. At G6PC2, we replicated a known fasting glucose-associated variant (rs34177044) and identified a second signal (rs2232326), a low-frequency (4%), probably damaging missense variant (S324P). A variant within the lead fasting glucose-associated signal at SIX3-SIX2 co-localized with pancreatic islet expression quantitative trait loci (eQTL) for SIX3, SIX2, and three noncoding transcripts. To identify variants functionally responsible for the fasting glucose association at SIX3-SIX2, we tested five candidate variants for allelic differences in regulatory function. The rs12712928-C allele, associated with higher fasting glucose and lower transcript expression level, showed lower transcriptional activity in reporter assays and increased binding to GABP compared to the rs12712928-G, suggesting that rs12712928-C contributes to elevated fasting glucose levels by disrupting an islet enhancer, resulting in reduced gene expression. Taken together, these analyses identified multiple loci associated with glycemic traits across China, and suggest a regulatory mechanism at the SIX3-SIX2 fasting glucose GWAS locus. PMID:29621232

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.

[Evaluation of accuracy and influence factors of bedside blood glucose monitoring in critically ill patients].

PubMed

Feng, Tao; Cao, Xiang-yuan

2012-08-01

To evaluate the accuracy and influence factors of point-of-care testing (POCT) for glucose in critically ill patients. Two hundred and forty critically ill patients aged ≥18 years in department of critical care medicine were enrolled. According to blood glucose level (BGL) during glucose control, patients were divided into three groups: (1) hypoglycemia group, BGL<4.5 mmol/L, n=32; (2) euglycemia group, BGL 4.5-8.3 mmol/L, n=138; (3) hyperglycemia group, BGL>8.3 mmol/L, n=70. The blood samples from vein, artery and capillary of patients were collected synchronically and the blood glucose of POCT were determined with glucose oxidase (GOD) and glucose dehydrogenase (GDH) methods, respectively, compared with blood glucose reference values of laboratory [hexokinase method (HK method)]. The accuracy of POCT for glucose and influence factors were analyzed statistically by the logistic regression method. (1) The inaccurate rates of glucose values in blood samples from vein, artery and capillary in hypoglycemia group (GDH method: 25.00%, 40.62%, 40.62%; GOD method: 59.38%, 71.88%, 71.88%) were significantly higher than those in euglycemia group (GDH method: 2.90%, 9.42%, 7.97%; GOD method: 18.12%, 27.54%, 27.54%) and hyperglycemia group (GDH method: 1.43%, 8.57%, 4.28%; GOD method: 11.43%, 8.57%, 11.43%, all P<0.01). (2) The average levels of difference for the glucose reference value of laboratory and the glucose value measured by glucometer in hypoglycemia group were 0.41-0.69 mmol/L (GDH method) and 0.92-1.18 mmol/L (GOD method), in euglycemia 0.16-0.33 mmol/L and 0.77-0.90 mmol/L, in hyperglycemia group -0.06-0.18 mmol/L and 0.56-0.76 mmol/L, respectively. (3) The correlation coefficients between the laboratory and glucometer in hypoglycemia group were respectively 0.812-0.853 (GDH method) and 0.723-0.816 (GOD method). The correlation coefficients in euglycemia group were 0.862-0.890 and 0.768-0.857. They were elevated to 0.922-0.957 and 0.896-0.922 in hyperglycemia group (all P<0.01). (4)On the influence factors of accuracy in POCT for glucose, BGL, acute physiology and chronic health evaluation II (APACHEII) score and hematocrit level were into the logistic regression equation. The accuracy of POCT for glucose was markedly affected by the BGL, severity of patients and hematocrit level during glucose control. Under hypoglycemia, the agreement between laboratory and glucometer measurements was obviously fallen and it tended to overestimate the patient's real glucose value.

Interactions among dietary boron, molybdenum, and magnesium in the chick

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

Hunt, C.D.; Nielsen, F.H.

The authors have previously reported that dietary B affects plasma Mo concentrations in chicks fed inadequate levels of Mg and cholecalciferol (vit. D/sub 3/). Because of this finding, they studied the effect of dietary Mo and Mg on the signs of B deficiency in vit. D/sub 3/ deprived chicks. In a fully crossed, 2 x 2 x 2 factorially arranged experiment, day-old cockerel chicks (19 per group) were fed a ground corn-casein-corn oil based diet (containing 0.850 mg B, 0.319 mg Mo, and 125 IU vit. D/sub 3//kg) supplemented with B at 0 or 3 mg/kg, Mo at 0 ormore » 20 mg/kg, and Mg at 300 or 500 mg/kg. After four weeks, B deprivation depressed growth and elevated the plasma glucose and the brain wt/body wt ratio. Low dietary Mo elevated the heart wt/body wt ratio. An interaction between B and Mg affected hemoglobin and plasma alkaline phosphatase and an interaction between B and Mo affected the heart wt/body wt and liver wt/body wt ratios. Mg deficiency gave usual signs including depressed growth, plasma alkaline phosphatase, glucose, and spleen and liver wt/body wt ratios and elevated hematocrit and brain wt/body wt ratio. The findings suggest that physiological levels of Mg and Mo affect B metabolism. The effects of low dietary Mo on vit. D/sub 3/ and/or Mg-deficient chicks needs to be elucidated.« less

