Sample records for affect glucose homeostasis

  1. Association of SSTR2 Polymorphisms and Glucose Homeostasis Phenotypes

    PubMed Central

    Sutton, Beth S.; Palmer, Nicholette D.; Langefeld, Carl D.; Xue, Bingzhong; Proctor, Alexandria; Ziegler, Julie T.; Haffner, Steven M.; Norris, Jill M.; Bowden, Donald W.

    2009-01-01

    OBJECTIVE This study evaluated the influence of somatostatin receptor type 2 (SSTR2) polymorphisms on measures of glucose homeostasis in the Insulin Resistance Atherosclerosis Family Study (IRASFS). SSTR2 is a G-protein–coupled receptor that, in response to somatostatin, mediates inhibition of insulin, glucagon, and growth hormone release and thus may affect glucose homeostasis. RESEARCH DESIGN AND METHODS Ten single nucleotide polymorphisms (SNPs) spanning the gene were chosen using a SNP density selection algorithm and genotyped on 1,425 Hispanic-American individuals from 90 families in the IRASFS. These families comprised two samples (set 1 and set 2), which were analyzed individually and as a combined set. Single SNP tests of association were performed for four glucose homeostasis measures—insulin sensitivity (SI), acute insulin response (AIR), disposition index (DI), and fasting blood glucose (FBG)—using generalized estimating equations. RESULTS The SSTR2 locus was encompassed by a single linkage disequilibrium (LD) block (D′ = 0.91–1.00; r2 = 0.09–0.97) that contained four of the ten SNPs evaluated. Within the SSTR2-containing LD block, evidence of association was observed in each of the two sets and in a combined analysis with decreased SI(βhomozygous = −0.16; Pmeta-analysis = 0.0024–0.0030), decreased DI (βhomozygous = −0.35 to −5.16; Pmeta-analysis = 0.0075–0.027), and increased FBG (βhomozygous = 2.30; Pmeta-analysis = 0.045). SNPs outside the SSTR2-containing LD block were not associated with measures of glucose homeostasis. CONCLUSIONS We observed evidence for association of SSTR2 polymorphisms with measures of glucose homeostasis. Thus, variants in SSTR2 may influence pathways of SIto modulate glucose homeostasis. PMID:19324939

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

    NASA Astrophysics Data System (ADS)

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

    2015-06-01

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

  3. Neonatal hypothyroidism affects testicular glucose homeostasis through increased oxidative stress in prepubertal mice: effects on GLUT3, GLUT8 and Cx43.

    PubMed

    Sarkar, D; Singh, S K

    2017-07-01

    Thyroid hormones (THs) play an important role in maintaining the link between metabolism and reproduction and the altered THs status is associated with induction of oxidative stress in various organs like brain, heart, liver and testis. Further, reactive oxygen species play a pivotal role in regulation of glucose homeostasis in several organs, and glucose utilization by Leydig cells is essential for testosterone biosynthesis and thus is largely dependent on glucose transporter 8 (GLUT8). Glucose uptake by Sertoli cells is mediated through glucose transporter 3 (GLUT3) under the influence of THs to meet energy requirement of developing germ cells. THs also modulate level of gap junctional protein such as connexin 43 (Cx43), a potential regulator of cell proliferation and apoptosis in the seminiferous epithelium. Although the role of transient neonatal hypothyroidism in adult testis in terms of testosterone production is well documented, the effect of THs deficiency in early developmental period and its role in testicular glucose homeostasis and oxidative stress with reference to Cx43 in immature mice remain unknown. Therefore, the present study was conducted to evaluate the effect of neonatal hypothyroidism on testicular glucose homeostasis and oxidative stress at postnatal days (PND) 21 and 28 in relation to GLUT3, GLUT8 and Cx43. Hypothyroidism induced by 6-propyl-2-thiouracil (PTU) markedly decreased testicular glucose level with considerable reduction in expression level of GLUT3 and GLUT8. Likewise, lactate dehydrogenase (LDH) activity and intratesticular concentration of lactate were also decreased in hypothyroid mice. There was also a rise in germ cell apoptosis with increased expression of caspase-3 in PTU-treated mice. Further, neonatal hypothyroidism affected germ cell proliferation with decreased expression of proliferating cell nuclear antigen (PCNA) and Cx43. In conclusion, our results suggest that neonatal hypothyroidism alters testicular glucose

  4. Proposed mechanisms of the effects of proanthocyanidins on glucose homeostasis.

    PubMed

    Yang, Kaiyuan; Chan, Catherine B

    2017-08-01

    Proanthocyanidins are a major group of flavonoids in the human diet, known for their strong antioxidant properties. Emerging evidence from clinical studies indicates a role of proanthocyanidins in modulating glucose homeostasis, and higher proanthocyanidin intake has been associated with reduced risk of diabetes. On the other hand, recent studies report limited bioavailability of proanthocyanidins. At relatively low concentrations in the systemic circulation, proanthocyanidins may act as cell-signaling molecules to modulate glucose homeostasis. For example, they affect hepatic glucose production via adenosine monophosphate-activated protein kinase and/or insulin-signaling pathways. There is also evidence for a direct role of proanthocyanidins in modulating several pancreatic β-cell functions: prevention of oxidative stress, enhancement of insulin secretion, and promotion of β-cell survival. Therefore, greater understanding of the potentially beneficial effects of proanthocyanidins on cell-signaling pathways implicated in glucose homeostasis is needed. In addition, further investigation to address the in vivo metabolism of proanthocyanidins and the comparative effectiveness of proanthocyanidin-derived metabolites is warranted. The dosage and the experimental model should be given special attention when results from mechanistic studies using proanthocyanidins are interpreted. © The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-12-01

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

  7. Impact of intermittent fasting on glucose homeostasis.

    PubMed

    Varady, Krista A

    2016-07-01

    This article provides an overview of the most recent human trials that have examined the impact of intermittent fasting on glucose homeostasis. Our literature search retrieved one human trial of alternate day fasting, and three trials of Ramadan fasting published in the past 12 months. Current evidence suggests that 8 weeks of alternate day fasting that produces mild weight loss (4% from baseline) has no effect on glucose homeostasis. As for Ramadan fasting, decreases in fasting glucose, insulin, and insulin resistance have been noted after 4 weeks in healthy normal weight individuals with mild weight loss (1-2% from baseline). However, Ramadan fasting may have little impact on glucoregulatory parameters in women with polycystic ovarian syndrome who failed to observe weight loss. Whether intermittent fasting is an effective means of regulating glucose homeostasis remains unclear because of the scarcity of studies in this area. Large-scale, longer-term randomized controlled trials will be required before the use of fasting can be recommended for the prevention and treatment of metabolic diseases.

  8. Anchored phosphatases modulate glucose homeostasis

    PubMed Central

    Hinke, Simon A; Navedo, Manuel F; Ulman, Allison; Whiting, Jennifer L; Nygren, Patrick J; Tian, Geng; Jimenez-Caliani, Antonio J; Langeberg, Lorene K; Cirulli, Vincenzo; Tengholm, Anders; Dell'Acqua, Mark L; Santana, L Fernando; Scott, John D

    2012-01-01

    Endocrine release of insulin principally controls glucose homeostasis. Nutrient-induced exocytosis of insulin granules from pancreatic β-cells involves ion channels and mobilization of Ca2+ and cyclic AMP (cAMP) signalling pathways. Whole-animal physiology, islet studies and live-β-cell imaging approaches reveal that ablation of the kinase/phosphatase anchoring protein AKAP150 impairs insulin secretion in mice. Loss of AKAP150 impacts L-type Ca2+ currents, and attenuates cytoplasmic accumulation of Ca2+ and cAMP in β-cells. Yet surprisingly AKAP150 null animals display improved glucose handling and heightened insulin sensitivity in skeletal muscle. More refined analyses of AKAP150 knock-in mice unable to anchor protein kinase A or protein phosphatase 2B uncover an unexpected observation that tethering of phosphatases to a seven-residue sequence of the anchoring protein is the predominant molecular event underlying these metabolic phenotypes. Thus anchored signalling events that facilitate insulin secretion and glucose homeostasis may be set by AKAP150 associated phosphatase activity. PMID:22940692

  9. Sleep duration and sleep quality are associated differently with alterations of glucose homeostasis.

    PubMed

    Byberg, S; Hansen, A-L S; Christensen, D L; Vistisen, D; Aadahl, M; Linneberg, A; Witte, D R

    2012-09-01

    Studies suggest that inadequate sleep duration and poor sleep quality increase the risk of impaired glucose regulation and diabetes. However, associations with specific markers of glucose homeostasis are less well explained. The objective of this study was to explore possible associations of sleep duration and sleep quality with markers of glucose homeostasis and glucose tolerance status in a healthy population-based study sample. The study comprised 771 participants from the Danish, population-based cross-sectional 'Health2008' study. Sleep duration and sleep quality were measured by self-report. Markers of glucose homeostasis were derived from a 3-point oral glucose tolerance test and included fasting plasma glucose, 2-h plasma glucose, HbA(1c), two measures of insulin sensitivity (the insulin sensitivity index(0,120) and homeostasis model assessment of insulin sensitivity), the homeostasis model assessment of β-cell function and glucose tolerance status. Associations of sleep duration and sleep quality with markers of glucose homeostasis and tolerance were analysed by multiple linear and logistic regression. A 1-h increment in sleep duration was associated with a 0.3 mmol/mol (0.3%) decrement in HbA(1c) and a 25% reduction in the risk of having impaired glucose regulation. Further, a 1-point increment in sleep quality was associated with a 2% increase in both the insulin sensitivity index(0,120) and homeostasis model assessment of insulin sensitivity, as well as a 1% decrease in homeostasis model assessment of β-cell function. In the present study, shorter sleep duration was mainly associated with later alterations in glucose homeostasis, whereas poorer sleep quality was mainly associated with earlier alterations in glucose homeostasis. Thus, adopting healthy sleep habits may benefit glucose metabolism in healthy populations. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  10. Brain glucose sensing, counterregulation, and energy homeostasis.

    PubMed

    Marty, Nell; Dallaporta, Michel; Thorens, Bernard

    2007-08-01

    Neuronal circuits in the central nervous system play a critical role in orchestrating the control of glucose and energy homeostasis. Glucose, beside being a nutrient, is also a signal detected by several glucose-sensing units that are located at different anatomical sites and converge to the hypothalamus to cooperate with leptin and insulin in controlling the melanocortin pathway.

  11. CD14 Deficiency Impacts Glucose Homeostasis in Mice through Altered Adrenal Tone

    PubMed Central

    Young, James L.; Mora, Alfonso; Cerny, Anna; Czech, Michael P.; Woda, Bruce; Kurt-Jones, Evelyn A.; Finberg, Robert W.; Corvera, Silvia

    2012-01-01

    The toll-like receptors comprise one of the most conserved components of the innate immune system, signaling the presence of molecules of microbial origin. It has been proposed that signaling through TLR4, which requires CD14 to recognize bacterial lipopolysaccharide (LPS), may generate low-grade inflammation and thereby affect insulin sensitivity and glucose metabolism. To examine the long-term influence of partial innate immune signaling disruption on glucose homeostasis, we analyzed knockout mice deficient in CD14 backcrossed into the diabetes-prone C57BL6 background at 6 or 12 months of age. CD14-ko mice, fed either normal or high-fat diets, displayed significant glucose intolerance compared to wild type controls. They also displayed elevated norepinephrine urinary excretion and increased adrenal medullary volume, as well as an enhanced norepinephrine secretory response to insulin-induced hypoglycemia. These results point out a previously unappreciated crosstalk between innate immune- and sympathoadrenal- systems, which exerts a major long-term effect on glucose homeostasis. PMID:22253759

  12. Genetically determined schizophrenia is not associated with impaired glucose homeostasis.

    PubMed

    Polimanti, Renato; Gelernter, Joel; Stein, Dan J

    2018-05-01

    Here, we used data from large genome-wide association studies to test the presence of causal relationships, conducting a Mendelian randomization analysis; and shared molecular mechanisms, calculating the genetic correlation, among schizophrenia, type 2 diabetes (T2D), and impaired glucose homeostasis. Although our Mendelian randomization analysis was well-powered, no causal relationship was observed between schizophrenia and T2D, or traits related to glucose impaired homeostasis. Similarly, we did not observe any global genetic overlap among these traits. These findings indicate that there is no causal relationships or shared mechanisms between schizophrenia and impaired glucose homeostasis. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. 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.

  14. Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus.

    PubMed

    Pal, M; Gupta, S

    2016-12-12

    Clinical studies have revealed that testosterone supplementation had a positive effect on glucose homeostasis in type 2 diabetes mellitus (T2DM), but did not address how testosterone supplementation affected insulin responsiveness in the liver, a key glucose homeostatic organ. In this study, we aimed to study the effect of testosterone supplementation on hepatic insulin responsiveness and glucose homeostasis through liver in male high-fat diet-induced T2DM mice. Testosterone treatment to T2DM animals showed reduced hepatic glucose output. Testosterone inhibited the insulin signaling in liver, thus increased insulin resistance. However, testosterone treatment inactivated GSK3α independent of PI3K/AKT pathway and inhibited FOXO1 By interaction of androgen receptor to FOXO1 and downregulated PEPCK, causing repression of gluconeogenic pathway, which is otherwise upregulated in T2DM, resulted in better glucose homeostasis.

  15. Glucose Homeostasis and Effect of Chelation on β Cell Function in Children With β-Thalassemia Major.

    PubMed

    Gomber, Sunil; Dabas, Aashima; Bagmar, Shilpa; Madhu, Sri Venkata

    2018-01-01

    To assess the prevalence of impaired glucose tolerance in β-thalassemia major and correlate it with chelation therapy. Sixty-seven subjects with β-thalassemia major, aged 1 to 20 years, were enrolled in our prospective cohort. Clinical details were recorded. Baseline oral glucose tolerance test, serum insulin, C peptide, and insulin resistance were measured. The biochemical profile was repeated after 6 months. The mean age of subjects was 7.43±4.48 years. Eight (11.9%) subjects had impaired fasting glucose, 7 (10.4%) had impaired glucose tolerance, and 1 (1.4%) subject had diabetes at baseline. Subjects with abnormal glucose profile had longer disease duration (95% confidence interval [CI] of difference=-6.64 to -0.68; P=0.019) and higher fasting blood glucose (95% CI of difference=-32.1 to -10.5; P=0.001) and serum ferritin (95% CI of difference=-219.8 to -3.4; P=0.001) than normoglycemic subjects. Insulin resistance and serum ferritin showed significant increase at 6 months (P<0.001 and P=0.001, respectively). Patients on deferiprone alone significantly improved glucose homeostasis on follow-up than those on desferrioxamine or combination therapy of desferrioxamine and deferiprone (P<0.05). Prolonged disease duration and higher serum ferritin adversely affects glucose homeostasis in thalassemic children. Deferiprone was the most effective chelator to improve glucose homeostasis in chronically transfused thalassemics.

  16. Dietary fructose and glucose differentially affect lipid and glucose homeostasis.

    PubMed

    Schaefer, Ernst J; Gleason, Joi A; Dansinger, Michael L

    2009-06-01

    Absorbed glucose and fructose differ in that glucose largely escapes first-pass removal by the liver, whereas fructose does not, resulting in different metabolic effects of these 2 monosaccharides. In short-term controlled feeding studies, dietary fructose significantly increases postprandial triglyceride (TG) levels and has little effect on serum glucose concentrations, whereas dietary glucose has the opposite effects. When dietary glucose and fructose have been directly compared at approximately 20-25% of energy over a 4- to 6-wk period, dietary fructose caused significant increases in fasting TG and LDL cholesterol concentrations, whereas dietary glucose did not, but dietary glucose did increase serum glucose and insulin concentrations in the postprandial state whereas dietary fructose did not. When fructose at 30-60 g ( approximately 4-12% of energy) was added to the diet in the free-living state, there were no significant effects on lipid or glucose biomarkers. Sucrose and high-fructose corn syrup (HFCS) contain approximately equal amounts of fructose and glucose and no metabolic differences between them have been noted. Controlled feeding studies at more physiologic dietary intakes of fructose and glucose need to be conducted. In our view, to decrease the current high prevalence of obesity, dyslipidemia, insulin resistance, and diabetes, the focus should be on restricting the intake of excess energy, sucrose, HFCS, and animal and trans fats and increasing exercise and the intake of vegetables, vegetable oils, fish, fruit, whole grains, and fiber.

  17. CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis.

    PubMed

    Kim, Hyunbae; Zheng, Ze; Walker, Paul D; Kapatos, Gregory; Zhang, Kezhong

    2017-07-15

    Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock. Functionally, CREBH is required in order to maintain circadian homeostasis of hepatic glycogen storage and blood glucose levels. CREBH regulates the rhythmic expression of the genes encoding the rate-limiting enzymes for glycogenolysis and gluconeogenesis, including liver glycogen phosphorylase (PYGL), phosphoenolpyruvate carboxykinase 1 (PCK1), and the glucose-6-phosphatase catalytic subunit (G6PC). CREBH interacts with peroxisome proliferator-activated receptor α (PPARα) to synergize its transcriptional activities in hepatic gluconeogenesis. The acetylation of CREBH at lysine residue 294 controls CREBH-PPARα interaction and synergy in regulating hepatic glucose metabolism in mice. CREBH deficiency leads to reduced blood glucose levels but increases hepatic glycogen levels during the daytime or upon fasting. In summary, our studies revealed that CREBH functions as a key metabolic regulator that controls glucose homeostasis across the circadian cycle or under metabolic stress. Copyright © 2017 American Society for Microbiology.

  18. CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis

    PubMed Central

    Kim, Hyunbae; Zheng, Ze; Walker, Paul D.; Kapatos, Gregory

    2017-01-01

    ABSTRACT Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock. Functionally, CREBH is required in order to maintain circadian homeostasis of hepatic glycogen storage and blood glucose levels. CREBH regulates the rhythmic expression of the genes encoding the rate-limiting enzymes for glycogenolysis and gluconeogenesis, including liver glycogen phosphorylase (PYGL), phosphoenolpyruvate carboxykinase 1 (PCK1), and the glucose-6-phosphatase catalytic subunit (G6PC). CREBH interacts with peroxisome proliferator-activated receptor α (PPARα) to synergize its transcriptional activities in hepatic gluconeogenesis. The acetylation of CREBH at lysine residue 294 controls CREBH-PPARα interaction and synergy in regulating hepatic glucose metabolism in mice. CREBH deficiency leads to reduced blood glucose levels but increases hepatic glycogen levels during the daytime or upon fasting. In summary, our studies revealed that CREBH functions as a key metabolic regulator that controls glucose homeostasis across the circadian cycle or under metabolic stress. PMID:28461393

  19. Cooperation between brain and islet in glucose homeostasis and diabetes

    PubMed Central

    Schwartz, Michael W.; Seeley, Randy J.; Tschöp, Matthias H.; Woods, Stephen C.; Morton, Gregory J.; Myers, Martin G.; D'Alessio, David

    2014-01-01

    Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as ‘glucose effectiveness’, account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not. PMID:24201279

  20. Sleep Architecture and Glucose and Insulin Homeostasis in Obese Adolescents

    PubMed Central

    Koren, Dorit; Levitt Katz, Lorraine E.; Brar, Preneet C.; Gallagher, Paul R.; Berkowitz, Robert I.; Brooks, Lee J.

    2011-01-01

    OBJECTIVE Sleep deprivation is associated with increased risk of adult type 2 diabetes mellitus (T2DM). It is uncertain whether sleep deprivation and/or altered sleep architecture affects glycemic regulation or insulin sensitivity or secretion. We hypothesized that in obese adolescents, sleep disturbances would associate with altered glucose and insulin homeostasis. RESEARCH DESIGN AND METHODS This cross-sectional observational study of 62 obese adolescents took place at the Clinical and Translational Research Center and Sleep Laboratory in a tertiary care children’s hospital. Subjects underwent oral glucose tolerance test (OGTT), anthropometric measurements, overnight polysomnography, and frequently sampled intravenous glucose tolerance test (FSIGT). Hemoglobin A1c (HbA1c) and serial insulin and glucose levels were obtained, indices of insulin sensitivity and secretion were calculated, and sleep architecture was assessed. Correlation and regression analyses were performed to assess the association of total sleep and sleep stages with measures of insulin and glucose homeostasis, adjusted for confounding variables. RESULTS We found significant U-shaped (quadratic) associations between sleep duration and both HbA1c and serial glucose levels on OGTT and positive associations between slow-wave sleep (N3) duration and insulin secretory measures, independent of degree of obesity, pubertal stage, sex, and obstructive sleep apnea measures. CONCLUSIONS Insufficient and excessive sleep was associated with short-term and long-term hyperglycemia in our obese adolescents. Decreased N3 was associated with decreased insulin secretion. These effects may be related, with reduced insulin secretory capacity leading to hyperglycemia. We speculate that optimizing sleep may stave off the development of T2DM in obese adolescents. PMID:21933909

  1. A closed-loop multi-level model of glucose homeostasis

    PubMed Central

    Uluseker, Cansu; Simoni, Giulia; Dauriz, Marco; Matone, Alice

    2018-01-01

    Background The pathophysiologic processes underlying the regulation of glucose homeostasis are considerably complex at both cellular and systemic level. A comprehensive and structured specification for the several layers of abstraction of glucose metabolism is often elusive, an issue currently solvable with the hierarchical description provided by multi-level models. In this study we propose a multi-level closed-loop model of whole-body glucose homeostasis, coupled with the molecular specifications of the insulin signaling cascade in adipocytes, under the experimental conditions of normal glucose regulation and type 2 diabetes. Methodology/Principal findings The ordinary differential equations of the model, describing the dynamics of glucose and key regulatory hormones and their reciprocal interactions among gut, liver, muscle and adipose tissue, were designed for being embedded in a modular, hierarchical structure. The closed-loop model structure allowed self-sustained simulations to represent an ideal in silico subject that adjusts its own metabolism to the fasting and feeding states, depending on the hormonal context and invariant to circadian fluctuations. The cellular level of the model provided a seamless dynamic description of the molecular mechanisms downstream the insulin receptor in the adipocytes by accounting for variations in the surrounding metabolic context. Conclusions/Significance The combination of a multi-level and closed-loop modeling approach provided a fair dynamic description of the core determinants of glucose homeostasis at both cellular and systemic scales. This model architecture is intrinsically open to incorporate supplementary layers of specifications describing further individual components influencing glucose metabolism. PMID:29420588

  2. Central insulin and leptin-mediated autonomic control of glucose homeostasis

    PubMed Central

    Marino, Joseph S.; Xu, Yong; Hill, Jennifer W.

    2016-01-01

    Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis. PMID:21489811

  3. Glucocorticoid receptor polymorphism in obesity and glucose homeostasis.

    PubMed

    Majer-Łobodzińska, Agnieszka; Adamiec-Mroczek, Joanna

    2017-01-01

    Glucocorticoid receptor (GR) activity plays a significant role in the etiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia and subsequent increased fat deposition. Several polymorphisms in the GR gene have been described, and at least three of them seem to be associated with altered glucocorticoid sensitivity and changes in glucose homeostasis, and other metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to glucocorticoides, increased insulin response to dexamethasone and increased plasma glucose level. BclI polymorphism is associated with increased abdominal obesity, hyperinsulinaemia and increased insulin resistance. Another polymorphism, ER22/23EK, in contrast to the others, is associated with relative resistance to glucocoricides actions and more beneficial metabolic profile-lower insulin resistance level, decreased lower cardiovascular risk and subseuent prolongation of life time. More research is still needed to understand the mechanisms behind these associations at the molecular level.

  4. Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism

    PubMed Central

    König, Matthias; Bulik, Sascha; Holzhütter, Hermann-Georg

    2012-01-01

    Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases. PMID:22761565

  5. Central insulin and leptin-mediated autonomic control of glucose homeostasis.

    PubMed

    Marino, Joseph S; Xu, Yong; Hill, Jennifer W

    2011-07-01

    Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Rictor/mTORC2 facilitates central regulation of energy and glucose homeostasis.

    PubMed

    Kocalis, Heidi E; Hagan, Scott L; George, Leena; Turney, Maxine K; Siuta, Michael A; Laryea, Gloria N; Morris, Lindsey C; Muglia, Louis J; Printz, Richard L; Stanwood, Gregg D; Niswender, Kevin D

    2014-07-01

    Insulin signaling in the central nervous system (CNS) regulates energy balance and peripheral glucose homeostasis. Rictor is a key regulatory/structural subunit of the mTORC2 complex and is required for hydrophobic motif site phosphorylation of Akt at serine 473. To examine the contribution of neuronal Rictor/mTORC2 signaling to CNS regulation of energy and glucose homeostasis, we utilized Cre-LoxP technology to generate mice lacking Rictor in all neurons, or in either POMC or AgRP expressing neurons. Rictor deletion in all neurons led to increased fat mass and adiposity, glucose intolerance and behavioral leptin resistance. Disrupting Rictor in POMC neurons also caused obesity and hyperphagia, fasting hyperglycemia and pronounced glucose intolerance. AgRP neuron specific deletion did not impact energy balance but led to mild glucose intolerance. Collectively, we show that Rictor/mTORC2 signaling, especially in POMC-expressing neurons, is important for central regulation of energy and glucose homeostasis.

  7. Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.

    PubMed

    Li, Lei O; Grevengoed, Trisha J; Paul, David S; Ilkayeva, Olga; Koves, Timothy R; Pascual, Florencia; Newgard, Christopher B; Muoio, Deborah M; Coleman, Rosalind A

    2015-01-01

    The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-specific deficiency of long-chain acyl-CoA synthetase (ACSL)1. ACSL1 deficiency caused a 91% loss of ACSL-specific activity and a 60-85% decrease in muscle FA oxidation. Acsl1(M-/-) mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1(M-/-) mice ran only 48% as far as controls. At the time that Acsl1(M-/-) mice were exhausted but control mice continued to run, liver and muscle glycogen and triacylglycerol stores were similar in both genotypes; however, plasma glucose concentrations in Acsl1(M-/-) mice were ∼40 mg/dL, whereas glucose concentrations in controls were ∼90 mg/dL. Excess use of glucose and the likely use of amino acids for fuel within muscle depleted glucose reserves and diminished substrate availability for hepatic gluconeogenesis. Surprisingly, the content of muscle acyl-CoA at exhaustion was markedly elevated, indicating that acyl-CoAs synthesized by other ACSL isoforms were not available for β-oxidation. This compartmentalization of acyl-CoAs resulted in both an excessive glucose requirement and severely compromised systemic glucose homeostasis. © 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.

  8. [Glucose homeostasis and gut-brain connection].

    PubMed

    De Vadder, Filipe; Mithieux, Gilles

    2015-02-01

    Since the XIX(th) century, the brain has been known for its role in regulating food intake (via the control of hunger sensation) and glucose homeostasis. Further interest has come from the discovery of gut hormones, which established a clear link between the gut and the brain in regulating glucose and energy homeostasis. The brain has two particular structures, the hypothalamus and the brainstem, which are sensitive to information coming either from peripheral organs or from the gut (via circulating hormones or nutrients) about the nutritional status of the organism. However, the efforts for a better understanding of these mechanisms have allowed to unveil a new gut-brain neural axis as a key regulator of the metabolic status of the organism. Certain nutrients control the hypothalamic homeostatic function via this axis. In this review, we describe how the gut is connected to the brain via different neural pathways, and how the interplay between these two organs drives the energy balance. © 2015 médecine/sciences – Inserm.

  9. Glucose Homeostasis Variables in Pregnancy versus Maternal and Infant Body Composition

    PubMed Central

    Henriksson, Pontus; Löf, Marie; Forsum, Elisabet

    2015-01-01

    Intrauterine factors influence infant size and body composition but the mechanisms involved are to a large extent unknown. We studied relationships between the body composition of pregnant women and variables related to their glucose homeostasis, i.e., glucose, HOMA-IR (homeostasis model assessment-insulin resistance), hemoglobin A1c and IGFBP-1 (insulin-like growth factor binding protein-1), and related these variables to the body composition of their infants. Body composition of 209 women in gestational week 32 and of their healthy, singleton and full-term one-week-old infants was measured using air displacement plethysmography. Glucose homeostasis variables were assessed in gestational week 32. HOMA-IR was positively related to fat mass index and fat mass (r2 = 0.32, p < 0.001) of the women. Maternal glucose and HOMA-IR values were positively (p ≤ 0.006) associated, while IGFBP-1was negatively (p = 0.001) associated, with infant fat mass. HOMA-IR was positively associated with fat mass of daughters (p < 0.001), but not of sons (p = 0.65) (Sex-interaction: p = 0.042). In conclusion, glucose homeostasis variables of pregnant women are related to their own body composition and to that of their infants. The results suggest that a previously identified relationship between fat mass of mothers and daughters is mediated by maternal insulin resistance. PMID:26184296

  10. SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

    PubMed Central

    Fleet, Tiffany; Zhang, Bin; Lin, Fumin; Zhu, Bokai; Dasgupta, Subhamoy; Stashi, Erin; Tackett, Bryan; Thevananther, Sundararajah; Rajapakshe, Kimal I.; Gonzales, Naomi; Dean, Adam; Mao, Jianqiang; Timchenko, Nikolai; Malovannaya, Anna; Qin, Jun; Coarfa, Cristian; DeMayo, Francesco; Dacso, Clifford C.; Foulds, Charles E.; O’Malley, Bert W.; York, Brian

    2015-01-01

    Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation. PMID:26487680

  11. Regulation of Glucose Homeostasis by GLP-1

    PubMed Central

    Nadkarni, Prashant; Chepurny, Oleg G.; Holz, George G.

    2014-01-01

    Glucagon-like peptide-1(7–36)amide (GLP-1) is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV). Released GLP-1 activates enteric and autonomic reflexes while also circulating as an incretin hormone to control endocrine pancreas function. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM). These therapeutic agents include GLP-1R agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and langlenatide) and DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Investigational agents for use in the treatment of T2DM include GPR119 and GPR40 receptor agonists that stimulate the release of GLP-1 from L cells. Summarized here is the role of GLP-1 to control blood glucose homeo-stasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics. PMID:24373234

  12. Physiology and role of irisin in glucose homeostasis

    PubMed Central

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

    2018-01-01

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

  13. Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight

    PubMed Central

    Arble, Deanna M.; Chambers, Adam P.; Gutierrez-Aguilar, Ruth; He, Yanlin; Xu, Yong; Gardner, David; Moore, David D.; Seeley, Randy J.; Sandoval, Darleen A.

    2016-01-01

    Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis. Indeed, we found that small doses of active vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3) (calcitriol), into the third ventricle of the brain improved glucose tolerance and markedly increased hepatic insulin sensitivity, an effect that is dependent upon VDR within the paraventricular nucleus of the hypothalamus. In addition, chronic central administration of 1,25D3 dramatically decreased body weight by lowering food intake in obese rodents. Our data indicate that 1,25D3-mediated changes in food intake occur through action within the arcuate nucleus. We found that VDR colocalized with and activated key appetite-regulating neurons in the arcuate, namely proopiomelanocortin neurons. Together, these findings define a novel pathway for vitamin D regulation of metabolism with unique and divergent roles for central nervous system VDR signaling. Specifically, our data suggest that vitamin D regulates glucose homeostasis via the paraventricular nuclei and energy homeostasis via the arcuate nuclei. PMID:27217488

  14. Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight.

    PubMed

    Sisley, Stephanie R; Arble, Deanna M; Chambers, Adam P; Gutierrez-Aguilar, Ruth; He, Yanlin; Xu, Yong; Gardner, David; Moore, David D; Seeley, Randy J; Sandoval, Darleen A

    2016-09-01

    Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis. Indeed, we found that small doses of active vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3) (calcitriol), into the third ventricle of the brain improved glucose tolerance and markedly increased hepatic insulin sensitivity, an effect that is dependent upon VDR within the paraventricular nucleus of the hypothalamus. In addition, chronic central administration of 1,25D3 dramatically decreased body weight by lowering food intake in obese rodents. Our data indicate that 1,25D3-mediated changes in food intake occur through action within the arcuate nucleus. We found that VDR colocalized with and activated key appetite-regulating neurons in the arcuate, namely proopiomelanocortin neurons. Together, these findings define a novel pathway for vitamin D regulation of metabolism with unique and divergent roles for central nervous system VDR signaling. Specifically, our data suggest that vitamin D regulates glucose homeostasis via the paraventricular nuclei and energy homeostasis via the arcuate nuclei. © 2016 by the American Diabetes Association.

  15. p53-upregulated-modulator-of-apoptosis (PUMA) deficiency affects food intake but does not impact on body weight or glucose homeostasis in diet-induced obesity.

    PubMed Central

    Litwak, Sara A.; Loh, Kim; Stanley, William J.; Pappas, Evan G.; Wali, Jibran A.; Selck, Claudia; Strasser, Andreas; Thomas, Helen E.; Gurzov, Esteban N.

    2016-01-01

    BCL-2 proteins have been implicated in the control of glucose homeostasis and metabolism in different cell types. Thus, the aim of this study was to determine the role of the pro-apoptotic BH3-only protein, p53-upregulated-modulator-of-apoptosis (PUMA), in metabolic changes mediated by diet-induced obesity, using PUMA deficient mice. At 10 weeks of age, knockout and wild type mice either continued consuming a low fat chow diet (6% fat), or were fed with a high fat diet (23% fat) for 14–17 weeks. We measured body composition, glucose and insulin tolerance, insulin response in peripheral tissues, energy expenditure, oxygen consumption, and respiratory exchange ratio in vivo. All these parameters were indistinguishable between wild type and knockout mice on chow diet and were modified equally by diet-induced obesity. Interestingly, we observed decreased food intake and ambulatory capacity of PUMA knockout mice on high fat diet. This was associated with increased adipocyte size and fasted leptin concentration in the blood. Our findings suggest that although PUMA is dispensable for glucose homeostasis in lean and obese mice, it can affect leptin levels and food intake during obesity. PMID:27033313

  16. p53-upregulated-modulator-of-apoptosis (PUMA) deficiency affects food intake but does not impact on body weight or glucose homeostasis in diet-induced obesity.

    PubMed

    Litwak, Sara A; Loh, Kim; Stanley, William J; Pappas, Evan G; Wali, Jibran A; Selck, Claudia; Strasser, Andreas; Thomas, Helen E; Gurzov, Esteban N

    2016-04-01

    BCL-2 proteins have been implicated in the control of glucose homeostasis and metabolism in different cell types. Thus, the aim of this study was to determine the role of the pro-apoptotic BH3-only protein, p53-upregulated-modulator-of-apoptosis (PUMA), in metabolic changes mediated by diet-induced obesity, using PUMA deficient mice. At 10 weeks of age, knockout and wild type mice either continued consuming a low fat chow diet (6% fat), or were fed with a high fat diet (23% fat) for 14-17 weeks. We measured body composition, glucose and insulin tolerance, insulin response in peripheral tissues, energy expenditure, oxygen consumption, and respiratory exchange ratio in vivo. All these parameters were indistinguishable between wild type and knockout mice on chow diet and were modified equally by diet-induced obesity. Interestingly, we observed decreased food intake and ambulatory capacity of PUMA knockout mice on high fat diet. This was associated with increased adipocyte size and fasted leptin concentration in the blood. Our findings suggest that although PUMA is dispensable for glucose homeostasis in lean and obese mice, it can affect leptin levels and food intake during obesity.

  17. Gastrointestinal Transit Time, Glucose Homeostasis and Metabolic Health: Modulation by Dietary Fibers

    PubMed Central

    Müller, Mattea; Canfora, Emanuel E.; Blaak, Ellen E.

    2018-01-01

    Gastrointestinal transit time may be an important determinant of glucose homeostasis and metabolic health through effects on nutrient absorption and microbial composition, among other mechanisms. Modulation of gastrointestinal transit may be one of the mechanisms underlying the beneficial health effects of dietary fibers. These effects include improved glucose homeostasis and a reduced risk of developing metabolic diseases such as obesity and type 2 diabetes mellitus. In this review, we first discuss the regulation of gastric emptying rate, small intestinal transit and colonic transit as well as their relation to glucose homeostasis and metabolic health. Subsequently, we briefly address the reported health effects of different dietary fibers and discuss to what extent the fiber-induced health benefits may be mediated through modulation of gastrointestinal transit. PMID:29495569

  18. Astrocytes in the nucleus of the solitary tract are activated by low glucose or glucoprivation: evidence for glial involvement in glucose homeostasis.

    PubMed

    McDougal, David H; Hermann, Gerlinda E; Rogers, Richard C

    2013-01-01

    Glucose homeostasis is maintained through interplay between central and peripheral control mechanisms which are aimed at storing excess glucose following meals and mobilizing these same stores during periods of fasting. The nucleus of the solitary tract (NST) in the dorsal medulla has long been associated with the central detection of glucose availability and the control of glucose homeostasis. Recent evidence has emerged which supports the involvement of astrocytes in glucose homeostasis. The aim of the present study was to investigate whether NST-astrocytes respond to physiologically relevant decreases in glucose availability, in vitro, as well as to the presence of the glucoprivic compound 2-deoxy-D-Glucose. This report demonstrates that some NST-astrocytes are capable of responding to low glucose or glucoprivation by increasing cytoplasmic calcium; a change that reverses with restoration of normal glucose availability. While some NST-neurons also demonstrate an increase in calcium signaling during low glucose availability, this effect is smaller and somewhat delayed compared to those observed in adjacent astrocytes. TTX did not abolish these hypoglycemia mediated responses of astrocytes, suggesting that NST-astrocytes may be directly sensing low glucose levels as opposed to responding to neuronal detection of hypoglycemia. Thus, chemodetection of low glucose by NST-astrocytes may play an important role in the autonomic regulation of glucose homeostasis.

  19. CNS-targets in control of energy and glucose homeostasis.

    PubMed

    Kleinridders, André; Könner, A Christine; Brüning, Jens C

    2009-12-01

    The exceeding efforts in understanding the signals initiated by nutrients and hormones in the central nervous system (CNS) to regulate glucose and energy homeostasis have largely revolutionized our understanding of the neurocircuitry in control of peripheral metabolism. The ability of neurons to sense nutrients and hormones and to adopt a coordinated response to these signals is of crucial importance in controlling food intake, energy expenditure, glucose and lipid metabolism. Anatomical lesion experiments, pharmacological inhibition of signaling pathways, and, more recently, the analysis of conditional mouse mutants with modifications of hormone and nutrient signaling in defined neuronal populations have broadened our understanding of these complex neurocircuits. This review summarizes recent findings regarding the role of the CNS in sensing and transmitting nutritional and hormonal signals to control energy and glucose homeostasis and aims to define them as potential novel drug targets for the treatment of obesity and type 2 diabetes mellitus.

  20. Maintenance of Gastrointestinal Glucose Homeostasis by the Gut-Brain Axis.

    PubMed

    Chen, Xiyue; Eslamfam, Shabnam; Fang, Luoyun; Qiao, Shiyan; Ma, Xi

    2017-01-01

    Gastrointestinal homeostasis is a dynamic balance under the interaction between the host, GI tract, nutrition and energy metabolism. Glucose is the main energy source in living cells. Thus, glucose metabolic disorders can impair normal cellular function and endanger organisms' health. Diseases that are associated with glucose metabolic disorders such as obesity, diabetes, hypertension, and other metabolic syndromes are in fact life threatening. Digestive system is responsible for food digestion and nutrient absorption. It is also involved in neuronal, immune, and endocrine pathways. In addition, the gut microbiota plays an essential role in initiating signal transduction, and communication between the enteric and central nervous system. Gut-brain axis is composed of enteric neural system, central neural system, and all the efferent and afferent neurons that are involved in signal transduction between the brain and gut-brain. Gut-brain axis is influenced by the gut-microbiota as well as numerous neurotransmitters. Properly regulated gut-brain axis ensures normal digestion, absorption, energy production, and subsequently maintenance of glucose homeostasis. Understanding the underlying regulatory mechanisms of gut-brain axis involved in gluose homeostasis would enable us develop more efficient means of prevention and management of metabolic disease such as diabetic, obesity, and hypertension. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Setting sail for glucose homeostasis with the AKAP150-PP2B-anchor.

    PubMed

    Teo, Adrian Kee Keong; Kulkarni, Rohit N

    2012-10-17

    Glucose-stimulated insulin secretion, controlled by multiple protein phosphorylation events, is critical for the regulation of glucose homeostasis. Protein kinase A (PKA) is known to play a role in β cell physiology, but the role of its anchoring protein is not fully understood. Hinke et al (2012) illustrate the significance of A-kinase anchoring protein 150 in tethering protein phosphatase 2B to mediate nutrient-stimulated insulin secretion and thus modulate glucose homeostasis.

  2. Effects of celiac superior mesenteric ganglionectomy on glucose homeostasis and hormonal changes during oral glucose tolerance testing in rats.

    PubMed

    Kumakura, Atsushi; Shikuma, Junpei; Ogihara, Norikazu; Eiki, Jun-ichi; Kanazawa, Masao; Notoya, Yōko; Kikuchi, Masatoshi; Odawara, Masato

    2013-01-01

    The liver plays an important role in maintaining glucose homeostasis in the body. In the prandial state, some of the glucose which is absorbed by the gastrointestinal tract is converted into glycogen and stored in the liver. In contrast, the liver produces glucose by glycogenolysis and gluconeogenesis while fasting. Thus, the liver contributes to maintaining blood glucose level within normoglycemic range. Glycogenesis and glycogenolysis are regulated by various mechanisms including hormones, the sympathetic and parasympathetic nervous systems and the hepatic glucose content. In this study, we examined a rat model in which the celiac superior mesenteric ganglion (CSMG) was resected. We attempted to elucidate how the celiac sympathetic nervous system is involved in regulating glucose homeostasis by assessing the effects of CSMG resection on glucose excursion during an oral glucose tolerance test, and by examining hepatic glycogen content and hepatic glycogen phosphorylase (GP) activity. On the oral glucose tolerance test, CSMG-resected rats demonstrated improved glucose tolerance and significantly increased GP activity compared with sham-operated rats, whereas there were no significant differences in insulin, glucagon or catecholamine levels between the 2 groups. These results suggest that the celiac sympathetic nervous system is involved in regulating the rate of glycogen consumption through GP activity. In conclusion, the examined rat model showed that the celiac sympathetic nervous system regulates hepatic glucose metabolism in conjunction with vagal nerve innervations and is a critical component in the maintenance of blood glucose homeostasis.

  3. Influence of Amino Acids in Dairy Products on Glucose Homeostasis: The Clinical Evidence.

    PubMed

    Chartrand, Dominic; Da Silva, Marine S; Julien, Pierre; Rudkowska, Iwona

    2017-06-01

    Dairy products have been hypothesized to protect against type 2 diabetes because of their high content of whey proteins, rich in branched-chain amino acids (BCAAs) - leucine, isoleucine and valine - and lysine, which may decrease postprandial glucose responses and stimulate insulin secretion. Paradoxically, epidemiologic studies also show that higher levels of plasma BCAAs have been linked to insulin resistance and type 2 diabetes. Therefore, the objective was to review the recent clinical evidence concerning the intake of amino acids found in dairy proteins so as to determine their impact on glucose homeostasis in healthy persons and in those with prediabetes and type 2 diabetes. Clinical studies have reported that the major dairy amino acids, namely, leucine, isoleucine, glutamine, phenylalanine, proline and lysine, have beneficial effects on glucose homeostasis. Yet the reported doses of amino acids investigated are too elevated to be reached through adequate dairy product intake. The minor dairy amino acids, arginine and glycine, may improve glucose homeostasis by improving other risk factors for type 2 diabetes. Further, the combination of amino acids may also improve glucose-related outcomes, suggesting additive or synergistic effects. Nevertheless, additional long-term studies in individuals with prediabetes and type 2 diabetes are needed to ascertain the benefits for glucose homeostasis of amino acids found in dairy foods. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

  4. Preoperative octreotide therapy and surgery in acromegaly: associations between glucose homeostasis and treatment response.

    PubMed

    Helseth, R; Carlsen, S M; Bollerslev, J; Svartberg, J; Øksnes, M; Skeie, S; Fougner, S L

    2016-02-01

    In acromegaly, high GH/IGF-1 levels associate with abnormal glucose metabolism. Somatostatin analogs (SSAs) reduce GH and IGF-1 but inhibit insulin secretion. We studied glucose homeostasis in de novo patients with acromegaly and changes in glucose metabolism after treatment with SSA and surgery. In this post hoc analysis from a randomized controlled trial, 55 de novo patients with acromegaly, not using antidiabetic medication, were included. Before surgery, 26 patients received SSAs for 6 months. HbA1c, fasting glucose, and oral glucose tolerance test were performed at baseline, after SSA pretreatment and at 3 months postoperative. Area under curve of glucose (AUC-G) was calculated. Glucose homeostasis was compared to baseline levels of GH and IGF-1, change after SSA pretreatment, and remission both after SSA pretreatment and 3 months postoperative. In de novo patients, IGF-1/GH levels did not associate with baseline glucose parameters. After SSA pretreatment, changes in GH/IGF-1 correlated positively to change in HbA1c levels (both p < 0.03). HbA1c, fasting glucose, and AUC-G increased significantly during SSA pretreatment in patients not achieving hormonal control (all p < 0.05) but did not change significantly in patients with normalized hormone levels. At 3 months postoperative, HbA1c, fasting glucose, and AUC-G were significantly reduced in both cured and not cured patients (all p < 0.05). To conclude, in de novo patients with acromegaly, disease activity did not correlate with glucose homeostasis. Surgical treatment of acromegaly improved glucose metabolism in both cured and not cured patients, while SSA pretreatment led to deterioration in glucose homeostasis in patients not achieving biochemical control.

  5. Helicobacter pylori colonization ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism.

    PubMed

    Bassaganya-Riera, Josep; Dominguez-Bello, Maria Gloria; Kronsteiner, Barbara; Carbo, Adria; Lu, Pinyi; Viladomiu, Monica; Pedragosa, Mireia; Zhang, Xiaoying; Sobral, Bruno W; Mane, Shrinivasrao P; Mohapatra, Saroj K; Horne, William T; Guri, Amir J; Groeschl, Michael; Lopez-Velasco, Gabriela; Hontecillas, Raquel

    2012-01-01

    There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI) interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag(-) strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes. To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99-305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM) and increased adipose tissue regulatory T cells (Treg) cells. Gene expression analyses demonstrated upregulation of gastric PPAR γ-responsive genes (i.e., CD36 and FABP4) in H. pylori-infected mice. The loss of PPAR γ in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding. Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue.

  6. Mechanisms and significance of brain glucose signaling in energy balance, glucose homeostasis, and food-induced reward.

    PubMed

    Devarakonda, Kavya; Mobbs, Charles V

    2016-12-15

    The concept that hypothalamic glucose signaling plays an important role in regulating energy balance, e.g., as instantiated in the so-called "glucostat" hypothesis, is one of the oldest in the field of metabolism. However the mechanisms by which neurons in the hypothalamus sense glucose, and the function of glucose signaling in the brain, has been difficult to establish. Nevertheless recent studies probing mechanisms of glucose signaling have also strongly supported a role for glucose signaling in regulating energy balance, glucose homeostasis, and food-induced reward. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Upper intestinal lipids regulate energy and glucose homeostasis.

    PubMed

    Cheung, Grace W C; Kokorovic, Andrea; Lam, Tony K T

    2009-09-01

    Upon the entry of nutrients into the small intestine, nutrient sensing mechanisms are activated to allow the body to adapt appropriately to the incoming nutrients. To date, mounting evidence points to the existence of an upper intestinal lipid-induced gut-brain neuronal axis to regulate energy homeostasis. Moreover, a recent discovery has also revealed an upper intestinal lipid-induced gut-brain-liver neuronal axis involved in the regulation of glucose homeostasis. In this mini-review, we will focus on the mechanisms underlying the activation of these respective neuronal axes by upper intestinal lipids.

  8. 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

  9. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity.

    PubMed

    Shi, Xuemei; Chacko, Shaji; Li, Feng; Li, Depei; Burrin, Douglas; Chan, Lawrence; Guan, Xinfu

    2017-11-01

    Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo. We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp. We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neurons NTS enhanced whole-body insulin sensitivity as indicated by increased glucose infusion rate as well as augmented insulin-suppression of endogenous glucose production and gluconeogenesis. In contrast, insulin-stimulation of glucose disposal was not altered significantly. We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  10. Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions

    PubMed Central

    Pattar, Guruprasad R.; Tackett, Lixuan; Liu, Ping; Elmendorf, Jeffrey S.

    2008-01-01

    Since trivalent chromium (Cr3+) enhances glucose metabolism, interest in the use of Cr3+as a therapy for type 2 diabetes has grown in the mainstream medical community. Moreover, accumulating evidence suggests that Cr3+ may also benefit cardiovascular disease (CVD) and atypical depression. We have found that cholesterol, a lipid implicated in both CVD and neurodegenerative disorders, also influences cellular glucose uptake. A recent study in our laboratory shows that exposure of 3T3-L1 adipocytes to chromium picolinate (CrPic, 10 nM) induces a loss of plasma membrane cholesterol. Concomitantly, accumulation of intracellularly sequestered glucose transporter GLUT4 at the plasma membrane was dependent on the CrPic-induced cholesterol loss. Since CrPic supplementation has the greatest benefit on glucose metabolism in hyperglycemic insulin-resistant individuals, we asked here if the CrPic effect on cells was glucose-dependent. We found that GLUT4 redistribution in cells treated with CrPic occurs only in cells cultured under high glucose (25 mM) conditions that resemble the diabetic-state, and not in cells cultured under non-diabetic (5.5 mM glucose) conditions. Examination of the effect of CrPic on proteins involved in cholesterol homeostasis revealed that the activity of sterol regulatory element-binding protein (SREBP), a membrane-bound transcription factor ultimately responsible for controlling cellular cholesterol balance, was upregulated by CrPic. In addition, ABCA1, a major player in mediating cholesterol efflux was decreased, consistent with SREBP transcriptional repression of the ABCA1 gene. Although the exact mechanism of Cr3+-induced cholesterol loss remains to be determined, these cellular responses highlight a novel and significant effect of chromium on cholesterol homeostasis. Furthermore, these findings provide an important clue to our understanding of how chromium supplementation might benefit hypercholesterolemia-associated disorders. PMID:16870493

  11. Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions.

    PubMed

    Pattar, Guruprasad R; Tackett, Lixuan; Liu, Ping; Elmendorf, Jeffrey S

    2006-11-07

    Since trivalent chromium (Cr(3+)) enhances glucose metabolism, interest in the use of Cr(3+)as a therapy for type 2 diabetes has grown in the mainstream medical community. Moreover, accumulating evidence suggests that Cr(3+) may also benefit cardiovascular disease (CVD) and atypical depression. We have found that cholesterol, a lipid implicated in both CVD and neurodegenerative disorders, also influences cellular glucose uptake. A recent study in our laboratory shows that exposure of 3T3-L1 adipocytes to chromium picolinate (CrPic, 10 nM) induces a loss of plasma membrane cholesterol. Concomitantly, accumulation of intracellularly sequestered glucose transporter GLUT4 at the plasma membrane was dependent on the CrPic-induced cholesterol loss. Since CrPic supplementation has the greatest benefit on glucose metabolism in hyperglycemic insulin-resistant individuals, we asked here if the CrPic effect on cells was glucose-dependent. We found that GLUT4 redistribution in cells treated with CrPic occurs only in cells cultured under high glucose (25 mM) conditions that resemble the diabetic-state, and not in cells cultured under non-diabetic (5.5 mM glucose) conditions. Examination of the effect of CrPic on proteins involved in cholesterol homeostasis revealed that the activity of sterol regulatory element-binding protein (SREBP), a membrane-bound transcription factor ultimately responsible for controlling cellular cholesterol balance, was upregulated by CrPic. In addition, ABCA1, a major player in mediating cholesterol efflux was decreased, consistent with SREBP transcriptional repression of the ABCA1 gene. Although the exact mechanism of Cr(3+)-induced cholesterol loss remains to be determined, these cellular responses highlight a novel and significant effect of chromium on cholesterol homeostasis. Furthermore, these findings provide an important clue to our understanding of how chromium supplementation might benefit hypercholesterolemia-associated disorders.

  12. Helicobacter pylori Colonization Ameliorates Glucose Homeostasis in Mice through a PPAR γ-Dependent Mechanism

    PubMed Central

    Bassaganya-Riera, Josep; Dominguez-Bello, Maria Gloria; Kronsteiner, Barbara; Carbo, Adria; Lu, Pinyi; Viladomiu, Monica; Pedragosa, Mireia; Zhang, Xiaoying; Sobral, Bruno W.; Mane, Shrinivasrao P.; Mohapatra, Saroj K.; Horne, William T.; Guri, Amir J.; Groeschl, Michael; Lopez-Velasco, Gabriela; Hontecillas, Raquel

    2012-01-01

    Background There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI) interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag− strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes. Methodology/Principal Findings To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99–305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM) and increased adipose tissue regulatory T cells (Treg) cells. Gene expression analyses demonstrated upregulation of gastric PPAR γ-responsive genes (i.e., CD36 and FABP4) in H. pylori-infected mice. The loss of PPAR γ in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding. Conclusions/Significance Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue. PMID:23166823

  13. Gut-Brain Glucose Signaling in Energy Homeostasis.

    PubMed

    Soty, Maud; Gautier-Stein, Amandine; Rajas, Fabienne; Mithieux, Gilles

    2017-06-06

    Intestinal gluconeogenesis is a recently identified function influencing energy homeostasis. Intestinal gluconeogenesis induced by specific nutrients releases glucose, which is sensed by the nervous system surrounding the portal vein. This initiates a signal positively influencing parameters involved in glucose control and energy management controlled by the brain. This knowledge has extended our vision of the gut-brain axis, classically ascribed to gastrointestinal hormones. Our work raises several questions relating to the conditions under which intestinal gluconeogenesis proceeds and may provide its metabolic benefits. It also leads to questions on the advantage conferred by its conservation through a process of natural selection. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Physical activity, fitness, glucose homeostasis, and brain morphology in twins.

    PubMed

    Rottensteiner, Mirva; Leskinen, Tuija; Niskanen, Eini; Aaltonen, Sari; Mutikainen, Sara; Wikgren, Jan; Heikkilä, Kauko; Kovanen, Vuokko; Kainulainen, Heikki; Kaprio, Jaakko; Tarkka, Ina M; Kujala, Urho M

    2015-03-01

    The main aim of the present study (FITFATTWIN) was to investigate how physical activity level is associated with body composition, glucose homeostasis, and brain morphology in young adult male monozygotic twin pairs discordant for physical activity. From a population-based twin cohort, we systematically selected 10 young adult male monozygotic twin pairs (age range, 32-36 yr) discordant for leisure time physical activity during the past 3 yr. On the basis of interviews, we calculated a mean sum index for leisure time and commuting activity during the past 3 yr (3-yr LTMET index expressed as MET-hours per day). We conducted extensive measurements on body composition (including fat percentage measured by dual-energy x-ray absorptiometry), glucose homeostasis including homeostatic model assessment index and insulin sensitivity index (Matsuda index, calculated from glucose and insulin values from an oral glucose tolerance test), and whole brain magnetic resonance imaging for regional volumetric analyses. According to pairwise analysis, the active twins had lower body fat percentage (P = 0.029) and homeostatic model assessment index (P = 0.031) and higher Matsuda index (P = 0.021) compared with their inactive co-twins. Striatal and prefrontal cortex (subgyral and inferior frontal gyrus) brain gray matter volumes were larger in the nondominant hemisphere in active twins compared with those in inactive co-twins, with a statistical threshold of P < 0.001. Among healthy adult male twins in their mid-30s, a greater level of physical activity is associated with improved glucose homeostasis and modulation of striatum and prefrontal cortex gray matter volume, independent of genetic background. The findings may contribute to later reduced risk of type 2 diabetes and mobility limitations.

  15. Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice.

    PubMed

    Claret, Marc; Smith, Mark A; Knauf, Claude; Al-Qassab, Hind; Woods, Angela; Heslegrave, Amanda; Piipari, Kaisa; Emmanuel, Julian J; Colom, André; Valet, Philippe; Cani, Patrice D; Begum, Ghazala; White, Anne; Mucket, Phillip; Peters, Marco; Mizuno, Keiko; Batterham, Rachel L; Giese, K Peter; Ashworth, Alan; Burcelin, Remy; Ashford, Michael L; Carling, David; Withers, Dominic J

    2011-03-01

    AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase β (CaMKKβ) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. Mice lacking either Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. Deletion of Camkkβ in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons.

  16. Simultaneous coffee caffeine intake and sleep deprivation alter glucose homeostasis in Iranian men: a randomized crossover trial.

    PubMed

    Rasaei, Behrouz; Talib, Ruzita Abd; Noor, Mohd Ismail; Karandish, Majid; Karim, Norimah A

    2016-12-01

    Sleep deprivation and coffee caffeine consumption have been shown to affect glucose homeostasis separately, but the combined effects of these two variables are unknown. Forty-two healthy Iranian men, aged 20-40 years old, were assigned to three groups in a randomised crossover trial involving three treatments with two-week washout periods. Subjects were moderate coffee consumers (<=3 cups/day), and had a Pittsburgh Sleep Quality Index <=5. Each treatment involved three nights of deprived sleep (4 hrs. in bed) plus 3×150 cc/cup of boiled water (BW treatment), decaffeinated coffee (DC treatment, without sugar, 99.9% caffeine-free), and caffeinated coffee (CC treatment, without sugar, 65 mg caffeine/ cup). DC and CC treatments were blinded. At the end of each treatment, fasting serum glucose (using enzyme assays) and insulin (using electrochemiluminescence immunoassay) were measured and, again, two hours after an oral glucose tolerance test (OGTT). Insulin resistance was quantified with the homeostasis model. Repeated measures ANOVA indicated no significant difference between the treatments in fasting serum glucose (p=0.248) or insulin resistance (p=0.079). However, ANOVA demonstrated differences between treatments in fasting serum insulin (p=0.004) and glucose, as well as insulin after OGTT (p<0.001). Pairwise comparisons test (within subjects) showed that the CC treatment yielded higher serum glucose and insulin after OGTT (p<0.001), higher fasting serum insulin (p=0.001), and increased insulin resistance (p=0.039) as compared to the DC treatment. Thus caffeinated coffee was more adverse for glucose homeostasis compared to decaffeinated coffee in individuals who were simultaneously sleep deprived.

  17. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis.

    PubMed

    Berglund, Eric D; Liu, Chen; Sohn, Jong-Woo; Liu, Tiemin; Kim, Mi Hwa; Lee, Charlotte E; Vianna, Claudia R; Williams, Kevin W; Xu, Yong; Elmquist, Joel K

    2013-12-01

    Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.

  18. Childhood cardiorespiratory fitness, muscular fitness and adult measures of glucose homeostasis.

    PubMed

    Fraser, Brooklyn J; Blizzard, Leigh; Schmidt, Michael D; Juonala, Markus; Dwyer, Terence; Venn, Alison J; Magnussen, Costan G

    2018-02-14

    To assess whether childhood cardiorespiratory fitness (CRF) and muscular fitness phenotypes (strength, power, endurance) predict adult glucose homeostasis measures. Prospective longitudinal study. Study examining participants who had physical fitness measured in childhood (aged 7-15 years) and who attended follow-up clinics approximately 20 years later and provided a fasting blood sample which was tested for glucose and insulin. Physical fitness measurements included muscular strength (right and left grip, shoulder flexion, shoulder and leg extension), power (standing long jump distance) and endurance (number of push-ups in 30s), and CRF (1.6km run duration). In adulthood, fasting glucose and insulin levels were used to derive glucose homeostasis measures of insulin resistance (HOMA2-IR) and beta cell function (HOMA2-β). A standard deviation increase in childhood CRF or muscular strength (males) was associated with fasting glucose (CRF: β=-0.06mmol/L), fasting insulin (CRF: β=-0.73mU/L; strength: β=-0.40mU/L), HOMA2-IR (CRF: β=-0.06; strength: β=-0.05) and HOMA2-β (CRF: β=-3.06%; strength: β=-2.62%) in adulthood, independent of the alternative fitness phenotype (all p<0.01). Adjustment for childhood waist circumference reduced the effect by 17-35% for CRF and 0-15% for muscular strength (males) and statistical significance remained for all associations expect between CRF, fasting glucose and HOMA2-β (p>0.06). CRF and muscular fitness in childhood were inversely associated with measures of fasting insulin, insulin resistance and beta cell function in adulthood. Childhood CRF and muscular fitness could both be potential independent targets for strategies to help reduce the development of adverse glucose homeostasis. Copyright © 2018 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  19. Wired on sugar: the role of the CNS in the regulation of glucose homeostasis

    PubMed Central

    Grayson, Bernadette E.; Seeley, Randy J.; Sandoval, Darleen A.

    2014-01-01

    Obesity and type 2 diabetes mellitus (T2DM) — disorders of energy homeostasis and glucose homeostasis, respectively — are tightly linked and the incidences of both conditions are increasing in parallel. The CNS integrates information regarding peripheral nutrient and hormonal changes and processes this information to regulate energy homeostasis. Recent findings indicate that some of the neural circuits and mechanisms underlying energy balance are also essential for the regulation of glucose homeostasis. We propose that disruption of these overlapping pathways links the metabolic disturbances associated with obesity and T2DM. A better understanding of these converging mechanisms may lead to therapeutic strategies that target both T2DM and obesity. PMID:23232606

  20. Leptin Rapidly Improves Glucose Homeostasis in Obese Mice by Increasing Hypothalamic Insulin Sensitivity

    PubMed Central

    Koch, Christiane; Augustine, Rachael A.; Steger, Juliane; Ganjam, Goutham K.; Benzler, Jonas; Pracht, Corinna; Lowe, Chrishanthi; Schwartz, Michael W.; Shepherd, Peter R.; Anderson, Greg M.; Grattan, David R.; Tups, Alexander

    2013-01-01

    Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lepob/ob mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes. PMID:21123564

  1. Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity.

    PubMed

    Koch, Christiane; Augustine, Rachael A; Steger, Juliane; Ganjam, Goutham K; Benzler, Jonas; Pracht, Corinna; Lowe, Chrishanthi; Schwartz, Michael W; Shepherd, Peter R; Anderson, Greg M; Grattan, David R; Tups, Alexander

    2010-12-01

    Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lep(ob/ob) mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes.

  2. Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice

    PubMed Central

    Claret, Marc; Smith, Mark A.; Knauf, Claude; Al-Qassab, Hind; Woods, Angela; Heslegrave, Amanda; Piipari, Kaisa; Emmanuel, Julian J.; Colom, André; Valet, Philippe; Cani, Patrice D.; Begum, Ghazala; White, Anne; Mucket, Phillip; Peters, Marco; Mizuno, Keiko; Batterham, Rachel L.; Giese, K. Peter; Ashworth, Alan; Burcelin, Remy; Ashford, Michael L.; Carling, David; Withers, Dominic J.

    2011-01-01

    OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin–dependent protein kinase kinase β (CaMKKβ) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS Mice lacking either Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS Deletion of Camkkβ in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte–stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. PMID:21266325

  3. Role of Galectin-3 in Obesity and Impaired Glucose Homeostasis

    PubMed Central

    Menini, Stefano; Iacobini, Carla; Blasetti Fantauzzi, Claudia; Pesce, Carlo M.; Pugliese, Giuseppe

    2016-01-01

    Galectin-3 is an important modulator of several biological functions. It has been implicated in numerous disease conditions, particularly in the long-term complications of diabetes because of its ability to bind the advanced glycation/lipoxidation end products that accumulate in target organs and exert their toxic effects by triggering proinflammatory and prooxidant pathways. Recent evidence suggests that galectin-3 may also participate in the development of obesity and type 2 diabetes. It has been shown that galectin-3 levels are higher in obese and diabetic individuals and parallel deterioration of glucose homeostasis. Two studies in galectin-3 knockout mice fed a high-fat diet (HFD) have shown increased adiposity and adipose tissue and systemic inflammation associated with altered glucose homeostasis, suggesting that galectin-3 negatively modulates the responsiveness of innate and adaptive immunity to overnutrition. However, these studies have also shown that impaired glucose homeostasis occurs in galectin-3 knockout animals independently of obesity. Moreover, another study reported decreased weight and fat mass in HFD-fed galectin-3 knockout mice. In vitro, galectin-3 was found to stimulate differentiation of preadipocytes into mature adipocytes. Altogether, these data indicate that galectin-3 deserves further attention in order to clarify its role as a potential player and therapeutic target in obesity and type 2 diabetes. PMID:26770660

  4. Prion protein modulates glucose homeostasis by altering intracellular iron.

    PubMed

    Ashok, Ajay; Singh, Neena

    2018-04-26

    The prion protein (PrP C ), a mainly neuronal protein, is known to modulate glucose homeostasis in mouse models. We explored the underlying mechanism in mouse models and the human pancreatic β-cell line 1.1B4. We report expression of PrP C on mouse pancreatic β-cells, where it promoted uptake of iron through divalent-metal-transporters. Accordingly, pancreatic iron stores in PrP knockout mice (PrP -/- ) were significantly lower than wild type (PrP +/+ ) controls. Silencing of PrP C in 1.1B4 cells resulted in significant depletion of intracellular (IC) iron, and remarkably, upregulation of glucose transporter GLUT2 and insulin. Iron overloading, on the other hand, resulted in downregulation of GLUT2 and insulin in a PrP C -dependent manner. Similar observations were noted in the brain, liver, and neuroretina of iron overloaded PrP +/+ but not PrP -/- mice, indicating PrP C -mediated modulation of insulin and glucose homeostasis through iron. Peripheral challenge with glucose and insulin revealed blunting of the response in iron-overloaded PrP +/+ relative to PrP -/- mice, suggesting that PrP C -mediated modulation of IC iron influences both secretion and sensitivity of peripheral organs to insulin. These observations have implications for Alzheimer's disease and diabetic retinopathy, known complications of type-2-diabetes associated with brain and ocular iron-dyshomeostasis.

  5. Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

    PubMed Central

    Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Porter, Craig; Annamalai, Palam; Enerbäck, Sven; Lidell, Martin E.; Saraf, Manish K.; Labbe, Sebastien M.; Hurren, Nicholas M.; Yfanti, Christina; Chao, Tony; Andersen, Clark R.; Cesani, Fernando; Hawkins, Hal

    2014-01-01

    Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans. PMID:25056438

  6. Pancreatic regulation of glucose homeostasis

    PubMed Central

    Röder, Pia V; Wu, Bingbing; Liu, Yixian; Han, Weiping

    2016-01-01

    In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed. PMID:26964835

  7. Glucose Homeostasis During Short-term and Prolonged Exposure to High Altitudes

    PubMed Central

    Ader, Marilyn; Bergman, Richard N.

    2015-01-01

    Most of the literature related to high altitude medicine is devoted to the short-term effects of high-altitude exposure on human physiology. However, long-term effects of living at high altitudes may be more important in relation to human disease because more than 400 million people worldwide reside above 1500 m. Interestingly, individuals living at higher altitudes have a lower fasting glycemia and better glucose tolerance compared with those who live near sea level. There is also emerging evidence of the lower prevalence of both obesity and diabetes at higher altitudes. The mechanisms underlying improved glucose control at higher altitudes remain unclear. In this review, we present the most current evidence about glucose homeostasis in residents living above 1500 m and discuss possible mechanisms that could explain the lower fasting glycemia and lower prevalence of obesity and diabetes in this population. Understanding the mechanisms that regulate and maintain the lower fasting glycemia in individuals who live at higher altitudes could lead to new therapeutics for impaired glucose homeostasis. PMID:25675133

  8. Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis

    PubMed Central

    Tarussio, David; Metref, Salima; Seyer, Pascal; Mounien, Lourdes; Vallois, David; Magnan, Christophe; Foretz, Marc; Thorens, Bernard

    2013-01-01

    How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function. PMID:24334455

  9. NPY modulates PYY function in the regulation of energy balance and glucose homeostasis.

    PubMed

    Zhang, L; Nguyen, A D; Lee, I-C J; Yulyaningsih, E; Riepler, S J; Stehrer, B; Enriquez, R F; Lin, S; Shi, Y-C; Baldock, P A; Sainsbury, A; Herzog, H

    2012-08-01

    Both the neuronal-derived neuropeptide Y (NPY) and the gut hormone peptide YY (PYY) have been implicated in the regulation of energy balance and glucose homeostasis. However, despite similar affinities for the same Y receptors, the co-ordinated actions of these two peptides in energy and glucose homeostasis remain largely unknown. To investigate the mechanisms and possible interactions between PYY with NPY in the regulation of these processes, we utilized NPY/PYY single and double mutant mouse models and examined parameters of energy balance and glucose homeostasis. PYY(-/-) mice exhibited increased fasting-induced food intake, enhanced fasting and oral glucose-induced serum insulin levels, and an impaired insulin tolerance, - changes not observed in NPY(-/-) mice. Interestingly, whereas PYY deficiency-induced impairment in insulin tolerance remained in NPY(-/-) PYY(-/-) mice, effects of PYY deficiency on fasting-induced food intake and serum insulin concentrations at baseline and after the oral glucose bolus were absent in NPY(-/-) PYY(-/-) mice, suggesting that NPY signalling may be required for PYY's action on insulin secretion and fasting-induced hyperphagia. Moreover, NPY(-/-) PYY(-/-) , but not NPY(-/-) or PYY(-/-) mice had significantly decreased daily food intake, indicating interactive control by NPY and PYY on spontaneous food intake. Furthermore, both NPY(-/-) and PYY(-/-) mice showed significantly reduced respiratory exchange ratio during the light phase, with no additive effects observed in NPY(-/-) PYY(-/-) mice, indicating that NPY and PYY may regulate oxidative fuel selection via partly shared mechanisms. Overall, physical activity and energy expenditure, however, are not significantly altered by NPY and PYY single or double deficiencies. These findings show significant and diverse interactions between NPY and PYY signalling in the regulation of different aspects of energy balance and glucose homeostasis. © 2012 Blackwell Publishing Ltd.

  10. Molecular aspects of glucose homeostasis in skeletal muscle--A focus on the molecular mechanisms of insulin resistance.

    PubMed

    Carnagarin, Revathy; Dharmarajan, Arun M; Dass, Crispin R

    2015-12-05

    Among all the varied actions of insulin, regulation of glucose homeostasis is the most critical and intensively studied. With the availability of glucose from nutrient metabolism, insulin action in muscle results in increased glucose disposal via uptake from the circulation and storage of excess, thereby maintaining euglycemia. This major action of insulin is executed by redistribution of the glucose transporter protein, GLUT4 from intracellular storage sites to the plasma membrane and storage of glucose in the form of glycogen which also involves modulation of actin dynamics that govern trafficking of all the signal proteins of insulin signal transduction. The cellular mechanisms responsible for these trafficking events and the defects associated with insulin resistance are largely enigmatic, and this review provides a consolidated overview of the various molecular mechanisms involved in insulin-dependent glucose homeostasis in skeletal muscle, as insulin resistance at this major peripheral site impacts whole body glucose homeostasis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Bisphenol S exposure impairs glucose homeostasis in male zebrafish (Danio rerio).

    PubMed

    Zhao, Fei; Jiang, Guobin; Wei, Penghao; Wang, Hongfang; Ru, Shaoguo

    2018-01-01

    Bisphenol S (BPS) is a substitute of the plastic additive bisphenol A (BPA). Its concentrations detected in surface waters and urine samples are on the same order of magnitude as BPA. Human exposure to BPA has been implicated in the development of diabetes mellitus; however, whether BPS can disrupt glucose homeostasis and increase blood glucose concentration remains unclear. We extensively investigated the effects of environmentally relevant concentrations of BPS on glucose metabolism in male zebrafish (Danio rerio) and the underlying mechanisms of these effects. Male zebrafish were exposed to 1, 10, or 100μg/L of BPS for 28 d. Fasting blood glucose (FBG) levels, glycogen levels in the liver and muscle, and mRNA levels of key glucose metabolic enzymes and the activities of the encoded proteins in tissues were evaluated to assess the effect of BPS on glucose metabolism. Plasma insulin levels and expression of preproinsulin and glucagon genes in the visceral tissue were also evaluated. Compared with the control group, exposure to 1 and 10μg/L of BPS significantly increased FBG levels but decreased insulin levels. Gluconeogenesis and glycogenolysis in the liver were promoted, and glycogen synthesis in the liver and muscle and glycolysis in the muscle were inhibited. Exposure to 100μg/L of BPS did not significantly alter plasma insulin and blood glucose levels, but nonetheless pronouncedly interfered with gluconeogenesis, glycogenolysis, glycolysis, and glycogen synthesis. Our data indicates that BPS at environmentally relevant concentrations impairs glucose homeostasis of male zebrafish possibly by hampering the physiological effect of insulin; higher BPS doses also pronouncedly interfered with glucose metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Central insulin action in energy and glucose homeostasis.

    PubMed

    Plum, Leona; Belgardt, Bengt F; Brüning, Jens C

    2006-07-01

    Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. An evolving body of evidence indicates that in the brain, insulin is involved in multiple regulatory mechanisms including neuronal survival, learning, and memory, as well as in regulation of energy homeostasis and reproductive endocrinology. Here we review insulin's role as a central homeostatic signal with regard to energy and glucose homeostasis and discuss the mechanisms by which insulin communicates information about the body's energy status to the brain. Particular emphasis is placed on the controversial current debate about the similarities and differences between hypothalamic insulin and leptin signaling at the molecular level.

  13. Effects of Taurine Supplementation on Neuronal Excitability and Glucose Homeostasis.

    PubMed

    El Idrissi, Abdeslem; El Hilali, Fatiha; Rotondo, Salvatore; Sidime, Francoise

    2017-01-01

    In this study we examined the role of chronic taurine supplementation on plasma glucose homeostasis and brain excitability through activation of the insulin receptor. FVB/NJ male mice were supplemented with taurine in drinking water (0.05% w/v) for 4 weeks and subjected to a glucose tolerance test (7.5 mg/kg BW) after 12 h fasting. We found that taurine-fed mice were slightly hypoglycemic prior to glucose injection and showed significantly reduced plasma glucose at 30 and 60 min post-glucose injection when compared to control mice. Previously, we reported that taurine supplementation induces biochemical changes that target the GABAergic system. Those studies show that taurine-fed mice are hyperexcitable, have reduced GABA A receptors expression and increased GAD and somatostatin expression in the brain. In this study, we found that taurine-fed mice had a significant increase in insulin receptor (IR) immuno-reactivity in the pancreas and all brain regions examined. At the mRNA level, we found that the IR showed differential regional expression. Surprisingly, we found that neurons express the gene for insulin and that taurine had a significant role in regulating insulin gene expression. We propose that increased insulin production and secretion in taurine-fed mice cause an increase activation of the central IR and may be partially responsible for the increased neuronal excitability observed in taurine supplemented mice. Furthermore, the high levels of neuronal insulin expression and its regulation by taurine implicates taurine in the regulation of metabolic homeostasis.

  14. Central Effects of Leptin on Glucose Homeostasis are Modified during Pregnancy in the Rat.

    PubMed

    Ladyman, S R; Grattan, D R

    2016-10-01

    Despite increased leptin concentrations during pregnancy, fat mass and food intake are increased. The satiety response to central leptin is suppressed, indicating a state of leptin insensitivity in the hypothalamus. Although the regulation of food intake is a major function of leptin, this hormone also influences a wide range of functions within the body. These actions include the regulation of glucose homeostasis, which undergoes major adaptation in the maternal body to generate optimal conditions for foetal development and growth. The present study aimed to investigate the effects of central leptin treatment on glucose homeostasis in pregnant rats to determine whether pregnancy-induced leptin insensitivity is functionally specific, and to further investigate changes in glucose homeostasis during pregnancy. After an overnight fast, nonpregnant and day 14 pregnant rats received an i.c.v. injection of leptin (100 ng or 4 μg) or vehicle then underwent a glucose tolerance test (GTT). Further groups of nonpregnant and day 14 pregnant rats were killed 30 min after leptin (doses ranging from 40 ng-4 μg) or vehicle i.c.v. injections for western blot analysis of phospho-signal transducer and activator of transcription 3 (STAT3) and phospho-Akt in various hypothalamic nuclei. Central leptin injection prior to a GTT lead to lowered basal insulin concentrations and impaired glucose tolerance in nonpregnant female rats, whereas the same doses of leptin had no significant effect on glucose tolerance in day 14 pregnant rats, indicating that, similar to the satiety actions of leptin, the effects of leptin on glucose homeostasis are suppressed during pregnancy. Furthermore, in the arcuate nucleus and ventromedial and dorsomedial nuclei of the hypothalamus, comprising three leptin-sensitive areas, there was no evidence that leptin induced Akt phosphorylation despite significant increases in phospho-STAT3, suggesting that leptin does not act through phospho-Akt in these areas

  15. Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis.

    PubMed

    Lansey, Melissa N; Walker, Natalie N; Hargett, Stefan R; Stevens, Joseph R; Keller, Susanna R

    2012-11-15

    Tight control of glucose uptake in skeletal muscles and adipocytes is crucial to glucose homeostasis and is mediated by regulating glucose transporter GLUT4 subcellular distribution. In cultured cells, Rab GAP AS160 controls GLUT4 intracellular retention and release to the cell surface and consequently regulates glucose uptake into cells. To determine AS160 function in GLUT4 trafficking in primary skeletal muscles and adipocytes and investigate its role in glucose homeostasis, we characterized AS160 knockout (AS160(-/-)) mice. We observed increased and normal basal glucose uptake in isolated AS160(-/-) adipocytes and soleus, respectively, while insulin-stimulated glucose uptake was impaired and GLUT4 expression decreased in both. No such abnormalities were found in isolated AS160(-/-) extensor digitorum longus muscles. In plasma membranes isolated from AS160(-/-) adipose tissue and gastrocnemius/quadriceps, relative GLUT4 levels were increased under basal conditions and remained the same after insulin treatment. Concomitantly, relative levels of cell surface-exposed GLUT4, determined with a glucose transporter photoaffinity label, were increased in AS160(-/-) adipocytes and normal in AS160(-/-) soleus under basal conditions. Insulin augmented cell surface-exposed GLUT4 in both. These observations suggest that AS160 is essential for GLUT4 intracellular retention and regulation of glucose uptake in adipocytes and skeletal muscles in which it is normally expressed. In vivo studies revealed impaired insulin tolerance in the presence of normal (male) and impaired (female) glucose tolerance. Concurrently, insulin-elicited increases in glucose disposal were abolished in all AS160(-/-) skeletal muscles and liver but not in AS160(-/-) adipose tissues. This suggests AS160 as a target for differential manipulation of glucose homeostasis.

  16. Ambient air pollution, adipokines, and glucose homeostasis: The Framingham Heart Study.

    PubMed

    Li, Wenyuan; Dorans, Kirsten S; Wilker, Elissa H; Rice, Mary B; Kloog, Itai; Schwartz, Joel D; Koutrakis, Petros; Coull, Brent A; Gold, Diane R; Meigs, James B; Fox, Caroline S; Mittleman, Murray A

    2018-02-01

    To examine associations of proximity to major roadways, sustained exposure to fine particulate matter (PM 2.5 ), and acute exposure to ambient air pollutants with adipokines and measures of glucose homeostasis among participants living in the northeastern United States. We included 5958 participants from the Framingham Offspring cohort examination cycle 7 (1998-2001) and 8 (2005-2008) and Third Generation cohort examination cycle 1 (2002-2005) and 2 (2008-2011), who did not have type 2 diabetes at the time of examination visit. We calculated 2003 annual average PM 2.5 at participants' home address, residential distance to the nearest major roadway, and daily PM 2.5 , black carbon (BC), sulfate, nitrogen oxides (NO x ), and ozone concentrations. We used linear mixed effects models for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) which were measured up to twice, and used linear regression models for adiponectin, resistin, leptin, and hemoglobin A1c (HbA1c) which were measured only once, adjusting for demographics, socioeconomic position, lifestyle, time, and seasonality. The mean age was 51years and 55% were women. Participants who lived 64m (25th percentile) from a major roadway had 0.28% (95% CI: 0.05%, 0.51%) higher fasting plasma glucose than participants who lived 413m (75th percentile) away, and the association appeared to be driven by participants who lived within 50m from a major roadway. Higher exposures to 3- to 7-day moving averages of BC and NO x were associated with higher glucose whereas the associations for ozone were negative. The associations otherwise were generally null and did not differ by median age, sex, educational attainment, obesity status, or prediabetes status. Living closer to a major roadway or acute exposure to traffic-related air pollutants were associated with dysregulated glucose homeostasis but not with adipokines among participants from the Framingham Offspring and Third Generation

  17. Perk Gene Dosage Regulates Glucose Homeostasis by Modulating Pancreatic β-Cell Functions

    PubMed Central

    Wang, Rong; Munoz, Elyse E.; Zhu, Siying; McGrath, Barbara C.; Cavener, Douglas R.

    2014-01-01

    Background Insulin synthesis and cell proliferation are under tight regulation in pancreatic β-cells to maintain glucose homeostasis. Dysfunction in either aspect leads to development of diabetes. PERK (EIF2AK3) loss of function mutations in humans and mice exhibit permanent neonatal diabetes that is characterized by insufficient β-cell mass and reduced proinsulin trafficking and insulin secretion. Unexpectedly, we found that Perk heterozygous mice displayed lower blood glucose levels. Methodology Longitudinal studies were conducted to assess serum glucose and insulin, intracellular insulin synthesis and storage, insulin secretion, and β-cell proliferation in Perk heterozygous mice. In addition, modulation of Perk dosage specifically in β-cells showed that the glucose homeostasis phenotype of Perk heterozygous mice is determined by reduced expression of PERK in the β-cells. Principal Findings We found that Perk heterozygous mice first exhibited enhanced insulin synthesis and secretion during neonatal and juvenile development followed by enhanced β-cell proliferation and a substantial increase in β-cell mass at the adult stage. These differences are not likely to entail the well-known function of PERK to regulate the ER stress response in cultured cells as several markers for ER stress were not differentially expressed in Perk heterozygous mice. Conclusions In addition to the essential functions of PERK in β-cells as revealed by severely diabetic phenotype in humans and mice completely deficient for PERK, reducing Perk gene expression by half showed that intermediate levels of PERK have a profound impact on β-cell functions and glucose homeostasis. These results suggest that an optimal level of PERK expression is necessary to balance several parameters of β-cell function and growth in order to achieve normoglycemia. PMID:24915520

  18. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

    PubMed Central

    2014-01-01

    The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiota-derived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance. GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3K-dependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85α interaction. Intracerebroventricular GLP-2 augments glucose tolerance, suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110α) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies. PMID:24990862

  19. Three-component homeostasis control

    NASA Astrophysics Data System (ADS)

    Xu, Jin; Hong, Hyunsuk; Jo, Junghyo

    2014-03-01

    Two reciprocal components seem to be sufficient to maintain a control variable constant. However, pancreatic islets adapt three components to control glucose homeostasis. They are α (secreting glucagon), β (insulin), and δ (somatostatin) cells. Glucagon and insulin are the reciprocal hormones for increasing and decreasing blood glucose levels, while the role of somatostatin is unknown. However, it has been known how each hormone affects other cell types. Based on the pulsatile hormone secretion and the cellular interactions, this system can be described as coupled oscillators. In particular, we used the Landau-Stuart model to consider both amplitudes and phases of hormone oscillations. We found that the presence of the third component, δ cell, was effective to resist under glucose perturbations, and to quickly return to the normal glucose level once perturbed. Our analysis suggested that three components are necessary for advanced homeostasis control.

  20. Effects of Ramadan fasting on glucose homeostasis and adiponectin levels in healthy adult males.

    PubMed

    Gnanou, Justin V; Caszo, Brinnell A; Khalil, Khalifah M; Abdullah, Shahidah L; Knight, Victor F; Bidin, Mohd Z

    2015-01-01

    Adiponectin is a hormone secreted by adipocytes during the fasting phase of the fast-fed cycle. Ramadan fasting involves prolonged fasting for up to twelve hours and thus could lead to increased secretion of adiponectin by adipocytes. However, studies on the role of adiponectin on glucose and body weight homeostasis during Ramadan fasting is still a matter of controversy. Thus the specific aim of this study was to assess the effect of fasting during Ramadan on the adiponectin levels, body weight and glucose homeostasis in healthy male Malaysian subjects. Twenty healthy male (19-23 years) Muslim subjects were followed up during the fasting month of Ramadan. Anthropometry and blood samples were taken one week before and during the fourth week of fasting. Plasma glucose, insulin and adiponectin were estimated and insulin sensitivity indices were estimated using the Homeostasis Model Assessment. Subjects experienced a significant decrease in body weight (2.4 %, p < 0.001) and body mass index (5.5 %, p < 0.01). There was also a significant decrease of 12.3 %, 52.8 % and 45.6 % of plasma glucose, insulin and adiponectin respectively (p < 0.01). The drop in adiponectin was positively correlated with the decrease in body weight (r = 0.45, p < 0.05). There was also a significant increase in insulin sensitivity and a decrease in insulin resistance (p < 0.01). These results indicate that Ramadan fasting in young healthy individuals has a positive impact on the maintenance of glucose homeostasis. It also shows that adiponectin levels dropped along with significant loss in weight. We feel caloric restriction during the Ramadan fasting is in itself sufficient to improve insulin sensitivity in healthy individuals.

  1. 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

  2. Targeted delivery of HGF to the skeletal muscle improves glucose homeostasis in diet-induced obese mice.

    PubMed

    Sanchez-Encinales, Viviana; Cozar-Castellano, Irene; Garcia-Ocaña, Adolfo; Perdomo, Germán

    2015-12-01

    Hepatocyte growth factor (HGF) is a cytokine that increases glucose transport ex vivo in skeletal muscle. The aim of this work was to decipher the impact of whether conditional overexpression of HGF in vivo could improve glucose homeostasis and insulin sensitivity in mouse skeletal muscle. Following tetracyclin administration, muscle HGF levels were augmented threefold in transgenic mice (SK-HGF) compared to control mice without altering plasma HGF levels. In conditions of normal diet, SK-HGF mice showed no differences in body weight, plasma triglycerides, blood glucose, plasma insulin and glucose tolerance compared to control mice. Importantly, obese SK-HGF mice exhibited improved whole-body glucose tolerance independently of changes in body weight or plasma triglyceride levels compared to control mice. This effect on glucose homeostasis was associated with significantly higher (∼80%) levels of phosphorylated protein kinase B in muscles from SK-HGF mice compared to control mice. In conclusion, muscle expression of HGF counteracts obesity-mediated muscle insulin resistance and improves glucose tolerance in mice.

  3. Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans.

    PubMed

    Lennerz, Belinda S; Vafai, Scott B; Delaney, Nigel F; Clish, Clary B; Deik, Amy A; Pierce, Kerry A; Ludwig, David S; Mootha, Vamsi K

    2015-01-01

    Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans

    PubMed Central

    Lennerz, Belinda; Vafai, Scott B.; Delaney, Nigel F.; Clish, Clary B.; Deik, Amy A.; Pierce, Kerry A.; Ludwig, David S.; Mootha, Vamsi K.

    2014-01-01

    Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure. PMID:25497115

  5. Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis.

    PubMed

    Hill, Jennifer W; Xu, Yong; Preitner, Frederic; Fukuda, Makota; Cho, You-Ree; Luo, Ji; Balthasar, Nina; Coppari, Roberto; Cantley, Lewis C; Kahn, Barbara B; Zhao, Jean J; Elmquist, Joel K

    2009-11-01

    Recent studies demonstrated a role for hypothalamic insulin and leptin action in the regulation of glucose homeostasis. This regulation involves proopiomelanocortin (POMC) neurons because suppression of phosphatidyl inositol 3-kinase (PI3K) signaling in these neurons blunts the acute effects of insulin and leptin on POMC neuronal activity. In the current study, we investigated whether disruption of PI3K signaling in POMC neurons alters normal glucose homeostasis using mouse models designed to both increase and decrease PI3K-mediated signaling in these neurons. We found that deleting p85alpha alone induced resistance to diet-induced obesity. In contrast, deletion of the p110alpha catalytic subunit of PI3K led to increased weight gain and adipose tissue along with reduced energy expenditure. Independent of these effects, increased PI3K activity in POMC neurons improved insulin sensitivity, whereas decreased PI3K signaling resulted in impaired glucose regulation. These studies show that activity of the PI3K pathway in POMC neurons is involved in not only normal energy regulation but also glucose homeostasis.

  6. Evaluating the mechanisms of improved glucose homeostasis after bariatric surgery in Ossabaw miniature swine.

    PubMed

    Sham, Jonathan G; Simianu, Vlad V; Wright, Andrew S; Stewart, Skye D; Alloosh, Mouhamad; Sturek, Michael; Cummings, David E; Flum, David R

    2014-01-01

    Roux-en-Y gastric bypass (RYGB) is the most common bariatric operation; however, the mechanism underlying the profound weight-independent effects on glucose homeostasis remains unclear. Large animal models of naturally occurring insulin resistance (IR), which have been lacking, would provide opportunities to elucidate such mechanisms. Ossabaw miniature swine naturally exhibit many features that may be useful in evaluating the anti diabetic effects of bariatric surgery. Glucose homeostasis was studied in 53 Ossabaw swine. Thirty-two received an obesogenic diet and were randomized to RYGB, gastrojejunostomy (GJ), gastrojejunostomy with duodenal exclusion (GJD), or Sham operations. Intravenous glucose tolerance tests and standardized meal tolerance tests were performed prior to, 1, 2, and 8 weeks after surgery and at a single time-point for regular diet control pigs. High-calorie-fed Ossabaws weighed more and had greater IR than regular diet controls, though only 70% developed IR. All operations caused weight-loss-independent improvement in IR, though only in pigs with high baseline IR. Only RYGB induced weight loss and decreased IR in the majority of pigs, as well as increasing AUCinsulin/AUCglucose. Similar to humans, Ossabaw swine exhibit both obesity-dependent and obesity-independent IR. RYGB promoted weight loss, IR improvement, and increased AUCinsulin/AUCglucose, compared to the smaller changes following GJ and GJD, suggesting a combination of upper and lower gut mechanisms in improving glucose homeostasis.

  7. Role of orexins in the central and peripheral regulation of glucose homeostasis: Evidences & mechanisms.

    PubMed

    Rani, Monika; Kumar, Raghuvansh; Krishan, Pawan

    2018-04-01

    Orexins (A & B), neuropeptides of hypothalamic origin, act through G-protein coupled receptors, orexin 1 receptor (OX 1 R) and orexin 2 receptor (OX 2 R). The wide projection of orexin neurons in the hypothalamic region allows them to interact with the other neurons and regulate food intake, emotional status, sleep wake cycle and energy metabolism. The autonomic nervous system plays an important regulatory role in the energy metabolism as well as glucose homeostasis. Orexin neurons are also under the control of GABAergic neurons. Emerging preclinical as well as clinical research has reported the role of orexins in the glucose homeostasis since orexins are involved in hypothalamic metabolism circuitry and also rely on sensing peripheral metabolic signals such as gut, adipose derived and pancreatic peptides. Apart from the hypothalamic origin, integration and control in various physiological functions, peripheral origin in wide organs, raises the possibility of use of orexins as a therapeutic biomarker in the management of metabolic disorders. The present review focuses the central as well as peripheral roles of orexins in the glucose homeostasis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. Perinatal exercise improves glucose homeostasis in adult offspring

    PubMed Central

    Carter, Lindsay G.; Lewis, Kaitlyn N.; Wilkerson, Donald C.; Tobia, Christine M.; Ngo Tenlep, Sara Y.; Shridas, Preetha; Garcia-Cazarin, Mary L.; Wolff, Gretchen; Andrade, Francisco H.; Charnigo, Richard J.; Esser, Karyn A.; Egan, Josephine M.; de Cabo, Rafael

    2012-01-01

    Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P < 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P < 0.05 and P < 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P < 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring. PMID:22932781

  9. Leptin Is Required for Glucose Homeostasis after Roux-en-Y Gastric Bypass in Mice.

    PubMed

    Mokadem, Mohamad; Zechner, Juliet F; Uchida, Aki; Aguirre, Vincent

    2015-01-01

    Leptin, the protein product of the ob gene, increases energy expenditure and reduces food intake, thereby promoting weight reduction. Leptin also regulates glucose homeostasis and hepatic insulin sensitivity via hypothalamic proopiomelanocortin neurons in mice. Roux-en-Y gastric bypass (RYGB) induces weight loss that is substantial and sustained despite reducing plasma leptin levels. In addition, patients who fail to undergo diabetes remission after RYGB are hypoletinemic compared to those who do and to lean controls. We have previously demonstrated that the beneficial effects of RYGB in mice require the melanocortin-4 receptor, a downstream effector of leptin action. Based on these observations, we hypothesized that leptin is required for sustained weight reduction and improved glucose homeostasis observed after RYGB. To investigate this hypothesis, we performed RYGB or sham operations on leptin-deficient ob/ob mice maintained on regular chow. To investigate whether leptin is involved in post-RYGB weight maintenance, we challenged post-surgical mice with high fat diet. RYGB reduced total body weight, fat and lean mass and caused reduction in calorie intake in ob/ob mice. However, it failed to improve glucose tolerance, glucose-stimulated plasma insulin, insulin tolerance, and fasting plasma insulin. High fat diet eliminated the reduction in calorie intake observed after RYGB in ob/ob mice and promoted weight regain, although not to the same extent as in sham-operated mice. We conclude that leptin is required for the effects of RYGB on glucose homeostasis but not body weight or composition in mice. Our data also suggest that leptin may play a role in post-RYGB weight maintenance.

  10. Mucosal Maltase-Glucoamylase Plays a Crucial Role in Starch Digestion and Prandial Glucose Homeostasis of Mice1–3

    PubMed Central

    Nichols, Buford L.; Quezada-Calvillo, Roberto; Robayo-Torres, Claudia C.; Ao, Zihua; Hamaker, Bruce R.; Butte, Nancy F.; Marini, Juan; Jahoor, Farook; Sterchi, Erwin E.

    2009-01-01

    Starch is the major source of food glucose and its digestion requires small intestinal α-glucosidic activities provided by the 2 soluble amylases and 4 enzymes bound to the mucosal surface of enterocytes. Two of these mucosal activities are associated with sucrase-isomaltase complex, while another 2 are named maltase-glucoamylase (Mgam) in mice. Because the role of Mgam in α-glucogenic digestion of starch is not well understood, the Mgam gene was ablated in mice to determine its role in the digestion of diets with a high content of normal corn starch (CS) and resulting glucose homeostasis. Four days of unrestricted ingestion of CS increased intestinal α-glucosidic activities in wild-type (WT) mice but did not affect the activities of Mgam-null mice. The blood glucose responses to CS ingestion did not differ between null and WT mice; however, insulinemic responses elicited in WT mice by CS consumption were undetectable in null mice. Studies of the metabolic route followed by glucose derived from intestinal digestion of 13C-labeled and amylase-predigested algal starch performed by gastric infusion showed that, in null mice, the capacity for starch digestion and its contribution to blood glucose was reduced by 40% compared with WT mice. The reduced α-glucogenesis of null mice was most probably compensated for by increased hepatic gluconeogenesis, maintaining prandial glucose concentration and total flux at levels comparable to those of WT mice. In conclusion, mucosal α-glucogenic activity of Mgam plays a crucial role in the regulation of prandial glucose homeostasis. PMID:19193815

  11. The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.

    PubMed

    Chambers, Adam P; Sorrell, Joyce E; Haller, April; Roelofs, Karen; Hutch, Chelsea R; Kim, Ki-Suk; Gutierrez-Aguilar, Ruth; Li, Bailing; Drucker, Daniel J; D'Alessio, David A; Seeley, Randy J; Sandoval, Darleen A

    2017-04-04

    Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-[9-39] (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and i.p. glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis.

    PubMed

    Prévost, Gaëtan; Jeandel, Lydie; Arabo, Arnaud; Coëffier, Moïse; El Ouahli, Mariama; Picot, Marie; Alexandre, David; Gobet, Françoise; Leprince, Jérôme; Berrahmoune, Hind; Déchelotte, Pierre; Malagon, Maria; Bonner, Caroline; Kerr-Conte, Julie; Chigr, Fatiha; Lefebvre, Hervé; Anouar, Youssef; Chartrel, Nicolas

    2015-08-01

    26RFa is a hypothalamic neuropeptide that promotes food intake. 26RFa is upregulated in obese animal models, and its orexigenic activity is accentuated in rodents fed a high-fat diet, suggesting that this neuropeptide might play a role in the development and maintenance of the obese status. As obesity is frequently associated with type 2 diabetes, we investigated whether 26RFa may be involved in the regulation of glucose homeostasis. In the current study, we show a moderate positive correlation between plasma 26RFa levels and plasma insulin in patients with diabetes. Plasma 26RFa concentration also increases in response to an oral glucose tolerance test. In addition, we found that 26RFa and its receptor GPR103 are present in human pancreatic β-cells as well as in the gut. In mice, 26RFa attenuates the hyperglycemia induced by a glucose load, potentiates insulin sensitivity, and increases plasma insulin concentrations. Consistent with these data, 26RFa stimulates insulin production by MIN6 insulinoma cells. Finally, we show, using in vivo and in vitro approaches, that a glucose load induces a massive secretion of 26RFa by the small intestine. Altogether, the present data indicate that 26RFa acts as an incretin to regulate glucose homeostasis. © 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.