Adeno-Associated Virus-Mediated Correction of a Canine Model of Glycogen Storage Disease Type Ia

PubMed Central

Weinstein, David A.; Correia, Catherine E.; Conlon, Thomas; Specht, Andrew; Verstegen, John; Onclin-Verstegen, Karine; Campbell-Thompson, Martha; Dhaliwal, Gurmeet; Mirian, Layla; Cossette, Holly; Falk, Darin J.; Germain, Sean; Clement, Nathalie; Porvasnik, Stacy; Fiske, Laurie; Struck, Maggie; Ramirez, Harvey E.; Jordan, Juan; Andrutis, Karl; Chou, Janice Y.; Byrne, Barry J.

2010-01-01

Abstract Glycogen storage disease type Ia (GSDIa; von Gierke disease; MIM 232200) is caused by a deficiency in glucose-6-phosphatase-α. Patients with GSDIa are unable to maintain glucose homeostasis and suffer from severe hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia, and lactic acidosis. The canine model of GSDIa is naturally occurring and recapitulates almost all aspects of the human form of disease. We investigated the potential of recombinant adeno-associated virus (rAAV) vector-based therapy to treat the canine model of GSDIa. After delivery of a therapeutic rAAV2/8 vector to a 1-day-old GSDIa dog, improvement was noted as early as 2 weeks posttreatment. Correction was transient, however, and by 2 months posttreatment the rAAV2/8-treated dog could no longer sustain normal blood glucose levels after 1 hr of fasting. The same animal was then dosed with a therapeutic rAAV2/1 vector delivered via the portal vein. Two months after rAAV2/1 dosing, both blood glucose and lactate levels were normal at 4 hr postfasting. With more prolonged fasting, the dog still maintained near-normal glucose concentrations, but lactate levels were elevated by 9 hr, indicating that partial correction was achieved. Dietary glucose supplementation was discontinued starting 1 month after rAAV2/1 delivery and the dog continues to thrive with minimal laboratory abnormalities at 23 months of age (18 months after rAAV2/1 treatment). These results demonstrate that delivery of rAAV vectors can mediate significant correction of the GSDIa phenotype and that gene transfer may be a promising alternative therapy for this disease and other genetic diseases of the liver. PMID:20163245

Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse.

PubMed

Head, W Steven; Orseth, Meredith L; Nunemaker, Craig S; Satin, Leslie S; Piston, David W; Benninger, Richard K P

2012-07-01

Insulin is secreted from the islets of Langerhans in coordinated pulses. These pulses are thought to lead to plasma insulin oscillations, which are putatively more effective in lowering blood glucose than continuous levels of insulin. Gap-junction coupling of β-cells by connexin-36 coordinates intracellular free calcium oscillations and pulsatile insulin release in isolated islets, however a role in vivo has not been shown. We test whether loss of gap-junction coupling disrupts plasma insulin oscillations and whether this impacts glucose tolerance. We characterized the connexin-36 knockout (Cx36(-/-)) mouse phenotype and performed hyperglycemic clamps with rapid sampling of insulin in Cx36(-/-) and control mice. Our results show that Cx36(-/-) mice are glucose intolerant, despite normal plasma insulin levels and insulin sensitivity. However, Cx36(-/-) mice exhibit reduced insulin pulse amplitudes and a reduction in first-phase insulin secretion. These changes are similarly found in isolated Cx36(-/-) islets. We conclude that Cx36 gap junctions regulate the in vivo dynamics of insulin secretion, which in turn is important for glucose homeostasis. Coordinated pulsatility of individual islets enhances the first-phase elevation and second-phase pulses of insulin. Because these dynamics are disrupted in the early stages of type 2 diabetes, dysregulation of gap-junction coupling could be an important factor in the development of this disease.

Beneficial effect of baicalin on insulin sensitivity in adipocytes of diet-induced obese mice.