  13. Rapamycin impairs HPD-induced beneficial effects on glucose homeostasis

    PubMed Central

    Chang, Geng-Ruei; Chiu, Yi-Shin; Wu, Ying-Ying; Lin, Yu-Chi; Hou, Po-Hsun; Mao, Frank Chiahung

    2015-01-01

    Background and Purpose Rapamycin, which is used clinically to treat graft rejection, has also been proposed to have an effect on metabolic syndrome; however, very little information is available on its effects in lean animals/humans. The purpose of this study was to characterize further the effects of the continuous use of rapamycin on glucose homeostasis in lean C57BL6/J mice. Experimental Approach Mice were fed a high-protein diet (HPD) for 12 weeks to develop a lean model and then were treated daily with rapamycin for 5 weeks while remaining on a HPD. Metabolic parameters, endocrine profiles, glucose tolerance tests, insulin sensitivity index, the expression of the glucose transporter GLUT4 and chromium distribution were measured in vivo. Key Results Lower body weight gain as well as a decreased caloric intake, fat pads, fatty liver scores, adipocyte size and glucose tolerance test values were observed in HPD-fed mice compared with mice fed a high-fat or standard diet. Despite these beneficial effects, rapamycin-treated lean mice showed greater glucose intolerance, reduced insulin sensitivity, lower muscle GLUT4 expression and changes in chromium levels in tissues even with high insulin levels. Conclusion and Implications Our findings demonstrate that continuous rapamycin administration may lead to the development of diabetes syndrome, as it was found to induce hyperglycaemia and glucose intolerance in a lean animal model. PMID:25884889

  14. Association between site-specific bone mineral density and glucose homeostasis and anthropometric traits in healthy men and women.

    PubMed

    Kim, Se-Min; Cui, Jinrui; Rhyu, Jane; Guo, Xiuqing; Chen, Yii-Der I; Hsueh, Willa A; Rotter, Jerome I; Goodarzi, Mark O

    2018-06-01

    Patients with type 2 diabetes mellitus have an increased risk of fracture despite normal or increased bone mineral density (BMD). Studies on the relationship of glucose homeostasis with BMD phenotypes have been inconclusive because distinguishing the roles of insulin resistance and hyperglycaemia in bone remodelling is challenging. In this study, we sought to define the relationship of site-specific BMD with glucose homeostasis traits and anthropometric traits. In a cross-sectional study, we examined 787 subjects from the Mexican-American Coronary Artery Disease (MACAD) cohort who had undergone euglycaemic-hyperinsulinaemic clamps, oral glucose tolerance testing and dual X-ray absorptiometry. Glucose homeostasis traits included insulinogenic index (IGI30), insulin sensitivity (M value), insulin clearance (MCRI), fasting insulin, fasting glucose and 2-hour glucose. Univariate and multivariate analyses were performed to assess the association of glucose homeostasis and anthropometric traits with site-specific BMD. Two-hour glucose was negatively associated with arm BMD in women, which remained significant in multivariate analysis (β = -.15, P = .0015). Positive correlations between fasting insulin and BMD at weight-bearing sites, including pelvis (β = .22, P < .0001) and legs (β = .17, P = .001) in women and pelvis (β = .33, P < .0001) in men, lost significance after multivariate adjustment. Lean mass exhibited strong independent positive associations with BMD at multiple sites in both sexes. Our findings suggest that (i) anabolic effects of insulin might work via mechanical loading from lean mass; (ii) a direct negative effect of increasing glucose might be more prominent at cortical-bone-rich sites in women; and (iii) lean mass is a strong positive predictor of bone mass. © 2018 John Wiley & Sons Ltd.

  15. Perinatal Bisphenol A Exposure and Adult Glucose Homeostasis: Identifying Critical Windows of Exposure

    PubMed Central

    Liu, Jingli; Yu, Pan; Qian, Wenyi; Li, Yan; Zhao, Jingjing; Huan, Fei; Wang, Jun; Xiao, Hang

    2013-01-01

    Bisphenol A (BPA) is a widespread endocrine-disrupting chemical used as the building block for polycarbonate plastics. Epidemiological evidence has correlated BPA exposure with higher risk of heart disease and type 2 diabetes. However, it remains unknown whether there are critical windows of susceptibility to BPA exposure on the development of dysglycemia. This study was an attempt to investigate the critical windows and the long-term consequences of perinatal exposure to BPA on glucose homeostasis. Pregnant mice were given either vehicle or BPA (100 µg/kg/day) at different time of perinatal stage: 1) on days 1–6 of pregnancy (P1–P6, preimplantation exposure); 2) from day 6 of pregnancy until postnatal day (PND) 0 (P6–PND0, fetal exposure); 3) from lactation until weaning (PND0–PND21, neonatal exposure); and 4) from day 6 of gestation until weaning (P6–PND21, fetal and neonatal exposure). At 3, 6 and 8 months of age, offspring in each group were challenged with glucose and insulin tolerance tests. Then islet morphometry and β-cell function were measured. The glucose homeostasis was impaired in P6-PND0 mice from 3 to 6 months of age, and this continued to 8 months in males, but not females. While in PND0-PND21 and P6-PND21 BPA-treated groups, only the 3-month-old male offspring developed glucose intolerance. Moreover, at the age of 3 months, perinatal exposure to BPA resulted in the increase of β-cell mass mainly due to the coordinate changes in cell replication, neogenesis, and apoptosis. The alterations of insulin secretion and insulin sensitivity, rather than β-cell mass, were consistent with the development of glucose intolerance. Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and the effects of BPA were dose, sex, and time-dependent. Fetal development stage may be the critical window of susceptibility to BPA exposure. PMID:23675523

  16. Calcium homeostasis during oral glucose load in healthy women.

    PubMed

    D'Erasmo, E; Pisani, D; Ragno, A; Raejntroph, N; Vecci, E; Acca, M

    1999-04-01

    It has been demonstrated that in healthy subjects during oral glucose tolerance test, serum calcium declines, while urinary calcium excretion increases, even if there is not a general agreement in this regard. The study was carried out in order to evaluate the effects of glucose oral load on calcium homeostasis in eight healthy adult women, also considering ionized calcium, plasma insulin and parathyroid hormone changes. The results showed a decline of total and ionized serum calcium (p < 0.05 and p < 0.01, respectively; maximum of the decrease at time 120'), in parallel with the increase of urinary calcium/ creatinine ratio (p < 0.05). Serum glucose and insulin increase (p < 0.0001 and p < 0.0005 respectively; maximum value at time 60'), while the parathyroid hormone level decreases (maximum decline at time 120', p < 0.01). No changes were observed in fasting control subjects for all parameters considered. The changes of these parameters with time suggest that the effects of glucose oral load on calcium metabolism in healthy adult women may be the consequence of parathyroid hormone suppression induced by acute hyperglycemia/hyperinsulinemia. The results confirm in vivo the PTH behaviour in vitro, on cultured bovine parathyroid cells, with high glucose concentration.

  17. Mathematical model of glucose-insulin homeostasis in healthy rats.

    PubMed

    Lombarte, Mercedes; Lupo, Maela; Campetelli, German; Basualdo, Marta; Rigalli, Alfredo

    2013-10-01

    According to the World Health Organization there are over 220 million people in the world with diabetes and 3.4 million people died in 2004 as a consequence of this pathology. Development of an artificial pancreas would allow to restore control of blood glucose by coupling an infusion pump to a continuous glucose sensor in the blood. The design of such a device requires the development and application of mathematical models which represent the gluco-regulatory system. Models developed by other research groups describe very well the gluco-regulatory system but have a large number of mathematical equations and require complex methodologies for the estimation of its parameters. In this work we propose a mathematical model to study the homeostasis of glucose and insulin in healthy rats. The proposed model consists of three differential equations and 8 parameters that describe the variation of: blood glucose concentration, blood insulin concentration and amount of glucose in the intestine. All parameters were obtained by setting functions to the values of glucose and insulin in blood obtained after oral glucose administration. In vivo and in silico validations were performed. Additionally, a qualitative analysis has been done to verify the aforementioned model. We have shown that this model has a single, biologically consistent equilibrium point. This model is a first step in the development of a mathematical model for the type I diabetic rat. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis.

    PubMed

    Armata, Heather L; Golebiowski, Diane; Jung, Dae Young; Ko, Hwi Jin; Kim, Jason K; Sluss, Hayla K

    2010-12-01

    Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis.

  19. PEDF attenuates insulin-dependent molecular pathways of glucose homeostasis in skeletal myocytes.

    PubMed

    Carnagarin, Revathy; Dharmarajan, Arun M; Dass, Crispin R

    2016-02-15

    Pigment epithelium-derived factor (PEDF) is an anti-angiogenic serpin associated with insulin resistance in metabolic disorders such as diabetes, metabolic syndrome, obesity and polycystic ovarian syndrome. While the mechanism of PEDF induced-insulin resistance of metabolic disorders has been attributed to its inflammatory and lipolytic effects, little evidence exists to support a direct role of PEDF in mediating insulin resistance. Here, we seminally provide evidence that PEDF can inhibit insulin signal transduction governing glucose homeostasis from the receptor to the effector phosphorylation through Akt/PKB-dependent and -independent pathways in mouse and human skeletal muscle cell lines. PEDF attenuates the insulin-dependent molecular axes of glucose metabolism. Exposure of skeletal myocytes to PEDF attenuates insulin-dependent insulin receptor autophosphorylation, tyrosine phosphorylation of insulin receptor substrate 1, and dual loop phosphorylation-activation of Akt. PEDF significantly inhibits the downstream effector - glycogen synthase kinase (and thereby the glycogenic axis of insulin signalling). PEDF turned off both the molecular switches of GLUT4 translocation: IRS-Akt/PKB-AS160 mediated and IR-pCbl-dependent GLUT4 translocation (the molecular axis of glucose uptake). These findings implicate a direct effect of PEDF on multiple insulin-dependent molecular mechanisms of glucose homeostasis in skeletal muscle cells, thereby enabling it to contribute to peripheral insulin resistance at the cellular level. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Transepithelial glucose transport and Na+/K+ homeostasis in enterocytes: an integrative model

    PubMed Central

    Drengstig, Tormod; Ruoff, Peter

    2014-01-01

    The uptake of glucose and the nutrient coupled transcellular sodium traffic across epithelial cells in the small intestine has been an ongoing topic in physiological research for over half a century. Driving the uptake of nutrients like glucose, enterocytes must have regulatory mechanisms that respond to the considerable changes in the inflow of sodium during absorption. The Na-K-ATPase membrane protein plays a major role in this regulation. We propose the hypothesis that the amount of active Na-K-ATPase in enterocytes is directly regulated by the concentration of intracellular Na+ and that this regulation together with a regulation of basolateral K permeability by intracellular ATP gives the enterocyte the ability to maintain ionic Na+/K+ homeostasis. To explore these regulatory mechanisms, we present a mathematical model of the sodium coupled uptake of glucose in epithelial enterocytes. Our model integrates knowledge about individual transporter proteins including apical SGLT1, basolateral Na-K-ATPase, and GLUT2, together with diffusion and membrane potentials. The intracellular concentrations of glucose, sodium, potassium, and chloride are modeled by nonlinear differential equations, and molecular flows are calculated based on experimental kinetic data from the literature, including substrate saturation, product inhibition, and modulation by membrane potential. Simulation results of the model without the addition of regulatory mechanisms fit well with published short-term observations, including cell depolarization and increased concentration of intracellular glucose and sodium during increased concentration of luminal glucose/sodium. Adding regulatory mechanisms for regulation of Na-K-ATPase and K permeability to the model show that our hypothesis predicts observed long-term ionic homeostasis. PMID:24898586

  1. Reviewing the Effects of l-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis

    PubMed Central

    Pedroso, João A.B.; Zampieri, Thais T.; Donato, Jose

    2015-01-01

    Leucine is a well-known activator of the mammalian target of rapamycin (mTOR). Because mTOR signaling regulates several aspects of metabolism, the potential of leucine as a dietary supplement for treating obesity and diabetes mellitus has been investigated. The objective of the present review was to summarize and discuss the available evidence regarding the mechanisms and the effects of leucine supplementation on the regulation of food intake, energy balance, and glucose homeostasis. Based on the available evidence, we conclude that although central leucine injection decreases food intake, this effect is not well reproduced when leucine is provided as a dietary supplement. Consequently, no robust evidence indicates that oral leucine supplementation significantly affects food intake, although several studies have shown that leucine supplementation may help to decrease body adiposity in specific conditions. However, more studies are necessary to assess the effects of leucine supplementation in already-obese subjects. Finally, although several studies have found that leucine supplementation improves glucose homeostasis, the underlying mechanisms involved in these potential beneficial effects remain unknown and may be partially dependent on weight loss. PMID:26007339

  2. Evidence of a link between resting energy expenditure and bone remodelling, glucose homeostasis and adipokine variations in adolescent girls with anorexia nervosa.

    PubMed

    Maïmoun, L; Guillaume, S; Lefebvre, P; Philibert, P; Bertet, H; Picot, M-C; Gaspari, L; Paris, F; Seneque, M; Dupuys, A-M; Courtet, P; Thomas, E; Mariano-Goulart, D; Bringer, J; Renard, E; Sultan, C

    2016-01-01

    Low bone mass is a consequence of anorexia nervosa (AN). This study assessed the effects of energy deficiency on various bone and hormonal parameters. The interrelationships between energy deficiency and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit demineralisation and hormonal alterations in AN patients. Low areal bone mineral density (aBMD) is a well-known consequence of AN. However, the impact of reduced energy expenditure on bone metabolism is unknown. This study assessed the effects of energy deficiency on bone remodelling and its potential interactions with glucose homeostasis and adipose tissue-derived hormones in AN, a clinical model for reduced energy expenditure. Fifty women with AN and 50 age-matched controls (mean age 18.1 ± 2.7 and 18.0 ± 2.1 years, respectively) were enrolled. aBMD was determined with DXA. Resting energy expenditure (REEm), a marker of energy status, was indirectly assessed by calorimetry. Bone turnover markers, undercarboxylated osteocalcin (ucOC), parameters of glucose homeostasis, adipokines and growth factors were concomitantly evaluated. AN patients presented low aBMD at all bone sites. REEm, bone formation markers, ucOC, glucose, insulin, HOMA-IR, leptin and IGF-1 were significantly reduced, whereas the bone resorption marker, leptin receptor (sOB-R) and adiponectin were elevated in AN compared with CON. In AN patients, REEm was positively correlated with weight, BMI, whole body (WB) fat mass, WB fat-free soft tissue, markers of bone formation, glucose, insulin, HOMA-IR, leptin and IGF-1 and negatively correlated with the bone resorption marker and sOB-R. Biological parameters, aBMD excepted, appeared more affected by the weight variation in the last 6 months than by the disease duration. The strong interrelationships between REEm and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency

  3. 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.

  4. Effect of chromium supplementation on the glucose homeostasis and anthropometry of type 2 diabetic patients: Double blind, randomized clinical trial: Chromium, glucose homeostasis and anthropometry.

    PubMed

    Guimarães, Marília Mendonça; Carvalho, Ana Clara Martins Silva; Silva, Maria Sebastiana

    2016-07-01

    To evaluate the effect of chromium supplementation on the glucose homeostasis and anthropometry of type 2 diabetic patients. Fifty-six individuals with type 2 Diabetes were randomized on a double blind clinical trial into three groups: placebo (NC0), 50μg (NC50) and 200μg (NC200) of chromium nicotinate. Glucose homeostasis, anthropometry and physical activity intensity were evaluated at the beginning, at day 45 and at day 90. Energy intake was evaluated at the beginning, between the beginning and 45 days, and between days 45 and 90 of the study. There were no differences within or between groups for HOMA-IR, waist circumference, body fat percentage, lean body mass percentage and total energy intake during the trial. There was an increase of the HOMA-β in group NC0 (p=0.0349) and a decrease of 1.08kg in group NC50 (p=0.0048) at 90 days. The relation between body mass index, body fat percentage and insulin sensitivity did not change in the placebo and supplemented groups (p>0.05). In the effect of the intervention, for each 1cm increase in waist circumference there was an increase of 1.90±0.63 in HOMA-IR (p=0.0087) and 16.31±5.27% in HOMA-β (p=0.0073) in group NC200. No difference was seen in the intensity of physical activity within the groups and in the comparison between the supplemented groups (NC50 and NC200) and placebo (NC0) at 90 days. There was an increase in energy expenditure in physical activity at 90days (p=0.0371) of intervention in the group subjects NC50. As for total energy intake, there were no differences within or between the groups during the study. 50μg and 200μg supplementation with chromium nicotinate for 90days did not promote improvements in glucose homeostasis and anthropometry in individuals with type 2 diabetes mellitus. Copyright © 2016 Elsevier GmbH. All rights reserved.

  5. 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

  6. 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

  7. Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice

    PubMed Central

    Smith, Mark A.; Katsouri, Loukia; Irvine, Elaine E.; Hankir, Mohammed K.; Pedroni, Silvia M.A.; Voshol, Peter J.; Gordon, Matthew W.; Choudhury, Agharul I.; Woods, Angela; Vidal-Puig, Antonio; Carling, David; Withers, Dominic J.

    2015-01-01

    Summary Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons. PMID:25865886

  8. Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A.

    PubMed

    Zhao, Jiejie; Xiong, Xuelian; Li, Yao; Liu, Xing; Wang, Tao; Zhang, Hong; Jiao, Yang; Jiang, Jingjing; Zhang, Huijie; Tang, Qiqun; Gao, Xin; Li, Xuejun; Lu, Yan; Liu, Bin; Hu, Cheng; Li, Xiaoying

    2018-05-01

    Type 2 diabetes mellitus (T2DM) has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p.Ala204Thr) in the Chinese population, which is associated with elevated blood glucose and T2DM risk. Notably, mice with liver-specific knockout of FBXW7 develop hyperglycemia, glucose intolerance, and insulin resistance even on a normal chow diet. Conversely, overexpression of FBXW7 in the liver not only prevents the development of high-fat diet-induced insulin resistance but also attenuates the disease signature of obese mice. Mechanistically, FBXW7 directly binds to hepatokine fetuin-A to induce its ubiquitination and subsequent proteasomal degradation, comprising an important mechanism maintaining glucose homeostasis. Thus, we provide evidence showing a beneficial role of FBXW7 in glucose homeostasis. © 2018 by the American Diabetes Association.

  9. Glucose is necessary to maintain neurotransmitter homeostasis during synaptic activity in cultured glutamatergic neurons.

    PubMed

    Bak, Lasse K; Schousboe, Arne; Sonnewald, Ursula; Waagepetersen, Helle S

    2006-10-01

    Glucose is the primary energy substrate for the adult mammalian brain. However, lactate produced within the brain might be able to serve this purpose in neurons. In the present study, the relative significance of glucose and lactate as substrates to maintain neurotransmitter homeostasis was investigated. Cultured cerebellar (primarily glutamatergic) neurons were superfused in medium containing [U-13C]glucose (2.5 mmol/L) and lactate (1 or 5 mmol/L) or glucose (2.5 mmol/L) and [U-13C]lactate (1 mmol/L), and exposed to pulses of N-methyl-D-aspartate (300 micromol/L), leading to synaptic activity including vesicular release. The incorporation of 13C label into intracellular lactate, alanine, succinate, glutamate, and aspartate was determined by mass spectrometry. The metabolism of [U-13C]lactate under non-depolarizing conditions was high compared with that of [U-13C]glucose; however, it decreased significantly during induced depolarization. In contrast, at both concentrations of extracellular lactate, the metabolism of [U-13C]glucose was increased during neuronal depolarization. The role of glucose and lactate as energy substrates during vesicular release as well as transporter-mediated influx and efflux of glutamate was examined using preloaded D-[3H]aspartate as a glutamate tracer and DL-threo-beta-benzyloxyaspartate to inhibit glutamate transporters. The results suggest that glucose is essential to prevent depolarization-induced reversal of the transporter (efflux), whereas vesicular release was unaffected by the choice of substrate. In conclusion, the present study shows that glucose is a necessary substrate to maintain neurotransmitter homeostasis during synaptic activity and that synaptic activity does not induce an upregulation of lactate metabolism in glutamatergic neurons.

  10. Hormones and the autonomic nervous system are involved in suprachiasmatic nucleus modulation of glucose homeostasis.

    PubMed

    Ruiter, Marieke; Buijs, Ruud M; Kalsbeek, Andries

    2006-05-01

    Glucose is one of the most important energy sources for the body in general, and the brain in particular. It is essential for survival to keep glucose levels within strict boundaries. Acute disturbances of glucose homeostasis are rapidly corrected by hormonal and neuronal mechanisms. Furthermore, changes in energy expenditure associated with the light-dark cycle induce variations in the plasma glucose concentration that are more gradual. Organisms take advantage of adapting their internal physiology to the predictable daily changes in energy expenditure, because it enables them to anticipate these changes and to prevent unnecessary disturbance of homeostasis. The hypothalamic biological clock, located in the suprachiasmatic nucleus (SCN), receives light information from the eyes and transmits this information to the rest of the body to synchronize physiology to the environment. Here we review several studies providing evidence for biological clock control of the daily variation in several aspects of glucose metabolism. Although both hormones and the autonomic nervous system can stimulate glucose uptake or production by organs in the periphery, we have shown that the biological clock control of glucose metabolism mostly occurs through the autonomic nervous system. The critical involvement of the biological clock is also indicated by several studies, indicating that disturbance of the biological clock is often associated with metabolic diseases, such as obesity, diabetes mellitus and hypertension.

  11. Importance of the gut-brain axis in the control of glucose homeostasis.

    PubMed

    Migrenne, Stéphanie; Marsollier, Nicolas; Cruciani-Guglielmacci, Céline; Magnan, Christophe

    2006-12-01

    Adult mammals finely match glucose production to glucose utilization, thus allowing glycaemia to be maintained in a physiological range of 0.8-1.2mg/dl whatever the energetic status of the mammal (i.e. fed or fasted, rested or exercised). To accomplish this, peripheral signals originating from the gut 'inform' the central nervous system, which in turn is able to monitor the status of both peripheral glucose stores and ongoing fuel availability. Indeed, both secretion and action of hormones regulating endogenous glucose production and utilization are regulated by the autonomic nervous system. These gut signals are either hormonal (e.g. glucagon-like peptide-1, ghrelin and cholecystokinine) or neuronal (e.g. afferent vagus nerve fibres). Recent data, combined with the development of incretin analogues for treatment of diabetes, highlight the importance of the gut-brain axis, especially glucagon-like peptide-1 and ghrelin, in the control of glucose homeostasis.

  12. Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice.

    PubMed

    Rancoule, C; Attané, C; Grès, S; Fournel, A; Dusaulcy, R; Bertrand, C; Vinel, C; Tréguer, K; Prentki, M; Valet, P; Saulnier-Blache, J S

    2013-06-01

    Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific G-protein-coupled receptors; its synthesis is modulated in obesity. We previously reported that reducing adipocyte LPA production in high-fat diet (HFD)-fed obese mice is associated with improved glucose tolerance, suggesting a negative impact of LPA on glucose homeostasis. Here, our aim was to test this hypothesis. First, glucose tolerance and plasma insulin were assessed after acute (30 min) injection of LPA (50 mg/kg) or of the LPA1/LPA3 receptor antagonist Ki16425 (5 mg kg(-1) day(-1), i.p.) in non-obese mice fed a normal diet (ND) and in obese/prediabetic (defined as glucose-intolerant) HFD mice. Glucose and insulin tolerance, pancreas morphology, glycogen storage, glucose oxidation and glucose transport were then studied after chronic treatment (3 weeks) of HFD mice with Ki16425. In ND and HFD mice, LPA acutely impaired glucose tolerance by inhibiting glucose-induced insulin secretion. These effects were blocked by pre-injection of Ki16425 (5 mg/kg, i.p.). Inhibition of glucose-induced insulin secretion by LPA also occurred in isolated mouse islets. Plasma LPA was higher in HFD mice than in ND mice and Ki16425 transiently improved glucose tolerance. The beneficial effect of Ki16425 became permanent after chronic treatment and was associated with increased pancreatic islet mass and higher fasting insulinaemia. Chronic treatment with Ki16425 also improved insulin tolerance and increased liver glycogen storage and basal glucose use in skeletal muscle. Exogenous and endogenous LPA exerts a deleterious effect on glucose disposal through a reduction of plasma insulin; pharmacological blockade of LPA receptors improves glucose homeostasis in obese/prediabetic mice.

  13. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats

    PubMed Central

    Qinna, Nidal A; Badwan, Adnan A

    2015-01-01

    Streptozotocin (STZ) is currently the most used diabetogenic agent in testing insulin and new antidiabetic drugs in animals. Due to the toxic and disruptive nature of STZ on organs, apart from pancreas, involved in preserving the body’s normal glucose homeostasis, this study aims to reassess the action of STZ in inducing different glucose response states in diabetic rats while testing insulin. Diabetic Sprague-Dawley rats induced with STZ were classified according to their initial blood glucose levels into stages. The effect of randomizing rats in such a manner was investigated for the severity of interrupting normal liver, pancreas, and kidney functions. Pharmacokinetic and pharmacodynamic actions of subcutaneously injected insulin in diabetic and nondiabetic rats were compared. Interruption of glucose homeostasis by STZ was challenged by single and repeated administrations of injected insulin and oral glucose to diabetic rats. In diabetic rats with high glucose (451–750 mg/dL), noticeable changes were seen in the liver and kidney functions compared to rats with lower basal glucose levels. Increased serum levels of recombinant human insulin were clearly indicated by a significant increase in the calculated maximum serum concentration and area under the concentration–time curve. Reversion of serum glucose levels to normal levels pre- and postinsulin and oral glucose administrations to STZ diabetic rats were found to be variable. In conclusion, diabetic animals were more responsive to insulin than nondiabetic animals. STZ was capable of inducing different levels of normal glucose homeostasis disruption in rats. Both pharmacokinetic and pharmacodynamic actions of insulin were altered when different initial blood glucose levels of STZ diabetic rats were selected for testing. Such findings emphasize the importance of selecting predefined and unified glucose levels when using STZ as a diabetogenic agent in experimental protocols evaluating new antidiabetic agents

  14. Transient Receptor Potential Canonical 3 (TRPC3) Channels Are Required for Hypothalamic Glucose Detection and Energy Homeostasis.

    PubMed

    Chrétien, Chloé; Fenech, Claire; Liénard, Fabienne; Grall, Sylvie; Chevalier, Charlène; Chaudy, Sylvie; Brenachot, Xavier; Berges, Raymond; Louche, Katie; Stark, Romana; Nédélec, Emmanuelle; Laderrière, Amélie; Andrews, Zane B; Benani, Alexandre; Flockerzi, Veit; Gascuel, Jean; Hartmann, Jana; Moro, Cédric; Birnbaumer, Lutz; Leloup, Corinne; Pénicaud, Luc; Fioramonti, Xavier

    2017-02-01

    The mediobasal hypothalamus (MBH) contains neurons capable of directly detecting metabolic signals such as glucose to control energy homeostasis. Among them, glucose-excited (GE) neurons increase their electrical activity when glucose rises. In view of previous work, we hypothesized that transient receptor potential canonical type 3 (TRPC3) channels are involved in hypothalamic glucose detection and the control of energy homeostasis. To investigate the role of TRPC3, we used constitutive and conditional TRPC3-deficient mouse models. Hypothalamic glucose detection was studied in vivo by measuring food intake and insulin secretion in response to increased brain glucose level. The role of TRPC3 in GE neuron response to glucose was studied by using in vitro calcium imaging on freshly dissociated MBH neurons. We found that whole-body and MBH TRPC3-deficient mice have increased body weight and food intake. The anorectic effect of intracerebroventricular glucose and the insulin secretory response to intracarotid glucose injection are blunted in TRPC3-deficient mice. TRPC3 loss of function or pharmacological inhibition blunts calcium responses to glucose in MBH neurons in vitro. Together, the results demonstrate that TRPC3 channels are required for the response to glucose of MBH GE neurons and the central effect of glucose on insulin secretion and food intake. © 2017 by the American Diabetes Association.

  15. p21-Activated protein kinases and their emerging roles in glucose homeostasis.

    PubMed

    Chiang, Yu-ting Alex; Jin, Tianru

    2014-04-01

    p21-Activated protein kinases (PAKs) are centrally involved in a plethora of cellular processes and functions. Their function as effectors of small GTPases Rac1 and Cdc42 has been extensively studied during the past two decades, particularly in the realms of cell proliferation, apoptosis, and hence tumorigenesis, as well as cytoskeletal remodeling and related cellular events in health and disease. In recent years, a large number of studies have shed light onto the fundamental role of group I PAKs, most notably PAK1, in metabolic homeostasis. In skeletal muscle, PAK1 was shown to mediate the function of insulin on stimulating GLUT4 translocation and glucose uptake, while in pancreatic β-cells, PAK1 participates in insulin granule localization and vesicle release. Furthermore, we demonstrated that PAK1 mediates the cross talk between insulin and Wnt/β-catenin signaling pathways and hence regulates gut proglucagon gene expression and the production of the incretin hormone glucagon-like peptide-1 (GLP-1). The utilization of chemical inhibitors of PAK and the characterization of Pak1(-/-) mice enabled us to gain mechanistic insights as well as to assess the overall contribution of PAKs in metabolic homeostasis. This review summarizes our current understanding of PAKs, with an emphasis on the emerging roles of PAK1 in glucose homeostasis.

  16. Pro-inflammatory mediators disrupt glucose homeostasis in airway surface liquid ‡

    PubMed Central

    Garnett, James P.; Nguyen, Trang T.; Moffatt, James D.; Pelham, Elizabeth R.; Kalsi, Kameljit K.; Baker, Emma H.; Baines, Deborah L.

    2012-01-01

    The glucose concentration of the airway surface liquid (ASL) is much lower than blood and is tightly regulated by the airway epithelium. ASL glucose is elevated in patients with viral colds, cystic fibrosis, chronic obstructive pulmonary disease (COPD) and asthma. Elevated ASL glucose is also associated with increased incidence of respiratory infection. However, the mechanism by which ASL glucose increases under inflammatory conditions is unknown. The aim of this study was to investigate the effect of pro-inflammatory mediators (PIMs) on the mechanisms governing airway glucose homeostasis in polarised monolayers of human airway (H441) and primary human bronchial epithelial (HBE) cells. Monolayers were treated with TNF-α, IFN-γ and LPS over 72 hours. PIM treatment led to increase in ASL glucose concentration and significantly reduced H441 and HBE transepithelial resistance (RT). This decline in RT was associated with an increase in paracellular permeability of glucose. Similar enhanced rates of paracellular glucose flux were also observed across excised trachea from LPS-treated mice. Interestingly, PIMs enhanced glucose uptake across the apical, but not the basolateral, membrane of H441 and HBE monolayers. This increase was predominantly via phloretin-sensitive GLUT-mediated uptake, which coincided with an increase in GLUT2 and GLUT10 abundance. In conclusion, exposure of airway epithelial monolayers to PIMs results in increased paracellular glucose flux, and apical GLUT-mediated glucose uptake. However uptake was insufficient to limit glucose accumulation in ASL. These data provide for the first time, a mechanism to support clinical findings that ASL glucose concentration is increased in patients with airway inflammation. PMID:22623330

  17. Intermittent Hypoxia Impairs Glucose Homeostasis in C57BL6/J Mice: Partial Improvement with Cessation of the Exposure

    PubMed Central

    Polak, Jan; Shimoda, Larissa A.; Drager, Luciano F.; Undem, Clark; McHugh, Holly; Polotsky, Vsevolod Y.; Punjabi, Naresh M.

    2013-01-01

    Objectives: Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Although several studies have suggested that intermittent hypoxia in obstructive sleep apnea may induce abnormalities in glucose homeostasis, it remains to be determined whether these abnormalities improve after discontinuation of the exposure. The objective of this study was to delineate the effects of intermittent hypoxia on glucose homeostasis, beta cell function, and liver glucose metabolism and to investigate whether the impairments improve after the hypoxic exposure is discontinued. Interventions: C57BL6/J mice were exposed to 14 days of intermittent hypoxia, 14 days of intermittent air, or 7 days of intermittent hypoxia followed by 7 days of intermittent air (recovery paradigm). Glucose and insulin tolerance tests were performed to estimate whole-body insulin sensitivity and calculate measures of beta cell function. Oxidative stress in pancreatic tissue and glucose output from isolated hepatocytes were also assessed. Results: Intermittent hypoxia increased fasting glucose levels and worsened glucose tolerance by 67% and 27%, respectively. Furthermore, intermittent hypoxia exposure was associated with impairments in insulin sensitivity and beta cell function, an increase in liver glycogen, higher hepatocyte glucose output, and an increase in oxidative stress in the pancreas. While fasting glucose levels and hepatic glucose output normalized after discontinuation of the hypoxic exposure, glucose intolerance, insulin resistance, and impairments in beta cell function persisted. Conclusions: Intermittent hypoxia induces insulin resistance, impairs beta cell function, enhances hepatocyte glucose output, and increases oxidative stress in the pancreas. Cessation of the hypoxic exposure does not fully reverse the observed changes in glucose metabolism. Citation: Polak J; Shimoda LA; Drager LF; Undem C; McHugh H; Polotsky VY; Punjabi NM

  18. Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice.

    PubMed

    Smith, Mark A; Katsouri, Loukia; Irvine, Elaine E; Hankir, Mohammed K; Pedroni, Silvia M A; Voshol, Peter J; Gordon, Matthew W; Choudhury, Agharul I; Woods, Angela; Vidal-Puig, Antonio; Carling, David; Withers, Dominic J

    2015-04-21

    Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Selective Reversible Inhibition of Liver Carnitine Palmitoyl-Transferase 1 by Teglicar Reduces Gluconeogenesis and Improves Glucose Homeostasis

    PubMed Central

    Conti, Roberto; Mannucci, Edoardo; Pessotto, Pompeo; Tassoni, Emanuela; Carminati, Paolo; Giannessi, Fabio; Arduini, Arduino

    2011-01-01

    OBJECTIVE We have developed a new antihyperglycemic agent (teglicar) through the selective and reversible inhibition of the liver isoform of carnitine palmitoyl-transferase 1 (L-CPT1). RESEARCH DESIGN AND METHODS Glucose production was investigated in isolated hepatocytes and during pancreatic clamps in healthy rats. Chronic treatments on C57BL/6J, db/db, high-fat fed mice, and rats were performed to understand glucose metabolism and insulin sensitivity. RESULTS In isolated hepatocytes, teglicar concentration dependently reduced ketone bodies and glucose production up to 72 and 50%, respectively. In rats, teglicar reduced the endogenous glucose production (−62%) without affecting peripheral glucose utilization. Heart 2-[3H]deoxyglucose uptake in mice was also not affected, confirming in vivo the drug selectivity toward L-CPT1. Chronic treatment in db/db mice (50 mg/kg/bid; 45 days) reduced postabsorptive glycemia (−38%), water consumption (−31%), and fructosamine (−30%). Such antidiabetic activity was associated with an improved insulin sensitivity assessed by the insulin tolerance test. A significant 50% increase in hepatic triglyceride content (HTGC) was found, although plasma alanineaminotransferase was not altered. In addition, long-term teglicar administration to high-fat fed C57BL/6J mice normalized glycemia (−19%) and insulinemia (−53%). Long-term teglicar administration (30 days, 80 mg/kg) in healthy overnight-fasted rats slightly reduced basal glycemia (−20%, ns), reduced basal insulin levels by 60%, doubled triglycerides, and increased free-fatty acids (+53%). HTGC was markedly increased, but liver and peripheral insulin sensitivity assessed by hyperinsulinemiceuglycemic clamp were not affected. CONCLUSIONS Teglicar, in vitro and in animal models, reduces gluconeogenesis and improves glucose homeostasis, refreshing the interest in selective and reversible L-CPT1 inhibition as a potential antihyperglycemic approach. PMID:21270274

  20. Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System.

    PubMed

    Daniele, Giuseppe; Iozzo, Patricia; Molina-Carrion, Marjorie; Lancaster, Jack; Ciociaro, Demetrio; Cersosimo, Eugenio; Tripathy, Devjit; Triplitt, Curtis; Fox, Peter; Musi, Nicolas; DeFronzo, Ralph; Gastaldelli, Amalia

    2015-10-01

    Glucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA1c of 5.7 ± 0.1%, fasting glucose of 114 ± 3 mg/dL, and 2-h glucose of 177 ± 11 mg/dL, exenatide (5 μg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMRglu) was measured by positron emission tomography after an injection of [(18)F]2-fluoro-2-deoxy-d-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO0-60 min (4.6 ± 1.4 vs. 13.1 ± 1.7 μmol/min ⋅ kg) and decreased the rise in mean glucose0-60 min (107 ± 6 vs. 138 ± 8 mg/dL) and insulin0-60 min (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0-60 min after exenatide was inversely correlated to CMRglu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state. © 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.

  1. Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

    USDA-ARS?s Scientific Manuscript database

    Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor a...

  2. T cell protein tyrosine phosphatase (TCPTP) deficiency in muscle does not alter insulin signalling and glucose homeostasis in mice.

    PubMed

    Loh, K; Merry, T L; Galic, S; Wu, B J; Watt, M J; Zhang, S; Zhang, Z-Y; Neel, B G; Tiganis, T

    2012-02-01

    Insulin activates insulin receptor protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The insulin receptor can serve as a substrate for the protein tyrosine phosphatase (PTP) 1B and T cell protein tyrosine phosphatase (TCPTP), which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the insulin receptor in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates insulin receptor signalling and gluconeogenesis in the liver. In this study we assessed for the first time the role of TCPTP in the regulation of insulin receptor signalling in muscle. We generated muscle-specific TCPTP-deficient (Mck-Cre;Ptpn2(lox/lox)) mice (Mck, also known as Ckm) and assessed the impact on glucose homeostasis and muscle insulin receptor signalling in chow-fed versus high-fat-fed mice. Blood glucose and insulin levels, insulin and glucose tolerance, and insulin-induced muscle insulin receptor activation and downstream PI3K/Akt signalling remained unaltered in chow-fed Mck-Cre;Ptpn2(lox/lox) versus Ptpn2(lox/lox) mice. In addition, body weight, adiposity, energy expenditure, insulin sensitivity and glucose homeostasis were not altered in high-fat-fed Mck-Cre;Ptpn2(lox/lox) versus Ptpn2(lox/lox) mice. These results indicate that TCPTP deficiency in muscle has no effect on insulin signalling and glucose homeostasis, and does not prevent high-fat diet-induced insulin resistance. Thus, despite their high degree of sequence identity, PTP1B and TCPTP contribute differentially to insulin receptor regulation in muscle. Our results are consistent with the notion that these two highly related PTPs make distinct contributions to insulin receptor regulation in different tissues.

  3. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity

    USDA-ARS?s Scientific Manuscript database

    Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the Brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose Homeostasis. The objective of this study was to determine whethe...

  4. A 12-week randomized clinical trial investigating the potential for sucralose to affect glucose homeostasis.

    PubMed

    Grotz, V Lee; Pi-Sunyer, Xavier; Porte, Daniel; Roberts, Ashley; Richard Trout, J

    2017-08-01

    The discovery of gut sweet taste receptors has led to speculations that non-nutritive sweeteners, including sucralose, may affect glucose control. A double-blind, parallel, randomized clinical trial, reported here and previously submitted to regulatory agencies, helps to clarify the role of sucralose in this regard. This was primarily an out-patient study, with 4-week screening, 12-week test, and 4-week follow-up phases. Normoglycemic male volunteers (47) consumed ∼333.3 mg encapsulated sucralose or placebo 3x/day at mealtimes. HbA1c, fasting glucose, insulin, and C-peptide were measured weekly. OGTTs were conducted in-clinic overnight, following overnight fasting twice during screening phase, twice during test phase, and once at follow-up. Throughout the study, glucose, insulin, C-peptide and HbA1c levels were within normal range. No statistically significant differences between sucralose and placebo groups in change from baseline for fasting glucose, insulin, C-peptide and HbA1c, no clinically meaningful differences in time to peak levels or return towards basal levels in OGTTs, and no treatment group differences in mean glucose, insulin, or C-peptide AUC change from baseline were observed. The results of other relevant clinical trials and studies of gastrointestinal sweet taste receptors are compared to these findings. The collective evidence supports that sucralose has no effect on glycemic control. Copyright © 2017 Heartland Food Products Group. Published by Elsevier Inc. All rights reserved.

  5. The impact of transsphenoidal surgery on glucose homeostasis and insulin resistance in acromegaly.

    PubMed

    Stelmachowska-Banaś, Maria; Zieliński, Grzegorz; Zdunowski, Piotr; Podgórski, Jan; Zgliczyński, Wocjiech

    2011-01-01

    Impaired glucose tolerance and overt diabetes mellitus are frequently associated with acro-megaly. The aim of this study was to find out whether these alterations could be reversed after transsphenoidal surgery. Two hundred and thirty-nine acromegalic patients were studied before and 6-12 months after transsphenoidal surgery. Diagnosis of active acromegaly was established on the basis of widely recognized criteria. In each patient, glucose and insulin concentrations were assessed during the 75 γ oral glucose tolerance test (OGTT). To estimate insulin resistance, we used homeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). At the moment of diagnosis, diabetes mellitus was present in 25% of the acromegalic patients. After surgery, the pre-valence of diabetes mellitus normalized to the level present in the general Polish population. We found a statistically significant reduction after surgery in plasma glucose levels both fasting (89.45 ± 13.92 mg/dL vs. 99.12 ± 17.33 mg/dL, p < 0.001) and during OGTT. Similarly, a prominent reduction in insulin secretion was found after surgery compared to the moment of diagnosis (15.44 ± 8.80 mIU/mL vs. 23.40 ± 10.24 mIU/mL, p < 0.001). After transsphenoidal surgery, there was a significant reduction in HOMA-IR (3.08 vs. 6.76, p < 0.0001) and a significant increase in QUICKI (0.32 vs. 0.29, p < 0.001). There were no statistically significant differences after surgery in fasting glucose and insulin levels between patients with controlled and in-adequately controlled disease. We conclude that in acromegalic patients glucose homeostasis alterations and insulin sensitivity can be normalized after transsphenoidal surgery, even if strict biochemical cure criteria are not fulfilled.

  6. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells.

    PubMed

    Kievit, Paul; Howard, Jane K; Badman, Michael K; Balthasar, Nina; Coppari, Roberto; Mori, Hiroyuki; Lee, Charlotte E; Elmquist, Joel K; Yoshimura, Akihiko; Flier, Jeffrey S

    2006-08-01

    Suppressor of cytokine signaling-3 (Socs-3) negatively regulates the action of various cytokines, as well as the metabolic hormones leptin and insulin. Mice with haploinsufficiency of Socs-3, or those with neuronal deletion of Socs-3, are lean and more leptin and insulin sensitive. To examine the role of Socs-3 within specific neurons critical to energy balance, we created mice with selective deletion of Socs-3 within pro-opiomelanocortin (POMC)-expressing cells. These mice had enhanced leptin sensitivity, measured by weight loss and food intake after leptin infusion. On chow diet, glucose homeostasis was improved despite normal weight gain. On a high-fat diet, the rate of weight gain was reduced, due to increased energy expenditure rather than decreased food intake; glucose homeostasis and insulin sensitivity were substantially improved. These studies demonstrate that Socs-3 within POMC neurons regulates leptin sensitivity and glucose homeostasis, and plays a key role in linking high-fat diet to disordered metabolism.

  7. Approach to Assessing Determinants of Glucose Homeostasis in the Conscious Mouse

    PubMed Central

    Hughey, Curtis C.; Wasserman, David H.; Lee-Young, Robert S.; Lantier, Louise

    2014-01-01

    Obesity and type 2 diabetes lessen the quality of life of those afflicted and place considerable burden on the healthcare system. Furthermore, the detrimental impact of these pathologies is expected to persist or even worsen. Diabetes is characterized by impaired insulin action and glucose homeostasis. This has led to a rapid increase in the number of mouse models of metabolic disease being used in the basic sciences to assist in facilitating a greater understanding of the metabolic dysregulation associated with obesity and diabetes, the identification of therapeutic targets, and the discovery of effective treatments. This review briefly describes the most frequently utilized models of metabolic disease. A presentation of standard methods and technologies on the horizon for assessing metabolic phenotypes in mice, with particular emphasis on glucose handling and energy balance, is provided. The article also addresses issues related to study design, selection and execution of metabolic tests of glucose metabolism, the presentation of data, and interpretation of results. PMID:25074441

  8. Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression.

    PubMed

    Serebrovska, Tetiana V; Portnychenko, Alla G; Drevytska, Tetiana I; Portnichenko, Vladimir I; Xi, Lei; Egorov, Egor; Gavalko, Anna V; Naskalova, Svitlana; Chizhova, Valentina; Shatylo, Valeriy B

    2017-09-01

    The present study aimed at examining beneficial effects of intermittent hypoxia training (IHT) under prediabetic conditions. We investigate the effects of three-week IHT on blood glucose level, tolerance to acute hypoxia, and leukocyte mRNA expression of hypoxia inducible factor 1α (HIF-1α) and its target genes, i.e. insulin receptor, facilitated glucose transporter-solute carrier family-2, and potassium voltage-gated channel subfamily J. Seven healthy and 11 prediabetic men and women (44-70 years of age) were examined before, next day and one month after three-week IHT (3 sessions per week, each session consisting 4 cycles of 5-min 12% O 2 and 5-min room air breathing). We found that IHT afforded beneficial effects on glucose homeostasis in patients with prediabetes reducing fasting glucose and during standard oral glucose tolerance test. The most pronounced positive effects were observed at one month after IHT termination. IHT also significantly increased the tolerance to acute hypoxia (i.e. SaO 2 level at 20th min of breathing with 12% O 2 ) and improved functional parameters of respiratory and cardiovascular systems. IHT stimulated HIF-1α mRNA expression in blood leukocytes in healthy and prediabetic subjects, but in prediabetes patients the maximum increase was lagged. The greatest changes in mRNA expression of HIF-1α target genes occurred a month after IHT and coincided with the largest decrease in blood glucose levels. The higher expression of HIF-1α was positively associated with higher tolerance to hypoxia and better glucose homeostasis. In conclusion, our results suggest that IHT may be useful for preventing the development of type 2 diabetes. Impact statement The present study investigated the beneficial effects of intermittent hypoxia training (IHT) in humans under prediabetic conditions. We found that three-week moderate IHT induced higher HIF-1α mRNA expressions as well as its target genes, which were positively correlated with higher tolerance

  9. Association of variants in gastric inhibitory polypeptide receptor gene with impaired glucose homeostasis in obese children and adolescents from Berlin.

    PubMed

    Sauber, Jeannine; Grothe, Jessica; Behm, Maria; Scherag, André; Grallert, Harald; Illig, Thomas; Hinney, Anke; Hebebrand, Johannes; Wiegand, Susanna; Grüters, Annette; Krude, Heiko; Biebermann, Heike

    2010-08-01

    In the past 20 years, obesity has become a major health problem due to associated diseases like type 2 diabetes mellitus. The gastric inhibitory polypeptide receptor (GIPR) modulates body weight and glucose homeostasis and, therefore, represents an interesting candidate gene for obesity and the comorbidity impaired glucose homeostasis. Recently, a GIPR variation was found to be associated with impaired insulin response in humans. In this study, we screened the GIPR gene for mutations and examined the association between three single-nucleotide polymorphisms (SNPs; rs8111428, rs2302382, rs1800437) and childhood obesity, as well as impaired glucose homeostasis. The coding region of the GIPR was screened for mutations by direct sequencing. We genotyped three known SNPs in 2280 healthy normal weight (1696) and obese (584) children and adolescents. Genotyping was performed using the SNaPshot protocol, the iplex, and matrix-assisted laser desorption ionization time-of-flight spectrometry technique. Obesity was defined by a body mass index SDS above 2; homeostatic model assessment was calculated. No evidence for an association was found between the SNPs and the obesity phenotype. Significant association was found between the minor allele C of the SNP rs1800437 and elevated homeostasis model of insulin resistance values (P=0.001). No further sequence variations in the GIPR were found to be associated with childhood obesity. Variations of the GIPR sequence are not associated with childhood obesity. This study points to a potential role for rs1800437 in glucose homeostasis. Further studies are necessary to confirm these results.

  10. The impact of ethnicity on glucose homeostasis after gestational diabetes mellitus.

    PubMed

    Ignell, Claes; Shaat, Nael; Ekelund, Magnus; Berntorp, Kerstin

    2013-12-01

    The objective of this study was to examine measures of insulin resistance and beta cell function in relation to ethnicity and the development of diabetes after gestational diabetes mellitus (GDM). Glucose homeostasis was assessed during a 75 g oral glucose tolerance test 1-2 years after delivery in 456 women with previous GDM (362 European, 94 non-European; including 41 Arab and 43 Asian women) and 133 control women. Insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). The insulinogenic index (I/G30) and the disposition index [(I/G30)/HOMA-IR] were used to quantify insulin secretion. Women developing diabetes after GDM were characterized by increased HOMA-IR [p = 0.010, adjusted for body mass index (BMI)], whereas the disposition index was decreased in all women with previous GDM irrespective of glucose tolerance, most pronounced in the presence of diabetes (BMI-adjusted p = 1 × 10(-5)). Non-European origin was associated with increased HOMA-IR (p = 0.001 vs. European), strengthened by adjustment for BMI in Asian women (p = 0.046 vs. p = 0.016), but eradicated among Arab women (p = 0.004 vs. p = 0.65). Non-European women exhibited an increased frequency of diabetes after GDM (17 % vs. European 4 %, p = 2 × 10(-5)). In addition to BMI, non-European and Asian origin was associated with the development of diabetes after GDM in a multivariate logistic regression analysis, whereas Arab origin was not. Our results highlight the importance of preventive measures to ensure a healthy lifestyle in women with GDM, particularly in high-risk ethnic groups.

  11. Effects of prenatal caffeine exposure on glucose homeostasis of adult offspring rats

    NASA Astrophysics Data System (ADS)

    Kou, Hao; Wang, Gui-hua; Pei, Lin-guo; Zhang, Li; Shi, Chai; Guo, Yu; Wu, Dong-fang; Wang, Hui

    2017-12-01

    Epidemiological evidences show that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR). The IUGR offspring also present glucose intolerance and type 2 diabetes mellitus after maturity. We have previously demonstrated that PCE induced IUGR and increased susceptibility to adult metabolic syndrome in rats. This study aimed to further investigate the effects of PCE on glucose homeostasis in adult offspring rats. Pregnant rats were administered caffeine (120 mg/kg/day, intragastrically) from gestational days 11 to 20. PCE offspring presented partial catch-up growth pattern after birth, characterizing by the increased body weight gain rates. Meanwhile, PCE had no significant influences on the basal blood glucose and insulin phenotypes of adult offspring but increased the glucose tolerance, glucose-stimulated insulin section and β cell sensitivity to glucose in female progeny. The insulin sensitivity of both male and female PCE offspring were enhanced accompanied with reduced β cell fraction and mass. Western blotting results revealed that significant augmentation in protein expression of hepatic insulin signaling elements of PCE females, including insulin receptor (INSR), insulin receptor substrate 1 (IRS-1) and the phosphorylation of serine-threonine protein kinase (Akt), was also potentiated. In conclusion, we demonstrated that PCE reduced the pancreatic β mass but increased the glucose tolerance in adult offspring rats, especially for females. The adaptive compensatory enhancement of β cell responsiveness to glucose and elevated insulin sensitivity mainly mediated by upregulated hepatic insulin signaling might coordinately contribute to the increased glucose tolerance.

  12. Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver

    EPA Science Inventory

    Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver D.B. Johnson, 1 W.O. Ward, 2 V.L. Bass, 2 M.C.J. Schladweiler, 2A.D. Ledbetter, 2 D. Andrews, and U.P. Kodavanti 2 1 Curriculum in Toxicology, UNC School of Medicine, Cha...

  13. Orally Administered Baker's Yeast β-Glucan Promotes Glucose and Lipid Homeostasis in the Livers of Obesity and Diabetes Model Mice.

    PubMed

    Cao, Yan; Sun, Ying; Zou, Siwei; Li, Mengxia; Xu, Xiaojuan

    2017-11-08

    Baker's yeast glucan (BYG) has been reported to be an anti-diabetic agent. In the work described herein, further study on the effect of orally administered BYG on glucose and lipid homeostasis in the livers of ob/ob mice was performed. It was found that BYG decreased the blood glucose and the hepatic glucose and lipid disorders. Western blotting analysis revealed that BYG up-regulated p-AKT and p-AMPK, and down-regulated p-Acc in the liver. Furthermore, RNA-Seq analysis indicated that BYG down-regulated genes responsible for gluconeogenesis (G6pase and Got1), fatty acid biosynthesis (Acly, Acc, Fas, etc.), glycerolipid synthesis (Gpam and Lipin1/2), and cholesterol synthesis (Hmgcr, Fdps, etc.). Additionally, BYG decreased glucose transporters SGLT1 and GLUT2, fat emulsification, and adipogenic genes/proteins in the intestine to decrease glucose and lipid absorption. All these findings demonstrated that BYG is beneficial for regulating glucose and lipid homeostasis in diabetic mice, and thus has potential applications in anti-diabetic foods or drugs.

  14. Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity.

    PubMed

    Bouret, Sebastien; Levin, Barry E; Ozanne, Susan E

    2015-01-01

    Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre- and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease. Copyright © 2015 the American Physiological Society.

  15. Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

    PubMed Central

    Bouret, Sebastien; Levin, Barry E.; Ozanne, Susan E.

    2015-01-01

    Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre- and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease. PMID:25540138

  16. Atypical antipsychotics and glucose homeostasis.

    PubMed

    Bergman, Richard N; Ader, Marilyn

    2005-04-01

    Persistent reports have linked atypical antipsychotics with diabetes, yet causative mechanisms responsible for this linkage are unclear. Goals of this review are to outline the pathogenesis of nonimmune diabetes and to survey the available literature related to why antipsychotics may lead to this disease. We accessed the literature regarding atypical antipsychotics and glucose homeostasis using PubMed. The search included English-language publications from 1990 through October 2004. Keywords used included atypical antipsychotics plus one of the following: glucose, insulin, glucose tolerance, obesity, or diabetes. In addition, we culled information from published abstracts from several national and international scientific meetings for the years 2001 through 2004, including the American Diabetes Association, the International Congress on Schizophrenia Research, and the American College of Neuropsychopharmacology. The latter search was necessary because of the paucity of well-controlled prospective studies. We examined publications with significant new data or publications that contributed to the overall comprehension of the impact of atypical antipsychotics on glucose metabolism. We favored original peer-reviewed articles and were less likely to cite single case studies and/or anecdotal information. Approximately 75% of the fewer than 150 identified articles were examined and included in this review. Validity of data was evaluated using the existence of peer-review status as well as our own experience with methodology described in the specific articles. The metabolic profile caused by atypical antipsychotic treatment resembles type 2 diabetes. These agents cause weight gain in treated subjects and may induce obesity in both visceral and subcutaneous depots, as occurs in diabetes. Insulin resistance, usually associated with obesity, occurs to varying degrees with different antipsychotics, although more comparative studies with direct assessment of resistance are

  17. Lipoprotein lipase in hypothalamus is a key regulator of body weight gain and glucose homeostasis in mice.

    PubMed

    Laperrousaz, Elise; Moullé, Valentine S; Denis, Raphaël G; Kassis, Nadim; Berland, Chloé; Colsch, Benoit; Fioramonti, Xavier; Philippe, Erwann; Lacombe, Amélie; Vanacker, Charlotte; Butin, Noémie; Bruce, Kimberley D; Wang, Hong; Wang, Yongping; Gao, Yuanqing; Garcia-Caceres, Cristina; Prévot, Vincent; Tschöp, Matthias H; Eckel, Robert H; Le Stunff, Hervé; Luquet, Serge; Magnan, Christophe; Cruciani-Guglielmacci, Céline

    2017-07-01

    Regulation of energy balance involves the participation of many factors, including nutrients, among which are circulating lipids, acting as peripheral signals informing the central nervous system of the energy status of the organism. It has been shown that neuronal lipoprotein lipase (LPL) participates in the control of energy balance by hydrolysing lipid particles enriched in triacylglycerols. Here, we tested the hypothesis that LPL in the mediobasal hypothalamus (MBH), a well-known nucleus implicated in the regulation of metabolic homeostasis, could also contribute to the regulation of body weight and glucose homeostasis. We injected an adeno-associated virus (AAV) expressing Cre-green fluorescent protein into the MBH of Lpl-floxed mice (and wild-type mice) to specifically decrease LPL activity in the MBH. In parallel, we injected an AAV overexpressing Lpl into the MBH of wild-type mice. We then studied energy homeostasis and hypothalamic ceramide content. The partial deletion of Lpl in the MBH in mice led to an increase in body weight compared with controls (37.72 ± 0.7 g vs 28.46 ± 0.12, p < 0.001) associated with a decrease in locomotor activity. These mice developed hyperinsulinaemia and glucose intolerance. This phenotype also displayed reduced expression of Cers1 in the hypothalamus as well as decreased concentration of several C18 species of ceramides and a 3-fold decrease in total ceramide intensity. Conversely, overexpression of Lpl specifically in the MBH induced a decrease in body weight. Our study shows that LPL in the MBH is an important regulator of body weight and glucose homeostasis.

  18. The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis

    PubMed Central

    Clegg, Deborah J.; Hevener, Andrea L.

    2013-01-01

    Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet β-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders. PMID:23460719

  19. Neuronal regulation of homeostasis by nutrient sensing.

    PubMed

    Lam, Tony K T

    2010-04-01

    In type 2 diabetes and obesity, the homeostatic control of glucose and energy balance is impaired, leading to hyperglycemia and hyperphagia. Recent studies indicate that nutrient-sensing mechanisms in the body activate negative-feedback systems to regulate energy and glucose homeostasis through a neuronal network. Direct metabolic signaling within the intestine activates gut-brain and gut-brain-liver axes to regulate energy and glucose homeostasis, respectively. In parallel, direct metabolism of nutrients within the hypothalamus regulates food intake and blood glucose levels. These findings highlight the importance of the central nervous system in mediating the ability of nutrient sensing to maintain homeostasis. Futhermore, they provide a physiological and neuronal framework by which enhancing or restoring nutrient sensing in the intestine and the brain could normalize energy and glucose homeostasis in diabetes and obesity.

  20. Glucose Homeostasis, Pancreatic Endocrine Function, and Outcomes in Advanced Heart Failure.

    PubMed

    Melenovsky, Vojtech; Benes, Jan; Franekova, Janka; Kovar, Jan; Borlaug, Barry A; Segetova, Marketa; Tura, Andrea; Pelikanova, Tereza

    2017-08-07

    The mechanisms and relevance of impaired glucose homeostasis in advanced heart failure (HF) are poorly understood. The study goals were to examine glucose regulation, pancreatic endocrine function, and metabolic factors related to prognosis in patients with nondiabetic advanced HF. In total, 140 advanced HF patients without known diabetes mellitus and 21 sex-, age-, and body mass index-matched controls underwent body composition assessment, oral glucose tolerance testing, and measurement of glucose-regulating hormones to model pancreatic β-cell secretory response. Compared with controls, HF patients had similar fasting glucose and insulin levels but higher levels after oral glucose tolerance testing. Insulin secretion was not impaired, but with increasing HF severity, there was a reduction in glucose, insulin, and insulin/glucagon ratio-a signature of starvation. The insulin/C-peptide ratio was decreased in HF, indicating enhanced insulin clearance, and this was correlated with lower cardiac output, hepatic insufficiency, right ventricular dysfunction, and body wasting. After a median of 449 days, 41% of patients experienced an adverse event (death, urgent transplant, or assist device). Increased glucagon and, paradoxically, low fasting plasma glucose displayed the strongest relations to outcome ( P =0.01). Patients in the lowest quartile of fasting plasma glucose (3.8-5.1 mmol·L -1 , 68-101 mg·dL -1 ) had 3-times higher event risk than in the top quartile (6.0-7.9 mmol·L -1 , 108-142 mg·dL -1 ; relative risk: 3.05 [95% confidence interval, 1.46-6.77]; P =0.002). Low fasting plasma glucose and increased glucagon are robust metabolic predictors of adverse events in advanced HF. Pancreatic insulin secretion is preserved in advanced HF, but levels decrease with increasing HF severity due to enhanced insulin clearance that is coupled with right heart failure and cardiac cachexia. © 2017 The Authors. Published on behalf of the American Heart Association, Inc

  1. 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.

  2. The Essential Role of Mbd5 in the Regulation of Somatic Growth and Glucose Homeostasis in Mice

    PubMed Central

    Du, Yarui; Liu, Bo; Guo, Fan; Xu, Guifang; Ding, Yuqiang; Liu, Yong; Sun, Xin; Xu, Guoliang

    2012-01-01

    Methyl-CpG binding domain protein 5 (MBD5) belongs to the MBD family proteins, which play central roles in transcriptional regulation and development. The significance of MBD5 function is highlighted by recent studies implicating it as a candidate gene involved in human 2q23.1 microdeletion syndrome. To investigate the physiological role of Mbd5, we generated knockout mice. The Mbd5-deficient mice showed growth retardation, wasting and pre-weaning lethality. The observed growth retardation was associated with the impairment of GH/IGF-1 axis in Mbd5-null pups. Conditional knockout of Mbd5 in the brain resulted in the similar phenotypes as whole body deletion, indicating that Mbd5 functions in the nervous system to regulate postnatal growth. Moreover, the mutant mice also displayed enhanced glucose tolerance and elevated insulin sensitivity as a result of increased insulin signaling, ultimately resulting in disturbed glucose homeostasis and hypoglycemia. These results indicate Mbd5 as an essential factor for mouse postnatal growth and maintenance of glucose homeostasis. PMID:23077600

  3. The essential role of Mbd5 in the regulation of somatic growth and glucose homeostasis in mice.

    PubMed

    Du, Yarui; Liu, Bo; Guo, Fan; Xu, Guifang; Ding, Yuqiang; Liu, Yong; Sun, Xin; Xu, Guoliang

    2012-01-01

    Methyl-CpG binding domain protein 5 (MBD5) belongs to the MBD family proteins, which play central roles in transcriptional regulation and development. The significance of MBD5 function is highlighted by recent studies implicating it as a candidate gene involved in human 2q23.1 microdeletion syndrome. To investigate the physiological role of Mbd5, we generated knockout mice. The Mbd5-deficient mice showed growth retardation, wasting and pre-weaning lethality. The observed growth retardation was associated with the impairment of GH/IGF-1 axis in Mbd5-null pups. Conditional knockout of Mbd5 in the brain resulted in the similar phenotypes as whole body deletion, indicating that Mbd5 functions in the nervous system to regulate postnatal growth. Moreover, the mutant mice also displayed enhanced glucose tolerance and elevated insulin sensitivity as a result of increased insulin signaling, ultimately resulting in disturbed glucose homeostasis and hypoglycemia. These results indicate Mbd5 as an essential factor for mouse postnatal growth and maintenance of glucose homeostasis.

  4. The ICET-A Recommendations for the Diagnosis and Management of Disturbances of Glucose Homeostasis in Thalassemia Major Patients

    PubMed Central

    De Sanctis, Vincenzo; Soliman, Ashraf T.; Elsedfy, Heba; Yaarubi, Saif AL; Skordis, Nicos; Khater, Doaa; El Kholy, Mohamed; Stoeva, Iva; Fiscina, Bernadette; Angastiniotis, Michael; Daar, Shahina; Kattamis, Christos

    2016-01-01

    Iron overload in patients with thalassemia major (TM) affects glucose regulation and is mediated by several mechanisms. The pathogenesis of glycaemic abnormalities in TM is complex and multifactorial. It has been predominantly attributed to a combination of reduced insulin secretory capacity and insulin resistance. The exact mechanisms responsible for progression from norm glycaemia to overt diabetes in these patients are still poorly understood but are attributed mainly to insulin deficiency resulting from the toxic effects of iron deposited in the pancreas and insulin resistance. A group of endocrinologists, haematologists and paediatricians, members of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) convened to formulate recommendations for the diagnosis and management of abnormalities of glucose homeostasis in thalassemia major patients on the basis of available evidence from clinical and laboratory data and consensus practice. The results of their work and discussions are described in this article. PMID:27872738

  5. The Action of Antidiabetic Plants of the Canadian James Bay Cree Traditional Pharmacopeia on Key Enzymes of Hepatic Glucose Homeostasis

    PubMed Central

    Nachar, Abir; Vallerand, Diane; Musallam, Lina; Lavoie, Louis; Arnason, John; Haddad, Pierre S.

    2013-01-01

    We determined the capacity of putative antidiabetic plants used by the Eastern James Bay Cree (Canada) to modulate key enzymes of gluconeogenesis and glycogen synthesis and key regulating kinases. Glucose-6-phosphatase (G6Pase) and glycogen synthase (GS) activities were assessed in cultured hepatocytes treated with crude extracts of seventeen plant species. Phosphorylation of AMP-dependent protein kinase (AMPK), Akt, and Glycogen synthase kinase-3 (GSK-3) were probed by Western blot. Seven of the seventeen plant extracts significantly decreased G6Pase activity, Abies balsamea and Picea glauca, exerting an effect similar to insulin. This action involved both Akt and AMPK phosphorylation. On the other hand, several plant extracts activated GS, Larix laricina and A. balsamea, far exceeding the action of insulin. We also found a significant correlation between GS stimulation and GSK-3 phosphorylation induced by plant extract treatments. In summary, three Cree plants stand out for marked effects on hepatic glucose homeostasis. P. glauca affects glucose production whereas L. laricina rather acts on glucose storage. However, A. balsamea has the most promising profile, simultaneously and powerfully reducing G6Pase and stimulating GS. Our studies thus confirm that the reduction of hepatic glucose production likely contributes to the therapeutic potential of several antidiabetic Cree traditional medicines. PMID:23864882

  6. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

    USDA-ARS?s Scientific Manuscript database

    The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiotaderived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine...

  7. Sucralose Affects Glycemic and Hormonal Responses to an Oral Glucose Load

    PubMed Central

    Pepino, M. Yanina; Tiemann, Courtney D.; Patterson, Bruce W.; Wice, Burton M.; Klein, Samuel

    2013-01-01

    OBJECTIVE Nonnutritive sweeteners (NNS), such as sucralose, have been reported to have metabolic effects in animal models. However, the relevance of these findings to human subjects is not clear. We evaluated the acute effects of sucralose ingestion on the metabolic response to an oral glucose load in obese subjects. RESEARCH DESIGN AND METHODS Seventeen obese subjects (BMI 42.3 ± 1.6 kg/m2) who did not use NNS and were insulin sensitive (based on a homeostasis model assessment of insulin resistance score ≤2.6) underwent a 5-h modified oral glucose tolerance test on two separate occasions preceded by consuming either sucralose (experimental condition) or water (control condition) 10 min before the glucose load in a randomized crossover design. Indices of β-cell function, insulin sensitivity (SI), and insulin clearance rates were estimated by using minimal models of glucose, insulin, and C-peptide kinetics. RESULTS Compared with the control condition, sucralose ingestion caused 1) a greater incremental increase in peak plasma glucose concentrations (4.2 ± 0.2 vs. 4.8 ± 0.3 mmol/L; P = 0.03), 2) a 20 ± 8% greater incremental increase in insulin area under the curve (AUC) (P < 0.03), 3) a 22 ± 7% greater peak insulin secretion rate (P < 0.02), 4) a 7 ± 4% decrease in insulin clearance (P = 0.04), and 5) a 23 ± 20% decrease in SI (P = 0.01). There were no significant differences between conditions in active glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, glucagon incremental AUC, or indices of the sensitivity of the β-cell response to glucose. CONCLUSIONS These data demonstrate that sucralose affects the glycemic and insulin responses to an oral glucose load in obese people who do not normally consume NNS. PMID:23633524

  8. Inositol 1,4,5-trisphosphate receptor 1 mutation perturbs glucose homeostasis and enhances susceptibility to diet-induced diabetes.

    PubMed

    Ye, Risheng; Ni, Min; Wang, Miao; Luo, Shengzhan; Zhu, Genyuan; Chow, Robert H; Lee, Amy S

    2011-08-01

    The inositol 1,4,5-trisphosphate receptors (IP3Rs) as ligand-gated Ca(2)(+) channels are key modulators of cellular processes. Despite advances in understanding their critical role in regulating neuronal function and cell death, how this family of proteins impact cell metabolism is just emerging. Unexpectedly, a transgenic mouse line (D2D) exhibited progressive glucose intolerance as a result of transgene insertion. Inverse PCR was used to identify the gene disruption in the D2D mice. This led to the discovery that Itpr1 is among the ten loci disrupted in chromosome 6. Itpr1 encodes for IP3R1, the most abundant IP3R isoform in mouse brain and also highly expressed in pancreatic β-cells. To study IP3R1 function in glucose metabolism, we used the Itpr1 heterozygous mutant mice, opt/+. Glucose homeostasis in male mice cohorts was examined by multiple approaches of metabolic phenotyping. Under regular diet, the opt/+ mice developed glucose intolerance but no insulin resistance. Decrease in second-phase glucose-stimulated blood insulin level was observed in opt/+ mice, accompanied by reduced β-cell mass and insulin content. Strikingly, when fed with high-fat diet, the opt/+ mice were more susceptible to the development of hyperglycemia, glucose intolerance, and insulin resistance. Collectively, our studies identify the gene Itpr1 being interrupted in the D2D mice and uncover a novel role of IP3R1 in regulation of in vivo glucose homeostasis and development of diet-induced diabetes.

  9. 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.

  10. Effects of Saturated Fat, Polyunsaturated Fat, Monounsaturated Fat, and Carbohydrate on Glucose-Insulin Homeostasis: A Systematic Review and Meta-analysis of Randomised Controlled Feeding Trials

    PubMed Central

    Micha, Renata; Wu, Jason H. Y.; de Oliveira Otto, Marcia C.; Mozaffarian, Dariush

    2016-01-01

    Background Effects of major dietary macronutrients on glucose-insulin homeostasis remain controversial and may vary by the clinical measures examined. We aimed to assess how saturated fat (SFA), monounsaturated fat (MUFA), polyunsaturated fat (PUFA), and carbohydrate affect key metrics of glucose-insulin homeostasis. Methods and Findings We systematically searched multiple databases (PubMed, EMBASE, OVID, BIOSIS, Web-of-Knowledge, CAB, CINAHL, Cochrane Library, SIGLE, Faculty1000) for randomised controlled feeding trials published by 26 Nov 2015 that tested effects of macronutrient intake on blood glucose, insulin, HbA1c, insulin sensitivity, and insulin secretion in adults aged ≥18 years. We excluded trials with non-isocaloric comparisons and trials providing dietary advice or supplements rather than meals. Studies were reviewed and data extracted independently in duplicate. Among 6,124 abstracts, 102 trials, including 239 diet arms and 4,220 adults, met eligibility requirements. Using multiple-treatment meta-regression, we estimated dose-response effects of isocaloric replacements between SFA, MUFA, PUFA, and carbohydrate, adjusted for protein, trans fat, and dietary fibre. Replacing 5% energy from carbohydrate with SFA had no significant effect on fasting glucose (+0.02 mmol/L, 95% CI = -0.01, +0.04; n trials = 99), but lowered fasting insulin (-1.1 pmol/L; -1.7, -0.5; n = 90). Replacing carbohydrate with MUFA lowered HbA1c (-0.09%; -0.12, -0.05; n = 23), 2 h post-challenge insulin (-20.3 pmol/L; -32.2, -8.4; n = 11), and homeostasis model assessment for insulin resistance (HOMA-IR) (-2.4%; -4.6, -0.3; n = 30). Replacing carbohydrate with PUFA significantly lowered HbA1c (-0.11%; -0.17, -0.05) and fasting insulin (-1.6 pmol/L; -2.8, -0.4). Replacing SFA with PUFA significantly lowered glucose, HbA1c, C-peptide, and HOMA. Based on gold-standard acute insulin response in ten trials, PUFA significantly improved insulin secretion capacity (+0.5 pmol/L/min; 0.2, 0

  11. Palmitic acid in the sn-2 position of dietary triacylglycerols does not affect insulin secretion or glucose homeostasis in healthy men and women

    PubMed Central

    Filippou, A; Teng, K-T; Berry, S E; Sanders, T A B

    2014-01-01

    Background/objectives: Dietary triacylglycerols containing palmitic acid in the sn-2 position might impair insulin release and increase plasma glucose. Subjects/Methods: We used a cross-over designed feeding trial in 53 healthy Asian men and women (20–50 years) to test this hypothesis by exchanging 20% energy of palm olein (PO; control) with randomly interesterified PO (IPO) or high oleic acid sunflower oil (HOS). After a 2-week run-in period on PO, participants were fed PO, IPO and HOS for 6 week consecutively in randomly allocated sequences. Fasting (midpoint and endpoint) and postprandial blood at the endpoint following a test meal (3.54 MJ, 14 g protein, 85 g carbohydrate and 50 g fat as PO) were collected for the measurement of C-peptide, insulin, glucose, plasma glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, lipids and apolipoproteins; pre-specified primary and secondary outcomes were postprandial changes in C-peptide and plasma glucose. Results: Low density lipoprotein cholesterol was 0.3 mmol/l (95% confidence interval (95% CI)) 0.1, 0.5; P<0.001) lower on HOS than on PO or IPO as predicted, indicating good compliance to the dietary intervention. There were no significant differences (P=0.58) between diets among the 10 male and 31 female completers in the incremental area under the curve (0–2 h) for C-peptide in nmol.120 min/l: GM (95% CI) were PO 220 (196, 245), IPO 212 (190, 235) and HOS 224 (204, 244). Plasma glucose was 8% lower at 2 h on IPO vs PO and HOS (both P<0.05). Conclusion: Palmitic acid in the sn-2 position does not adversely impair insulin secretion and glucose homeostasis. PMID:25052227

  12. Palmitic acid in the sn-2 position of dietary triacylglycerols does not affect insulin secretion or glucose homeostasis in healthy men and women.

    PubMed

    Filippou, A; Teng, K-T; Berry, S E; Sanders, T A B

    2014-09-01

    Dietary triacylglycerols containing palmitic acid in the sn-2 position might impair insulin release and increase plasma glucose. We used a cross-over designed feeding trial in 53 healthy Asian men and women (20-50 years) to test this hypothesis by exchanging 20% energy of palm olein (PO; control) with randomly interesterified PO (IPO) or high oleic acid sunflower oil (HOS). After a 2-week run-in period on PO, participants were fed PO, IPO and HOS for 6 week consecutively in randomly allocated sequences. Fasting (midpoint and endpoint) and postprandial blood at the endpoint following a test meal (3.54 MJ, 14 g protein, 85 g carbohydrate and 50 g fat as PO) were collected for the measurement of C-peptide, insulin, glucose, plasma glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, lipids and apolipoproteins; pre-specified primary and secondary outcomes were postprandial changes in C-peptide and plasma glucose. Low density lipoprotein cholesterol was 0.3 mmol/l (95% confidence interval (95% CI)) 0.1, 0.5; P<0.001) lower on HOS than on PO or IPO as predicted, indicating good compliance to the dietary intervention. There were no significant differences (P=0.58) between diets among the 10 male and 31 female completers in the incremental area under the curve (0-2 h) for C-peptide in nmol.120 min/l: GM (95% CI) were PO 220 (196, 245), IPO 212 (190, 235) and HOS 224 (204, 244). Plasma glucose was 8% lower at 2 h on IPO vs PO and HOS (both P<0.05). Palmitic acid in the sn-2 position does not adversely impair insulin secretion and glucose homeostasis.

  13. 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.

  14. Sex Differences in the Association of Urinary Bisphenol-A Concentration with Selected Indices of Glucose Homeostasis among U.S. adults

    PubMed Central

    Beydoun, Hind A.; Khanal, Suraj; Zonderman, Alan B.; Beydoun, May A.

    2013-01-01

    Purpose Emerging evidence suggests that exposure to endocrine disruptors may initiate or exacerbate adiposity and associated health problems. This study examined sex differences in the association of urinary level of bisphenol-A (BPA) with selected indices of glucose homeostasis among U.S. adults. Methods Data analyses were performed using a sample of 1,586 participants from the 2005–2008 National Health and Nutrition Examination Surveys. BPA level and the ratio of BPA-to-creatinine level were defined as log-transformed variables and in quartiles. Selected indices of glucose homeostasis were defined using fasting glucose and insulin data. Multivariate linear and logistic regression models for the hypothesized relationships were constructed after controlling for age, sex, race, education, marital status, smoking status, physical activity, total dietary intake and urinary creatinine concentration. Results Taking 1st quartile as a referent, 3rd quartile of BPA level was positively associated with log-transformed level of insulin and β-cell function (HOMA-β) as well as insulin resistance (log-transformed HOMA-IR; HOMA-IR≥2.5), with significant BPA-by-sex interaction; these associations were stronger among males than among females. Irrespective of sex, the ratio of BPA-to-creatinine level was not predictive of indices of glucose homeostasis. Conclusions A complex association may exist between BPA and hyperinsulinemia among adult U.S. men. Prospective cohort studies are needed to further elucidate endocrine disruptors as determinants of adiposity-related disturbances. PMID:23954568

  15. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons.

    PubMed

    Claret, Marc; Smith, Mark A; Batterham, Rachel L; Selman, Colin; Choudhury, Agharul I; Fryer, Lee G D; Clements, Melanie; Al-Qassab, Hind; Heffron, Helen; Xu, Allison W; Speakman, John R; Barsh, Gregory S; Viollet, Benoit; Vaulont, Sophie; Ashford, Michael L J; Carling, David; Withers, Dominic J

    2007-08-01

    Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRP alpha 2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.

  16. Imidacloprid insecticide exposure induces stress and disrupts glucose homeostasis in male rats.

    PubMed

    Khalil, Samah R; Awad, Ashraf; Mohammed, Hesham H; Nassan, Mohamed Abdo

    2017-10-01

    In the present study, we evaluated the stress response in adult rats who were administered imidacloprid (IMI) orally in two doses (0.5 and 1.0mg/kg bw for 60days). It led to an alteration in the levels of cortisone and catecholamines and induced behavioral deficits, particularly in the animals exposed to the dose of 1.0mg/kg. IMI was further analyzed for the effect on glucose homeostasis in developing and adult rats at a dose of 1.0mg/kg bw where it elicited a hyperglycemic effect. Moreover, we observed an alteration in the mRNA levels of glucose transporters. Histopathological and immunohistochemical data displayed structural perturbations in pancreatic tissue with a decline in the expression of insulin and GLUT4, particularly in the developing rats. Collectively, IMI treatment resulted in stress represented by behavioral and biochemical changes, particularly at a dose of 1.0mg/kg bw. Moreover, IMI perturbed the glucose regulation through hyperglycemic activity in both developing and adult rats, an observation clearly evident in the developing rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Cortical delta-opioid receptors potentiate K+ homeostasis during anoxia and oxygen-glucose deprivation.

    PubMed

    Chao, Dongman; Donnelly, David F; Feng, Yin; Bazzy-Asaad, Alia; Xia, Ying

    2007-02-01

    Central neurons are extremely vulnerable to hypoxic/ischemic insult, which is a major cause of neurologic morbidity and mortality as a consequence of neuronal dysfunction and death. Our recent work has shown that delta-opioid receptor (DOR) is neuroprotective against hypoxic and excitotoxic stress, although the underlying mechanisms remain unclear. Because hypoxia/ischemia disrupts ionic homeostasis with an increase in extracellular K(+), which plays a role in neuronal death, we asked whether DOR activation preserves K(+) homeostasis during hypoxic/ischemic stress. To test this hypothesis, extracellular recordings with K(+)-sensitive microelectrodes were performed in mouse cortical slices under anoxia or oxygen-glucose deprivation (OGD). The main findings in this study are that (1) DOR activation with [D-Ala(2), D-Leu(5)]-enkephalinamide attenuated the anoxia- and OGD-induced increase in extracellular K(+) and decrease in DC potential in cortical slices; (2) DOR inhibition with naltrindole, a DOR antagonist, completely abolished the DOR-mediated prevention of increase in extracellular K(+) and decrease in DC potential; (3) inhibition of protein kinase A (PKA) with N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide dihydrochloride had no effect on the DOR protection; and (4) inhibition of protein kinase C (PKC) with chelerythrine chloride reduced the DOR protection, whereas the PKC activator (phorbol 12-myristate 13-acetate) mimicked the effect of DOR activation on K(+) homeostasis. These data suggest that activation of DOR protects the cortex against anoxia- or ODG-induced derangement of potassium homeostasis, and this protection occurs via a PKC-dependent and PKA-independent pathway. We conclude that an important aspect of DOR-mediated neuroprotection is its early action against derangement of K(+) homeostasis during anoxia or ischemia.

  18. Sex-Related Differences in the Effects of the Mediterranean Diet on Glucose and Insulin Homeostasis

    PubMed Central

    Bédard, Alexandra; Corneau, Louise; Lamarche, Benoît; Dodin, Sylvie; Lemieux, Simone

    2014-01-01

    Objective. To document sex differences in the impact of the Mediterranean diet (MedDiet) on glucose/insulin homeostasis and to verify whether these sex-related effects were associated with changes in nonesterified fatty acids (NEFA). Methods. All foods were provided to 38 men and 32 premenopausal women (24–53 y) during 4 weeks. Variables were measured during a 180 min OGTT before and after the MedDiet. Results. A sex-by-time interaction for plasma insulin iAUC was found (men: −17.8%, P = 0.02; women: +9.4%, P = 0.63; P for sex-by-time interaction = 0.005). A sex-by-time interaction was also observed for insulin sensitivity (Cederholm index, P = 0.03), for which only men experienced improvements (men: +8.1%, P = 0.047; women: −5.9%, P = 0.94). No sex difference was observed for glucose and C-peptide responses. Trends toward a decrease in NEFA AUC (P = 0.06) and an increase in NEFA suppression rate (P = 0.06) were noted, with no sex difference. Changes in NEFA were not associated with change in insulin sensitivity. Conclusions. Results suggest that the more favorable changes in glucose/insulin homeostasis observed in men compared to women in response to the MedDiet are not explained by sex differences in NEFA response. This clinical trial is registered with clinicaltrials.gov NCT01293344. PMID:25371817

  19. Cucurbitane Triterpenoids from the Fruits of Momordica Charantia Improve Insulin Sensitivity and Glucose Homeostasis in Streptozotocin-Induced Diabetic Mice.

    PubMed

    Han, Joo-Hui; Tuan, Nguyen Quoc; Park, Min-Ho; Quan, Khong Trong; Oh, Joonseok; Heo, Kyung-Sun; Na, MinKyun; Myung, Chang-Seon

    2018-04-01

    Momordica charantia (M. charantia) has antidiabetic effects, and cucurbitane-type triterpenoid is one of the compounds of M. charantia. This study aims to investigate whether the new cucurbitane-type triterpenoids affect insulin sensitivity both in vitro and in vivo, and the underlying mechanisms. Four compounds (C1-C4) isolated from the ethanol extract of M. charantia enhance glucose uptake in C2C12 myotubes via insulin receptor substrate-1 (IRS-1) rather than via adenosine monophosphate-activated protein kinase. The most potent, compound 2 (C2), significantly increases the activation of IRS-1 and downstream signaling pathways, resulting in glucose transporter 4 translocation. Furthermore, these C2-induced in vitro effects are blocked by specific signal inhibitors. We further evaluate the antidiabetic effect of C2 using a streptozotocin (STZ)-induced diabetic mouse model. Consistent with in vitro data, treatment with C2 (1.68 mg kg -1 ) significantly decreases blood glucose level and enhances glycogen storage in STZ-injected mice. These effects appear to be mediated by the IRS-1 signaling pathway in skeletal muscle, not in adipose and liver tissues, suggesting that C2 improves hyperglycemia by increasing glucose uptake into skeletal muscle. Our findings demonstrate that the new cucurbitane-type triterpenoids have potential for prevention and management of diabetes by improving insulin sensitivity and glucose homeostasis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Melanocortin-4-receptors Expressed by Cholinergic Neurons Regulate Energy Balance and Glucose Homeostasis

    PubMed Central

    Rossi, Jari; Balthasar, Nina; Olson, David; Scott, Michael; Berglund, Eric; Lee, Charlotte E.; Choi, Michelle J.; Lauzon, Danielle; Lowell, Bradford B.; Elmquist, Joel K.

    2011-01-01

    Summary Melanocortin-4-receptor (MC4R) mutations cause dysregulation of energy balance and hyperinsulinemia. We have used mouse models to study the physiological roles of extrahypothalamic MC4Rs. Re-expression of MC4Rs in cholinergic neurons (ChAT-Cre, loxTB MC4R mice) modestly reduced body weight gain without altering food intake and was sufficient to normalize energy expenditure and attenuate hyperglycemia and hyperinsulinemia. In contrast, restoration of MC4R expression in brainstem neurons including those in the dorsal motor nucleus of the vagus (Phox2b-Cre, loxTB MC4R mice) was sufficient to attenuate hyperinsulinemia, while the hyperglycemia and energy balance were not normalized. Additionally, hepatic insulin action and insulin mediated-suppression of hepatic glucose production were improved in ChAT-Cre, loxTB MC4R mice. These findings suggest that MC4Rs expressed by cholinergic neurons regulate energy expenditure and hepatic glucose production. Our results also provide further evidence of the dissociation in pathways mediating the effects of melanocortins on energy balance and glucose homeostasis. PMID:21284986

  1. Revisiting "Vegetables" to combat modern epidemic of imbalanced glucose homeostasis.

    PubMed

    Tiwari, Ashok Kumar

    2014-04-01

    Vegetables have been part of human food since prehistoric times and are considered nutritionally necessary and good for health. Vegetables are rich natural resource of biological antioxidants and possess capabilities of maintaining glucose homeostasis. When taken before starch-rich diet, juice also of vegetables such as ridge gourd, bottle gourd, ash gourd, chayote and juice of leaves of vegetables such as radish, Indian Dill, ajwain, tropical green amaranth, and bladder dock are reported to arrest significantly the rise in postprandial blood glucose level. Juice of vegetables such as ash gourd, squash gourd, and tropical green amaranth leaves are observed to tone-down sweet-beverages such as sucrose, fructose, and glucose-induced postprandial glycemic excursion. On the other hand, juice of egg-plant and juice of leaves of Ceylon spinach, Joyweed, and palak are reported to augment starch-induced postprandial glycemic excursion; and juice of leaves of Ceylon spinach, Joyweed, and radish supplement to the glucose-induced postprandial glycemia. Vegetables possess multifaceted antihyperglycemic activities such as inhibition of pancreatic α-amylase and intestinal α-glucosidase, inhibition of protein-tyrosine phosphatase 1β in liver and skeletal muscles, and insulin mimetic and secretagogue activities. Furthermore, they are also reported to influence polyol pathway in favor of reducing development of oxidative stress, and consequently the development of diabetic complications. In the wake of emergence of modern maladaptive diet-induced hyperglycemic epidemic therefore, vegetables may offer cost-effective dietary regimen to control diet-induced glycemic over load and future development of diabetes mellitus. However, for vegetables have been reported to do both, mitigate as well as supplement to the diet-induced postprandial glycemic load, care is required in selection of vegetables when considered as medicament.

  2. Effect of high-dose pitavastatin on glucose homeostasis in patients at elevated risk of new-onset diabetes: insights from the CAPITAIN and PREVAIL-US studies.

    PubMed

    Chapman, M J; Orsoni, A; Robillard, P; Hounslow, N; Sponseller, C A; Giral, P

    2014-05-01

    Statin treatment may impair glucose homeostasis and increase the risk of new-onset diabetes mellitus, although this may depend on the statin, dose and patient population. We evaluated the effects of pitavastatin 4 mg/day on glucose homeostasis in patients with metabolic syndrome in the CAPITAIN trial. Findings were validated in a subset of patients enrolled in PREVAIL-US. Participants with a well defined metabolic syndrome phenotype were recruited to CAPITAIN to reduce the influence of confounding factors. Validation and comparison datasets were selected comprising phenotypically similar subsets of individuals enrolled in PREVAIL-US and treated with pitavastatin or pravastatin, respectively. Mean change from baseline in parameters of glucose homeostasis (fasting plasma glucose [FPG], glycated hemoglobin [HbA1c], insulin, quantitative insulin-sensitivity check index [QUICKI] and homeostasis model of assessment-insulin resistance [HOMA-IR]) and plasma lipid profile were assessed at 6 months (CAPITAIN) and 3 months (PREVAIL-US) after initiating treatment. In CAPITAIN (n = 12), no significant differences from baseline in HbA1c, insulin, HOMA-IR and QUICKI were observed at day 180 in patients treated with pitavastatin. A small (4%) increase in FPG from baseline to day 180 (P < 0.05), was observed. In the validation dataset (n = 9), no significant differences from baseline in glycemic parameters were observed at day 84 (all comparisons P > 0.05). Similar results were observed for pravastatin in the comparison dataset (n = 14). Other than a small change in FPG in the CAPITAIN study, neutral effects of pitavastatin on glucose homeostasis were observed in two cohorts of patients with metabolic syndrome, independent of its efficacy in reducing levels of atherogenic lipoproteins. The small number of patients and relatively short follow-up period represent limitations of the study. Nevertheless, these data suggest that statin-induced diabetogenesis may

  3. A low-protein diet combined with low-dose endotoxin leads to changes in glucose homeostasis in weanling rats.

    PubMed

    Bandsma, Robert H J; Ackerley, Cameron; Koulajian, Khajag; Zhang, Ling; van Zutphen, Tim; van Dijk, Theo H; Xiao, Changting; Giacca, Adria; Lewis, Gary F

    2015-09-01

    Severe malnutrition is a leading cause of global childhood mortality, and infection and hypoglycemia or hyperglycemia are commonly present. The etiology behind the changes in glucose homeostasis is poorly understood. Here, we generated an animal model of severe malnutrition with and without low-grade inflammation to investigate the effects on glucose homeostasis. Immediately after weaning, rats were fed diets containing 5 [low-protein diet (LP)] or 20% protein [control diet (CTRL)], with or without repeated low-dose intraperitoneal lipopolysaccharide (LPS; 2 mg/kg), to mimic inflammation resulting from infections. After 4 wk on the diets, hyperglycemic clamps or euglycemic hyperinsulinemic clamps were performed with infusion of [U-(13)C6]glucose and [2-(13)C]glycerol to assess insulin secretion, action, and hepatic glucose metabolism. In separate studies, pancreatic islets were isolated for further analyses of insulin secretion and islet morphometry. Glucose clearance was reduced significantly by LP feeding alone (16%) and by LP feeding with LPS administration (43.8%) compared with control during the hyperglycemic clamps. This was associated with a strongly reduced insulin secretion in LP-fed rats in vivo as well as ex vivo in islets but signficantly enhanced whole body insulin sensitivity. Gluconeogenesis rates were unaffected by LP feeding, but glycogenolysis was higher after LP feeding. A protein-deficient diet in young rats leads to a susceptibility to low-dose endotoxin-induced impairment in glucose clearance with a decrease in the islet insulin secretory pathway. A protein-deficient diet is associated with enhanced peripheral insulin sensitivity but impaired insulin-mediated suppression of hepatic glycogenolysis. Copyright © 2015 the American Physiological Society.

  4. Central control of glucose homeostasis: the brain--endocrine pancreas axis.

    PubMed

    Thorens, B

    2010-10-01

    A large body of data gathered over the last decades has delineated the neuronal pathways that link the central nervous system with the autonomic innervation of the endocrine pancreas, which controls alpha- and beta-cell secretion activity and mass. These are important regulatory functions that are certainly keys for preserving the capacity of the endocrine pancreas to control glucose homeostasis over a lifetime. Identifying the cells involved in controlling the autonomic innervation of the endocrine pancreas, in response to nutrient, hormonal and environmental cues and how these cues are detected to activate neuronal activity are important goals of current research. Elucidation of these questions may possibly lead to new means for preserving or restoring defects in insulin and glucagon secretion associated with type 2 diabetes. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  5. The Exercise-Induced Irisin Is Associated with Improved Levels of Glucose Homeostasis Markers in Pregnant Women Participating in 8-Week Prenatal Group Fitness Program: A Pilot Study.

    PubMed

    Szumilewicz, Anna; Worska, Aneta; Piernicka, Magdalena; Kuchta, Agnieszka; Kortas, Jakub; Jastrzębski, Zbigniew; Radzimiński, Łukasz; Jaworska, Joanna; Micielska, Katarzyna; Ziemann, Ewa

    2017-01-01

    Both exercise and pregnancy influence serum irisin concentration. To determine how the interaction of pregnancy and exercise affects irisin level and whether various patterns of exercise adherence had different effect on irisin concentration. It was a one-group pretest-posttest study among 9 Caucasian nulliparous healthy women in normal pregnancy (age 23 ± 3 years, 21 ± 2 weeks of gestation; mean ± SD) who participated in 8-week group fitness program. Before and after exercise intervention, we determined serum concentrations of irisin and selected parameters of lipid profile and glucose homeostasis markers. In active women, irisin slightly decreased with the development of pregnancy. After 8 weeks of exercising, irisin correlated negatively with fasting glucose ( R = -0.922; p = 0.001), glycated hemoglobin ( R = -0.784; p = 0.012), and insulin concentrations ( R = -0.845; p = 0.004). In women exercising below recommended level, we observed a significant drop in irisin concentration, whereas in women exercising at least three times a week this myokine slightly increased (31% difference; 90% confidence limits ±28; a large, clear effect). Irisin stimulated by prenatal exercise may improve glucose homeostasis markers in healthy women and compensate for metabolic changes induced by pregnancy. Moreover, the frequency of exercise may regulate the changes in exercise-induced irisin concentration.

  6. Assessment of glucose homeostasis in crossbred steer progeny sired by Brahman bulls that experienced prenatal transportation stress

    USDA-ARS?s Scientific Manuscript database

    The objective of this experiment was to assess glucose homeostasis of crossbred male progeny whose Brahman sires experienced prenatal transportation stress (PS) in utero. Sixteen steers (PNS group) sired by 3 PS bulls gestating dams were transported for 2 h at 60, 80, 100, 120, and 140 ± 5 d of gest...

  7. The short-chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis.

    PubMed

    Fuller, Miles; Priyadarshini, Medha; Gibbons, Sean M; Angueira, Anthony R; Brodsky, Michael; Hayes, M Geoffrey; Kovatcheva-Datchary, Petia; Bäckhed, Fredrik; Gilbert, Jack A; Lowe, William L; Layden, Brian T

    2015-11-15

    The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene (Ffar2) expression is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Together, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis.

  8. [Glucose-monitoring neurons of the medial ventrolateral prefrontal (orbitofrontal) cortex are involved in the maintenance of homeostasis].

    PubMed

    Szabó, István; Hormay, Edina; Csetényi, Bettina; Nagy, Bernadett; Karádi, Zoltán

    2017-05-01

    The medial orbitofrontal cortex is involved in the regulation of feeding and metabolism. Little is known, however, about the role of local glucose-monitoring neurons in these processes, and our knowledge is also poor about characteristics of these cells. The functional significance of these chemosensory neurons was to be elucidated. Electrophysiology, by the multibarreled microelectrophoretic technique, and metabolic investigations, after streptozotocin induced selective destruction of the chemosensory neurons, were employed. Fifteen percent of the neurons responded to glucose, and these chemosensory cells displayed differential neurotransmitter and taste sensitivities. In acute glucose tolerance test, at the 30th and 60th minutes, blood glucose level in the streptozotocin-treated rats was significantly higher than that in the controls. The plasma triglyceride concentrations were also higher in the streptozotocin-treated group. Glucose-monitoring neurons of the medial orbitofrontal cortex integrate internal and external environmental signals, and monitor metabolic processes, thus, are indispensable to maintain the healthy homeostasis. Orv Hetil. 2017; 158(18): 692-700.

  9. Dietary restriction slightly affects glucose homeostasis and delays plasma cholesterol removal in rabbits with dietary lipid lowering.

    PubMed

    Yu, Qi; Liu, Ruihan; Han, Lijuan; Zhang, Guangwei; Guan, Hua; Pan, Qi; Wang, Siwang; Liu, Enqi

    2018-04-15

    Dietary restriction (DR) has been reported to promote the beneficial effects on atherosclerotic progression, lipid and glucose metabolism, but little is known about these effects can be enhanced or weakened by dietary lipid lowering. After 12 weeks of the high-cholesterol diet (HCD) feeding, hypercholesterolemic rabbits were fed with either a chow diet ad libitum (AL) or a chow diet with DR for 16 weeks of dietary lipid lowering. Here, we found the DR group exhibited a loss in body weight, small internal organs and the reduced fat mass, but the AL group accumulated more subcutaneous fat than the baseline group. DR treatment slightly worsened glucose tolerance but enhanced insulin sensitivity, and a slight effect of DR on insulin secretion was also observed. After diet cholesterol withdrawal, rabbits showed persistently lowering of total cholesterol and triglyceride in plasma. The DR group had significantly higher plasma total cholesterol than the AL group at the most time points during 7 to 16 weeks of lipid lowering. Although both AL and DR groups developed more severe atherosclerosis than baseline group, DR did not improve atherosclerotic progression and the accumulation of macrophages and smooth muscle cells as well. We concluded that DR affected glucose and lipid metabolism but did not ameliorate atherosclerosis in rabbits when associated with lipid lowering by the dietary cholesterol withdrawal.

  10. Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis.

    PubMed

    Mir-Coll, Joan; Duran, Jordi; Slebe, Felipe; García-Rocha, Mar; Gomis, Ramon; Gasa, Rosa; Guinovart, Joan J

    2016-05-01

    Glycogen accumulation occurs in beta cells of diabetic patients and has been proposed to partly mediate glucotoxicity-induced beta cell dysfunction. However, the role of glycogen metabolism in beta cell function and its contribution to diabetes pathophysiology remain poorly understood. We investigated the function of beta cell glycogen by studying glucose homeostasis in mice with (1) defective glycogen synthesis in the pancreas; and (2) excessive glycogen accumulation in beta cells. Conditional deletion of the Gys1 gene and overexpression of protein targeting to glycogen (PTG) was accomplished by Cre-lox recombination using pancreas-specific Cre lines. Glucose homeostasis was assessed by determining fasting glycaemia, insulinaemia and glucose tolerance. Beta cell mass was determined by morphometry. Glycogen was detected histologically by periodic acid-Schiff's reagent staining. Isolated islets were used for the determination of glycogen and insulin content, insulin secretion, immunoblots and gene expression assays. Gys1 knockout (Gys1 (KO)) mice did not exhibit differences in glucose tolerance or basal glycaemia and insulinaemia relative to controls. Insulin secretion and gene expression in isolated islets was also indistinguishable between Gys1 (KO) and controls. Conversely, despite effective glycogen overaccumulation in islets, mice with PTG overexpression (PTG(OE)) presented similar glucose tolerance to controls. However, under fasting conditions they exhibited lower glycaemia and higher insulinaemia. Importantly, neither young nor aged PTG(OE) mice showed differences in beta cell mass relative to age-matched controls. Finally, a high-fat diet did not reveal a beta cell-autonomous phenotype in either model. Glycogen metabolism is not required for the maintenance of beta cell function. Glycogen accumulation in beta cells alone is not sufficient to trigger the dysfunction or loss of these cells, or progression to diabetes.