PubMed

Fang, Penghua; Yu, Mei; Min, Wen; Han, Shiyu; Shi, Mingyi; Zhang, Zhenwen; Bo, Ping

2018-05-01

Although baicalin has been shown to increase glucose uptake and insulin sensitivity in skeletal muscle of mice, there is no literature available about the effect of baicalin on insulin sensitivity in adipocytes of diet-induced obese mice. In the present study, diet-induced obese mice were given 50 mg/kg baicalin intraperitoneally (i.p.) once a day for 21 days, and 3T3-L1 cells were treated with 100, 200, 400 μM baicalin for 3 h. Then insulin resistance indexes and insulin signal protein levels were examined to elucidate whether baicalin increased glucose uptake and GLUT4 translocation in adipocytes of diet-induced obese mice. The present findings showed that administration of baicalin decreased food intake, body weight, HOMA-IR and p-p38 MAPK and pERK levels, but enhanced pAKT and PGC-1α contents, as well as GLUT4 mRNA, PGC-1α mRNA expression in adipocytes, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in diet-induced obese mice. Moreover, baicalin treatment increased GLUT4 concentration in plasma membranes of adipocytes. These data demonstrated that baicalin accelerated GLUT4 translocation from intracellular membrane compartments to plasma membranes in adipocytes. Baicalin plays a significant role in elevation of glucose uptake and insulin sensitivity to promote glucose clearance. Copyright © 2018 Elsevier B.V. All rights reserved.

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

Serum Aminotransferase Levels are Associated with Markers of Hypoxia in Patients with Obstructive Sleep Apnea

PubMed Central

Norman, Daniel; Bardwell, Wayne A.; Arosemena, Farah; Nelesen, Richard; Mills, Paul J.; Loredo, Jose S.; Lavine, Joel E.; Dimsdale, Joel E.

2008-01-01

Study Objectives: Nonalcoholic fatty liver disease (NAFLD) is a disorder that often presents with elevated serum aminotransferase levels. Although it has classically been linked with the metabolic syndrome, recent studies suggest NAFLD may also be associated with obstructive sleep apnea (OSA). This study evaluates the association between serum aminotransferase levels and factors connected with: either the metabolic syndrome (elevated body mass index [BMI], lipid profile, blood pressure, fasting glucose), or with OSA severity (apnea hypopnea index, lowest oxygen saturation level, oxygen desaturation index, percent of time below 90% saturation [%T<90]). Design: Retrospective case series. Patients and Setting: 109 adult patients with OSA at a university hospital general clinical research center. Measurements and Results: Markers of hypoxia (lowest oxygen saturation level and %T<90), correlated significantly with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (Pearson's r = −0.31 to −0.38, P <0.003), while apnea hypopnea index, body mass index, blood pressure, fasting glucose, triglyceride, and cholesterol levels did not. Hierarchical linear regression was then done to determine the best predictors of aminotransferase levels. Markers of metabolic syndrome were entered as one block and markers of sleep apnea as another. Regression analyses explained 16.3% of the variance in AST and 18.9% of the variance in ALT, with %T<90 playing the largest role. Conclusions: In patients with obstructive sleep apnea, serum aminotransferase levels are better predicted by markers of oxygen desaturation than by factors traditionally associated with the metabolic syndrome. Citation: Norman D; Bardwell WA; Arosemena F; Nelesen R; Mills PJ; Loredo JS; Lavine JE; Dimsdale JE. Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea. SLEEP 2008;31(1):-121-126. PMID:18220085

[Levels of obesity, fasting glycemia and physical condition in Chilean students].

PubMed

Delgado Floody, Pedro; Caamaño Navarrete, Felipe; Guzmán Guzmán, Iris Paola; Jerez Mayorga, Daniel; Ramírez-Campillo, Rodrigo; Campos Jara, Christian; Ríos Lagos, Gonzalo; Díaz Inostroza, Hugo

2015-06-01

Chile has drastically altered eating patterns and physical activity. The main nutritional problem faced by Chilean society is overweight, which arises progressively from an early age. The aim of this study is to determine the nutritional status and compare fitness levels and fasting glucose in students. A descriptive cross-sectional comparative study was conducted, making a comparison by gender and nutritional status, with 100 students (56 men and 44 women) aged 12-15 years old. Body composition, fasting glucose and fitness were evaluated. Women had a higher prevalence of overweight and obesity than men (22.73% and 19.65%). In the comparison of gender differences statistics were reported in one repetition maximum (1RM) (p = 0.001), abdominal strength (p = 0.004) and velocity (p = 0.001), there were no significant differences in body mass index (BMI) (p = 0.24) and fasting glucose (p = 0.99). In the comparison of nutritional status, the students classified as obese had a higher waist perimeter (p = 0.001), more time to walk 400 m (p = 0.008). There were no significant differences in other variables. Women have a higher prevalence of overweight and obesity than men. Obese students have a waist circumference more elevated, more time to walk 400 meters (p = <0.05) and they have increased levels of basal glucose. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.