  11. Vitamin D and prebiotics may benefit the intestinal microbacteria and improve glucose homeostasis in prediabetes and type 2 diabetes.

    PubMed

    Barengolts, Elena

    2013-01-01

    To review the role of human large bowel microbacteria (microbiota) in the glucose homeostasis, to address vitamin D (VD) and prebiotics interactions with microbiota, and to summarize recent randomized clinical trials (RCTs) of VD and prebiotics supplementation in prediabetes (PreDM) and type 2 diabetes mellitus (T2DM). Primary literature was reviewed in the following areas: composition and activity of human microbiota associated with PreDM and T2DM, interactions between microbiota and glucose homeostasis, the interaction of microbiota with VD/prebiotics, and RCTs of VD/prebiotics in subjects with PreDM or T2DM. The human microbiota is comprised of 100 trillion bacteria with an aggregate genome that is 150-fold larger than the human genome. Data from the animal models and human studies reveal that an "obesogenic" diet results into the initial event of microbiota transformation from symbiosis to dysbiosis. The microbial antigens, such as Gram(-) bacteria and lipopolysaccharide (LPS), translocate to the host interior and trigger increased energy harvesting and Toll-like receptor (TLR) activation with subsequent inflammatory pathways signaling. The "double hit" of steatosis (ectopic fat accumulation) and "-itis" (inflammation) and contribution of "corisks" (e.g., vitamin D deficiency [VDD]) are required to activate molecular signaling, including impaired insulin signaling and secretion, that ends with T2DM and associated diseases. Dietary changes (e.g., prebiotics, VD supplementation) may ameliorate this process if initiated prior to the process becoming irreversible. Emerging evidence suggests an important role of microbiota in glucose homeostasis. VD supplementation and prebiotics may be useful in managing PreDM and T2DM.

  12. Diagnostic Accuracies of Glycated Hemoglobin, Fructosamine, and Homeostasis Model Assessment of Insulin Resistance in Predicting Impaired Fasting Glucose, Impaired Glucose Tolerance, or New Onset Diabetes After Transplantation.

    PubMed

    Rosettenstein, Kerri; Viecelli, Andrea; Yong, Kenneth; Nguyen, Hung Do; Chakera, Aron; Chan, Doris; Dogra, Gursharan; Lim, Ee Mun; Wong, Germaine; Lim, Wai H

    2016-07-01

    New onset diabetes after transplantation (NODAT) is associated with a 3-fold greater risk of cardiovascular disease events, with early identification and treatment potentially attenuating this risk. The optimal screening test to identify those with NODAT remains unclear, and the aim of this study was to examine the diagnostic accuracies of 4 screening tests in identifying impaired fasting glucose, impaired glucose tolerance (IGT), and NODAT. This is a single-center prospective cohort study of 83 nondiabetic kidney transplant recipients between 2008 and 2011. Oral glucose tolerance test was considered the gold standard in identifying IFG/IGT or NODAT. Diagnostic accuracies of random blood glucose, glycated hemoglobin (HBA1c), fructosamine, and Homeostasis Model Assessment-Insulin Resistance in predicting IFG/IGT or NODAT were assessed using the area under the receiver operating characteristic curve. Forty (48%) recipients had IFG/IGT or NODAT. Compared with HBA1c with adjusted area under the curve (AUC) of 0.88 (95% confidence interval [95% CI], 0.77-0.93), fructosamine was the most accurate test with adjusted AUC of 0.92 (95% CI, 0.83-0.96). The adjusted AUCs of random blood glucose and Homeostasis Model Assessment-Insulin Resistance in identifying IFG/IGT were between 0.81 and 0.85. Restricting to identifying IGT/NODAT using 2-hour oral glucose tolerance test (n = 66), fructosamine was the most accurate diagnostic test with adjusted AUC of 0.93 (95% CI, 0.84-0.99), but not statistically different to HBA1c with adjusted AUC of 0.88 (95% CI, 0.76-0.96). Although HBA1c is an acceptable and widely used screening test in detecting IFG/IGT or NODAT, fructosamine may be a more accurate diagnostic test but this needs to be further examined in larger cohorts.

  13. Variation in Glucose Homeostasis Traits Associated With P2RX7 Polymorphisms in Mice and Humans

    PubMed Central

    Todd, Jennifer N.; Poon, Wenny; Lyssenko, Valeriya; Groop, Leif; Nichols, Brendan; Wilmot, Michael; Robson, Simon; Enjyoji, Keiichi; Herman, Mark A.; Hu, Cheng; Zhang, Rong; Jia, Weiping; Ma, Ronald

    2015-01-01

    Context: Extracellular nucleotide receptors are expressed in pancreatic B-cells. Purinergic signaling via these receptors may regulate pancreatic B-cell function. Objective: We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction. Design: In humans, we mined genome-wide meta-analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes. We performed additional testing in two genomic regions (P2RX4/P2RX7 and P2RY1) in a cohort from the Prevalence, Prediction, and Prevention of Diabetes in Botnia (n = 3504), which includes more refined measures of glucose homeostasis. In mice, we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background. Results: Variants in five genes were associated with glycemic traits and in three genes with diabetes risk. In the Prevalence, Prediction, and Prevention of Diabetes in Botnia study, the minor allele in the missense functional variant rs1718119 (A348T) in P2RX7 was associated with increased insulin sensitivity and secretion, consistent with its known effect on increased pore function. Both male and female P2x7-C57 mice demonstrated impaired glucose tolerance compared with matched P2x7-129 mice. Insulin tolerance testing showed that P2x7-C57 mice were also less responsive to insulin than P2x7-129 mice. Conclusions: We show association of the purinergic signaling pathway in general and hypofunctioning P2X7 variants in particular with impaired glucose homeostasis in both mice and humans. PMID:25719930

  14. Revisiting “Vegetables” to combat modern epidemic of imbalanced glucose homeostasis

    PubMed Central

    Tiwari, Ashok Kumar

    2014-01-01

    Vegetables have been part of human food since prehistoric times and are considered nutritionally necessary and good for health. Vegetables are rich natural resource of biological antioxidants and possess capabilities of maintaining glucose homeostasis. When taken before starch-rich diet, juice also of vegetables such as ridge gourd, bottle gourd, ash gourd, chayote and juice of leaves of vegetables such as radish, Indian Dill, ajwain, tropical green amaranth, and bladder dock are reported to arrest significantly the rise in postprandial blood glucose level. Juice of vegetables such as ash gourd, squash gourd, and tropical green amaranth leaves are observed to tone-down sweet-beverages such as sucrose, fructose, and glucose-induced postprandial glycemic excursion. On the other hand, juice of egg-plant and juice of leaves of Ceylon spinach, Joyweed, and palak are reported to augment starch-induced postprandial glycemic excursion; and juice of leaves of Ceylon spinach, Joyweed, and radish supplement to the glucose-induced postprandial glycemia. Vegetables possess multifaceted antihyperglycemic activities such as inhibition of pancreatic α-amylase and intestinal α-glucosidase, inhibition of protein-tyrosine phosphatase 1β in liver and skeletal muscles, and insulin mimetic and secretagogue activities. Furthermore, they are also reported to influence polyol pathway in favor of reducing development of oxidative stress, and consequently the development of diabetic complications. In the wake of emergence of modern maladaptive diet-induced hyperglycemic epidemic therefore, vegetables may offer cost-effective dietary regimen to control diet-induced glycemic over load and future development of diabetes mellitus. However, for vegetables have been reported to do both, mitigate as well as supplement to the diet-induced postprandial glycemic load, care is required in selection of vegetables when considered as medicament. PMID:24991093

  15. The short chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis

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

    Fuller, Miles; Priyadarshini, Medha; Gibbons, Sean M.

    The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene ( Ffar2) expressionmore » is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Altogether, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis.« less

  16. The short chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis

    DOE PAGES

    Fuller, Miles; Priyadarshini, Medha; Gibbons, Sean M.; ...

    2015-09-22

    The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene ( Ffar2) expressionmore » is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Altogether, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis.« less

  17. The Exercise-Induced Irisin Is Associated with Improved Levels of Glucose Homeostasis Markers in Pregnant Women Participating in 8-Week Prenatal Group Fitness Program: A Pilot Study

    PubMed Central

    Worska, Aneta; Piernicka, Magdalena; Kortas, Jakub; Jastrzębski, Zbigniew; Radzimiński, Łukasz; Jaworska, Joanna; Micielska, Katarzyna

    2017-01-01

    Background Both exercise and pregnancy influence serum irisin concentration. Aim To determine how the interaction of pregnancy and exercise affects irisin level and whether various patterns of exercise adherence had different effect on irisin concentration. Methods It was a one-group pretest-posttest study among 9 Caucasian nulliparous healthy women in normal pregnancy (age 23 ± 3 years, 21 ± 2 weeks of gestation; mean ± SD) who participated in 8-week group fitness program. Before and after exercise intervention, we determined serum concentrations of irisin and selected parameters of lipid profile and glucose homeostasis markers. Results In active women, irisin slightly decreased with the development of pregnancy. After 8 weeks of exercising, irisin correlated negatively with fasting glucose (R = −0.922; p = 0.001), glycated hemoglobin (R = −0.784; p = 0.012), and insulin concentrations (R = −0.845; p = 0.004). In women exercising below recommended level, we observed a significant drop in irisin concentration, whereas in women exercising at least three times a week this myokine slightly increased (31% difference; 90% confidence limits ±28; a large, clear effect). Conclusions Irisin stimulated by prenatal exercise may improve glucose homeostasis markers in healthy women and compensate for metabolic changes induced by pregnancy. Moreover, the frequency of exercise may regulate the changes in exercise-induced irisin concentration. PMID:29226153

  18. Hypothalamic neurones governing glucose homeostasis.

    PubMed

    Coppari, R

    2015-06-01

    The notion that the brain directly controls the level of glucose in the blood (glycaemia) independent of its known action on food intake and body weight has been known ever since 1849. That year, the French physiologist Dr Claude Bernard reported that physical puncture of the floor of the fourth cerebral ventricle rapidly leads to an increased level of sugar in the blood (and urine) in rabbits. Despite this important discovery, it took approximately 150 years before significant efforts aimed at understanding the underlying mechanism of brain-mediated control of glucose metabolism were made. Technological developments allowing for genetically-mediated manipulation of selected molecular pathways in a neurone-type-specific fashion unravelled the importance of specific molecules in specific neuronal populations. These neuronal pathways govern glucose metabolism in the presence and even in the absence of insulin. Also, a peculiarity of these pathways is that certain biochemically-defined neurones govern glucose metabolism in a tissue-specific fashion. © 2015 British Society for Neuroendocrinology.

  19. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis.

    PubMed

    Varela, Luis; Horvath, Tamas L

    2012-12-01

    With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti-related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted.

  20. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis

    PubMed Central

    Varela, Luis; Horvath, Tamas L

    2012-01-01

    With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti-related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted. PMID:23146889

  1. Chronobiology, endocrinology, and energy- and food-reward homeostasis.

    PubMed

    Gonnissen, H K J; Hulshof, T; Westerterp-Plantenga, M S

    2013-05-01

    Energy- and food-reward homeostasis is the essential component for maintaining energy balance and its disruption may lead to metabolic disorders, including obesity and diabetes. Circadian alignment, quality sleep and sleep architecture in relation to energy- and food-reward homeostasis are crucial. A reduced sleep duration, quality sleep and rapid-eye movement sleep affect substrate oxidation, leptin and ghrelin concentrations, sleeping metabolic rate, appetite, food reward, hypothalamic-pituitary-adrenal (HPA)-axis activity, and gut-peptide concentrations, enhancing a positive energy balance. Circadian misalignment affects sleep architecture and the glucose-insulin metabolism, substrate oxidation, homeostasis model assessment of insulin resistance (HOMA-IR) index, leptin concentrations and HPA-axis activity. Mood disorders such as depression occur; reduced dopaminergic neuronal signaling shows decreased food reward. A good sleep hygiene, together with circadian alignment of food intake, a regular meal frequency, and attention for protein intake or diets, contributes in curing sleep abnormalities and overweight/obesity features by preventing overeating; normalizing substrate oxidation, stress, insulin and glucose metabolism including HOMA-IR index, and leptin, GLP-1 concentrations, lipid metabolism, appetite, energy expenditure and substrate oxidation; and normalizing food reward. Synchrony between circadian and metabolic processes including meal patterns plays an important role in the regulation of energy balance and body-weight control. Additive effects of circadian alignment including meal patterns, sleep restoration, and protein diets in the treatment of overweight and obesity are suggested. © 2013 The Authors. obesity reviews © 2013 International Association for the Study of Obesity.

  2. The Contribution of Intestinal Gluconeogenesis to Glucose Homeostasis Is Low in 2-Day-Old Pigs.

    PubMed

    Cherbuy, Claire; Vaugelade, Pierre; Labarthe, Simon; Honvo-Houeto, Edith; Darcy-Vrillon, Béatrice; Watford, Malcolm; Duée, Pierre-Henri

    2017-03-01

    -old piglets. Conclusion: Our results indicate that there is a low contribution to glucose homeostasis from intestinal gluconeogenesis in 2-d-old piglets. © 2017 American Society for Nutrition.

  3. Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis.

    PubMed

    Bauer, Paige V; Duca, Frank A; Waise, T M Zaved; Dranse, Helen J; Rasmussen, Brittany A; Puri, Akshita; Rasti, Mozhgan; O'Brien, Catherine A; Lam, Tony K T

    2018-03-06

    Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

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

    PubMed Central

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

    2016-01-01

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

  5. Neuronal calcium sensor synaptotagmin-9 is not involved in the regulation of glucose homeostasis or insulin secretion.

    PubMed

    Gustavsson, Natalia; Wang, Xiaorui; Wang, Yue; Seah, Tingting; Xu, Jun; Radda, George K; Südhof, Thomas C; Han, Weiping

    2010-11-09

    Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define the identities of proteins that are responsible for sensing calcium changes and for transmitting the calcium signal to release machineries. Synaptotagmins are primarily expressed in brain and endocrine cells and exhibit diverse calcium binding properties. Synaptotagmin-1, -2 and -9 are calcium sensors for fast neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium-dependent insulin secretion, thus suggesting that other calcium-sensors must participate in the regulation of insulin secretion. Of the other synaptotagmin isoforms that are present in pancreatic islets, the neuronal calcium sensor synaptotagmin-9 is expressed at the highest level after synaptotagmin-7. In this study we tested whether synaptotagmin-9 participates in the regulation of glucose-stimulated insulin release by using pancreas-specific synaptotagmin-9 knockout (p-S9X) mice. Deletion of synaptotagmin-9 in the pancreas resulted in no changes in glucose homeostasis or body weight. Glucose tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice. Thus, synaptotagmin-9, although a major calcium sensor in the brain, is not involved in the regulation of glucose-stimulated insulin release from pancreatic β-cells.

  6. Association of glucose homeostasis measures with heart rate variability among Hispanic/Latino adults without diabetes: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

    PubMed

    Meyer, Michelle L; Gotman, Nathan M; Soliman, Elsayed Z; Whitsel, Eric A; Arens, Raanan; Cai, Jianwen; Daviglus, Martha L; Denes, Pablo; González, Hector M; Moreiras, Juan; Talavera, Gregory A; Heiss, Gerardo

    2016-03-16

    Reduced heart rate variability (HRV), a measure of cardiac autonomic function, is associated with an increased risk of cardiovascular disease (CVD) and mortality. Glucose homeostasis measures are associated with reduced cardiac autonomic function among those with diabetes, but inconsistent associations have been reported among those without diabetes. This study aimed to examine the association of glucose homeostasis measures with cardiac autonomic function among diverse Hispanic/Latino adults without diabetes. The Hispanic community Health Study/Study of Latinos (HCHS/SOL; 2008-2011) used two-stage area probability sampling of households to enroll 16,415 self-identified Hispanics/Latinos aged 18-74 years from four USA communities. Resting, standard 12-lead electrocardiogram recordings were used to estimate the following ultrashort-term measures of HRV: RR interval (RR), standard deviation of all normal to normal RR (SDNN) and root mean square of successive differences in RR intervals (RMSSD). Multivariable regression analysis was used to estimate associations between glucose homeostasis measures with HRV using data from 11,994 adults without diabetes (mean age 39 years; 52 % women). Higher fasting glucose was associated with lower RR, SDNN, and RMSSD. Fasting insulin and the homeostasis model assessment of insulin resistance was negatively associated with RR, SDNN, and RMSSD, and the association was stronger among men compared with women. RMSSD was, on average, 26 % lower in men with higher fasting insulin and 29 % lower in men with lower insulin resistance; for women, the corresponding estimates were smaller at 4 and 9 %, respectively. Higher glycated hemoglobin was associated with lower RR, SDNN, and RMSSD in those with abdominal adiposity, defined by sex-specific cut-points for waist circumference, after adjusting for demographics and medication use. There were no associations between glycated hemoglobin and HRV measures among those without abdominal adiposity

  7. Association between ADIPOQ SNPs with plasma adiponectin and glucose homeostasis and adiposity phenotypes in the IRAS Family Study.

    PubMed

    An, S Sandy; Hanley, Anthony J G; Ziegler, Julie T; Brown, W Mark; Haffner, Steven M; Norris, Jill M; Rotter, Jerome I; Guo, Xiuqing; Chen, Y-D Ida; Wagenknecht, Lynne E; Langefeld, Carl D; Bowden, Donald W; Palmer, Nicholette D

    2012-12-01

    Adiponectin is an adipocytokine associated with a variety of metabolic traits. These associations in human studies, in conjunction with functional studies in model systems, have implicated adiponectin in multiple metabolic processes. We hypothesize that genetic variants associated with plasma adiponectin would also be associated with glucose homeostasis and adiposity phenotypes. The Insulin Resistance Atherosclerosis Family Study was designed to identify the genetic and environmental basis of insulin resistance and adiposity in the Hispanic- (n=1,424) and African-American (n=604) population. High quality metabolic phenotypes, e.g. insulin sensitivity (S(I)), acute insulin response (AIR), disposition index (DI), fasting glucose, body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and waist circumference, were explored. Based on association analysis of more than 40 genetic polymorphisms in the adiponectin gene (ADIPOQ), we found no consistent association of ADIPOQ variants with plasma adiponectin levels and adiposity phenotypes. However, there were two promoter variants, rs17300539 and rs822387, associated with plasma adiponectin levels (P=0.0079 and 0.021, respectively) in the Hispanic-American cohort that were also associated with S(I) (P=0.0067 and 0.013, respectively). In contrast, there was only a single promoter SNP, rs17300539, associated with plasma adiponectin levels (P=0.0018) and fasting glucose (P=0.042) in the African-American cohort. Strikingly, high impact coding variants did not show evidence of association. The lack of consistent patterns of association between variants, adiponectin levels, glucose homeostasis, and adiposity phenotypes suggests a reassessment of the influence of adiponectin in these pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. The influence of parenteral glutamine supplementation on glucose homeostasis in critically ill polytrauma patients--A randomized-controlled clinical study.

    PubMed

    Grintescu, Ioana Marina; Luca Vasiliu, Irina; Cucereanu Badica, Ioana; Mirea, Liliana; Pavelescu, Daniela; Balanescu, Andreea; Grintescu, Ioana Cristina

    2015-06-01

    Rapid onset of resistance to insulin is a prominent component of stress metabolism in multiple trauma patients. Recent studies have clarified the role of amino acids (especially glutamine) in glucose transportation and the benefits of parenteral alanyl-glutamine supplementation (0.3-0.6 g/kg/day) in glucose homeostasis. The aims of this study are to evaluate the incidence of hyperglycemic episodes and the need for exogenous insulin to maintain stable glucose levels in critically ill polytrauma patients supplemented with parenteral glutamine dipeptide (Dipeptiven(®)) versus standard nutritional support. This was an open-label randomized-controlled trial of 82 polytrauma patients aged 20-60 years old, randomly assigned into two equal groups independent of sex, age and Injury Severity Score. We excluded patients with diabetes mellitus, or renal or hepatic failure. One group received parenteral Dipeptiven(®) supplementation of 0.5 g/kg/day and the other received standard isocaloric isoproteinic nutritional support. We found that 63% of patients in the glutamine-supplemented group had no hyperglycemic episodes; only 37% required exogenous insulin (mean daily requirement of 44 units/day). In the control group, 51% of patients required insulin (mean daily requirement 63 unit/day; p = 0.0407). The effect of glutamine supplementation on glucose homeostasis is associated with a lower incidence of hyperglycemia among critically ill polytrauma patients, and leads to a lower mean daily dose of insulin. Controlled-trials.com Identifier: ISRCTN71592366 (http://www.controlled-trials.com/ISRCTN71592366/ISRCTN71592366). Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

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

    PubMed

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

    2017-11-01

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

  10. Exposure to low level of arsenic and lead in drinking water from Antofagasta city induces gender differences in glucose homeostasis in rats.

    PubMed

    Palacios, Javier; Roman, Domingo; Cifuentes, Fredi

    2012-08-01

    Populations chronically exposed to arsenic in drinking water often have increased prevalence of diabetes mellitus. The purpose of this study was to compare the glucose homeostasis of male and female rats exposed to low levels of heavy metals in drinking water. Treated groups were Sprague-Dawley male and female rats exposed to drinking water from Antofagasta city, with total arsenic of 30 ppb and lead of 53 ppb for 3 months; control groups were exposed to purified water by reverse osmosis. The two treated groups in both males and females showed arsenic and lead in the hair of rats. The δ-aminolevulinic acid dehydratase was used as a sensitive biomarker of arsenic toxicity and lead. The activity of δ-aminolevulinic acid dehydratase was reduced only in treated male rats, compared to the control group. Treated males showed a significantly sustained increase in blood glucose and plasma insulin levels during oral glucose tolerance test compared to control group. The oral glucose tolerance test and the homeostasis model assessment of insulin resistance demonstrated that male rats were insulin resistant, and females remained sensitive to insulin after treatment. The total cholesterol and LDL cholesterol increased in treated male rats vs. the control, and triglyceride increased in treated female rats vs. the control. The activity of intestinal Na+/glucose cotransporter in male rats increased compared to female rats, suggesting a significant increase in intestinal glucose absorption. The findings indicate that exposure to low levels of arsenic and lead in drinking water could cause gender differences in insulin resistance.

  11. Coffee Consumption, Newly Diagnosed Diabetes, and Other Alterations in Glucose Homeostasis: A Cross-Sectional Analysis of the Longitudinal Study of Adult Health (ELSA-Brasil)

    PubMed Central

    Yarmolinsky, James; Mueller, Noel T.; Duncan, Bruce B.; Bisi Molina, Maria del Carmen; Goulart, Alessandra C.; Schmidt, Maria Inês

    2015-01-01

    Introduction Observational studies have reported fairly consistent inverse associations between coffee consumption and risk of type 2 diabetes, but this association has been little investigated with regard to lesser degrees of hyperglycemia and other alterations in glucose homeostasis. Additionally, the association between coffee consumption and diabetes has been rarely investigated in South American populations. We examined the cross-sectional relationships of coffee intake with newly diagnosed diabetes and measures of glucose homeostasis, insulin sensitivity, and insulin secretion, in a large Brazilian cohort of middle-aged and elderly individuals. Methods We used baseline data from 12,586 participants of the Longitudinal Study of Adult Health (ELSA-Brasil). Logistic regression analyses were performed to examine associations between coffee consumption and newly diagnosed diabetes. Analysis of covariance was used to assess coffee intake in relation to two-hour glucose from an oral glucose tolerance test, fasting glucose, glycated hemoglobin, fasting and –2-hour postload insulin and measures of insulin sensitivity. Results We found an inverse association between coffee consumption and newly diagnosed diabetes, after adjusting for multiple covariates [23% and 26% lower odds of diabetes for those consuming coffee 2–3 and >3 times per day, respectively, compared to those reporting never or almost never consuming coffee, (p = .02)]. An inverse association was also found for 2-hour postload glucose [Never/almost never: 7.57 mmol/L, ≤1 time/day: 7.48 mmol/L, 2-3 times/day: 7.22 mmol/L, >3 times/day: 7.12 mol/L, p<0.0001] but not with fasting glucose concentrations (p = 0.07). Coffee was additionally associated with 2-hour postload insulin [Never/almost never: 287.2 pmol/L, ≤1 time/day: 280.1 pmol/L, 2–3 times/day: 275.3 pmol/L, >3 times/day: 262.2 pmol/L, p = 0.0005) but not with fasting insulin concentrations (p = .58). Conclusion Our present study provides

  12. Factors Affecting Accuracy and Time Requirements of a Glucose Oxidase-Peroxidase Assay for Determination of Glucose

    USDA-ARS?s Scientific Manuscript database

    Accurate and rapid assays for glucose are desirable for analysis of glucose and starch in food and feedstuffs. An established colorimetric glucose oxidase-peroxidase method for glucose was modified to reduce analysis time, and evaluated for factors that affected accuracy. Time required to perform t...

  13. Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

    PubMed Central

    Smith, Brennan K.; Ford, Rebecca J.; Desjardins, Eric M.; Green, Alex E.; Hughes, Meghan C.; Houde, Vanessa P.; Day, Emily A.; Marcinko, Katarina; Crane, Justin D.; Mottillo, Emilio P.; Perry, Christopher G.R.; Kemp, Bruce E.; Tarnopolsky, Mark A.; Steinberg, Gregory R.

    2017-01-01

    Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMPK via the β1 subunit, but whether salsalate requires AMPK-β1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK-β1–knockout (AMPK-β1KO) mice were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (~1 mmol/L). Salsalate treatment increased VO2, lowered fasting glucose, improved glucose tolerance, and led to an ~55% reduction in liver lipid content. These effects were observed in both WT and AMPK-β1KO mice. To explain these AMPK-independent effects, we found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial proton conductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of uncoupling protein 1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling. PMID:27554471

  14. Impaired glucose homeostasis in non-diabetic Greek hypertensives with diabetes family history. Effect of the obesity status.

    PubMed

    Vyssoulis, Gregory P; Liakos, Charalampos I; Karpanou, Eva A; Triantafyllou, Athanasios I; Michaelides, Andreas P; Tzamou, Vanessa E; Markou, Maria I; Stefanadis, Christodoulos I

    2013-01-01

    Arterial hypertension (AH) and diabetes mellitus (DM) are established cardiovascular risk factors. Impaired glucose homeostasis (IGH; impaired fasting glucose or/and impaired glucose tolerance) or pre-diabetes, obesity, and DM family history identify individuals at risk for type 2 DM in whom preventive interventions are necessary. The aim of this study was to determine the glycemic profile in non-diabetic Greek adult hypertensive men and women according to DM family history and the obesity status. Diabetes family history, obesity markers (waist-to-hip ratio, WHR; body mass index, BMI), glycemic parameters (fasting and 2-hour post-load plasma glucose, if necessary; glycated hemoglobin, HbA1c; fasting insulin), insulin resistance indices (homeostasis model assessment, HOMA; quantitative insulin sensitivity check index, QUICKI; Bennett; McAuley), and IGH prevalence were determined in a large cohort of 11,540 Greek hypertensives referred to our institutions. Positive DM family history was associated with elevated fasting glucose (98.6 ± 13.1 vs 96.5 ± 12.3 mg/dL), HbA1c (5.58% ± 0.49% vs 5.50% ± 0.46%), fasting insulin (9.74 ± 4.20 vs 9.21 ± 3.63 μU/mL) and HOMA (2.43 ± 1.19 vs 2.24 ± 1.01) values, lower QUICKI (0.342 ± 0.025 vs 0.345 ± 0.023), Bennett (0.285 ± 0.081 vs 0.292 ± 0.078) and McAuley (6.73 ± 3.43 vs 6.95 ± 3.44) values, and higher IGH prevalence (45.3% vs 38.7%); P < .01 for all comparisons. The difference in the prevalence of IGH according to DM family history was significant (P < .01) in both genders and every WHR and BMI subgroup (except for women with BMI <20 kg/m(2)). Non-diabetic hypertensives with positive DM family history present with higher IGH prevalence and worse glycemic indices levels compared with those with negative family history, especially in the higher WHR/BMI subgroups. Copyright © 2013 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  15. 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.

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

    PubMed

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

    2016-04-01

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

  17. Gsα Deficiency in the Ventromedial Hypothalamus Enhances Leptin Sensitivity and Improves Glucose Homeostasis in Mice on a High-Fat Diet.

    PubMed

    Berger, Alta; Kablan, Ahmed; Yao, Catherine; Ho, Thuy; Podyma, Brandon; Weinstein, Lee S; Chen, Min

    2016-02-01

    In both mice and patients with Albright hereditary osteodystrophy, heterozygous inactivating mutations of Gsα, a ubiquitously expressed G protein that mediates receptor-stimulated intracellular cAMP production, lead to obesity and insulin resistance but only when the mutation is present on the maternal allele. This parent-of-origin effect in mice was shown to be due to Gsα imprinting in one or more brain regions. The ventromedial hypothalamus (VMH) is involved in the regulation of energy and glucose homeostasis, but the role of Gsα in VMH on metabolic regulation is unknown. To examine this, we created VMH-specific Gsα-deficient mice by mating Gsα-floxed mice with SF1-cre mice. Heterozygotes with Gsα mutation on either the maternal or paternal allele had a normal metabolic phenotype, and there was no molecular evidence of Gsα imprinting, indicating that the parent-of-origin metabolic effects associated with Gsα mutations is not due to Gsα deficiency in VMH SF1 neurons. Homozygous VMH Gsα knockout mice (VMHGsKO) showed no changes in body weight on either a regular or high-fat diet. However, glucose metabolism (fasting glucose, glucose tolerance, insulin sensitivity) was significantly improved in male VMHGsKO mice, with the difference more dramatic on the high-fat diet. In addition, male VMHGsKO mice on the high-fat diet showed a greater anorexigenic effect and increased VMH signal transducer and activator of transcription-3 phosphorylation in response to leptin. These results indicate that VMH Gsα/cyclic AMP signaling regulates glucose homeostasis and alters leptin sensitivity in mice, particularly in the setting of excess caloric intake.

  18. Skeletal muscle neuronal nitric oxide synthase micro protein is reduced in people with impaired glucose homeostasis and is not normalized by exercise training.

    PubMed

    Bradley, Scott J; Kingwell, Bronwyn A; Canny, Benedict J; McConell, Glenn K

    2007-10-01

    Skeletal muscle inducible nitric oxide synthase (NOS) protein is greatly elevated in people with type 2 diabetes mellitus, whereas endothelial NOS is at normal levels. Diabetic rat studies suggest that skeletal muscle neuronal NOS (nNOS) micro protein expression may be reduced in human insulin resistance. The aim of this study was to determine whether skeletal muscle nNOSmicro protein expression is reduced in people with impaired glucose homeostasis and whether exercise training increases nNOSmicro protein expression in these individuals because exercise training increases skeletal muscle nNOSmicro protein in rats. Seven people with type 2 diabetes mellitus or prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and 7 matched (sex, age, fitness, body mass index, blood pressure, lipid profile) healthy controls aged 36 to 60 years participated in this study. Vastus lateralis muscle biopsies for nNOSmicro protein determination were obtained, aerobic fitness was measured (peak pulmonary oxygen uptake [Vo(2) peak]), and glucose tolerance and insulin homeostasis were assessed before and after 1 and 4 weeks of cycling exercise training (60% Vo(2) peak, 50 minutes x 5 d wk(-1)). Skeletal muscle nNOSmicro protein was significantly lower (by 32%) in subjects with type 2 diabetes mellitus or prediabetes compared with that in controls before training (17.7 +/- 1.2 vs 26.2 +/- 3.4 arbitrary units, P < .05). The Vo(2) peak and indicators of insulin sensitivity improved with exercise training in both groups (P < .05), but there was no effect of exercise training on skeletal muscle nNOSmicro protein in either group. In conclusion, individuals with impaired glucose homeostasis have reduced skeletal muscle nNOSmicro protein content. However, because exercise training improves insulin sensitivity without influencing skeletal muscle nNOSmicro protein expression, it seems that changes in skeletal muscle nNOSmicro protein are not central to the control of insulin

  19. Catalpic acid decreases abdominal fat deposition, improves glucose homeostasis and upregulates PPAR alpha expression in adipose tissue.

    PubMed

    Hontecillas, Raquel; Diguardo, Maggie; Duran, Elisa; Orpi, Marcel; Bassaganya-Riera, Josep

    2008-10-01

    Catalpic acid (CAT) is a conjugated linolenic acid (CLN) isomer containing trans-9, trans-11, cis-13 double bonds in an 18-carbon chain and it is found primarily in the seed oil of ornamental and medicinal trees and shrubs of the family Bignoniaceae. The objective of this study was to investigate whether CAT decreases obesity and ameliorates insulin sensitivity and glucose tolerance in mice fed high-fat diets. To test the efficacy of CAT in decreasing obesity and diabetes we used both a model of diet-induced obesity (DIO) and a genetic model of obesity (i.e., mice lacking the leptin receptor). Blood was collected on days 0, 7, 14, 21 and 28 for determining fasting glucose and insulin concentrations in plasma. In addition, a glucose tolerance test was administered on day 28. We found that dietary CAT (1g/100g) decreased fasting plasma glucose and insulin concentrations, ameliorated the glucose normalizing ability following glucose challenge and decreased abdominal white adipose tissue accumulation. In white adipose tissue (WAT), CAT upregulated peroxisome proliferator-activated receptor (PPAR) alpha and its responsive genes [i.e., stearoyl-coenzyme A desaturase (SCD1) and enoyl-coenzyme A hydratase (ECH)], increased concentrations of high-density lipoprotein (HDL) cholesterol and decreased plasma triglyceride (TG) levels. CAT decreased abdominal fat deposition, increased HDL cholesterol, decreased TG concentrations, decreased glucose and insulin homeostasis and modulated WAT gene expression in a manner reminiscent of the actions of the PPAR alpha-activating fibrate class of lipid-lowering drugs.

  20. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis.

    PubMed

    McGlashon, Jacob M; Gorecki, Michelle C; Kozlowski, Amanda E; Thirnbeck, Caitlin K; Markan, Kathleen R; Leslie, Kirstie L; Kotas, Maya E; Potthoff, Matthew J; Richerson, George B; Gillum, Matthew P

    2015-05-05

    Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the CNS are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1b(f/f)ePet1(Cre) mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Global Identification of Genes Affecting Iron-Sulfur Cluster Biogenesis and Iron Homeostasis

    PubMed Central

    Hidese, Ryota; Kurihara, Tatsuo; Esaki, Nobuyoshi

    2014-01-01

    Iron-sulfur (Fe-S) clusters are ubiquitous cofactors that are crucial for many physiological processes in all organisms. In Escherichia coli, assembly of Fe-S clusters depends on the activity of the iron-sulfur cluster (ISC) assembly and sulfur mobilization (SUF) apparatus. However, the underlying molecular mechanisms and the mechanisms that control Fe-S cluster biogenesis and iron homeostasis are still poorly defined. In this study, we performed a global screen to identify the factors affecting Fe-S cluster biogenesis and iron homeostasis using the Keio collection, which is a library of 3,815 single-gene E. coli knockout mutants. The approach was based on radiolabeling of the cells with [2-14C]dihydrouracil, which entirely depends on the activity of an Fe-S enzyme, dihydropyrimidine dehydrogenase. We identified 49 genes affecting Fe-S cluster biogenesis and/or iron homeostasis, including 23 genes important only under microaerobic/anaerobic conditions. This study defines key proteins associated with Fe-S cluster biogenesis and iron homeostasis, which will aid further understanding of the cellular mechanisms that coordinate the processes. In addition, we applied the [2-14C]dihydrouracil-labeling method to analyze the role of amino acid residues of an Fe-S cluster assembly scaffold (IscU) as a model of the Fe-S cluster assembly apparatus. The analysis showed that Cys37, Cys63, His105, and Cys106 are essential for the function of IscU in vivo, demonstrating the potential of the method to investigate in vivo function of proteins involved in Fe-S cluster assembly. PMID:24415728

  2. Dimethyl amiloride improves glucose homeostasis in mouse models of type 2 diabetes.

    PubMed

    Gunawardana, Subhadra C; Head, W Steven; Piston, David W

    2008-06-01

    Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta-cell. DMA also enhances time-dependent potentiation (TDP) and enables TDP to occur in situations where it is normally absent. As we have demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine. Thus both DMA and arginine have the potential to correct the secretory defect in diabetes by enabling or enhancing TDP. In the current study we have demonstrated the ability of these agents to improve blood glucose homeostasis in three mouse models of type 2 diabetes. The pattern of TDP under different conditions indicates that inhibition of NOS is not the only mechanism through which DMA exerts its positive effects. Thus we also have explored another possible mechanism through which DMA enables/enhances TDP, via the activation of mitochondrial alpha-ketoglutarate dehydrogenase.

  3. The effects of an amino acid supplement on glucose homeostasis, inflammatory markers, and incretins after laparoscopic gastric bypass.

    PubMed

    Breitman, Igal; Saraf, Neha; Kakade, Manasi; Yellumahanthi, Kishore; White, Merritt; Hackett, Jo Ann; Clements, Ronald H

    2011-04-01

    Protein supplements are routinely used after a laparoscopic gastric bypass (LGB). The aim of this study was to evaluate the impact of an amino acid supplement on glucose homeostasis and hormonal and inflammatory markers after LGB. Thirty patients undergoing LGB were randomized to receive or not 24 g of an oral supplement containing a leucine metabolite, glutamine, and arginine twice daily. Changes in weight, glucose, insulin, C-peptide, insulin sensitivity, interleukin (IL) 6, C-reactive protein (CRP), leptin, insulin-like growth factor (IGF) 1, ghrelin, and incretins were assessed preoperatively and 2 weeks and 8 weeks postoperatively. Thirty patients (96.7% female, age 46.9 ± 8.4 years, body mass index 43.3 ± 4.1 kg/m(2)) were randomized. The experimental (n = 14) and control (n = 16) groups were not significantly different at baseline. Weight loss was similar for the 2 groups. Fasting glucose decreased significantly at 2 and 8 weeks compared with base line (p < 0.0001) with no difference between the experimental and control groups (p = 0.8), but insulin and calculated insulin sensitivity, which were similar at baseline, became significantly worse in the experimental group 8 weeks after surgery (p = 0.02 for insulin; p = 0.04 for the homeostasis model assessment of insulin resistance). CRP and IL-6, which were similar at baseline, were found to be significantly higher at 8 weeks in the experimental group (p = 0.018 and p = 0.05, respectively). Leptin and IGF-1 levels decreased significantly from baseline at 2 and 8 weeks (p < 0.0001), but there was no difference between the 2 groups. No significant changes in GLP-1, ghrelin, or gastric inhibitory polypeptide were noticed after 8 weeks. An amino acid supplement had no effect on the early postoperative incretins after LGB. It may have a negative influence on glucose kinetics and degree of inflammation. Future studies are needed to clarify these effects. Copyright © 2011 American College of Surgeons. Published by

  4. The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: has it been overlooked?

    PubMed Central

    Stark, Romana; Kibbey, Richard G.

    2013-01-01

    Background Plasma glucose levels are tightly regulated within a narrow physiologic range. Insulin-mediated glucose uptake by tissues must be balanced by the appearance of glucose from nutritional sources, glycogen stores, or gluconeogenesis. In this regard, a common pathway regulating both glucose clearance and appearance has not been described. The metabolism of glucose to produce ATP is generally considered to be the primary stimulus for insulin release from beta-cells. Similarly, gluconeogenesis from phosphoenolpyruvate (PEP) is believed to be the primarily pathway via the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). These models cannot adequately explain the regulation of insulin secretion or gluconeogenesis. Scope of review A metabolic sensing pathway involving mitochondrial GTP (mtGTP) and PEP synthesis by the mitochondrial isoform of PEPCK (PEPCK-M) is associated with glucose-stimulated insulin secretion from pancreatic beta-cells. Here we examine whether there is evidence for a similar mtGTP-dependent pathway involved in gluconeogenesis. In both islets and the liver, mtGTP is produced at the substrate level by the enzyme succinyl CoA synthetase (SCS-GTP) with a rate proportional to the TCA cycle. In the beta-cell PEPCK-M then hydrolyzes mtGTP in the production of PEP that, unlike mtGTP, can escape the mitochondria to generate a signal for insulin release. Similarly, PEPCK-M and mtGTP might also provide a significant source of PEP in gluconeogenic tissues for the production of glucose. This review will focus on the possibility that PEPCK-M, as a sensor for TCA cycle flux, is a key mechanism to regulate both insulin secretion and gluconeogenesis suggesting conservation of this biochemical mechanism in regulating multiple aspects of glucose homeostasis. Moreover, we propose that this mechanism may be more important for regulating insulin secretion and gluconeogenesis compared to canonical nutrient sensing pathways. Major conclusions PEPCK

  5. Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis.

    PubMed

    Jordan, Sabine D; Könner, A Christine; Brüning, Jens C

    2010-10-01

    The central nervous system (CNS) is capable of gathering information on the body's nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus.

  6. Cognitive Performance: A Cross-Sectional Study on Serum Vitamin D and Its Interplay With Glucose Homeostasis in Dutch Older Adults.

    PubMed

    Brouwer-Brolsma, Elske M; Dhonukshe-Rutten, Rosalie A M; van Wijngaarden, Janneke P; van de Zwaluw, Nikita L; in 't Veld, Paulette H; Wins, Sophie; Swart, Karin M A; Enneman, Anke W; Ham, Annelies C; van Dijk, Suzanne C; van Schoor, Natasja M; van der Velde, Nathalie; Uitterlinden, Andre G; Lips, Paul; Kessels, Roy P C; Steegenga, Wilma T; Feskens, Edith J M; de Groot, Lisette C P G M

    2015-07-01

    First, the association between serum 25-hydroxyvitamin D (25[OH]D) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose homeostasis in the association with cognitive performance. Associations were studied using cross-sectional data of 776 (3 domains) up to 2722 (1 domain) Dutch community-dwelling older adults, aged 65 years or older. Serum 25(OH)D, plasma glucose, and insulin concentrations were obtained. Cognitive performance was assessed with an extensive cognitive test battery. Prevalence ratios (PRs) were calculated to quantify the association between 25(OH)D and cognition; poor performance was defined as the worst 10% of the distribution of the cognitive scores. The overall median MMSE score was 29 (IQR 28-30). Higher serum 25(OH)D was associated with better attention and working memory, PR 0.50 (95% CI 0.29-0.84) for the third serum 25(OH)D tertile, indicating a 50% lower probability of being a poor performer than participants in the lowest tertile. Beneficial trends were shown for 25(OH)D with executive function and episodic memory. Serum 25(OH)D was not associated with plasma glucose or insulin. Plasma insulin only modified the association between serum 25(OH)D and executive function (P for interaction: .001), suggesting that the improvement in executive function with high 25(OH)D concentrations is stronger in participants with high plasma insulin concentrations compared with those with low plasma insulin concentrations. Higher 25(OH)D concentrations significantly associated with better attention and working memory performance. This study does not demonstrate an interplay between serum 25(OH)D and glucose homeostasis in the association with cognitive performance. Copyright © 2015 AMDA - The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

  7. Consumption of added sugars from liquid but not solid sources predicts impaired glucose homeostasis and insulin resistance among youth at risk of obesity.

    PubMed

    Wang, Jiawei; Light, Kelly; Henderson, Mélanie; O'Loughlin, Jennifer; Mathieu, Marie-Eve; Paradis, Gilles; Gray-Donald, Katherine

    2014-01-01

    Little is known about longitudinal associations between added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis among youth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n = 564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes were examined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage, energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer). Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fat mass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of added sugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higher fasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4 unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P < 0.01). No associations were observed with consumption of added sugars from solid sources. Overweight/obese children at baseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases in Matsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid or solid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor for the development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk of obesity.

  8. Leptin and leptin receptor gene polymorphisms and changes in glucose homeostasis in response to regular exercise in nondiabetic individuals: the HERITAGE family study.

    PubMed

    Lakka, Timo A; Rankinen, Tuomo; Weisnagel, S John; Chagnon, Yvon C; Lakka, Hanna-Maaria; Ukkola, Olavi; Boulé, Normand; Rice, Treva; Leon, Arthur S; Skinner, James S; Wilmore, Jack H; Rao, D C; Bergman, Richard; Bouchard, Claude

    2004-06-01

    We recently reported that a genomic region close to the leptin locus was linked to fasting insulin response to exercise training in nondiabetic white subjects. We tested the hypothesis that common exonic variants in the leptin (LEP) and leptin receptor (LEPR) genes modify the effects of regular physical activity on glucose homeostasis in nondiabetic whites (n = 397) and blacks (n = 143). In whites, exercise increased insulin sensitivity index (P = 0.041) and disposition index (P = 0.046) in the LEPR 109R allele carriers but not in the K109K homozygotes, increased glucose disappearance index more in the R109R homozygotes than in the K109 allele carriers (P = 0.039), and decreased fasting glucose only in the 109R allele carriers (P = 0.018). We also found an interaction between the LEP A19G and LEPR K109R polymorphisms on the change in fasting insulin in whites (P = 0.010). The association between the LEP A19G polymorphism and the change in insulin was evident only in the LEPR 109R carriers (P = 0.019). The decrease in insulin was strongest in the LEP A19A homozygotes who carried the LEPR 109R allele. Similar interaction was observed in blacks (P = 0.046). Variations in the LEP and LEPR genes are associated with the magnitude of the effects of regular exercise on glucose homeostasis in nondiabetic individuals.

  9. Hepatic OATP Transporter and Thyroid Hormone Receptor Interplay Determines Cholesterol and Glucose Homeostasis

    PubMed Central

    Meyer zu Schwabedissen, Henriette E.; Ware, Joseph A.; Finkelstein, David; Chaudhry, Amarjit S.; Lemay, Sara; Leon-Ponte, Matilde; Strom, Stephen C.; Zaher, Hani; Schwarz, Ute I.; Freeman, David J.; Schuetz, Erin G.; Tirona, Rommel G.; Kim, Richard B.

    2011-01-01

    The role of Organic Anion Transporting Polypeptides (OATPs), particularly the members of OATP1B-subfamily, in hepatocellular handling of endogenous and exogenous compounds is an important and emerging area of research. Using a mouse model lacking Slco1b2, the murine ortholog of the OATP1B-subfamily, we previously demonstrated that genetic ablation causes reduced hepatic clearance capacity for substrates. In this report we focused on the physiological function of the hepatic OATP1B transporters. First we studied the influence of the Oatp1b2 deletion on bile acid metabolism showing that lack of the transporter results in a significantly reduced expression of Cyp7a1 the key enzyme of bile acid synthesis, resulting in elevated cholesterol levels after high dietary fat challenge. Furthermore, Slco1b2−/− mice exhibited delayed clearance after oral glucose challenge resulting from reduced hepatic glucose uptake. In addition to increased hepatic glycogen content, Slco1b2−/−exhibited reduced glucose output after pyruvate challenge. This is in accordance with reduced hepatic expression of PEPCK in knockout mice. We show this phenotype is due to the loss of liver-specific Oatp1b2-mediated hepatocellular thyroid hormone entry, which then leads to reduced transcriptional activation of target genes of hepatic thyroid hormone receptor (TR) including the prior mentioned Cyp7a1 and Pepck, but also Dio1 and Glut2. Importantly, we assessed human relevance using a cohort of archived human livers where OATP1B1 expression was noted to be highly associated with TR target genes, especially for GLUT2. Furthermore, GLUT2 expression was significantly decreased in livers harboring a common genetic polymorphism in SLCO1B1. Conclusion Our findings reveal that OATP1B-mediated hepatic thyroid hormone entry is a key determinant of cholesterol and glucose homeostasis. PMID:21538436

  10. Perturbation of Serotonin Homeostasis during Adulthood Affects Serotonergic Neuronal Circuitry.

    PubMed

    Pratelli, Marta; Migliarini, Sara; Pelosi, Barbara; Napolitano, Francesco; Usiello, Alessandro; Pasqualetti, Massimo

    2017-01-01

    Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2 fl ° x conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion. Strikingly, these defects are rescued following reestablishment of brain 5-HT signaling via administration of the serotonin precursor 5-hydroxytryptophan (5-HTP). Finally, 3D reconstruction of serotonergic fibers reveals that changes in serotonin homeostasis affect axonal branching complexity. These data demonstrate that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring.

  11. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity.

    PubMed

    Ozcan, Lale; Wong, Catherine C L; Li, Gang; Xu, Tao; Pajvani, Utpal; Park, Sung Kyu Robin; Wronska, Anetta; Chen, Bi-Xing; Marks, Andrew R; Fukamizu, Akiyoshi; Backs, Johannes; Singer, Harold A; Yates, John R; Accili, Domenico; Tabas, Ira

    2012-05-02

    Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here, we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary hepatocytes and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects. Importantly, the suppressive effect of CaMKII deficiency on glucose metabolism is abrogated by transduction with constitutively nuclear FoxO1, indicating that the effect of CaMKII deficiency requires nuclear exclusion of FoxO1. This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity

    PubMed Central

    Ozcan, Lale; Wong, Catherine C.L.; Li, Gang; Xu, Tao; Pajvani, Utpal; Park, Sung Kyu Robin; Wronska, Anetta; Chen, Bi-Xing; Marks, Andrew R.; Fukamizu, Akiyoshi; Backs, Johannes; Singer, Harold A.; Yates, John R.; Accili, Domenico; Tabas, Ira

    2012-01-01

    SUMMARY Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary HCs and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects. Importantly, the suppressive effect of CaMKII deficiency on glucose metabolism is abrogated by transduction with constitutively nuclear FoxO1, indicating that the effect of CaMKII deficiency requires nuclear exclusion of FoxO1. This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis. PMID:22503562

  13. Hypothalamic control of energy and glucose metabolism.

    PubMed

    Sisley, Stephanie; Sandoval, Darleen

    2011-09-01

    The central nervous system (CNS), generally accepted to regulate energy homeostasis, has been implicated in the metabolic perturbations that either cause or are associated with obesity. Normally, the CNS receives hormonal, metabolic, and neuronal input to assure adequate energy levels and maintain stable energy homeostasis. Recent evidence also supports that the CNS uses these same inputs to regulate glucose homeostasis and this aspect of CNS regulation also becomes impaired in the face of dietary-induced obesity. This review focuses on the literature surrounding hypothalamic regulation of energy and glucose homeostasis and discusses how dysregulation of this system may contribute to obesity and T2DM.

  14. Ceylon cinnamon does not affect postprandial plasma glucose or insulin in subjects with impaired glucose tolerance.

    PubMed

    Wickenberg, Jennie; Lindstedt, Sandra; Berntorp, Kerstin; Nilsson, Jan; Hlebowicz, Joanna

    2012-06-01

    Previous studies on healthy subjects have shown that the intake of 6 g Cinnamomum cassia reduces postprandial glucose and that the intake of 3 g C. cassia reduces insulin response, without affecting postprandial glucose concentrations. Coumarin, which may damage the liver, is present in C. cassia, but not in Cinnamomum zeylanicum. The aim of the present study was to study the effect of C. zeylanicum on postprandial concentrations of plasma glucose, insulin, glycaemic index (GI) and insulinaemic index (GII) in subjects with impaired glucose tolerance (IGT). A total of ten subjects with IGT were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT) was administered together with placebo or C. zeylanicum capsules. Finger-prick capillary blood samples were taken for glucose measurements and venous blood for insulin measurements, before and at 15, 30, 45, 60, 90, 120, 150 and 180 min after the start of the OGTT. The ingestion of 6 g C. zeylanicum had no significant effect on glucose level, insulin response, GI or GII. Ingestion of C. zeylanicum does not affect postprandial plasma glucose or insulin levels in human subjects. The Federal Institute for Risk Assessment in Europe has suggested the replacement of C. cassia by C. zeylanicum or the use of aqueous extracts of C. cassia to lower coumarin exposure. However, the positive effects seen with C. cassia in subjects with poor glycaemic control would then be lost.

  15. Parameters of Glucose and Lipid Metabolism Affect the Occurrence of Colorectal Adenomas Detected by Surveillance Colonoscopies

    PubMed Central

    Kim, Nam Hee; Suh, Jung Yul; Park, Jung Ho; Park, Dong Il; Cho, Yong Kyun; Sohn, Chong Il; Choi, Kyuyong

    2017-01-01

    Purpose Limited data are available regarding the associations between parameters of glucose and lipid metabolism and the occurrence of metachronous adenomas. We investigated whether these parameters affect the occurrence of adenomas detected on surveillance colonoscopy. Materials and Methods This longitudinal study was performed on 5289 subjects who underwent follow-up colonoscopy between 2012 and 2013 among 62171 asymptomatic subjects who underwent an initial colonoscopy for a health check-up between 2010 and 2011. The risk of adenoma occurrence was assessed using Cox proportional hazards modeling. Results The mean interval between the initial and follow-up colonoscopy was 2.2±0.6 years. The occurrence of adenomas detected by the follow-up colonoscopy increased linearly with the increasing quartiles of fasting glucose, hemoglobin A1c (HbA1c), insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglycerides measured at the initial colonoscopy. These associations persisted after adjusting for confounding factors. The adjusted hazard ratios for adenoma occurrence comparing the fourth with the first quartiles of fasting glucose, HbA1c, insulin, HOMA-IR, and triglycerides were 1.50 [95% confidence interval (CI), 1.26–1.77; ptrend<0.001], 1.22 (95% CI, 1.04–1.43; ptrend=0.024), 1.22 (95% CI, 1.02–1.46; ptrend=0.046), 1.36 (95% CI, 1.14–1.63; ptrend=0.004), and 1.19 (95% CI, 0.99–1.42; ptrend=0.041), respectively. In addition, increasing quartiles of low-density lipoprotein-cholesterol and apolipoprotein B were associated with an increasing occurrence of adenomas. Conclusion The levels of parameters of glucose and lipid metabolism were significantly associated with the occurrence of adenomas detected on surveillance colonoscopy. Improving the parameters of glucose and lipid metabolism through lifestyle changes or medications may be helpful in preventing metachronous adenomas. PMID:28120565

  16. Effects of oral administration of titanium dioxide fine-sized particles on plasma glucose in mice.

    PubMed

    Gu, Ning; Hu, Hailong; Guo, Qian; Jin, Sanli; Wang, Changlin; Oh, Yuri; Feng, Yujie; Wu, Qiong

    2015-12-01

    Titanium dioxide (TiO2) is an authorized additive used as a food colorant, is composed of nano-sized particles (NP) and fine-sized particles (FP). Previous study reported that oral administration of TiO2 NPs triggers an increase in plasma glucose of mice. However, no previous studies have focused on toxic effects of TiO2 FPs on plasma glucose homeostasis following oral administration. In the current study, mice were orally administered TiO2 FPs greater than 100 nm in size (64 mg/kg body weight per day), and effects on plasma glucose levels examined. Our results showed that titanium levels was not changed in mouse blood, livers and pancreases after mice were orally administered TiO2 FPs. Biochemical analyzes showed that plasma glucose and ROS levels were not affected by TiO2 FPs. Histopathological results showed that TiO2 FPs did not induce pathology changes in organs, especially plasma glucose homeostasis regulation organs, such as pancreas and liver. Western blotting showed that oral administration of TiO2 FPs did not induce insulin resistance (IR) in mouse liver. These results showed that, TiO2 FPs cannot be absorbed via oral administration and affect plasma glucose levels in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. The UPR reduces glucose metabolism via IRE1 signaling.

    PubMed

    van der Harg, Judith M; van Heest, Jessica C; Bangel, Fabian N; Patiwael, Sanne; van Weering, Jan R T; Scheper, Wiep

    2017-04-01

    Neurons are highly dependent on glucose. A disturbance in glucose homeostasis therefore poses a severe risk that is counteracted by activation of stress responses to limit damage and restore the energy balance. A major stress response that is activated under conditions of glucose deprivation is the unfolded protein response (UPR) that is aimed to restore proteostasis in the endoplasmic reticulum. The key signaling of the UPR involves the transient activation of a transcriptional program and an overall reduction of protein synthesis. Since the UPR is strategically positioned to sense and integrate metabolic stress signals, it is likely that - apart from its adaptive response to restore proteostasis - it also directly affects metabolic pathways. Here we investigate the direct role of the UPR in glucose homeostasis. O-GlcNAc is a post-translational modification that is highly responsive to glucose fluctuations. We find that UPR activation results in decreased O-GlcNAc modification, in line with reduced glucose metabolism. Our data indicate that UPR activation has no direct impact on the upstream processes in glucose metabolism; glucose transporter expression, glucose uptake and hexokinase activity. In contrast, prolonged UPR activation decreases glycolysis and mitochondrial metabolism. Decreased mitochondrial respiration is not accompanied by apoptosis or a structural change in mitochondria indicating that the reduction in metabolic rate upon UPR activation is a physiological non-apoptotic response. Metabolic decrease is prevented if the IRE1 pathway of the UPR is inhibited. This indicates that activation of IRE1 signaling induces a reduction in glucose metabolism, as part of an adaptive response. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency☆ab

    PubMed Central

    Mokadem, Mohamad; Zechner, Juliet F.; Margolskee, Robert F.; Drucker, Daniel J.; Aguirre, Vincent

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB). While intact GLP-1exerts its metabolic effects via the classical GLP-1 receptor (GLP-1R), proteolytic processing of circulating GLP-1 yields metabolites such as GLP-1(9–36)amide/GLP-1(28–36)amide, that exert similar effects independent of the classical GLP-1R. We investigated the hypothesis that GLP-1, acting via these metabolites or through its known receptor, is required for the beneficial effects of RYGB using two models of functional GLP-1 deficiency – α-gustducin-deficient (α-Gust−/−) mice, which exhibit attenuated nutrient-stimulated GLP-1 secretion, and GLP-1R-deficient mice. We show that the effect of RYGB to enhance glucose-stimulated GLP-1 secretion was greatly attenuated in α-Gust−/− mice. In both genetic models, RYGB reduced body weight and improved glucose homeostasis to levels observed in lean control mice. Therefore, GLP-1, acting through its classical GLP-1R or its bioactive metabolites, does not seem to be involved in the effects of RYGB on body weight and glucose homeostasis. PMID:24634822

  19. The Effect of Selenium Supplementation on Glucose Homeostasis and the Expression of Genes Related to Glucose Metabolism.

    PubMed

    Jablonska, Ewa; Reszka, Edyta; Gromadzinska, Jolanta; Wieczorek, Edyta; Krol, Magdalena B; Raimondi, Sara; Socha, Katarzyna; Borawska, Maria H; Wasowicz, Wojciech

    2016-12-13

    The aim of the study was to evaluate the effect of selenium supplementation on the expression of genes associated with glucose metabolism in humans, in order to explain the unclear relationship between selenium and the risk of diabetes. For gene expression analysis we used archival samples of cDNA from 76 non-diabetic subjects supplemented with selenium in the previous study. The supplementation period was six weeks and the daily dose of selenium was 200 µg (as selenium yeast). Blood for mRNA isolation was collected at four time points: before supplementation, after two and four weeks of supplementation, and after four weeks of washout. The analysis included 15 genes encoding selected proteins involved in insulin signaling and glucose metabolism. In addition, HbA1c and fasting plasma glucose were measured at three and four time points, respectively. Selenium supplementation was associated with a significantly decreased level of HbA1c but not fasting plasma glucose (FPG) and significant down-regulation of seven genes: INSR , ADIPOR1 , LDHA , PDHA , PDHB , MYC , and HIF1AN . These results suggest that selenium may affect glycemic control at different levels of regulation, linked to insulin signaling, glycolysis, and pyruvate metabolism. Further research is needed to investigate mechanisms of such transcriptional regulation and its potential implication in direct metabolic effects.

  20. Stilbene Glucoside, a Putative Sleep Promoting Constituent from Polygonum multiflorum Affects Sleep Homeostasis by Affecting the Activities of Lactate Dehydrogenase and Salivary Alpha Amylase.

    PubMed

    Wei, Qian; Ta, Guang; He, Wenjing; Wang, Wei; Wu, Qiucheng

    2017-01-01

    Chinese herbal medicine (CHM) has been used for treating insomnia for centuries. The most used CHM for insomnia was Polygonum multiflorum. However, the molecular mechanism for CHM preventing insomnia is unknown. Stilbene glucoside (THSG), an important active component of P. multiflorum, may play an important role for treating insomnia. To test the hypothesis, Kunming mice were treated with different dosages of THSG. To examine the sleep duration, a computer-controlled sleep-wake detection system was implemented. Electroencephalogram (EEG) and electromyogram (EMG) electrodes were implanted to determine sleep-wake state. RT-PCR and Western blot was used to measure the levels of lactate dehydrogenase (LDH) and saliva alpha amylase. Spearman's rank correlation coefficient was used to identify the strength of correlation between the variables. The results showed that THSG significantly prolonged the sleep time of the mice (p<0.01). THSG changed sleep profile by reducing wake and rapid eye movement (REM) period, and increasing non-REM period. RT-PCR and Western blot analysis showed that THSG could down-regulate the levels of LDH and saliva alpha amylase (p<0.05). The level of lactate and glucose was positively related with the activity of LDH and saliva alpha amylase (p<0.05), respectively. On the other hand, the activities of LDH and amylase were negatively associated with sleep duration (p<0.05). The levels of lactate and glucose affect sleep homeostasis. Thus, THSG may prevent insomnia by regulating sleep duration via LDH and salivary alpha amylase.

  1. 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.

  2. Oxygen Glucose Deprivation in Rat Hippocampal Slice Cultures Results in Alterations in Carnitine Homeostasis and Mitochondrial Dysfunction

    PubMed Central

    Rau, Thomas F.; Lu, Qing; Sharma, Shruti; Sun, Xutong; Leary, Gregory; Beckman, Matthew L.; Hou, Yali; Wainwright, Mark S.; Kavanaugh, Michael; Poulsen, David J.; Black, Stephen M.

    2012-01-01

    Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR) supplementation. Utilizing neonatal rat hippocampal slice cultures we found that oxygen glucose deprivation (OGD) decreased the levels of free carnitines (FC) and increased the acylcarnitine (AC): FC ratio. These changes in carnitine homeostasis correlated with decreases in the protein levels of carnitine palmitoyl transferase (CPT) 1 and 2. LCAR supplementation prevented the decrease in CPT1 and CPT2, enhanced both FC and the AC∶FC ratio and increased slice culture metabolic viability, the mitochondrial membrane potential prior to OGD and prevented the subsequent loss of neurons during later stages of reperfusion through a reduction in apoptotic cell death. Finally, we found that LCAR supplementation preserved the structural integrity and synaptic transmission within the hippocampus after OGD. Thus, we conclude that LCAR supplementation preserves the key enzymes responsible for maintaining carnitine homeostasis and preserves both cell viability and synaptic transmission after OGD. PMID:22984394

  3. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet

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

    Zhang, Yu-Kun Jennifer; Wu, Kai Connie; Liu, Jie

    Nrf2, a master regulator of intracellular redox homeostasis, is indicated to participate in fatty acid metabolism in liver. However, its role in diet-induced obesity remains controversial. In the current study, genetically engineered Nrf2-null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks. The results indicate that the absence or enhancement of Nrf2 activity did not prevent diet-induced obesity, had limited effects on lipid metabolism, but affected blood glucose homeostasis. Whereas the Nrf2-null mice were resistant to HFD-induced glucose intolerance, the Nrf2-activated K1-KD mice exhibited prolonged elevation of circulatingmore » glucose during a glucose tolerance test even on the control diet. Feeding a HFD did not activate the Nrf2 signaling pathway in mouse livers. Fibroblast growth factor 21 (Fgf21) is a liver-derived anti-diabetic hormone that exerts glucose- and lipid-lowering effects. Fgf21 mRNA and protein were both elevated in livers of Nrf2-null mice, and Fgf21 protein was lower in K1-KD mice than WT mice. The inverse correlation between Nrf2 activity and hepatic expression of Fgf21 might explain the improved glucose tolerance in Nrf2-null mice. Furthermore, a more oxidative cellular environment in Nrf2-null mice could affect insulin signaling in liver. For example, mRNA of insulin-like growth factor binding protein 1, a gene repressed by insulin in hepatocytes, was markedly elevated in livers of Nrf2-null mice. In conclusion, genetic alteration of Nrf2 does not prevent diet-induced obesity in mice, but deficiency of Nrf2 improves glucose homeostasis, possibly through its effects on Fgf21 and/or insulin signaling. -- Highlights: ► Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. ► The anti-diabetic hormone, Fgf21, is highly expressed in livers of Nrf2-null mice. ► The absence of Nrf2 increases the insulin-regulated Igfbp-1 mRNA in

  4. Gliotransmission and Brain Glucose Sensing

    PubMed Central

    Lanfray, Damien; Arthaud, Sébastien; Ouellet, Johanne; Compère, Vincent; Do Rego, Jean-Luc; Leprince, Jérôme; Lefranc, Benjamin; Castel, Hélène; Bouchard, Cynthia; Monge-Roffarello, Boris; Richard, Denis; Pelletier, Georges; Vaudry, Hubert; Tonon, Marie-Christine; Morin, Fabrice

    2013-01-01

    Hypothalamic glucose sensing is involved in the control of feeding behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process. Diazepam-binding inhibitor (DBI) and its processing product the octadecaneuropeptide (ODN), collectively named endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor. Therefore, we investigated the involvement of endozepines in brain glucose sensing. First, we showed that intracerebroventricular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes. We then demonstrated that glucose stimulates endozepine secretion from hypothalamic explants. Feeding experiments indicate that the anorexigenic effect of central administration of glucose was blunted by coinjection of an ODN antagonist. Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an ODN agonist. The anorexigenic effects of centrally injected glucose or ODN agonist were suppressed by blockade of the melanocortin-3/4 receptors, suggesting that glucose sensing involves endozepinergic control of the melanocortin pathway. Finally, we found that brain endozepines modulate blood glucose levels, suggesting their involvement in a feedback loop controlling whole-body glucose homeostasis. Collectively, these data indicate that endozepines are a critical relay in brain glucose sensing and potentially new targets in treatment of metabolic disorders. PMID:23160530

  5. Positive affect predicts cerebral glucose metabolism in late middle-aged adults

    PubMed Central

    Nicholas, Christopher R.; Hoscheidt, Siobhan M.; Clark, Lindsay R.; Racine, Annie M.; Berman, Sara E.; Koscik, Rebecca L.; Maritza Dowling, N.; Asthana, Sanjay; Christian, Bradley T.; Sager, Mark A.

    2017-01-01

    Abstract Positive affect is associated with a number of health benefits; however, few studies have examined the relationship between positive affect and cerebral glucose metabolism, a key energy source for neuronal function and a possible index of brain health. We sought to determine if positive affect was associated with cerebral glucose metabolism in late middle-aged adults (n = 133). Participants completed the positive affect subscale of the Center for Epidemiological Studies Depression Scale at two time points over a two-year period and underwent 18F-fluorodeoxyglucose-positron emission tomography scanning. After controlling for age, sex, perceived health status, depressive symptoms, anti-depressant use, family history of Alzheimer’s disease, APOE ε4 status and interval between visits, positive affect was associated with greater cerebral glucose metabolism across para-/limbic, frontal, temporal and parietal regions. Our findings provide evidence that positive affect in late midlife is associated with greater brain health in regions involved in affective processing and also known to be susceptible to early neuropathological processes. The current findings may have implications for interventions aimed at increasing positive affect to attenuate early neuropathological changes in at-risk individuals. PMID:28402542

  6. BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis.

    PubMed

    Sanderson, Michael P; Apgar, Joshua; Garin-Chesa, Pilar; Hofmann, Marco H; Kessler, Dirk; Quant, Jens; Savchenko, Alexander; Schaaf, Otmar; Treu, Matthias; Tye, Heather; Zahn, Stephan K; Zoephel, Andreas; Haaksma, Eric; Adolf, Günther R; Kraut, Norbert

    2015-12-01

    Inhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach of pharmacologic intervention in cancer, owing to the roles of the IGF1R and INSRA in promoting cell proliferation and survival. However, the central role of the INSRB isoform in glucose homeostasis suggests that prolonged inhibition of this kinase could result in metabolic toxicity. We describe here the profile of the novel compound BI 885578, a potent and selective ATP-competitive IGF1R/INSR tyrosine kinase inhibitor distinguished by rapid intestinal absorption and a short in vivo half-life as a result of rapid metabolic clearance. BI 885578, administered daily per os, displayed an acceptable tolerability profile in mice at doses that significantly reduced the growth of xenografted human GEO and CL-14 colon carcinoma tumors. We found that treatment with BI 885578 is accompanied by increases in circulating glucose and insulin levels, which in turn leads to compensatory hyperphosphorylation of muscle INSRs and subsequent normalization of blood glucose within a few hours. In contrast, the normalization of IGF1R and INSR phosphorylation in GEO tumors occurs at a much slower rate. In accordance with this, BI 885578 led to a prolonged inhibition of cell proliferation and induction of apoptosis in GEO tumors. We propose that the remarkable therapeutic window observed for BI 885578 is achieved by virtue of the distinctive pharmacokinetic properties of the compound, capitalizing on the physiologic mechanisms of glucose homeostasis and differential levels of IGF1R and INSR expression in tumors and normal tissues. ©2015 American Association for Cancer Research.

  7. Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial.

    PubMed

    Shepherd, Anthony I; Wilkerson, Daryl P; Fulford, Jon; Winyard, Paul G; Benjamin, Nigel; Shore, Angela C; Gilchrist, Mark

    2016-09-01

    Nitric oxide alters gastric blood flow, improves vascular function, and mediates glucose uptake within the intestines and skeletal muscle. Dietary nitrate, acting as a source of nitric oxide, appears to be a potential low-cost therapy that may help maintain glucose homeostasis. In a randomized, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardized breakfast, supplemented with either nitrate-rich beetroot juice (11.91 mmol nitrate) or nitrate-depleted beetroot juice as placebo (0.01 mmol nitrate). MRI was used to assess apparent diffusion coefficient (ADC), portal vein flux, and velocity. Plasma glucose, incretin, and C-peptide concentrations and blood pressure were assessed. Outcome variables were measured at baseline and hourly for 3 h. Compared with a placebo, beetroot juice resulted in a significant elevation in plasma nitrate and plasma nitrite concentration. No differences were seen for the young or older adult cohorts between placebo and beetroot juice for ADC, or portal vein flux. There was an interaction effect in the young adults between visits for portal vein velocity. Nitrate supplementation did not reduce plasma glucose, active GLP-1, total GLP-1, or plasma C-peptide concentrations for the young or older adult cohorts. Despite a significant elevation in plasma nitrite concentration following an acute dose of (11.91 mmol) nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults. Copyright © 2016 the American Physiological Society.

  8. Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial

    PubMed Central

    Wilkerson, Daryl P.; Fulford, Jon; Winyard, Paul G.; Benjamin, Nigel; Shore, Angela C.

    2016-01-01

    Nitric oxide alters gastric blood flow, improves vascular function, and mediates glucose uptake within the intestines and skeletal muscle. Dietary nitrate, acting as a source of nitric oxide, appears to be a potential low-cost therapy that may help maintain glucose homeostasis. In a randomized, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardized breakfast, supplemented with either nitrate-rich beetroot juice (11.91 mmol nitrate) or nitrate-depleted beetroot juice as placebo (0.01 mmol nitrate). MRI was used to assess apparent diffusion coefficient (ADC), portal vein flux, and velocity. Plasma glucose, incretin, and C-peptide concentrations and blood pressure were assessed. Outcome variables were measured at baseline and hourly for 3 h. Compared with a placebo, beetroot juice resulted in a significant elevation in plasma nitrate and plasma nitrite concentration. No differences were seen for the young or older adult cohorts between placebo and beetroot juice for ADC, or portal vein flux. There was an interaction effect in the young adults between visits for portal vein velocity. Nitrate supplementation did not reduce plasma glucose, active GLP-1, total GLP-1, or plasma C-peptide concentrations for the young or older adult cohorts. Despite a significant elevation in plasma nitrite concentration following an acute dose of (11.91 mmol) nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults. PMID:27418682

  9. Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

    PubMed

    Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

    2016-05-01

    GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1.

  10. Evidence for brain glucose dysregulation in Alzheimer's disease.

    PubMed

    An, Yang; Varma, Vijay R; Varma, Sudhir; Casanova, Ramon; Dammer, Eric; Pletnikova, Olga; Chia, Chee W; Egan, Josephine M; Ferrucci, Luigi; Troncoso, Juan; Levey, Allan I; Lah, James; Seyfried, Nicholas T; Legido-Quigley, Cristina; O'Brien, Richard; Thambisetty, Madhav

    2018-03-01

    It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis. Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose. Higher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations. Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms. Copyright © 2017 the Alzheimer's Association. All rights reserved.

  11. Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice.

    PubMed

    Hargett, Stefan R; Walker, Natalie N; Hussain, Syed S; Hoehn, Kyle L; Keller, Susanna R

    2015-08-01

    Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1(-/-)) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1(-/-) mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1(-/-) mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1(-/-) mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1(-/-) mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1(-/-) mice and between male Tbc1d1(-/-) mice in different studies due to variations in body composition and nutrient handling. Copyright © 2015 the American Physiological Society.

  12. Improvements in glucose homeostasis in response to regular exercise are influenced by the PPARG Pro12Ala variant: results from the HERITAGE Family Study.

    PubMed

    Ruchat, S-M; Rankinen, T; Weisnagel, S J; Rice, T; Rao, D C; Bergman, R N; Bouchard, C; Pérusse, L

    2010-04-01

    Exercise training improves glucose homeostasis, but large inter-individual differences are reported, suggesting a role of genetic factors. We investigated whether variants either confirmed or newly identified as diabetes susceptibility variants through genome-wide association studies (GWAS) modulate changes in phenotypes derived from an IVGTT in response to an endurance training programme. We analysed eight polymorphisms in seven type 2 diabetes genes (CDKAL1 rs7756992; CDKN2A and CDKN2B rs10811661 and rs564398; HHEX rs7923837; IGF2BP2 rs4402960; KCNJ11 rs5215; PPARG rs1801282; and TCF7L2 rs7903146) in a maximum of 481 sedentary, non-diabetic white individuals, who participated in a 20-week endurance training programme. Associations were tested between the variants and changes in IVGTT-derived phenotypes. The only evidence of association with training response was found with PPARG rs1801282 (Pro12Ala). We observed that Ala carriers experienced greater increase in overall glucose tolerance (Deltaglucose disappearance index Ala/Ala 0.22 +/- 0.22, Pro/Ala 0.14 +/- 0.06, Pro/Pro 0.004 +/- 0.03; p = 0.0008), glucose effectiveness (Ala/Ala 0.28 +/- 0.41, Pro/Ala 0.44 +/- 0.14, Pro/Pro 0.09 +/- 0.06; p = 0.004), acute insulin response to glucose (Ala/Ala 64.21 +/- 37.73, Pro/Ala -11.92 +/- 40.30, Pro/Pro -46.30 +/- 14.70; p = 0.03) and disposition index (Ala/Ala 551.8 +/- 448.5, Pro/Ala 534.6 +/- 218.3, Pro/Pro -7.44 +/- 88.18; p = 0.003). Compared with Pro/Pro individuals, PPARG Ala carriers experienced greater improvements in glucose and insulin metabolism in response to regular endurance training. However, we did not find evidence of association between type 2 diabetes susceptibility variants recently identified through GWAS and glucose homeostasis response to exercise. Our results extend those of previous studies showing that Ala carriers appear to be more responsive to beneficial health effects of lifestyle interventions.

  13. Glucosensing in the gastrointestinal tract: Impact on glucose metabolism

    PubMed Central

    Fournel, Audren; Marlin, Alysson; Abot, Anne; Pasquio, Charles; Cirillo, Carla; Cani, Patrice D.

    2016-01-01

    The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases. PMID:26939867

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

    PubMed

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

    2016-02-25

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

  15. Contribution of galactose and fructose to glucose homeostasis

    USDA-ARS?s Scientific Manuscript database

    To determine the contributions of galactose and fructose to glucose formation, 6 subjects (26 +/- 2 years old; body mass index, 22.4 +/-0.2 kg/m2) (mean +/- SE) were studied during fasting conditions. Three subjects received a primed constant intravenous infusion of[6,6-2H2] glucose for 3 hours foll...

  16. Lactate rescues neuronal sodium homeostasis during impaired energy metabolism.

    PubMed

    Karus, Claudia; Ziemens, Daniel; Rose, Christine R

    2015-01-01

    Recently, we established that recurrent activity evokes network sodium oscillations in neurons and astrocytes in hippocampal tissue slices. Interestingly, metabolic integrity of astrocytes was essential for the neurons' capacity to maintain low sodium and to recover from sodium loads, indicating an intimate metabolic coupling between the 2 cell types. Here, we studied if lactate can support neuronal sodium homeostasis during impaired energy metabolism by analyzing whether glucose removal, pharmacological inhibition of glycolysis and/or addition of lactate affect cellular sodium regulation. Furthermore, we studied the effect of lactate on sodium regulation during recurrent network activity and upon inhibition of the glial Krebs cycle by sodium-fluoroacetate. Our results indicate that lactate is preferentially used by neurons. They demonstrate that lactate supports neuronal sodium homeostasis and rescues the effects of glial poisoning by sodium-fluoroacetate. Altogether, they are in line with the proposed transfer of lactate from astrocytes to neurons, the so-called astrocyte-neuron-lactate shuttle.

  17. Lactate rescues neuronal sodium homeostasis during impaired energy metabolism

    PubMed Central

    Karus, Claudia; Ziemens, Daniel; Rose, Christine R

    2015-01-01

    Recently, we established that recurrent activity evokes network sodium oscillations in neurons and astrocytes in hippocampal tissue slices. Interestingly, metabolic integrity of astrocytes was essential for the neurons' capacity to maintain low sodium and to recover from sodium loads, indicating an intimate metabolic coupling between the 2 cell types. Here, we studied if lactate can support neuronal sodium homeostasis during impaired energy metabolism by analyzing whether glucose removal, pharmacological inhibition of glycolysis and/or addition of lactate affect cellular sodium regulation. Furthermore, we studied the effect of lactate on sodium regulation during recurrent network activity and upon inhibition of the glial Krebs cycle by sodium-fluoroacetate. Our results indicate that lactate is preferentially used by neurons. They demonstrate that lactate supports neuronal sodium homeostasis and rescues the effects of glial poisoning by sodium-fluoroacetate. Altogether, they are in line with the proposed transfer of lactate from astrocytes to neurons, the so-called astrocyte-neuron-lactate shuttle. PMID:26039160

  18. Serine racemase is expressed in islets and contributes to the regulation of glucose homeostasis.

    PubMed

    Lockridge, Amber D; Baumann, Daniel C; Akhaphong, Brian; Abrenica, Alleah; Miller, Robert F; Alejandro, Emilyn U

    2016-11-01

    NMDA receptors (NMDARs) have recently been discovered as functional regulators of pancreatic β-cell insulin secretion. While these excitatory receptor channels have been extensively studied in the brain for their role in synaptic plasticity and development, little is known about how they work in β-cells. In neuronal cells, NMDAR activation requires the simultaneous binding of glutamate and a rate-limiting co-agonist, such as D-serine. D-serine levels and availability in most of the brain rely on endogenous synthesis by the enzyme serine racemase (Srr). Srr transcripts have been reported in human and mouse islets but it is not clear whether Srr is functionally expressed in β-cells or what its role in the pancreas might be. In this investigation, we reveal that Srr protein is highly expressed in primary human and mouse β-cells. Mice with whole body deletion of Srr (Srr KO) show improved glucose tolerance through enhanced insulin secretory capacity, possibly through Srr-mediated alterations in islet NMDAR expression and function. We observed elevated insulin sensitivity in some animals, suggesting Srr metabolic regulation in other peripheral organs as well. Srr expression in neonatal and embryonic islets, and adult deficits in Srr KO pancreas weight and islet insulin content, point toward a potential role for Srr in pancreatic development. These data reveal the first evidence that Srr may regulate glucose homeostasis in peripheral tissues and provide circumstantial evidence that D-serine may be an endogenous islet NMDAR co-agonist in β-cells.

  19. The Effects of an Amino Acid Supplement on Glucose Homeostasis, Inflammatory Markers, and Incretins after Laparoscopic Gastric Bypass

    PubMed Central

    Breitman, Igal; Saraf, Neha; Kakade, Manasi; Yellumahanthi, Kishore; White, Merritt; Hackett, Jo Ann; Clements, Ronald H.

    2011-01-01

    Background Protein supplements are routinely used after a laparoscopic gastric bypass (LGB). The aim of this study is to evaluate the impact of an amino acid supplement on glucose homeostasis, hormonal and inflammatory markers after LGB. Methods 30 patients undergoing LGB were randomized to receive or not to receive 24g of an oral supplement containing a leucine metabolite, glutamine and arginine twice daily for 8 weeks. Changes in weight, BMI, ghrelin, GLP-1, GIP, glucose, insulin, C-peptide, insulin sensitivity, IL-6, CRP, leptin and IGF-1 were assessed preoperatively, 2 weeks and 8-weeks postoperatively. Results 30 patients (96.7% females, 46.9 ± 8.4 years, 113.4 ± 11.6 kg and BMI 43.3 ± 4.1 kg/m2) were randomized. The experimental (N=14) and control groups (N=16) were not significantly different at baseline. Weight and BMI were decreased significantly at two weeks and at eight weeks (p<0.0001 for each variable), but no statistical significance was observed between the two groups. Fasting glucose decreased significantly at 2 & 8 weeks as compared to base line (p<0.0001) with no difference between experimental and control groups (p=0.8), but insulin and calculated insulin sensitivity, that were similar at baseline, become significantly worse in the experimental group 8 weeks after surgery ( p=0.02 for insulin, p=0.04 for the homeostasis model assessment (HOMA) index). CRP, which was similar at baseline, was found to be significantly lower at 8 weeks in control vs. experimental group, (P=0.018). IL-6 decreased significantly from baseline at 2 weeks and rebounded at 8 weeks in both groups, there was a trend of higher IL-6 in the experimental group that becomes significant at 8 weeks (p=0.05). Leptin and IGF-1 levels decreased significantly from baseline at 2 & 8 weeks (p<0.0001) but there was no difference between the two groups. No significant change in GLP-1, ghrelin or GIP were noticed after 8 weeks. Conclusion An amino acid supplement had no effect on the

  20. 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.

  1. A Novel Arabidopsis Vacuolar Glucose Exporter Is Involved in Cellular Sugar Homeostasis and Affects the Composition of Seed Storage Compounds1[W][OA

    PubMed Central

    Poschet, Gernot; Hannich, Barbara; Raab, Sabine; Jungkunz, Isabel; Klemens, Patrick A.W.; Krueger, Stephan; Wic, Stefan; Neuhaus, H. Ekkehard; Büttner, Michael

    2011-01-01

    Subcellular sugar partitioning in plants is strongly regulated in response to developmental cues and changes in external conditions. Besides transitory starch, the vacuolar sugars represent a highly dynamic pool of instantly accessible metabolites that serve as energy source and osmoprotectant. Here, we present the molecular identification and functional characterization of the vacuolar glucose (Glc) exporter Arabidopsis (Arabidopsis thaliana) Early Responsive to Dehydration-Like6 (AtERDL6). We demonstrate tonoplast localization of AtERDL6 in plants. In Arabidopsis, AtERDL6 expression is induced in response to factors that activate vacuolar Glc pools, like darkness, heat stress, and wounding. On the other hand, AtERDL6 transcript levels drop during conditions that trigger Glc accumulation in the vacuole, like cold stress and external sugar supply. Accordingly, sugar analyses revealed that Aterdl6 mutants have elevated vacuolar Glc levels and that Glc flux across the tonoplast is impaired under stress conditions. Interestingly, overexpressor lines indicated a very similar function for the ERDL6 ortholog Integral Membrane Protein from sugar beet (Beta vulgaris). Aterdl6 mutant plants display increased sensitivity against external Glc, and mutant seeds exhibit a 10% increase in seed weight due to enhanced levels of seed sugars, proteins, and lipids. Our findings underline the importance of vacuolar Glc export during the regulation of cellular Glc homeostasis and the composition of seed reserves. PMID:21984725

  2. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis.

    PubMed

    Ren, Decheng; Zhou, Yingjiang; Morris, David; Li, Minghua; Li, Zhiqin; Rui, Liangyou

    2007-02-01

    SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.

  3. Glucosensing in the gastrointestinal tract: Impact on glucose metabolism.

    PubMed

    Fournel, Audren; Marlin, Alysson; Abot, Anne; Pasquio, Charles; Cirillo, Carla; Cani, Patrice D; Knauf, Claude

    2016-05-01

    The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases. Copyright © 2016 the American Physiological Society.

  4. Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis.

    PubMed

    Chen, V P; Gao, Y; Geng, L; Brimijoin, S

    2017-09-01

    Ghrelin is the only orexigenic hormone known to stimulate food intake and promote obesity and insulin resistance. We recently showed that plasma ghrelin is controlled by butyrylcholinesterase (BChE), which has a strong impact on feeding and weight gain. BChE knockout (KO) mice are prone to obesity on high-fat diet, but hepatic BChE gene transfer rescues normal food intake and obesity resistance. However, these mice lack brain BChE and still develop hyperinsulinemia and insulin resistance, suggesting essential interactions between BChE and ghrelin within the brain. To test the hypothesis we used four experimental groups: (1) untreated wild-type mice, (2) BChE KO mice with LUC delivered by adeno-associated virus (AAV) in combined intravenous (i.v.) and intracerebral (i.c.) injections, (3) KO mice given AAV for mouse BChE (i.v. only) and (4) KO mice given the same vector both i.v. and i.c. All mice ate a 45% calorie high-fat diet from the age of 1 month. Body weight, body composition, daily caloric intake and serum parameters were monitored throughout, and glucose tolerance and insulin tolerance tests were performed at intervals. Circulating ghrelin levels dropped substantially in the KO mice after i.v. AAV-BChE delivery, which led to normal food intake and healthy body weight. BChE KO mice that received AAV-BChE through i.v. and i.c. combined treatments not only resisted weight gain on high-fat diet but also retained normal glucose and insulin tolerance. These data indicate a central role for BChE in regulating both insulin and glucose homeostasis. BChE gene transfer could be a useful therapy for complications linked to diet-induced obesity and insulin resistance.

  5. Visual food cues decrease postprandial glucose concentrations in lean and obese men without affecting food intake and related endocrine parameters.

    PubMed

    Brede, Swantje; Sputh, Annika; Hartmann, Ann-Christin; Hallschmid, Manfred; Lehnert, Hendrik; Klement, Johanna

    2017-10-01

    The abundance of highly palatable food items in our environment represents a possible cause of overconsumption. Neuroimaging studies in humans have demonstrated that watching pictures of food increases activation in brain areas involved in homeostatic and hedonic food cue processing. Nevertheless, the impact of food cues on actual food intake and metabolic parameters has not been systematically investigated. We tested the hypothesis that watching high-calorie food cues increases food intake and modifies anticipatory blood parameters in lean and especially in obese men. In 20 normal-weight and 20 obese healthy fasted men, we assessed the effects of watching pictures of high-calorie food items versus neutral contents on food intake measured during a standardized test buffet and subsequent snacking as well as on glucose homeostasis and endocrine parameters. Compared to neutral pictures, viewing food pictures reduced postprandial blood glucose concentrations in lean (p = 0.016) and obese (p = 0.044) subjects, without any differences in insulin or C-peptide concentrations (all p > 0.4). Viewing food pictures did not affect total calorie intake during the buffet (all p > 0.5) and snack consumption (all p > 0.4). Concentrations of ghrelin, adrenocorticotropic hormone (ACTH), cortisol, and glucagon also remained unaffected (all p > 0.08). These data indicate that preprandial processing of food cues curbs postprandial blood glucose excursions, without immediately affecting eating behavior in normal-weight and obese men. Findings indicate that exposure to food cues does not acutely trigger calorie overconsumption but rather improves the glucoregulatory response to food intake. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. The GLP-1 response to glucose does not mediate beta and alpha cell dysfunction in Hispanics with abnormal glucose metabolism.

    PubMed

    Adams, Elizabeth; Genter, Pauline; Keefe, Emma; Sandow, Kevin; Gray, Virginia; Rotter, Jerome I; Chen, Yii-Der Ida; Ipp, Eli

    2018-01-01

    Glucagon-like peptide-1 (GLP-1) contributes to insulin secretion after meals. Though Hispanics have increased risk for type 2 diabetes mellitus, it is unknown if impaired GLP-1 secretion contributes to this risk. We therefore studied plasma GLP-1 secretion and action in Hispanic adults. Hispanic (H; n = 31) and non-Hispanic (nH; n = 15) participants underwent an oral glucose tolerance test (OGTT). All participants were categorized by glucose tolerance into four groups: normal glucose tolerant non-Hispanic (NGT-nH; n = 15), normal glucose tolerant Hispanic (NGT-H; n = 12), impaired glucose tolerant Hispanic (IGT-H; n = 11), or newly diagnosed type 2 diabetes mellitus, Hispanic (T2D-H; n = 8). Glucose-induced increments in plasma GLP-1 (Δ-GLP-1) were not different in NGT-H and NGT-nH (p = .38), nor amongst Hispanic subgroups with varying degrees of glucose homeostasis (p = .6). In contrast, the insulinogenic index in T2D-H group was lower than the other groups (p = .016). Subjects with abnormal glucose homeostasis (AGH), i.e., T2D-H plus IGT-H, had a diminished glucagon suppression index compared to patients with normal glucose homeostasis (NGT-H plus NGT-nH) (p = .035). GLP-1 responses to glucose were similar in Hispanic and Non-Hispanic NGT. Despite similar glucose-induced Δ-GLP-1, insulin and glucagon responses were abnormal in T2D-H and AGH, respectively. Thus, impaired GLP-1 secretion is unlikely to play a role in islet dysfunction in T2D. Although GLP-1 therapeutics enhance insulin secretion and glucagon suppression, it is likely due to pharmacological amplification of the GLP-1 pathways rather than treatment of hormonal deficiency. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Eating carbohydrate mostly at lunch and protein mostly at dinner within a covert hypocaloric diet influences morning glucose homeostasis in overweight/obese men.

    PubMed

    Alves, Raquel Duarte Moreira; de Oliveira, Fernanda Cristina Esteves; Hermsdorff, Helen Hermana Miranda; Abete, Itziar; Zulet, María Angeles; Martínez, José Alfredo; Bressan, Josefina

    2014-02-01

    To evaluate the effects of two dietary patterns in which carbohydrates and proteins were eaten mostly at lunch or dinner on body weight and composition, energy metabolism, and biochemical markers in overweight/obese men. Fifty-eight men (30.0 ± 7.4 years; 30.8 ± 2.4 kg/m(2)) followed a covert hypocaloric balanced diet (-10 % of daily energy requirements) during 8 weeks. Subjects were randomly assigned to three groups: control diet (CT); diurnal carbohydrate/nocturnal protein (DCNP); and nocturnal carbohydrate/diurnal protein (NCDP). Main analyzed outcomes were weight loss, body composition, diet-induced thermogenesis (DIT), and glucose/lipid profile. In all groups, a significant decrease in body weight, BMI, and fat mass (kg and %) was verified, without differences between groups. Interestingly, within group analyses showed that the fat-free mass (kg) significantly decreased in NCDP and in CT after 8-week intervention, but not in DCNP. A detrimental increase in fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMAIR) was verified only in DCNP, while NCDP and CT groups presented a non-significant reduction. Moreover, significant differences between DCNP and the other groups were detected for fasting insulin and HOMAIR. After the adjustments, NCDP presented a significantly higher DIT and energy expenditure after lunch, compared with DCNP, but after dinner, there were no differences among groups. Eating carbohydrates mostly at dinner and protein mostly at lunch within a hypocaloric balanced diet had similar effect on body composition and biochemical markers, but higher effect on DIT compared with control diet. Moreover, eating carbohydrates mostly at lunch and protein mostly at dinner had a deleterious impact on glucose homeostasis.

  8. Role of proximal gut exclusion from food on glucose homeostasis in patients with Type 2 diabetes.

    PubMed

    Cohen, R; le Roux, C W; Papamargaritis, D; Salles, J E; Petry, T; Correa, J L; Pournaras, D J; Galvao Neto, M; Martins, B; Sakai, P; Schiavon, C A; Sorli, C

    2013-12-01

    To report Type 2 diabetes-related outcomes after the implantation of a duodenal-jejunal bypass liner device and to investigate the role of proximal gut exclusion from food in glucose homeostasis using the model of this device. Sixteen patients with Type 2 diabetes and BMI <36 kg/m(2) were evaluated before and 1, 12 and 52 weeks after duodenal-jejunal bypass liner implantation and 26 weeks after explantation. Mixed-meal tolerance tests were conducted over a period of 120 min and glucose, insulin and C-peptide levels were measured. The Matsuda index and the homeostatic model of assessment of insulin resistance were used for the estimation of insulin sensitivity and insulin resistance. The insulin secretion rate was calculated using deconvolution of C-peptide levels. Body weight decreased by 1.3 kg after 1 week and by 2.4 kg after 52 weeks (P < 0.001). One year after duodenal-jejunal bypass liner implantation, the mean (sem) HbA(1c) level decreased from 71.3 (2.4) mmol/mol (8.6[0.2]%) to 58.1 (4.4) mmol/mol (7.5 [0.4]%) and mean (sem) fasting glucose levels decreased from 203.3 (13.5) mg/dl to 155.1 (13.1) mg/dl (both P < 0.001). Insulin sensitivity improved by >50% as early as 1 week after implantation as measured by the Matsuda index and the homeostatic model of assessment of insulin resistance (P < 0.001), but there was a trend towards deterioration in all the above-mentioned variables 26 weeks after explantation. Fasting insulin levels, insulin area under the curve, fasting C-peptide, C-peptide area under the curve, fasting insulin and total insulin secretion rates did not change during the duodenal-jejunal bypass liner implantation period or after explantation. The duodenal-jejunal bypass liner improves glycaemia in overweight and obese patients with Type 2 diabetes by rapidly improving insulin sensitivity. A reduction in hepatic glucose output is the most likely explanation for this improvement. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

  9. Differential Effects of Oral and Intravenous Lipid Administration on Key Molecules Related to Energy Homeostasis

    PubMed Central

    Vamvini, Maria T.; Hamnvik, Ole-Petter; Sahin-Efe, Ayse; Gavrieli, Anna; Dincer, Fadime; Farr, Olivia M.

    2016-01-01

    Context: The spectrum of lipid-induced changes in the secretion of hormones important in energy homeostasis has not yet been fully elucidated. Objective: To identify potential incretin-like effects in response to lipid administration, we examined the short-term effect of iv vs oral lipids on key molecules regulating energy homeostasis. Design, Intervention, and Participants: After a 10-hour overnight fast, 26 subjects were randomized to receive an oral lipid load, a 10% iv lipid emulsion, a 20% iv lipid emulsion, or an iv saline infusion. We obtained blood samples at 30-minute intervals for the first 2 hours and hourly thereafter for a total of 6 hours. Main Outcome Measures: Circulating levels of insulin, glucose, c-peptide, free fatty acids, incretins (glucagon-like peptide-1, gastric inhibitory polypeptide), glucagon, peptide YY, ghrelin, fibroblast growth factor 21, fetuin A, irisin, omentin, and adiponectin were measured. Results: Oral lipid ingestion resulted in higher glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, and peptide YY levels, compared with the other three groups (incremental area under the curve P = .003, P < .001, P < .001, P < .001, respectively). The 20% lipid emulsion, leading to higher free fatty acid levels, resulted in greater insulin, c-peptide, and fibroblast growth factor 21 responses compared with placebo and the other two groups (incremental area under the curve P = .002, P = .005, P < .001, P < .001, respectively). Omentin, adiponectin, fetuin A, and irisin levels were not affected by either mode of lipid administration. Conclusions: Metabolic responses to lipids depend on the route of administration. Only iv lipids trigger a dose-dependent fibroblast growth factor 21 secretion, which is nonglucagon mediated. Intravenous lipids also induce hyperinsulinemia without concurrent decreases in glucose, a phenomenon observed in insulin-resistant states. Orally administered lipids mostly affect gastrointestinal tract

  10. The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

    PubMed Central

    Shah, Kaushik; DeSilva, Shanal; Abbruscato, Thomas

    2012-01-01

    The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain. PMID:23202918

  11. Glucokinase activity in the arcuate nucleus regulates glucose intake

    PubMed Central

    Hussain, Syed; Richardson, Errol; Ma, Yue; Holton, Christopher; De Backer, Ivan; Buckley, Niki; Dhillo, Waljit; Bewick, Gavin; Zhang, Shuai; Carling, David; Bloom, Steve; Gardiner, James

    2014-01-01

    The brain relies on a constant supply of glucose, its primary fuel, for optimal function. A taste-independent mechanism within the CNS that promotes glucose delivery to the brain has been postulated to maintain glucose homeostasis; however, evidence for such a mechanism is lacking. Here, we determined that glucokinase activity within the hypothalamic arcuate nucleus is involved in regulation of dietary glucose intake. In fasted rats, glucokinase activity was specifically increased in the arcuate nucleus but not other regions of the hypothalamus. Moreover, pharmacologic and genetic activation of glucokinase in the arcuate nucleus of rodent models increased glucose ingestion, while decreased arcuate nucleus glucokinase activity reduced glucose intake. Pharmacologic targeting of potential downstream glucokinase effectors revealed that ATP-sensitive potassium channel and P/Q calcium channel activity are required for glucokinase-mediated glucose intake. Additionally, altered glucokinase activity affected release of the orexigenic neurotransmitter neuropeptide Y in response to glucose. Together, our results suggest that glucokinase activity in the arcuate nucleus specifically regulates glucose intake and that appetite for glucose is an important driver of overall food intake. Arcuate nucleus glucokinase activation may represent a CNS mechanism that underlies the oft-described phenomena of the “sweet tooth” and carbohydrate craving. PMID:25485685

  12. Fluconazole affects the alkali-metal-cation homeostasis and susceptibility to cationic toxic compounds of Candida glabrata.

    PubMed

    Elicharova, Hana; Sychrova, Hana

    2014-08-01

    Candida glabrata is a salt-tolerant and fluconazole (FLC)-resistant yeast species. Here, we analyse the contribution of plasma-membrane alkali-metal-cation exporters, a cation/proton antiporter and a cation ATPase to cation homeostasis and the maintenance of membrane potential (ΔΨ). Using a series of single and double mutants lacking CNH1 and/or ENA1 genes we show that the inability to export potassium and toxic alkali-metal cations leads to a slight hyperpolarization of the plasma membrane of C. glabrata cells; this hyperpolarization drives more cations into the cells and affects cation homeostasis. Surprisingly, a much higher hyperpolarization of C. glabrata plasma membrane was produced by incubating cells with subinhibitory concentrations of FLC. FLC treatment resulted in a substantially increased sensitivity of cells to various cationic drugs and toxic cations that are driven into the cell by negative-inside plasma-membrane potential. The effect of the combination of FLC plus cationic drug treatment was enhanced by the malfunction of alkali-metal-cation transporters that contribute to the regulation of membrane potential and cation homeostasis. In summary, we show that the combination of subinhibitory concentrations of FLC and cationic drugs strongly affects the growth of C. glabrata cells. © 2014 The Authors.

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

    PubMed

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

    2017-12-05

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

  14. Duodenal mucosal protein kinase C-δ regulates glucose production in rats.

    PubMed

    Kokorovic, Andrea; Cheung, Grace W C; Breen, Danna M; Chari, Madhu; Lam, Carol K L; Lam, Tony K T

    2011-11-01

    Activation of protein kinase C (PKC) enzymes in liver and brain alters hepatic glucose metabolism, but little is known about their role in glucose regulation in the gastrointestinal tract. We investigated whether activation of PKC-δ in the duodenum is sufficient and necessary for duodenal nutrient sensing and regulates hepatic glucose production through a neuronal network in rats. In rats, we inhibited duodenal PKC and evaluated whether nutrient-sensing mechanisms, activated by refeeding, have disruptions in glucose regulation. We then performed gain- and loss-of-function pharmacologic and molecular experiments to target duodenal PKC-δ; we evaluated the impact on glucose production regulation during the pancreatic clamping, while basal levels of insulin were maintained. PKC-δ was detected in the mucosal layer of the duodenum; intraduodenal infusion of PKC inhibitors disrupted glucose homeostasis during refeeding, indicating that duodenal activation of PKC-δ is necessary and sufficient to regulate glucose homeostasis. Intraduodenal infusion of the PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) specifically activated duodenal mucosal PKC-δ and a gut-brain-liver neuronal pathway to reduce glucose production. Molecular and pharmacologic inhibition of duodenal mucosal PKC-δ negated the ability of duodenal OAG and lipids to reduce glucose production. In the duodenal mucosa, PKC-δ regulates glucose homeostasis. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  15. Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis.

    PubMed

    Liu, Mingyao; Cao, Hongwei; Hou, Yuting; Sun, Guopeng; Li, Deshan; Wang, Wenfei

    2018-01-01

    The liver is a vital organ in vertebrates and has a wide range of functions, including glucose absorption, glycogen storage and glucose production. Fibroblast growth factor (FGF)-21 is a metabolic regulator that is primarily produced by the liver. In this paper, we studied the effect of FGF-21 on glucose metabolism in the liver. The glucose uptake of cells was detected by 2-Deoxy-d-[3H] glucose; the synergy between insulin and FGF-21 was evaluated. The mRNA expression of GLUT1-4, G6Pase and PEPCK was detected by real-time PCR. Glycogen synthesis was examined by the anthrone method. Blood samples to monitor glucose in db/db diabetic mice were obtained by tail snip. Glucose metabolism in the liver and adipose tissues was observed by fluorescence microscopy. In this study, FGF-21 stimulated glucose uptake by liver cells in both a dose and time-dependent manner, and at the same time, FGF-21 specifically stimulated GLUT1 expression in the liver cells. Furthermore, FGF-21 demonstrated a synergistic effect with insulin on glucose absorption, which is in accordance with enhanced GLUT-1 and -4 expression. Treatment with FGF-21 increased glycogen storage in liver cells. Consistent with in vitro results, FGF-21 lowered the plasma glucose level and stimulated GLUT1 expression and glycogen synthesis in db/db diabetic mice. Simultaneously, FGF-21 inhibited the gene expression of G6Pase and PEPCK. Our results suggest that FGF-21 clears up plasma glucose by stimulating glucose absorption in the liver of diabetic animals and decreases glucose release from the liver by inhibiting gluconeogenesis. Overall, these data indicate that the liver is an important target organ of FGF-21 to regulate glucose metabolism. © 2018 The Author(s). Published by S. Karger AG, Basel.

  16. The modulatory role of alpha-melanocyte stimulating hormone administered spinally in the regulation of blood glucose level in d-glucose-fed and restraint stress mouse models.

    PubMed

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

    2014-08-01

    Alpha-melanocyte stimulating hormone (α-MSH) is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of α-MSH located in the spinal cord in the regulation of the blood glucose level were investigated in d-glucose-fed and immobilization stress (IMO) mouse models. We found in the present study that intrathecal (i.t.) injection with α-MSH alone did not affect the blood glucose level. However, i.t. administration with α-MSH reduced the blood glucose level in d-glucose-fed model. The plasma insulin level was increased in d-glucose-fed model and was further increased by α-MSH, whereas α-MSH did not affect plasma corticosterone level in d-glucose-fed model. In addition, i.t. administration with glucagon alone enhanced blood glucose level and, i.t. injection with glucagon also increased the blood glucose level in d-glucose-fed model. In contrasted to results observed in d-glucose-fed model, i.t. treatment with α-MSH caused enhancement of the blood glucose level in IMO model. The plasma insulin level was increased in IMO model. The increased plasma insulin level by IMO was reduced by i.t. treatment with α-MSH, whereas i.t. pretreatment with α-MSH did not affect plasma corticosterone level in IMO model. Taken together, although spinally located α-MSH itself does not alter the blood glucose level, our results suggest that the activation of α-MSH system located in the spinal cord play important modulatory roles for the reduction of the blood glucose level in d-glucose fed model whereas α-MSH is responsible for the up-regulation of the blood glucose level in IMO model. The enhancement of insulin release may be responsible for modulatory action of α-MSH in down-regulation of the blood glucose in d-glucose fed model whereas reduction of insulin release may be responsible for modulatory action of α-MSH in up-regulation of the blood glucose in IMO model. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. [Role of peripheral serotonin in the insulin secretion and glucose homeostasis].

    PubMed

    Cataldo, Luis Rodrigo; Cortés, Víctor Antonio; Galgani, José Eduardo; Olmos, Pablo Roberto; Santos, José Luis

    2014-09-01

    The most studied roles of serotonin (5-hydroxytryptamine, 5HT) have been related to its action in the Central Nervous System (CNS). However, most of 5HT is produced outside the CNS, mainly in the enterochromaffin cells of the gut. Additionally, other tissues such as the endocrine pancreas, particularly β-cells, have its own serotonin system able to synthesize, secrete and respond to extracellular 5HT through cell surface receptors subtypes that have been grouped in 7 families (HTR1-7). Interestingly, 5HT is stored in granules and released together with insulin from β-cells and its biological significance is likely a combination of intra and extracellular actions. The expression of enzymes involved in 5HT synthesis and their receptors varied markedly in β-pancreatic cells during pregnancy, in parallel with an increase in their insulin secretion potential (probably through the action of Htr3a) and an increase in β-cell mass (through the action of Htr2b and Htr1d). In addition, it has been suggested that gut-derived 5HT may promote hepatic gluconeogenesis during prolonged fasting through Htr2b receptor. Taken together, these findings suggest that peripheral 5HT plays an important role in the regulation of glucose homeostasis through the differential expression and activation of 5-HT membrane receptors on the surface of hepatocytes, adipocytes and pancreatic β-cells. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  18. Compound- and sex-specific effects on programming of energy and immune homeostasis in adult C57BL/6JxFVB mice after perinatal TCDD and PCB 153

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

    Esterik, J.C.J. van, E-mail: joantine.van.esterik@rivm.nl; Department of Chemistry and Biology, Institute for Environmental Studies; Verharen, H.W., E-mail: henny.verharen@rivm.nl

    Early life exposure to endocrine disrupting compounds has been linked to chronic diseases later in life, like obesity and related metabolic disorders. We exposed C57BL/6JxFVB hybrid mice to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the constitutive androstane receptor/pregnane X receptor agonist polychlorinated biphenyl 153 (PCB 153) in an experimental design relevant for human exposure. Exposure occurred during gestation and lactation via maternal feed to a wide dose range (TCDD: 10–10,000 pg/kg body weight/day; PCB 153: 0.09–1406 μg/kg body weight/d). Then exposure was ceased and offspring were followed up to 1 year of age. Metabolic parameters like body weight,more » fat pad weights, glucose tolerance, endocrine serum profile, and neurobehavioral and immunological parameters were determined. Body weight was transiently affected by both compounds throughout the follow-up. TCDD-exposed males showed decreased fat pad and spleen weights and an increase in IL-4 production of splenic immune cells. In contrast, females showed increased fat pad weights and production of IFNγ. PCB 153-exposed males showed an increase in glucose, whereas females showed an increase in glucagon, a decrease in pancreas weight, and an increase in thymus weight. In conclusion, early life exposure to TCDD appears to affect programming of energy and immune homeostasis in offspring, whereas the effects of perinatal PCB 153 were mainly on programming of glucose homeostasis. Both compounds act sex-specifically. Lowest derived BMDLs (lower bounds of the (two sided) 90%-confidence interval for the benchmark dose) for both compounds are not lower than current tolerable daily intakes. - Highlights: • Early life exposure to TCDD affects programming of energy and immune homeostasis. • Early life exposure to PCB 153 affects programming of energy homeostasis. • Both compounds act sex-specifically. • Lowest derived BMDLs for both TCDD and PCB 153

  19. 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.

  20. 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.

  1. Role of FAT/CD36 in fatty acid sensing, energy, and glucose homeostasis regulation in DIO and DR rats.

    PubMed

    Le Foll, Christelle; Dunn-Meynell, Ambrose A; Levin, Barry E

    2015-02-01

    Hypothalamic fatty acid (FA) sensing neurons alter their activity utilizing the FA translocator/receptor, FAT/CD36. Depletion of ventromedial hypothalamus (VMH) CD36 with adeno-associated viral vector expressing CD36 shRNA (AAV CD36 shRNA) leads to redistribution of adipose stores and insulin resistance in outbred rats. This study assessed the requirement of VMH CD36-mediated FA sensing for the regulation of energy and glucose homeostasis in postnatal day 5 (P5) and P21 selectively bred diet-induced obese (DIO) and diet-resistant (DR) rats using VMH AAV CD36 shRNA injections. P5 CD36 depletion altered VMH neuronal FA sensing predominantly in DIO rats. After 10 wk on a 45% fat diet, DIO rats injected with VMH AAV CD36 shRNA at P21 ate more and gained more weight than DIO AAV controls, while DR AAV CD36 shRNA-injected rats gained less weight than DR AAV controls. VMH CD36 depletion increased inguinal fat pad weights and leptin levels in DIO and DR rats. Although DR AAV CD36 shRNA-injected rats became as obese as DIO AAV controls, only DIO control and CD36 depleted rats became insulin-resistant on a 45% fat diet. VMH CD36 depletion stunted linear growth in DIO and DR rats. DIO rats injected with AAV CD36 shRNA at P5 had increased fat mass, mostly due to a 45% increase in subcutaneous fat. They were also insulin-resistant with an associated 71% increase of liver triglycerides. These results demonstrate that VMH CD36-mediated FA sensing is a critical factor in the regulation of energy and glucose homeostasis and fat deposition in DIO and DR rats.

  2. Ambient Air Pollutants Have Adverse Effects on Insulin and Glucose Homeostasis in Mexican Americans

    PubMed Central

    Chen, Zhanghua; Salam, Muhammad T.; Toledo-Corral, Claudia; Watanabe, Richard M.; Xiang, Anny H.; Buchanan, Thomas A.; Habre, Rima; Bastain, Theresa M.; Lurmann, Fred; Wilson, John P.; Trigo, Enrique

    2016-01-01

    OBJECTIVE Recent studies suggest that air pollution plays a role in type 2 diabetes (T2D) incidence and mortality. The underlying physiological mechanisms have yet to be established. We hypothesized that air pollution adversely affects insulin sensitivity and secretion and serum lipid levels. RESEARCH DESIGN AND METHODS Participants were selected from BetaGene (n = 1,023), a study of insulin resistance and pancreatic β-cell function in Mexican Americans. All participants underwent DXA and oral and intravenous glucose tolerance tests and completed dietary and physical activity questionnaires. Ambient air pollutant concentrations (NO2, O3, and PM2.5) for short- and long-term periods were assigned by spatial interpolation (maximum interpolation radius of 50 km) of data from air quality monitors. Traffic-related air pollution from freeways (TRAP) was estimated using the dispersion model as NOx. Variance component models were used to analyze individual and multiple air pollutant associations with metabolic traits. RESULTS Short-term (up to 58 days cumulative lagged averages) exposure to PM2.5 was associated with lower insulin sensitivity and HDL-to-LDL cholesterol ratio and higher fasting glucose and insulin, HOMA-IR, total cholesterol, and LDL cholesterol (LDL-C) (all P ≤ 0.036). Annual average PM2.5 was associated with higher fasting glucose, HOMA-IR, and LDL-C (P ≤ 0.043). The effects of short-term PM2.5 exposure on insulin sensitivity were largest among obese participants. No statistically significant associations were found between TRAP and metabolic outcomes. CONCLUSIONS Exposure to ambient air pollutants adversely affects glucose tolerance, insulin sensitivity, and blood lipid concentrations. Our findings suggest that ambient air pollutants may contribute to the pathophysiology in the development of T2D and related sequelae. PMID:26868440

  3. Limited daily feeding and intermittent feeding have different effects on regional brain energy homeostasis during aging.

    PubMed

    Smiljanic, Kosara; Todorovic, Smilja; Mladenovic Djordjevic, Aleksandra; Vanmierlo, Tim; Lütjohann, Dieter; Ivkovic, Sanja; Kanazir, Selma

    2018-04-01

    Albeit aging is an inevitable process, the rate of aging is susceptible to modifications. Dietary restriction (DR) is a vigorous nongenetic and nonpharmacological intervention that is known to delay aging and increase healthspan in diverse species. This study aimed to compare the impact of different restricting feeding regimes such as limited daily feeding (LDF, 60% AL) and intermittent feeding (IF) on brain energy homeostasis during aging. The analysis was focused on the key molecules in glucose and cholesterol metabolism in the cortex and hippocampus of middle-aged (12-month-old) and aged (24-month-old) male Wistar rats. We measured the impact of different DRs on the expression levels of AMPK, glucose transporters (GLUT1, GLUT3, GLUT4), and the rate-limiting enzyme in the cholesterol synthesis pathway (HMGCR). Additionally, we assessed the changes in the amounts of cholesterol, its metabolite, and precursors following LDF and IF. IF decreased the levels of AMPK and pAMPK in the cortex while the increased levels were detected in the hippocampus. Glucose metabolism was more affected in the cortex, while cholesterol metabolism was more influenced in the hippocampus. Overall, the hippocampus was more resilient to the DRs, with fewer changes compared to the cortex. We showed that LDF and IF differently affected the brain energy homeostasis during aging and that specific brain regions exhibited distinct vulnerabilities towards DRs. Consequently, special attention should be paid to the DR application among elderly as different phases of aging do not respond equally to altered nutritional regimes.

  4. Alternative indices of glucose homeostasis as biochemical diagnostic tests for abnormal glucose tolerance in an African setting.

    PubMed

    Kengne, Andre Pascal; Erasmus, Rajiv T; Levitt, Naomi S; Matsha, Tandi E

    2017-04-01

    Accurate diabetes diagnosis is important in Africa, where rates are increasing, and the disease largely undiagnosed. The cumbersome oral glucose tolerance test (OGTT) remains the reference standard, while alternative diagnostic methods are not yet established in Africans. We assessed the ability of fasting plasma glucose (FPG), HbA1c and fructosamine, to diagnose OGTT-based abnormal glucose tolerance in mixed-ancestry South Africans. Mixed-ancestry adults, residing in Cape Town were examined between February and November 2015. OGTT values were used to classify glucose tolerance status as: screen-detected diabetes, prediabetes, dysglycaemia (combination of diabetes and prediabetes) and normal glucose tolerance. Of the 793 participants included, 65 (8.2%) had screen-detected diabetes, 157 (19.8%) prediabetes and 571 (72.0%) normal glucose tolerance. Correlations of FPG and 2-h glucose with HbA1c (r=0.51 and 0.52) were higher than those with fructosamine (0.34 and 0.30), both p<0.0001. The highest c-statistic for the prediction of abnormal glucose tolerance was recorded with 2-h glucose [c-statistic=0.997 (screen-detected diabetes), 0.979 (prediabetes) and 0.984 (dysglycaemia)] and the lowest with fructosamine (0.865, 0.596 and 0.677). At recommended or data-specific optimal cut-offs, no combination of FPG, HbA1c and fructosamine did better than 2-h glucose, while FPG was better than HbA1c and fructosamine on a range of performance measures. Abnormal glucose tolerance in this population is overwhelmingly expressed through 2-h glucose's abnormalities; and no combination of FPG, HbA1c and fructosamine was effective at accurately discriminating OGTT-defined abnormal glucose tolerance. Tested non-glucose based strategies are unreliable alternatives to OGTT for dysglycaemia diagnosis in this population. Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

  5. Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic POMC promoter methylation in mouse offspring.

    PubMed

    Zheng, Jia; Xiao, Xinhua; Zhang, Qian; Yu, Miao; Xu, Jianping; Wang, Zhixin; Qi, Cuijuan; Wang, Tong

    2015-10-01

    Substantial evidence demonstrated that maternal dietary nutrients can significantly determine the susceptibility to developing metabolic disorders in the offspring. Therefore, we aimed to investigate the later-life effects of maternal and postweaning diets interaction on epigenetic modification of the central nervous system in the offspring. We examined the effects of dams fed a high-fat, high-sucrose (FS) diet during pregnancy and lactation and weaned to FS diet continuously until 32 weeks of age. Then, DNA methylation and gene expressions of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in the offspring. Offspring of FS diet had heavier body weight, impaired glucose tolerance, decreased insulin sensitivity and higher serum leptin level at 32-week age (p < 0.05). The expression of POMC and MC4R genes were significantly increased in offspring exposed to FS diet during gestation, lactation and into 32-week age (p < 0.05). Consistently, hypomethylation of POMC promoter in the hypothalamus occurred in the FS diet offspring (p < 0.05), compared with the C group. However, no methylation was detected of MC4R promoter in both the two groups. Furthermore, POMC-specific methylation (%) was negatively associated with glucose response to a glucose load (r = -0.273, p = 0.039). Maternal and post-weaning high-fat diet predisposes the offspring for obesity, glucose intolerance and insulin resistance in later life. Our findings can advance our thinking around the DNA methylation status of the promoter of the POMC and MC4R genes between long-term high-fat, high-sucrose diet and glucose homeostasis in mouse.

  6. BH3-Only protein bmf is required for the maintenance of glucose homeostasis in an in vivo model of HNF1α-MODY diabetes.

    PubMed

    Pfeiffer, S; Halang, L; Düssmann, H; Byrne, M M; Prehn, Jhm

    2015-01-01

    Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1α (HNF-1α) gene can lead to diminished amounts of functional HNF-1α, resulting in the onset of a particularly severe form of maturity-onset diabetes of the young (MODY). We have previously shown that induction of a dominant-negative mutant of HNF-1α (DNHNF-1α) results in the activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), preceding the onset of apoptosis and the induction of pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor) as a mediator of DNHNF-1α-induced apoptosis. Through the knockout of bmf in a transgenic mouse model with DNHNF-1α suppression of HNF-1α function in pancreatic beta-cells, this study aimed to examine the effect of loss-of-function of this BH3-only protein on the disease pathology and progression, and further elucidate the role of Bmf in mediating DNHNF-1α-induced beta-cell loss. Morphological analysis revealed an attenuation in beta-cell loss in bmf-deficient diabetic male mice and preserved insulin content. Surprisingly, bmf deficiency was found to exacerbate hyperglycemia in both diabetic male and hyperglycemic female mice, and ultimately resulted in a decreased glucose-stimulated insulin response, implicating a role for Bmf in glucose homeostasis regulation independent of an effect on beta-cell loss. Collectively, our data demonstrate that Bmf contributes to the decline in beta-cells in a mouse model of HNF1A-MODY but is also required for the maintenance of glucose homeostasis in vivo.

  7. BH3-Only protein bmf is required for the maintenance of glucose homeostasis in an in vivo model of HNF1α-MODY diabetes

    PubMed Central

    Pfeiffer, S; Halang, L; Düssmann, H; Byrne, MM; Prehn, JHM

    2015-01-01

    Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1α (HNF-1α) gene can lead to diminished amounts of functional HNF-1α, resulting in the onset of a particularly severe form of maturity-onset diabetes of the young (MODY). We have previously shown that induction of a dominant-negative mutant of HNF-1α (DNHNF-1α) results in the activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), preceding the onset of apoptosis and the induction of pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor) as a mediator of DNHNF-1α-induced apoptosis. Through the knockout of bmf in a transgenic mouse model with DNHNF-1α suppression of HNF-1α function in pancreatic beta-cells, this study aimed to examine the effect of loss-of-function of this BH3-only protein on the disease pathology and progression, and further elucidate the role of Bmf in mediating DNHNF-1α-induced beta-cell loss. Morphological analysis revealed an attenuation in beta-cell loss in bmf-deficient diabetic male mice and preserved insulin content. Surprisingly, bmf deficiency was found to exacerbate hyperglycemia in both diabetic male and hyperglycemic female mice, and ultimately resulted in a decreased glucose-stimulated insulin response, implicating a role for Bmf in glucose homeostasis regulation independent of an effect on beta-cell loss. Collectively, our data demonstrate that Bmf contributes to the decline in beta-cells in a mouse model of HNF1A-MODY but is also required for the maintenance of glucose homeostasis in vivo. PMID:27551471

  8. An aqueous extract of Curcuma longa (turmeric) rhizomes stimulates insulin release and mimics insulin action on tissues involved in glucose homeostasis in vitro.

    PubMed

    Mohankumar, Sureshkumar; McFarlane, James R

    2011-03-01

    Curcuma longa (turmeric) has been used widely as a spice, particularly in Asian countries. It is also used in the Ayurvedic system of medicine as an antiinflammatory and antimicrobial agent and for numerous other curative properties. The aim of this study was to investigate the effects of an aqueous extract of Curcuma longa (AEC) on tissues involved in glucose homeostasis. The extract was prepared by soaking 100 g of ground turmeric in 1 L of water, which was filtered and stored at -20°C prior to use. Pancreas and muscle tissues of adult mice were cultured in DMEM with 5 or 12 mmol/L glucose and varying doses of extract. The AEC stimulated insulin secretion from mouse pancreatic tissues under both basal and hyperglycaemic conditions, although the maximum effect was only 68% of that of tolbutamide. The AEC induced stepwise stimulation of glucose uptake from abdominal muscle tissues in the presence and absence of insulin, and the combination of AEC and insulin significantly potentiated the glucose uptake into abdominal muscle tissue. However, this effect was attenuated by wortmannin, suggesting that AEC possibly acts via the insulin-mediated glucose uptake pathway. In summary, water soluble compounds of turmeric exhibit insulin releasing and mimicking actions within in vitro tissue culture conditions. Copyright © 2010 John Wiley & Sons, Ltd.

  9. Comparative Study of Glucose Homeostasis, Lipids and Lipoproteins, HDL Functionality, and Cardiometabolic Parameters in Modestly Severely Obese African Americans and White Americans With Prediabetes: Implications for the Metabolic Paradoxes

    PubMed Central

    Healy, Sara J.; Osei, Kwame

    2015-01-01

    OBJECTIVE To determine whether modestly severe obesity modifies glucose homeostasis, levels of cardiometabolic markers, and HDL function in African Americans (AAs) and white Americans (WAs) with prediabetes. RESEARCH DESIGN AND METHODS We studied 145 subjects with prediabetes (N = 61 WAs, N = 84 AAs, mean age 46.5 ± 11.2 years, mean BMI 37.8 ± 6.3 kg/m2). We measured fasting levels of lipids, lipoproteins, and an inflammatory marker (C-reactive protein [CRP]); HDL functionality (i.e., levels of paraoxonase 1 [PON1]); and levels of oxidized LDL, adiponectin, and interleukin-6 (IL-6). We measured serum levels of glucose, insulin, and C-peptide during an oral glucose tolerance test. Values for insulin sensitivity index (Si), glucose effectiveness index (Sg), glucose effectiveness at zero insulin (GEZI), and acute insulin response to glucose (AIRg) were derived using a frequently sampled intravenous glucose tolerance test (using MINMOD software). RESULTS Mean levels of fasting and incremental serum glucose, insulin, and C-peptide tended to be higher in WAs versus AAs. The mean Si was not different in WAs versus AAs (2.6 ± 2.3 vs. 2.9 ± 3.0 × 10−4 × min−1 [μU/mL]−1). Mean values for AIRg and disposition index as well as Sg and GEZI were lower in WAs than AAs. WAs had higher serum triglyceride levels than AAs (116.1 ± 55.5 vs. 82.7 ± 44.2 mg/dL, P = 0.0002). Mean levels of apolipoprotein (apo) A1, HDL cholesterol, PON1, oxidized LDL, CRP, adiponectin, and IL-6 were not significantly different in obese AAs versus WAs with prediabetes. CONCLUSIONS Modestly severe obesity attenuated the ethnic differences in Si, but not in Sg and triglyceride levels in WAs and AAs with prediabetes. Despite the lower Si and PON1 values, AAs preserved paradoxical relationships between the Si and HDL/apoA1/triglyceride ratios. We conclude that modestly severe obesity has differential effects on the pathogenic mechanisms underlying glucose homeostasis and atherogenesis in obese

  10. comparative study of glucose homeostasis, lipids and lipoproteins, HDL functionality, and cardiometabolic parameters in modestly severely obese African Americans and White Americans with prediabetes: implications for the metabolic paradoxes.

    PubMed

    Healy, Sara J; Osei, Kwame; Gaillard, Trudy

    2015-02-01

    To determine whether modestly severe obesity modifies glucose homeostasis, levels of cardiometabolic markers, and HDL function in African Americans (AAs) and white Americans (WAs) with prediabetes. We studied 145 subjects with prediabetes (N = 61 WAs, N = 84 AAs, mean age 46.5 ± 11.2 years, mean BMI 37.8 ± 6.3 kg/m(2)). We measured fasting levels of lipids, lipoproteins, and an inflammatory marker (C-reactive protein [CRP]); HDL functionality (i.e., levels of paraoxonase 1 [PON1]); and levels of oxidized LDL, adiponectin, and interleukin-6 (IL-6). We measured serum levels of glucose, insulin, and C-peptide during an oral glucose tolerance test. Values for insulin sensitivity index (Si), glucose effectiveness index (Sg), glucose effectiveness at zero insulin (GEZI), and acute insulin response to glucose (AIRg) were derived using a frequently sampled intravenous glucose tolerance test (using MINMOD software). Mean levels of fasting and incremental serum glucose, insulin, and C-peptide tended to be higher in WAs versus AAs. The mean Si was not different in WAs versus AAs (2.6 ± 2.3 vs. 2.9 ± 3.0 × 10(-4) × min(-1) [μU/mL](-1)). Mean values for AIRg and disposition index as well as Sg and GEZI were lower in WAs than AAs. WAs had higher serum triglyceride levels than AAs (116.1 ± 55.5 vs. 82.7 ± 44.2 mg/dL, P = 0.0002). Mean levels of apolipoprotein (apo) A1, HDL cholesterol, PON1, oxidized LDL, CRP, adiponectin, and IL-6 were not significantly different in obese AAs versus WAs with prediabetes. Modestly severe obesity attenuated the ethnic differences in Si, but not in Sg and triglyceride levels in WAs and AAs with prediabetes. Despite the lower Si and PON1 values, AAs preserved paradoxical relationships between the Si and HDL/apoA1/triglyceride ratios. We conclude that modestly severe obesity has differential effects on the pathogenic mechanisms underlying glucose homeostasis and atherogenesis in obese AAs and WAs with prediabetes. © 2015 by the American

  11. Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs.

    PubMed

    Hofer-Inteeworn, Natalie; Panciera, David L; Monroe, William E; Saker, Korinn E; Davies, Rebecca Hegstad; Refsal, Kent R; Kemnitz, Joseph W

    2012-04-01

    To determine the effects of hypothyroidism on insulin sensitivity, glucose tolerance, and concentrations of hormones counter-regulatory to insulin in dogs. 8 anestrous mixed-breed bitches with experimentally induced hypothyroidism and 8 euthyroid control dogs. The insulin-modified frequently sampled IV glucose tolerance test and minimal model analysis were used to determine basal plasma insulin and glucose concentrations, acute insulin response to glucose, insulin sensitivity, glucose effectiveness, and disposition index. Growth hormone response was assessed by stimulation and suppression tests. Additionally, basal serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations and urine cortisol-to-creatinine concentration ratios were measured and dual energy x-ray absorptiometry was performed to evaluate body composition. Insulin sensitivity was lower in the hypothyroid group than in the euthyroid group, whereas acute insulin response to glucose was higher. Glucose effectiveness and disposition index were not different between groups. Basal serum GH and IGF-1 concentrations as well as abdominal fat content were high in hypothyroid dogs, but urine cortisol-to-creatinine concentration ratios were unchanged. Hypothyroidism appeared to negatively affect glucose homeostasis by inducing insulin resistance, but overall glucose tolerance was maintained by increased insulin secretion in hypothyroid dogs. Possible factors affecting insulin sensitivity are high serum GH and IGF-1 concentrations and an increase in abdominal fat. In dogs with diseases involving impaired insulin secretion such as diabetes mellitus, concurrent hypothyroidism can have important clinical implications.

  12. Dynamic Changes in Cytosolic ATP Levels in Cultured Glutamatergic Neurons During NMDA-Induced Synaptic Activity Supported by Glucose or Lactate.

    PubMed

    Lange, Sofie C; Winkler, Ulrike; Andresen, Lars; Byhrø, Mathilde; Waagepetersen, Helle S; Hirrlinger, Johannes; Bak, Lasse K

    2015-12-01

    We have previously shown that synaptic transmission fails in cultured neurons in the presence of lactate as the sole substrate. Thus, to test the hypothesis that the failure of synaptic transmission is a consequence of insufficient energy supply, ATP levels were monitored employing the ATP biosensor Ateam1.03YEMK. While inducing synaptic activity by subjecting cultured neurons to two 30 s pulses of NMDA (30 µM) with a 4 min interval, changes in relative ATP levels were measured in the presence of lactate (1 mM), glucose (2.5 mM) or the combination of the two. ATP levels reversibly declined following NMDA-induced neurotransmission activity, as indicated by a reversible 10-20 % decrease in the response of the biosensor. The responses were absent when the NMDA receptor antagonist memantine was present. In the presence of lactate alone, the ATP response dropped significantly more than in the presence of glucose following the 2nd pulse of NMDA (approx. 10 vs. 20 %). Further, cytosolic Ca(2+) homeostasis during NMDA-induced synaptic transmission is partially inhibited by verapamil indicating that voltage-gated Ca(2+) channels are activated. Lastly, we showed that cytosolic Ca(2+) homeostasis is supported equally well by both glucose and lactate, and that a pulse of NMDA causes accumulation of Ca(2+) in the mitochondrial matrix. In summary, we have shown that ATP homeostasis during neurotransmission activity in cultured neurons is supported by both glucose and lactate. However, ATP homeostasis seems to be negatively affected by the presence of lactate alone, suggesting that glucose is needed to support neuronal energy metabolism during activation.

  13. Anaesthesia and changes in parameters that reflect glucose metabolism in pigs - a pilot study.

    PubMed

    Manell, Elin; Jensen-Waern, Marianne; Hedenqvist, Patricia

    2017-10-01

    Pigs are commonly used in diabetes research due to their many physiological similarities to humans. They are especially useful in imaging procedures because of their large size. However, to achieve imaging procedures the pig must lie completely still, and thus needs to be anaesthetized. Most anaesthetic drugs used in laboratory animals affect carbohydrate metabolism by the inhibition of insulin release. The aim of this pilot study was primarily to develop an anaesthetic protocol for pigs that did not have an effect on blood glucose levels throughout the 3 h of anaesthesia; and secondly, to evaluate the most promising protocol in combination with an oral glucose tolerance test (OGTT). Two anaesthetic protocols were used in four growing pigs. Intravenous propofol infusion caused hyperglycaemia in three out of four pigs within 5-10 min after induction and was therefore excluded. Intravenous infusion with tiletamine, zolazepam and butorphanol (TZB) for 3 h did not affect blood glucose levels. The pigs underwent OGTT twice, once without anaesthesia and once with TZB induction after glucose intake. Anaesthesia during OGTT resulted in a lower area under the curve (AUC) of glucose ( P < 0.05), higher AUC of glucagon ( P < 0.05) and an insulin response less than 10% of that during OGTT without anaesthesia. In conclusion, long-term infusion anaesthesia with TZB does not affect glucose homeostasis in pigs. However, the protocol is not effective when combined with OGTT, as glucose, insulin and glucagon levels are affected.

  14. Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism.

    PubMed

    Cariou, Bertrand; Zaïr, Yassine; Staels, Bart; Bruckert, Eric

    2011-09-01

    We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator-activated receptor α/δ agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means -16.7% [95% one-sided CI -∞ to -5.3], P = 0.005; S2: -24.8% [-∞ to -10.5], P = 0.0003) and increased HDL cholesterol (S1: 7.8% [3.0 to ∞], P = 0.004; S2: 9.3% [1.7 to ∞], P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (-11.0% [ -∞ to -3.5], P = 0.002). In S2, GFT505 did not reduce 2-h glucose (-0.52 mmol/L [-∞ to 0.61], P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance (-31.4% [-∞ to 12.5], P = 0.001), fasting plasma glucose (-0.37 mmol/L [-∞ to -0.10], P = 0.01) and fructosamine (-3.6% [-∞ to -0.20], P = 0.02). GFT505 also reduced γ glutamyl transferase levels in both studies (S1: -19.9% [-∞ to -12.8], P < 0.0001; S2: -15.1% [-∞ to -1.1], P = 0.004). No specific adverse safety signals were reported during the studies. GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome.

  15. Self-Control, Daily Negative Affect and Blood Glucose Control in Adolescents with Type 1 Diabetes

    PubMed Central

    Lansing, Amy Hughes; Berg, Cynthia A.; Butner, Jonathan; Wiebe, Deborah J.

    2016-01-01

    Objective For adolescents with type 1 diabetes, maintaining optimal daily blood glucose control is a complex self-regulatory process that likely requires self-control. This study examined whether higher self-control was associated with lower daily negative affect about diabetes and, in turn, better daily blood glucose control, i.e., lower mean daily blood glucose (MBG) and smaller standard deviations of daily blood glucose (SDBG), through two paths: 1) self-control maintaining lower mean level of negative affect and 2) self-control buffering the association of the number of daily diabetes problems with daily negative affect. Methods Adolescents (M age=12.87 years) with type 1 diabetes (n=180) completed an initial survey containing a self-report measure of self-control. Nightly electronic diaries were completed for 14 days where adolescents reported daily problems with and negative affect about diabetes, and used a study-provided blood glucose meter. Results Hypotheses were examined through multilevel modeling. Lower mean levels of daily negative affect partially mediated the relation between higher adolescent self-control and lower MBG. Adolescent self-control also buffered the association of the number of daily problems with daily negative affect, and smaller fluctuations in daily negative affect were associated with lower SDBG. Conclusions Adolescent self-control is associated with daily affect regulatory processes that may influence MBG. However, fluctuations in daily negative affect about diabetes may represent a unique within-person daily process associated with SDBG. These findings suggest that studies examining daily disease processes and interventions targeting daily affect regulation may be important to improving health in adolescents with type 1 diabetes. PMID:26914647

  16. 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.

  17. A brain-liver circuit regulates glucose homeostasis.

    PubMed

    Pocai, Alessandro; Obici, Silvana; Schwartz, Gary J; Rossetti, Luciano

    2005-01-01

    Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia.

  18. Impulsiveness, postprandial blood glucose, and glucoregulation affect measures of behavioral flexibility.

    PubMed

    Riby, Leigh M; Lai Teik Ong, Derek; Azmie, Nurulnadia Binti Mohamad; Ooi, Ee Lyn; Regina, Caroline; Yeo, Eugene Ki Wai; Massa, Jacqueline; Aquili, Luca

    2017-12-01

    Behavioral flexibility (BF) performance is influenced by both psychological and physiological factors. Recent evidence suggests that impulsivity and blood glucose can affect executive function, of which BF is a subdomain. Here, we hypothesized that impulsivity, fasting blood glucose (FBG), glucose changes (ie, glucoregulation) from postprandial blood glucose (PBG) following the intake of a 15-g glucose beverage could account for variability in BF performance. The Stroop Color-Word Test and the Wisconsin Card Sorting Test (WCST) were used as measures of BF, and the Barratt Impulsiveness Scale (BIS-11) to quantify participants' impulsivity. In Study 1, neither impulsivity nor FBG could predict performance on the Stroop or the WCST. In Study 2, we tested whether blood glucose levels following the intake of a sugary drink, and absolute changes in glucose levels following the intake of the glucose beverage could better predict BF. Results showed that impulsivity and the difference in blood glucose between time 1 (postprandial) and time 2, but not blood glucose levels at time 2 per se could account for variation in performance on the WCST but not on the Stroop task. More specifically, lower impulsivity scores on the BIS-11, and smaller differences in blood glucose levels from time 1 to time 2 predicted a decrease in the number of total and perseverative errors on the WCST. Our results show that measures of impulsivity and glucoregulation can be used to predict BF. Importantly our data extend the work on glucose and cognition to a clinically relevant domain of cognition. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    PubMed

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

    2018-04-01

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

  20. Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism

    NASA Astrophysics Data System (ADS)

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

    2005-08-01

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

  1. Could post-weaning dietary chia seed mitigate the development of dyslipidemia, liver steatosis and altered glucose homeostasis in offspring exposed to a sucrose-rich diet from utero to adulthood?

    PubMed

    Fortino, M A; Oliva, M E; Rodriguez, S; Lombardo, Y B; Chicco, A

    2017-01-01

    The present work analyzes the effects of dietary chia seeds during postnatal life in offspring exposed to a sucrose-rich diet (SRD) from utero to adulthood. At weaning, chia seed (rich in α-linolenic acid) replaced corn oil (rich in linoleic acid) in the SRD. At 150 days of offspring life, anthropometrical parameters, blood pressure, plasma metabolites, hepatic lipid metabolism and glucose homeostasis were analyzed. Results showed that chia was able to prevent the development of hypertension, liver steatosis, hypertriglyceridemia and hypercholesterolemia. Normal triacylglycerol secretion and triacylglycerol clearance were accompanied by an improvement of de novo hepatic lipogenic and carnitine-palmitoyl transferase-1 enzymatic activities, associated with an accretion of n-3 polyunsaturated fatty acids in the total composition of liver homogenate. Glucose homeostasis and plasma free fatty acid levels were improved while visceral adiposity was slightly decreased. These results confirm that the incorporation of chia seed in the diet in postnatal life may provide a viable therapeutic option for preventing/mitigating adverse outcomes induced by an SRD from utero to adulthood. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Modulation of hippocampal neural plasticity by glucose-related signaling.

    PubMed

    Mainardi, Marco; Fusco, Salvatore; Grassi, Claudio

    2015-01-01

    Hormones and peptides involved in glucose homeostasis are emerging as important modulators of neural plasticity. In this regard, increasing evidence shows that molecules such as insulin, insulin-like growth factor-I, glucagon-like peptide-1, and ghrelin impact on the function of the hippocampus, which is a key area for learning and memory. Indeed, all these factors affect fundamental hippocampal properties including synaptic plasticity (i.e., synapse potentiation and depression), structural plasticity (i.e., dynamics of dendritic spines), and adult neurogenesis, thus leading to modifications in cognitive performance. Here, we review the main mechanisms underlying the effects of glucose metabolism on hippocampal physiology. In particular, we discuss the role of these signals in the modulation of cognitive functions and their potential implications in dysmetabolism-related cognitive decline.

  3. Brain glucose sensing and neural regulation of insulin and glucagon secretion.

    PubMed

    Thorens, B

    2011-10-01

    Glucose homeostasis requires the tight regulation of glucose utilization by liver, muscle and white or brown fat, and glucose production and release in the blood by liver. The major goal of maintaining glycemia at ∼ 5 mM is to ensure a sufficient flux of glucose to the brain, which depends mostly on this nutrient as a source of metabolic energy. This homeostatic process is controlled by hormones, mainly glucagon and insulin, and by autonomic nervous activities that control the metabolic state of liver, muscle and fat tissue but also the secretory activity of the endocrine pancreas. Activation or inhibition of the sympathetic or parasympathetic branches of the autonomic nervous systems are controlled by glucose-excited or glucose-inhibited neurons located at different anatomical sites, mainly in the brainstem and the hypothalamus. Activation of these neurons by hyper- or hypoglycemia represents a critical aspect of the control of glucose homeostasis, and loss of glucose sensing by these cells as well as by pancreatic β-cells is a hallmark of type 2 diabetes. In this article, aspects of the brain-endocrine pancreas axis are reviewed, highlighting the importance of central glucose sensing in the control of counterregulation to hypoglycemia but also mentioning the role of the neural control in β-cell mass and function. Overall, the conclusions of these studies is that impaired glucose homeostasis, such as associated with type 2 diabetes, but also defective counterregulation to hypoglycemia, may be caused by initial defects in glucose sensing. © 2011 Blackwell Publishing Ltd.

  4. ABCA1 in adipocytes regulates adipose tissue lipid content, glucose tolerance, and insulin sensitivity.

    PubMed

    de Haan, Willeke; Bhattacharjee, Alpana; Ruddle, Piers; Kang, Martin H; Hayden, Michael R

    2014-03-01

    Adipose tissue contains one of the largest reservoirs of cholesterol in the body. Adipocyte dysfunction in obesity is associated with intracellular cholesterol accumulation, and alterations in cholesterol homeostasis have been shown to alter glucose metabolism in cultured adipocytes. ABCA1 plays a major role in cholesterol efflux, suggesting a role for ABCA1 in maintaining cholesterol homeostasis in the adipocyte. However, the impact of adipocyte ABCA1 on adipose tissue function and glucose metabolism is unknown. Our aim was to determine the impact of adipocyte ABCA1 on adipocyte lipid metabolism, body weight, and glucose metabolism in vivo. To address this, we used mice lacking ABCA1 specifically in adipocytes (ABCA1(-ad/-ad)). When fed a high-fat, high-cholesterol diet, ABCA1(-ad/-ad) mice showed increased cholesterol and triglyceride stores in adipose tissue, developed enlarged fat pads, and had increased body weight. Associated with these phenotypic changes, we observed significant changes in the expression of genes involved in cholesterol and glucose homeostasis, including ldlr, abcg1, glut-4, adiponectin, and leptin. ABCA1(-ad/-ad) mice also demonstrated impaired glucose tolerance, lower insulin sensitivity, and decreased insulin secretion. We conclude that ABCA1 in adipocytes influences adipocyte lipid metabolism, body weight, and whole-body glucose homeostasis.

  5. The yeast protein kinase Sch9 adjusts V-ATPase assembly/disassembly to control pH homeostasis and longevity in response to glucose availability.

    PubMed

    Wilms, Tobias; Swinnen, Erwin; Eskes, Elja; Dolz-Edo, Laura; Uwineza, Alice; Van Essche, Ruben; Rosseels, Joëlle; Zabrocki, Piotr; Cameroni, Elisabetta; Franssens, Vanessa; De Virgilio, Claudio; Smits, Gertien J; Winderickx, Joris

    2017-06-01

    The conserved protein kinase Sch9 is a central player in the nutrient-induced signaling network in yeast, although only few of its direct substrates are known. We now provide evidence that Sch9 controls the vacuolar proton pump (V-ATPase) to maintain cellular pH homeostasis and ageing. A synthetic sick phenotype arises when deletion of SCH9 is combined with a dysfunctional V-ATPase, and the lack of Sch9 has a significant impact on cytosolic pH (pHc) homeostasis. Sch9 physically interacts with, and influences glucose-dependent assembly/disassembly of the V-ATPase, thereby integrating input from TORC1. Moreover, we show that the role of Sch9 in regulating ageing is tightly connected with V-ATPase activity and vacuolar acidity. As both Sch9 and the V-ATPase are highly conserved in higher eukaryotes, it will be interesting to further clarify their cooperative action on the cellular processes that influence growth and ageing.

  6. Effects of parity and periconceptional metabolic state of Holstein-Friesian dams on the glucose metabolism and conformation in their newborn calves.

    PubMed

    Bossaert, P; Fransen, E; Langbeen, A; Stalpaert, M; Vandenbroeck, I; Bols, P E; Leroy, J L

    2014-06-01

    The metabolic state of pregnant mammals influences the offspring's development and risk of metabolic disease in postnatal life. The metabolic state in a lactating dairy cow differs immensely from that in a non-lactating heifer around the time of conception, but consequences for their calves are poorly understood. The hypothesis of this study was that differences in metabolic state between non-lactating heifers and lactating cows during early pregnancy would affect insulin-dependent glucose metabolism and development in their neonatal calves. Using a mixed linear model, concentrations of glucose, IGF-I and non-esterified fatty acids (NEFAs) were compared between 13 non-lactating heifers and 16 high-yielding dairy cows in repeated blood samples obtained during the 1st month after successful insemination. Calves born from these dams were weighed and measured at birth, and subjected to intravenous glucose and insulin challenges between 7 and 14 days of age. Eight estimators of insulin-dependent glucose metabolism were determined: glucose and insulin peak concentration, area under the curve and elimination rate after glucose challenge, glucose reduction rate after insulin challenge, and quantitative insulin sensitivity check index. Effects of dam parity and calf sex on the metabolic and developmental traits were analysed in a two-way ANOVA. Compared with heifers, cows displayed lower glucose and IGF-I and higher NEFA concentrations during the 1st month after conception. However, these differences did not affect developmental traits and glucose homeostasis in their calves: birth weight, withers height, heart girth, and responses to glucose and insulin challenges in the calves were unaffected by their dam's parity. In conclusion, differences in the metabolic state of heifers and cows during early gestation under field conditions could not be related to their offspring's development and glucose homeostasis.

  7. Hibiscus rosa sinensis Linn. Petals Modulates Glycogen Metabolism and Glucose Homeostasis Signalling Pathway in Streptozotocin-Induced Experimental Diabetes.

    PubMed

    Pillai, Sneha S; Mini, S

    2016-03-01

    The prevalence of diabetes mellitus is becoming more and more serious and reaches epidemic proportions worldwide. Scientific research is constantly looking for new agents that could be used as dietary functional ingredients in the fight against diabetes. The objective of the present study was to evaluate the effect of ethyl acetate fraction of Hibiscus rosa sinensis Linn. petals on experimental diabetes at a dose of 25 mg/kg body weight and it was compared with standard anti-diabetic drug metformin. The elevated levels of serum glucose (398.56 ± 35.78) and glycated haemoglobin (12.89 ± 1.89) in diabetic rats were significantly decreased (156.89 ± 14.45 and 6.12 ± 0.49, respectively) by Hibiscus rosa sinensis petals (EHRS) administration. Hepatotoxicity marker enzyme levels in serum were normalized. The fraction supplementation restored the glycogen content by regulating the activities of glycogen metabolizing enzymes. It significantly modulated the expressions of marker genes involved in glucose homeostasis signalling pathway. Histopathological analysis of liver and pancreas supported our findings. The overall effect was comparable with metformin. Hence, our study reveals the role of hibiscus petals for alleviation of diabetes complications, thus it can be propagated as a nutraceutical agent.

  8. GPR40 partial agonist MK-2305 lower fasting glucose in the Goto Kakizaki rat via suppression of endogenous glucose production

    PubMed Central

    Kirkland, Melissa E.; Kosinski, Daniel T.; Mane, Joel; Bunzel, Michelle; Cao, Jin; Souza, Sarah; Thomas-Fowlkes, Brande; Di Salvo, Jerry; Weinglass, Adam B.; Li, Xiaoyan; Myers, Robert W.; Knagge, Kevin; Carrington, Paul E.; Hagmann, William K.

    2017-01-01

    GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects in vivo. Several reports illustrate that GPR40 agonists exert glucose lowering in diabetic humans. To assess the mechanisms by which GPR40 partial agonists improve glucose homeostasis, we evaluated the effects of MK-2305, a potent and selective partial GPR40 agonist, in diabetic Goto Kakizaki rats. MK-2305 decreased fasting glucose after acute and chronic treatment. MK-2305-mediated changes in glucose were coupled with increases in plasma insulin during hyperglycemia and glucose challenges but not during fasting, when glucose was normalized. To determine the mechanism(s) mediating these changes in glucose metabolism, we measured the absolute contribution of precursors to glucose production in the presence or absence of MK-2305. MK-2305 treatment resulted in decreased endogenous glucose production (EGP) driven primarily through changes in gluconeogenesis from substrates entering at the TCA cycle. The decrease in EGP was not likely due to a direct effect on the liver, as isolated perfused liver studies showed no effect of MK-2305 ex vivo and GPR40 is not expressed in the liver. Taken together, our results suggest MK-2305 treatment increases glucose stimulated insulin secretion (GSIS), resulting in changes to hepatic substrate handling that improve glucose homeostasis in the diabetic state. Importantly, these data extend our understanding of the underlying mechanisms by which GPR40 partial agonists reduce hyperglycemia. PMID:28542610

  9. Natural products, an important resource for discovery of multitarget drugs and functional food for regulation of hepatic glucose metabolism.

    PubMed

    Li, Jian; Yu, Haiyang; Wang, Sijian; Wang, Wei; Chen, Qian; Ma, Yanmin; Zhang, Yi; Wang, Tao

    2018-01-01

    Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs). Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound-multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs.

  10. Natural products, an important resource for discovery of multitarget drugs and functional food for regulation of hepatic glucose metabolism

    PubMed Central

    Wang, Sijian; Wang, Wei; Chen, Qian; Ma, Yanmin; Zhang, Yi; Wang, Tao

    2018-01-01

    Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs). Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound–multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs. PMID:29391777

  11. Hypothalamic Leucine Metabolism Regulates Liver Glucose Production

    PubMed Central

    Su, Ya; Lam, Tony K.T.; He, Wu; Pocai, Alessandro; Bryan, Joseph; Aguilar-Bryan, Lydia; Gutiérrez-Juárez, Roger

    2012-01-01

    Amino acids profoundly affect insulin action and glucose metabolism in mammals. Here, we investigated the role of the mediobasal hypothalamus (MBH), a key center involved in nutrient-dependent metabolic regulation. Specifically, we tested the novel hypothesis that the metabolism of leucine within the MBH couples the central sensing of leucine with the control of glucose production by the liver. We performed either central (MBH) or systemic infusions of leucine in Sprague-Dawley male rats during basal pancreatic insulin clamps in combination with various pharmacological and molecular interventions designed to modulate leucine metabolism in the MBH. We also examined the role of hypothalamic ATP-sensitive K+ channels (KATP channels) in the effects of leucine. Enhancing the metabolism of leucine acutely in the MBH lowered blood glucose through a biochemical network that was insensitive to rapamycin but strictly dependent on the hypothalamic metabolism of leucine to α-ketoisocaproic acid and, further, insensitive to acetyl- and malonyl-CoA. Functional KATP channels were also required. Importantly, molecular attenuation of this central sensing mechanism in rats conferred susceptibility to developing hyperglycemia. We postulate that the metabolic sensing of leucine in the MBH is a previously unrecognized mechanism for the regulation of hepatic glucose production required to maintain glucose homeostasis. PMID:22187376

  12. Effects of the New Dual PPARα/δ Agonist GFT505 on Lipid and Glucose Homeostasis in Abdominally Obese Patients With Combined Dyslipidemia or Impaired Glucose Metabolism

    PubMed Central

    Cariou, Bertrand; Zaïr, Yassine; Staels, Bart; Bruckert, Eric

    2011-01-01

    OBJECTIVE We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator–activated receptor α/δ agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. RESEARCH DESIGN AND METHODS The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. RESULTS In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means −16.7% [95% one-sided CI −∞ to −5.3], P = 0.005; S2: −24.8% [−∞ to −10.5], P = 0.0003) and increased HDL cholesterol (S1: 7.8% [3.0 to ∞], P = 0.004; S2: 9.3% [1.7 to ∞], P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (−11.0% [ −∞ to −3.5], P = 0.002). In S2, GFT505 did not reduce 2-h glucose (−0.52 mmol/L [−∞ to 0.61], P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance (−31.4% [−∞ to 12.5], P = 0.001), fasting plasma glucose (−0.37 mmol/L [−∞ to −0.10], P = 0.01) and fructosamine (−3.6% [−∞ to −0.20], P = 0.02). GFT505 also reduced γ glutamyl transferase levels in both studies (S1: −19.9% [−∞ to −12.8], P < 0.0001; S2: −15.1% [−∞ to −1.1], P = 0.004). No specific adverse safety signals were reported during the studies. CONCLUSIONS GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome. PMID:21816979

  13. In vitro fertilization affects growth and glucose metabolism in a sex-specific manner in an outbred mouse model.

    PubMed

    Donjacour, Annemarie; Liu, Xiaowei; Lin, Wingka; Simbulan, Rhodel; Rinaudo, Paolo F

    2014-04-01

    The preimplantation period is a time of reprogramming that may be vulnerable to disruption. This question has wide clinical relevance since the number of children conceived by in vitro fertilization (IVF) is rising. To examine this question, outbred mice (CF1 × B6D2F1) conceived by IVF and cultured using Whitten medium and 20% O2 (IVFWM group, less optimal) or K simplex optimized medium with amino acids and 5% O2 (IVFKAA group, more optimal and similar to conditions used in human IVF) were studied postnatally. We found that flushed blastocysts transferred to recipient mice provided the best control group (FB group), as this accounted for the effects of superovulation, embryo transfer, and litter size. We observed that many physiological parameters were normal. Reassuringly, IVFKAA offspring did not differ significantly from FB offspring. However, male IVFWM mice (but not females) were larger during the first 19 wk of life and exhibited glucose intolerance. Male IVFWM mice also showed enlarged left heart despite normal blood pressure. Expression of candidate imprinted genes (H19, Igf2, and Slc38a4) in multiple adult tissues did not show differences among the groups; only Slc38a4 was down-regulated following IVF (in both culture conditions) in female adipose tissue. These studies demonstrate that adult metabolism is affected by the type of conditions encountered during the preimplantation stage. Further, the postnatal growth trajectory and glucose homeostasis following ex vivo manipulation may be sexual dimorphic. Future work on the long-term effects of IVF offspring should focus on glucose metabolism and the cardiovascular system.

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

    PubMed

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

    2016-04-01

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

  15. Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis.

    PubMed

    Stark, Romana; Reichenbach, Alex; Andrews, Zane B

    2015-12-15

    The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin

  16. UCP2 regulates mitochondrial fission and ventromedial nucleus control of glucose responsiveness

    PubMed Central

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

    2016-01-01

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

  17. Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice.

    PubMed

    Jung, Dae Young; Ko, Hwi Jin; Lichtman, Eben I; Lee, Eunjung; Lawton, Elizabeth; Ong, Helena; Yu, Kristine; Azuma, Yoshihiro; Friedline, Randall H; Lee, Ki Won; Kim, Jason K

    2013-05-01

    Obesity is a major cause of insulin resistance, and weight loss is shown to improve glucose homeostasis. But the underlying mechanism and the role of inflammation remain unclear. Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 wk. After HFD, weight loss was induced by changing to a low-fat diet (LFD) or exercise with continuous HFD. The weight loss effects on energy balance and insulin sensitivity were determined using metabolic cages and hyperinsulinemic euglycemic clamps in awake mice. Diet and exercise intervention for 3 wk caused a modest weight loss and improved glucose homeostasis. Weight loss dramatically reduced local inflammation in skeletal muscle, liver, and heart but not in adipose tissue. Exercise-mediated weight loss increased muscle glucose metabolism without affecting Akt phosphorylation or lipid levels. LFD-mediated weight loss reduced lipid levels and improved insulin sensitivity selectively in liver. Both weight loss interventions improved cardiac glucose metabolism. These results demonstrate that a short-term weight loss with exercise or diet intervention attenuates obesity-induced local inflammation and selectively improves insulin sensitivity in skeletal muscle and liver. Our findings suggest that local factors, not adipose tissue inflammation, are involved in the beneficial effects of weight loss on glucose homeostasis.

  18. [Role of the sweet taste receptor in glucose metabolism: no sweets for diabetes?].

    PubMed

    Nomura, Masatoshi; Kawahara, Yuta

    2015-01-01

    Type 2 diabetes is closely associated with our daily diets and has become a global health problem with increasing number of patients. Maintaining energy homeostasis is essentially required for the treatment of diabetes. Energy metabolism starts with taking in a meal. Nutrients including amino acids, fatty acids and glucose in the digest have been shown to act on the neuroendocrine cells in the gastrointestinal (GI) tract, and thereby play important roles in energy homeostasis. Therefore, the GI tract is now recognized as a sensor system for nutrient signals. Taste receptor type 1 member 2 (T1R2) is known to function as a co-receptor with T1R3 to detect sweet chemicals in the taste buds. It has been proposed that the T1R2/T1R3 receptor complex acts as sweet sensor in the intestine, and plays a pivotal role in sensing sugars and maintaining glucose homeostasis through incretin secretion. To clarify the physiological roles of T1R2 in glucose homeostasis, T1r2-lacZ knock-in/knock-out mice were generated. We found lacZ gene expression in the GI tract where T1r3 expression has been reported. Interestingly, the T1r2-lacZ knock-in mice showed impaired glucose tolerance on oral glucose challenge but not on intraperitoneal injection. However, the fasting glucose level in T1r2-lacZ knock-in mice was comparable to that in wild type mice. These results suggest an important role of the sweet taste receptor system in the intestine when stimulated by glucose. Therefore, the roles of T1R2 will be presented and the mechanism for metabolic homeostasis will be discussed.

  19. Ghrelin administered spinally increases the blood glucose level in mice.

    PubMed

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

    2014-04-01

    Ghrelin is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of ghrelin located in the spinal cord in the regulation of the blood glucose level were investigated in ICR mice. We found that intrathecal (i.t.) injection with ghrelin (from 1 to 10 μg) caused an elevation of the blood glucose level. In addition, i.t. pretreatment with YIL781 (ghrelin receptor antagonist; from 0.1 to 5 μg) markedly attenuated ghrelin-induced hyperglycemic effect. The plasma insulin level was increased by ghrelin. The enhanced plasma insulin level by ghrelin was reduced by i.t. pretreatment with YIL781. However, i.t. pretreatment with glucagon-like peptide-1 (GLP-1; 5 μg) did not affect the ghrelin-induced hyperglycemia. Furthermore, i.t. administration with ghrelin also elevated the blood glucose level, but in an additive manner, in d-glucose-fed model. Our results suggest that the activation of ghrelin receptors located in the spinal cord plays important roles for the elevation of the blood glucose level. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Sweet taste receptor in the hypothalamus: a potential new player in glucose sensing in the hypothalamus.

    PubMed

    Kohno, Daisuke

    2017-07-01

    The hypothalamic feeding center plays an important role in energy homeostasis. The feeding center senses the systemic energy status by detecting hormone and nutrient levels for homeostatic regulation, resulting in the control of food intake, heat production, and glucose production and uptake. The concentration of glucose is sensed by two types of glucose-sensing neurons in the feeding center: glucose-excited neurons and glucose-inhibited neurons. Previous studies have mainly focused on glucose metabolism as the mechanism underlying glucose sensing. Recent studies have indicated that receptor-mediated pathways also play a role in glucose sensing. This review describes sweet taste receptors in the hypothalamus and explores the role of sweet taste receptors in energy homeostasis.

  1. The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis.

    PubMed

    Üner, Aykut; Gonçalves, Gabriel H M; Li, Wenjing; Porceban, Matheus; Caron, Nicole; Schönke, Milena; Delpire, Eric; Sakimura, Kenji; Bjørbæk, Christian

    2015-10-01

    Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown. We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies. We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lep (ob/ob) mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lep (ob/ob) mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions. GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action.

  2. 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.

  3. A preliminary trial of the effect of recombinant human growth hormone on short-term linear growth and glucose homeostasis in children with Crohn's disease.

    PubMed

    Wong, S C; Kumar, P; Galloway, P J; Blair, J C; Didi, M; Dalzell, A M; Hassan, K; McGrogan, P; Ahmed, S Faisal

    2011-05-01

    It is unclear whether recombinant human growth hormone (rhGH) improves linear growth in children with Crohn's disease (CD). To investigate the effects of rhGH on height velocity (HV) and glucose homeostasis over a 6-month period. Randomized controlled trial in two tertiary children's hospitals in 22 children with inflammatory bowel disease amongst whom 21 had CD. Duration of disease from diagnosis and number of acute relapses requiring either exclusive enteral nutrition or therapeutic dose of oral prednisolone were similar in the treatment and control groups. Either rhGH (0·067 mg/kg per day) as daily subcutaneous injections (rhGH group; n, 11) or no rhGH, (Ctrl; n, 11) for 6 months. Percentage change in HV after 6 months in the two groups. Auxology, puberty, skeletal age, disease factors, treatment and glucose homeostasis were also assessed. Median HV increased from 4·5 (range, 0·6, 8·9) at baseline to 10·8 (6·1, 15·0) cm/year at 6 month (P = 0·003) in the rhGH group, whereas in the Ctrl group, it was 3·8 (1·4, 6·7) and 3·5 cm/year (2·0, 9·6), respectively (P = 0·58). Median percentage increase in HV after 6 months in the rhGH group was 140% (16·7, 916·7) compared with 17·4% (-42·1%, 97·7%) in the Ctrl group (P < 0·001). There were no significant differences in disease activity and proinflammatory cytokines at baseline and 6 months in both groups and change in bone age for chronological age was also similar in the two groups. In the rhGH group, fasting insulin increased from 4·0 (2·0, 11·0) to 7·0 mU/l (2·0, 16·0) (P = 0·02), whereas in the Ctrl group, it was 3·0 (1·2, 12·7) and 3·8 mU/l (2·1, 7·0) (P = 0·72), respectively. Although this pilot trial shows that rhGH can improve short-term linear growth in children with CD, the clinical efficacy of this therapy needs to be further studied in longer-term studies of growth, glucose homeostasis and disease status. © 2011 Blackwell Publishing Ltd.

  4. Clonazepam increases in vivo striatal extracellular glucose in diabetic rats after glucose overload.

    PubMed

    Gomez, Rosane; Barros, Helena M T

    2003-12-01

    Hyperglycemia modulates brain function, including neuronal excitability, neurotransmitter release and behavioral changes. There may be connections between the GABAergic system, glucose sensing neurons and glucose in the neuronal environment that shed light on the mechanism by which GABA(A) agents influence depressive behavior in diabetic rats submitted to the forced swimming test. We aimed to investigate whether clonazepam (CNZ), a GABA(A) receptor positive modulator, modifies in vivo striatal extracellular glucose levels in diabetic rats under fasting condition or after oral glucose overload. Streptozotocin diabetic and nondiabetic rats were submitted to in vivo striatal microdialysis. Perfusate samples were collected at baseline, during fasting and following administration of CNZ (0.25 mg/kg) and oral glucose overload. Blood glucose and striatal extracellular glucose were measured simultaneously at several time points. Fasting striatal glucose levels were higher in diabetic than in nondiabetic rats and the differences between these animals were maintained after glucose overload. The increases in extracellular striatal glucose after glucose overload were around 40% and blood to brain transference was decreased in diabetics. CNZ treatment paradoxically increased striatal glucose after glucose overload in diabetic rats, which may mark the dysfunction in brain glucose homeostasis.

  5. Inhibition of adipose tissue PPARγ prevents increased adipocyte expansion after lipectomy and exacerbates a glucose-intolerant phenotype.

    PubMed

    Booth, A D; Magnuson, A M; Cox-York, K A; Wei, Y; Wang, D; Pagliassotti, M J; Foster, M T

    2017-04-01

    Adipose tissue plays a fundamental role in glucose homeostasis. For example, fat removal (lipectomy, LipX) in lean mice, resulting in a compensatory 50% increase in total fat mass, is associated with significant improvement in glucose tolerance. This study was designed to further examine the link between fat removal, adipose tissue compensation and glucose homeostasis using a peroxisome proliferator-activated receptor γ (PPAR γ; activator of adipogenesis) knockout mouse. The study involved PPARγ knockout (FKOγ) or control mice (CON), subdivided into groups that received LipX or Sham surgery. We reasoned that as the ability of adipose tissue to expand in response to LipX would be compromised in FKOγ mice, so would improvements in glucose homeostasis. In CON mice, LipX increased total adipose depot mass (~60%), adipocyte number (~45%) and changed adipocyte distribution to smaller cells. Glucose tolerance was improved (~30%) in LipX CON mice compared to Shams. In FKOγ mice, LipX did not result in any significant changes in adipose depot mass, adipocyte number or distribution. LipX FKOγ mice were also characterized by reduction of glucose tolerance (~30%) compared to shams. Inhibition of adipose tissue PPARγ prevented LipX-induced increases in adipocyte expansion and produced a glucose-intolerant phenotype. These data support the notion that adipose tissue expansion is critical to maintain and/or improvement in glucose homeostasis. © 2016 John Wiley & Sons Ltd.

  6. Transmissible microbial and metabolomic remodeling by soluble dietary fiber improves metabolic homeostasis

    PubMed Central

    He, Baokun; Nohara, Kazunari; Ajami, Nadim J.; Michalek, Ryan D.; Tian, Xiangjun; Wong, Matthew; Losee-Olson, Susan H.; Petrosino, Joseph F.; Yoo, Seung-Hee; Shimomura, Kazuhiro; Chen, Zheng

    2015-01-01

    Dietary fibers are increasingly appreciated as beneficial nutritional components. However, a requisite role of gut microbiota in fiber function and the overall impact of fibers on metabolomic flux remain unclear. We herein showed enhancing effects of a soluble resistant maltodextrin (RM) on glucose homeostasis in mouse metabolic disease models. Remarkably, fecal microbiota transplantation (FMT) caused pronounced and time-dependent improvement in glucose tolerance in RM recipient mice, indicating a causal relationship between microbial remodeling and metabolic efficacy. Microbial 16S sequencing revealed transmissible taxonomic changes correlated with improved metabolism, notably enrichment of probiotics and reduction of Alistipes and Bacteroides known to associate with high fat/protein diets. Metabolomic profiling further illustrated broad changes, including enrichment of phenylpropionates and decreases in key intermediates of glucose utilization, cholesterol biosynthesis and amino acid fermentation. These studies elucidate beneficial roles of RM-dependent microbial remodeling in metabolic homeostasis, and showcase prevalent health-promoting potentials of dietary fibers. PMID:26040234

  7. A Thyroid Hormone Challenge in Hypothyroid Rats Identifies T3 Regulated Genes in the Hypothalamus and in Models with Altered Energy Balance and Glucose Homeostasis

    PubMed Central

    Herwig, Annika; Campbell, Gill; Mayer, Claus-Dieter; Boelen, Anita; Anderson, Richard A.; Ross, Alexander W.; Mercer, Julian G.

    2014-01-01

    Background: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms. Methods: Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA. Results: Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (±1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic

  8. Hepatic expression and cellular distribution of the glucose transporter family

    PubMed Central

    Karim, Sumera; Adams, David H; Lalor, Patricia F

    2012-01-01

    Glucose and other carbohydrates are transported into cells using members of a family of integral membrane glucose transporter (GLUT) molecules. To date 14 members of this family, also called the solute carrier 2A proteins have been identified which are divided on the basis of transport characteristics and sequence similarities into several families (Classes 1 to 3). The expression of these different receptor subtypes varies between different species, tissues and cellular subtypes and each has differential sensitivities to stimuli such as insulin. The liver is a contributor to metabolic carbohydrate homeostasis and is a major site for synthesis, storage and redistribution of carbohydrates. Situations in which the balance of glucose homeostasis is upset such as diabetes or the metabolic syndrome can lead metabolic disturbances that drive chronic organ damage and failure, confirming the importance of understanding the molecular regulation of hepatic glucose homeostasis. There is a considerable literature describing the expression and function of receptors that regulate glucose uptake and release by hepatocytes, the most import cells in glucose regulation and glycogen storage. However there is less appreciation of the roles of GLUTs expressed by non parenchymal cell types within the liver, all of which require carbohydrate to function. A better understanding of the detailed cellular distribution of GLUTs in human liver tissue may shed light on mechanisms underlying disease pathogenesis. This review summarises the available literature on hepatocellular expression of GLUTs in health and disease and highlights areas where further investigation is required. PMID:23239915

  9. Activation of Short and Long Chain Fatty Acid Sensing Machinery in the Ileum Lowers Glucose Production in Vivo.

    PubMed

    Zadeh-Tahmasebi, Melika; Duca, Frank A; Rasmussen, Brittany A; Bauer, Paige V; Côté, Clémence D; Filippi, Beatrice M; Lam, Tony K T

    2016-04-15

    Evidence continues to emerge detailing the myriad of ways the gut microbiota influences host energy homeostasis. Among the potential mechanisms, short chain fatty acids (SCFAs), the byproducts of microbial fermentation of dietary fibers, exhibit correlative beneficial metabolic effects in humans and rodents, including improvements in glucose homeostasis. The underlying mechanisms, however, remain elusive. We here report that one of the main bacterially produced SCFAs, propionate, activates ileal mucosal free fatty acid receptor 2 to trigger a negative feedback pathway to lower hepatic glucose production in healthy rats in vivo We further demonstrate that an ileal glucagon-like peptide-1 receptor-dependent neuronal network is necessary for ileal propionate and long chain fatty acid sensing to regulate glucose homeostasis. These findings highlight the potential to manipulate fatty acid sensing machinery in the ileum to regulate glucose homeostasis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Newly identified protein Imi1 affects mitochondrial integrity and glutathione homeostasis in Saccharomyces cerevisiae.

    PubMed

    Kowalec, Piotr; Grynberg, Marcin; Pająk, Beata; Socha, Anna; Winiarska, Katarzyna; Fronk, Jan; Kurlandzka, Anna

    2015-09-01

    Glutathione homeostasis is crucial for cell functioning. We describe a novel Imi1 protein of Saccharomyces cerevisiae affecting mitochondrial integrity and involved in controlling glutathione level. Imi1 is cytoplasmic and, except for its N-terminal Flo11 domain, has a distinct solenoid structure. A lack of Imi1 leads to mitochondrial lesions comprising aberrant morphology of cristae and multifarious mtDNA rearrangements and impaired respiration. The mitochondrial malfunctioning is coupled to significantly decrease the level of intracellular reduced glutathione without affecting oxidized glutathione, which decreases the reduced/oxidized glutathione ratio. These defects are accompanied by decreased cadmium sensitivity and increased phytochelatin-2 level. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. ABCA1 in adipocytes regulates adipose tissue lipid content, glucose tolerance, and insulin sensitivity[S

    PubMed Central

    de Haan, Willeke; Bhattacharjee, Alpana; Ruddle, Piers; Kang, Martin H.; Hayden, Michael R.

    2014-01-01

    Adipose tissue contains one of the largest reservoirs of cholesterol in the body. Adipocyte dysfunction in obesity is associated with intracellular cholesterol accumulation, and alterations in cholesterol homeostasis have been shown to alter glucose metabolism in cultured adipocytes. ABCA1 plays a major role in cholesterol efflux, suggesting a role for ABCA1 in maintaining cholesterol homeostasis in the adipocyte. However, the impact of adipocyte ABCA1 on adipose tissue function and glucose metabolism is unknown. Our aim was to determine the impact of adipocyte ABCA1 on adipocyte lipid metabolism, body weight, and glucose metabolism in vivo. To address this, we used mice lacking ABCA1 specifically in adipocytes (ABCA1−ad/−ad). When fed a high-fat, high-cholesterol diet, ABCA1−ad/−ad mice showed increased cholesterol and triglyceride stores in adipose tissue, developed enlarged fat pads, and had increased body weight. Associated with these phenotypic changes, we observed significant changes in the expression of genes involved in cholesterol and glucose homeostasis, including ldlr, abcg1, glut-4, adiponectin, and leptin. ABCA1−ad/−ad mice also demonstrated impaired glucose tolerance, lower insulin sensitivity, and decreased insulin secretion. We conclude that ABCA1 in adipocytes influences adipocyte lipid metabolism, body weight, and whole-body glucose homeostasis. PMID:24443560

  12. Hepatic glucose sensing is required to preserve β cell glucose competence

    PubMed Central

    Seyer, Pascal; Vallois, David; Poitry-Yamate, Carole; Schütz, Frédéric; Metref, Salima; Tarussio, David; Maechler, Pierre; Staels, Bart; Lanz, Bernard; Grueter, Rolf; Decaris, Julie; Turner, Scott; da Costa, Anabela; Preitner, Frédéric; Minehira, Kaori; Foretz, Marc; Thorens, Bernard

    2013-01-01

    Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr–/– mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link. PMID:23549084

  13. Lepidium peruvianum chacon restores homeostasis impaired by restraint stress.

    PubMed

    López-Fando, A; Gómez-Serranillos, M P; Iglesias, I; Lock, O; Upamayta, U P; Carretero, M E

    2004-06-01

    Lepidium peruvianum root has been traditionally utilized by native Peruvians, since before the time of the Incas, for both nutritional and putative medicinal purposes as an adaptogen and also to enhance fertility in humans and animals. The present research was conducted to evaluate the anti-stress activity of the methanolic extract of Lepidium peruvianum. The drug is capable of attenuating or even eliminating variations in homeostasis produced by stress since it reduces or abolishes stress-induced ulcers, elevated corticosterone levels, the reduction of glucose and the increase in the weight of adrenal glands produced by stress. It also eliminates the decrease in free fatty-acids (FFA) in plasma produced by stress and we obtain a positive result in the forced-swimming test. Thus, it did not appear to affect restraint stress-induced immunosuppression.

  14. Clinical assessment of blood glucose homeostasis in horses: comparison of a continuous glucose monitoring system with a combined intravenous glucose and insulin test protocol.

    PubMed

    Johnson, P J; Wiedmeyer, C E; LaCarrubba, A; Messer, N T; Dingfelder, H A; Cogswell, A M; Amorim, J R R; Ganjam, V K

    2011-01-01

    The combined glucose-insulin test (CGIT) is helpful for evaluating insulin sensitivity. A continuous glucose monitoring system (CGMS) reports changes in interstitial glucose concentrations as they occur in the blood. Use of the CGMS minimizes animal contact and may be useful when performing a CGIT. Results obtained using a CGMS are useful for the evaluation of glucose responses during the evaluation of insulin sensitivity in equids. Seven mature, obese ponies. Ponies were equipped with CGMS for determination of interstitial glucose concentrations. Glucose (150 mg/kg, i.v.) and insulin (0.1 U/kg, i.v.) were administered and blood glucose concentrations determined at (minutes after time zero) 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, and 120 with a hand-held glucometer. Blood chemistry results were compared with simultaneously obtained results using CGMS. Concordance coefficients determined for comparison of blood glucose concentrations determined by a hand-held glucometer and those determined by CGMS after the zero time point were 0.623, 0.764, 0.834, 0.854, and 0.818 (for delays of 0, 5, 10, 15, and 20 minutes, respectively). Interstitial glucose concentrations obtained by the CGMS compared favorably to blood glucose concentrations. CGMS may be useful for assessment of glucose dynamics in the CGIT. Copyright © 2010 by the American College of Veterinary Internal Medicine.

  15. 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

  16. Regulation of. beta. -cell glucose transporter gene expression

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

    Chen, Ling; Alam, Tausif; Johnson, J.H.

    1990-06-01

    It has been postulated that a glucose transporter of {beta} cells (GLUT-2) may be important in glucose-stimulated insulin secretion. To determine whether this transporter is constitutively expressed or regulated, the authors subjected conscious unrestrained Wistar rats to perturbations in glucose homeostasis and quantitated {beta}-cell GLUT-2 mRNA by in situ hybridization. After 3 hr of hypoglycemia, GLUT-2 and proinsulin mRNA signal densities were reduced by 25% of the level in control rats. After 4 days, GLUT-2 and proinsulin mRNA densities were reduced by 85% and 65%, respectively. After 12 days of hypoglycemia, the K{sub m} for 3-O-methyl-D-glucose transport in isolated ratmore » islets, normally 18-20 mM, was 2.5 mM. This provides functional evidence of a profound reduction of high K{sub m} glucose transporter in {beta} cells. In contrast, GLUT-2 was only slightly reduced by hypoglycemia in liver. To determine the effect of prolonged hyperglycemia, they also infused animals with 50% (wt/vol) glucose for 5 days. Hyperglycemic clamping increased GLUT-2 mRNA by 46% whereas proinsulin mRNA doubled. They conclude that GLUT-2 expression in {beta} cells, but not liver, is subject to regulation by certain perturbations in blood glucose homeostasis.« less

  17. Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis.

    PubMed

    Sarruf, David A; Yu, Fang; Nguyen, Hong T; Williams, Diana L; Printz, Richard L; Niswender, Kevin D; Schwartz, Michael W

    2009-02-01

    In addition to increasing insulin sensitivity and adipogenesis, peroxisome proliferator-activated receptor (PPAR)-gamma agonists cause weight gain and hyperphagia. Given the central role of the brain in the control of energy homeostasis, we sought to determine whether PPARgamma is expressed in key brain areas involved in metabolic regulation. Using immunohistochemistry, PPARgamma distribution and its colocalization with neuron-specific protein markers were investigated in rat and mouse brain sections spanning the hypothalamus, the ventral tegmental area, and the nucleus tractus solitarius. In several brain areas, nuclear PPARgamma immunoreactivity was detected in cells that costained for neuronal nuclei, a neuronal marker. In the hypothalamus, PPARgamma immunoreactivity was observed in a majority of neurons in the arcuate (including both agouti related protein and alpha-MSH containing cells) and ventromedial hypothalamic nuclei and was also present in the hypothalamic paraventricular nucleus, the lateral hypothalamic area, and tyrosine hydroxylase-containing neurons in the ventral tegmental area but was not expressed in the nucleus tractus solitarius. To validate and extend these histochemical findings, we generated mice with neuron-specific PPARgamma deletion using nestin cre-LoxP technology. Compared with littermate controls, neuron-specific PPARgamma knockout mice exhibited dramatic reductions of both hypothalamic PPARgamma mRNA levels and PPARgamma immunoreactivity but showed no differences in food intake or body weight over a 4-wk study period. We conclude that: 1) PPARgamma mRNA and protein are expressed in the hypothalamus, 2) neurons are the predominant source of PPARgamma in the central nervous system, although it is likely expressed by nonneuronal cell types as well, and 3) arcuate nucleus neurons that control energy homeostasis and glucose metabolism are among those in which PPARgamma is expressed.

  18. Nuclear and Membrane Actions of Estrogen Receptor Alpha: Contribution to the Regulation of Energy and Glucose Homeostasis.

    PubMed

    Guillaume, Maeva; Montagner, Alexandra; Fontaine, Coralie; Lenfant, Françoise; Arnal, Jean-François; Gourdy, Pierre

    2017-01-01

    Estrogen receptor alpha (ERα) has been demonstrated to play a key role in reproduction but also to exert numerous functions in nonreproductive tissues. Accordingly, ERα is now recognized as a key regulator of energy homeostasis and glucose metabolism and mediates the protective effects of estrogens against obesity and type 2 diabetes. This chapter attempts to summarize our current understanding of the mechanisms of ERα activation and their involvement in the modulation of energy balance and glucose metabolism. We first focus on the experimental studies that constitute the basis of the understanding of ERα as a nuclear receptor and more specifically on the key roles played by its two activation functions (AFs). We depict the consequences of the selective inactivation of these AFs in mouse models, which further underline the prominent role of nuclear ERα in the prevention of obesity and diabetes, as on the reproductive tract and the vascular system. Besides these nuclear actions, a fraction of ERα is associated with the plasma membrane and activates nonnuclear signaling from this site. Such rapid effects, called membrane-initiated steroid signals (MISS), have been characterized in a variety of cell lines and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS as well as the generation of mice expressing an ERα protein impeded for membrane localization has just begun to unravel the physiological role of MISS in vivo and their contribution to ERα-mediated metabolic protection. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators.

  19. The Brain–to–Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions

    PubMed Central

    Rosario, Wilfredo; Singh, Inderroop; Wautlet, Arnaud; Patterson, Christa; Flak, Jonathan; Becker, Thomas C.; Ali, Almas; Tamarina, Natalia; Philipson, Louis H.; Enquist, Lynn W.; Myers, Martin G.

    2016-01-01

    The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia. PMID:27207534

  20. The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions.

    PubMed

    Rosario, Wilfredo; Singh, Inderroop; Wautlet, Arnaud; Patterson, Christa; Flak, Jonathan; Becker, Thomas C; Ali, Almas; Tamarina, Natalia; Philipson, Louis H; Enquist, Lynn W; Myers, Martin G; Rhodes, Christopher J

    2016-09-01

    The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia. © 2016 by the American Diabetes Association.

  1. Perceived diabetes task competence mediates the relationship of both negative and positive affect with blood glucose in adolescents with type 1 diabetes.

    PubMed

    Fortenberry, Katherine T; Butler, Jorie M; Butner, Jonathan; Berg, Cynthia A; Upchurch, Renn; Wiebe, Deborah J

    2009-02-01

    Adolescents dealing with type 1 diabetes experience disruptions in affect and diabetes management that may influence their blood glucose. A daily diary format examined whether daily fluctuations in both negative and positive affect were associated with adolescents' perceived diabetes task competence (DTC) and blood glucose, and whether perceived DTC mediated the relationship between daily affect and blood glucose. Sixty-two adolescents with type 1 diabetes completed a 2-week daily diary, which included daily measures of affect and perceived DTC, then recorded their blood glucose readings at the end of the day. We utilized hierarchical linear modeling to examine whether daily perceived DTC mediated the relationship between daily emotion and blood glucose. Daily perceived DTC mediated the relationship of both negative and positive affect with daily blood glucose. This study suggests that within the ongoing process of self-regulation, daily affect may be associated with blood glucose by influencing adolescents' perception of competence on daily diabetes tasks.

  2. Ablation of ghrelin O-acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background.

    PubMed

    Kirchner, Henriette; Heppner, Kristy M; Holland, Jenna; Kabra, Dhiraj; Tschöp, Matthias H; Pfluger, Paul T

    2013-01-01

    Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two ghrelin isoforms acyl- and desacyl ghrelin in regulating glucose homeostasis. Therefore ghrelin activating enzyme Ghrelin-O-acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl ghrelin deficiency or desacyl ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl ghrelin nor the increased ratio of desacyl/acyl ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency.

  3. Green tea extract does not affect exogenous glucose appearance but reduces insulinemia with glucose ingestion in exercise recovery.

    PubMed

    Martin, Brian J; McGlory, Chris; MacInnis, Martin J; Allison, Mary K; Phillips, Stuart M; Gibala, Martin J

    2016-12-01

    We reported that supplementation with green tea extract (GTE) lowered the glycemic response to an oral glucose load following exercise, but via an unknown mechanism (Martin BJ, MacInnis MJ, Gillen JB, Skelly LE, Gibala MJ. Appl Physiol Nutr Metab 41: 1057-1063, 2016. Here we examined the effect of supplementation with GTE on plasma glucose kinetics on ingestion of a glucose beverage during exercise recovery. Eleven healthy, sedentary men (21 ± 2 yr old; body mass index = 23 ± 4 kg/m 2 , peak O 2 uptake = 38 ± 7 ml·kg -1 ·min -1 ; means ± SD) ingested GTE (350 mg) or placebo (PLA) thrice daily for 7 days in a double-blind, crossover design. In the fasted state, a primed constant infusion of [U- 13 C 6 ]glucose was started, and 1 h later, subjects performed a graded exercise test (25 W/3 min) on a cycle ergometer. Immediately postexercise, subjects ingested a 75-g glucose beverage containing 2 g of [6,6- 2 H 2 ]glucose, and blood samples were collected every 10 min for 3 h of recovery. The rate of carbohydrate oxidation was lower during exercise after GTE vs. PLA (1.26 ± 0.34 vs. 1.48 ± 0.51 g/min, P = 0.04). Glucose area under the curve (AUC) was not different between treatments after drink ingestion (GTE = 1,067 ± 133 vs. PLA = 1,052 ± 91 mM/180 min, P = 0.91). Insulin AUC was lower after GTE vs. PLA (5,673 ± 2,153 vs. 7,039 ± 2,588 µIU/180 min, P = 0.05), despite similar rates of glucose appearance (GTE = 0.42 ± 0.16 vs. PLA = 0.43 ± 0.13 g/min, P = 0.74) and disappearance (GTE = 0.43 ± 0.14 vs. PLA = 0.44 ± 0.14 g/min, P = 0.57). We conclude that short-term GTE supplementation did not affect glucose kinetics following ingestion of an oral glucose load postexercise; however, GTE was associated with attenuated insulinemia. These findings suggest GTE lowers the insulin required for a given glucose load during postexercise recovery, which warrants further mechanistic studies in humans. Copyright © 2016 the American Physiological Society.

  4. Green tea extract does not affect exogenous glucose appearance but reduces insulinemia with glucose ingestion in exercise recovery

    PubMed Central

    Martin, Brian J.; McGlory, Chris; MacInnis, Martin J.; Allison, Mary K.; Phillips, Stuart M.

    2016-01-01

    We reported that supplementation with green tea extract (GTE) lowered the glycemic response to an oral glucose load following exercise, but via an unknown mechanism (Martin BJ, MacInnis MJ, Gillen JB, Skelly LE, Gibala MJ. Appl Physiol Nutr Metab 41: 1057–1063, 2016. Here we examined the effect of supplementation with GTE on plasma glucose kinetics on ingestion of a glucose beverage during exercise recovery. Eleven healthy, sedentary men (21 ± 2 yr old; body mass index = 23 ± 4 kg/m2, peak O2 uptake = 38 ± 7 ml·kg−1·min−1; means ± SD) ingested GTE (350 mg) or placebo (PLA) thrice daily for 7 days in a double-blind, crossover design. In the fasted state, a primed constant infusion of [U-13C6]glucose was started, and 1 h later, subjects performed a graded exercise test (25 W/3 min) on a cycle ergometer. Immediately postexercise, subjects ingested a 75-g glucose beverage containing 2 g of [6,6-2H2]glucose, and blood samples were collected every 10 min for 3 h of recovery. The rate of carbohydrate oxidation was lower during exercise after GTE vs. PLA (1.26 ± 0.34 vs. 1.48 ± 0.51 g/min, P = 0.04). Glucose area under the curve (AUC) was not different between treatments after drink ingestion (GTE = 1,067 ± 133 vs. PLA = 1,052 ± 91 mM/180 min, P = 0.91). Insulin AUC was lower after GTE vs. PLA (5,673 ± 2,153 vs. 7,039 ± 2,588 µIU/180 min, P = 0.05), despite similar rates of glucose appearance (GTE = 0.42 ± 0.16 vs. PLA = 0.43 ± 0.13 g/min, P = 0.74) and disappearance (GTE = 0.43 ± 0.14 vs. PLA = 0.44 ± 0.14 g/min, P = 0.57). We conclude that short-term GTE supplementation did not affect glucose kinetics following ingestion of an oral glucose load postexercise; however, GTE was associated with attenuated insulinemia. These findings suggest GTE lowers the insulin required for a given glucose load during postexercise recovery, which warrants further mechanistic studies in humans. PMID:27763877

  5. Linking neuronal brain activity to the glucose metabolism.

    PubMed

    Göbel, Britta; Oltmanns, Kerstin M; Chung, Matthias

    2013-08-29

    Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported.

  6. Linking neuronal brain activity to the glucose metabolism

    PubMed Central

    2013-01-01

    Background Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. Methods First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Results Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. Conclusions The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported. PMID:23988084

  7. Diglycosyl diselenides alter redox homeostasis and glucose consumption of infective African trypanosomes.

    PubMed

    Franco, Jaime; Sardi, Florencia; Szilágyi, László; Kövér, Katalin E; Fehér, Krisztina; Comini, Marcelo A

    2017-12-01

    With the aim to develop compounds able to target multiple metabolic pathways and, thus, to lower the chances of drug resistance, we investigated the anti-trypanosomal activity and selectivity of a series of symmetric diglycosyl diselenides and disulfides. Of 18 compounds tested the fully acetylated forms of di-β-D-glucopyranosyl and di-β-D-galactopyranosyl diselenides (13 and 15, respectively) displayed strong growth inhibition against the bloodstream stage of African trypanosomes (EC 50 0.54 μM for 13 and 1.49 μM for 15) although with rather low selectivity (SI < 10 assayed with murine macrophages). Nonacetylated versions of the same sugar diselenides proved to be, however, much less efficient or completely inactive to suppress trypanosome growth. Significantly, the galactosyl (15), and to a minor extent the glucosyl (13), derivative inhibited glucose catabolism but not its uptake. Both compounds induced redox unbalance in the pathogen. In vitro NMR analysis indicated that diglycosyl diselenides react with glutathione, under physiological conditions, via formation of selenenylsulfide bonds. Our results suggest that non-specific cellular targets as well as actors of the glucose and the redox metabolism of the parasite may be affected. These molecules are therefore promising leads for the development of novel multitarget antitrypanosomal agents. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

    PubMed

    Kim, Ji Yeon; Park, Keon Jae; Hwang, Joo-Yeon; Kim, Gyu Hee; Lee, DaeYeon; Lee, Yoo Jeong; Song, Eun Hyun; Yoo, Min-Gyu; Kim, Bong-Jo; Suh, Young Ho; Roh, Gu Seob; Gao, Bin; Kim, Won; Kim, Won-Ho

    2017-08-01

    predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D. Copyright © 2017 European Association for the Study of the Liver. All rights reserved.

  9. The Destiny of Glucose from a MicroRNA Perspective.

    PubMed

    Mirra, Paola; Nigro, Cecilia; Prevenzano, Immacolata; Leone, Alessia; Raciti, Gregory Alexander; Formisano, Pietro; Beguinot, Francesco; Miele, Claudia

    2018-01-01

    Glucose serves as a primary, and for some tissues the unique, fuel source in order to generate and maintain the biological functions. Hyperglycemia is a hallmark of type 2 diabetes and is the direct consequence of perturbations in the glucose homeostasis. Insulin resistance, referred to as a reduced response of target tissues to the hormone, contributes to the development of hyperglycemia. The molecular mechanisms responsible for the altered glucose homeostasis are numerous and not completely understood. MicroRNAs (miRNAs) are now recognized as regulators of the lipid and glucose metabolism and are involved in the onset of metabolic diseases. Indeed, these small non-coding RNA molecules operate in the RNA silencing and posttranscriptional regulation of gene expression and may modulate the levels of kinases and enzymes in the glucose metabolism. Therefore, a better characterization of the function of miRNAs and a deeper understanding of their role in disease may represent a fundamental step toward innovative treatments addressing the causes, not only the symptoms, of hyperglycemia, using approaches aimed at restoring either miRNAs or their specific targets. In this review, we outline the current understanding regarding the impact of miRNAs in the glucose metabolism and highlight the need for further research focused on altered key kinases and enzymes in metabolic diseases.

  10. Ca2+ homeostasis in microvascular endothelial cells from an insulin-dependent diabetic model: role of endosomes/lysosomes

    NASA Astrophysics Data System (ADS)

    Sanka, Shankar C.; Bennett, David C.; Rojas, Jose D.; Tasby, Geraldine B.; Meininger, Cynthia J.; Wu, Guoyao; Wesson, Donald E.; Pfarr, Curtis M.; Martinez-Zaguilan, Raul

    2000-04-01

    Cytosolic Ca2+ ([Ca2+]cyt) regulates several cellular functions, e.g. cell growth, contraction, secretion, etc. In many cell types, ion homeostasis appears to be coupled with glucose metabolism. In certain cell types, a strict coupling between glycolysis and the activity of Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPases (SERCA) has been suggested. Glucose metabolism is altered in diabetes. We hypothesize that: (1) Ca2+ homeostasis is altered in microvascular endothelial cells from diabetic animals due to the dysfunction of glycolysis coupling the activity of SERCA; (2) endosomal/lysosomal compartments expressing SERCA are involved in the dysfunction associated with diabetes.

  11. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians

    USDA-ARS?s Scientific Manuscript database

    BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. OBJECTIVE: We investigated the associations of mea...

  12. The SH2B1 obesity locus and abnormal glucose homeostasis: lack of evidence for association from a meta-analysis in individuals of European ancestry.

    PubMed

    Prudente, S; Copetti, M; Morini, E; Mendonca, C; Andreozzi, F; Chandalia, M; Baratta, R; Pellegrini, F; Mercuri, L; Bailetti, D; Abate, N; Frittitta, L; Sesti, G; Florez, J C; Doria, A; Trischitta, V

    2013-11-01

    The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association. The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448). Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89-1.04) or in the meta-analysis (OR = 1.01; 0.98-1.05). Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Exposure to Bisphenol-A during Pregnancy Partially Mimics the Effects of a High-Fat Diet Altering Glucose Homeostasis and Gene Expression in Adult Male Mice

    PubMed Central

    García-Arevalo, Marta; Alonso-Magdalena, Paloma; Rebelo Dos Santos, Junia; Quesada, Ivan; Carneiro, Everardo M.; Nadal, Angel

    2014-01-01

    Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group); BPA treated mice that also ate a normal chow diet (BPA); vehicle treated animals that had a high fat diet (HFD) and BPA treated animals that were fed HFD (HFD-BPA). The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA) in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity. PMID:24959901

  14. Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice.

    PubMed

    García-Arevalo, Marta; Alonso-Magdalena, Paloma; Rebelo Dos Santos, Junia; Quesada, Ivan; Carneiro, Everardo M; Nadal, Angel

    2014-01-01

    Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group); BPA treated mice that also ate a normal chow diet (BPA); vehicle treated animals that had a high fat diet (HFD) and BPA treated animals that were fed HFD (HFD-BPA). The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA) in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity.

  15. Effects of intravenous lipopolysaccharide infusion on glucose and insulin dynamics in horses with equine metabolic syndrome.

    PubMed

    Tadros, Elizabeth M; Frank, Nicholas; De Witte, Fiamma Gomez; Boston, Raymond C

    2013-07-01

    To test the hypothesis that glucose and insulin dynamics during endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). 6 healthy adult mares and 6 horses with EMS. Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline insulin-modified frequently sampled IV glucose tolerance tests were performed 27 hours before and then repeated at 0.5 and 21 hours after infusion. Results were assessed via minimal model analysis and area under the curve values for plasma glucose and serum insulin concentrations. Lipopolysaccharide infusion decreased insulin sensitivity and increased area under the serum insulin concentration curve (treatment × time) in both healthy and EMS-affected horses, compared with findings following saline solution administration. The magnitude of increase in area under the plasma glucose curve following LPS administration was greater for the EMS-affected horses than it was for the healthy horses. Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time. Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations.

  16. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

    PubMed Central

    Timper, Katharina; Brüning, Jens C.

    2017-01-01

    ABSTRACT The ‘obesity epidemic’ represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed. PMID:28592656

  17. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity.

    PubMed

    Timper, Katharina; Brüning, Jens C

    2017-06-01

    The 'obesity epidemic' represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed. © 2017. Published by The Company of Biologists Ltd.

  18. 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.

  19. Effects of the Soluble Fiber Complex PolyGlycopleX® on Glucose Homeostasis and Body Weight in Young Zucker Diabetic Rats

    PubMed Central

    Grover, Gary James; Koetzner, Lee; Wicks, Joan; Gahler, Roland J.; Lyon, Michael R.; Reimer, Raylene A.; Wood, Simon

    2011-01-01

    Dietary fiber can reduce insulin resistance, body weight, and hyperlipidemia depending on fiber type, water solubility, and viscosity. PolyGlycopleX® (PGX®) is a natural, novel water soluble, non-starch polysaccharide complex that with water forms a highly viscous gel compared to other naturally occurring dietary fiber. We determined the effect of dietary PGX® vs. cellulose and inulin on the early development of insulin resistance, body weight, hyperlipidemia, and glycemia-induced tissue damage in young Zucker diabetic rats (ZDFs) in fasted and non-fasted states. ZDFs (5 weeks old) were fed a diet containing 5% (wgt/wgt) cellulose, inulin, or PGX® for 8 weeks. Body weight, lipids, insulin, and glucose levels were determined throughout the study and homeostasis model assessment (HOMA) was used to measure insulin sensitivity throughout the study in fasted animals. At study termination, insulin sensitivity (oral glucose tolerance test, OGTT) and kidney, liver, and pancreatic histopathology were determined. Body weight and food intake were significantly reduced by PGX® vs. inulin and cellulose. Serum insulin in fasted and non-fasted states was significantly reduced by PGX® as was non-fasted blood glucose. Insulin resistance, measured as a HOMA score, was significantly reduced by PGX® in weeks 5 through 8 as well as terminal OGTT scores in fed and fasted states. Serum total cholesterol was also significantly reduced by PGX®. PGX® significantly reduced histological kidney and hepatic damage in addition to reduced hepatic steatosis and cholestasis. A greater mass of pancreatic β-cells was found in the PGX® group. PGX® therefore may be a useful dietary additive in the control of the development of the early development of the metabolic syndrome. PMID:21922008

  20. The Allelochemical MDCA Inhibits Lignification and Affects Auxin Homeostasis1[OPEN

    PubMed Central

    Steenackers, Ward; Corneillie, Sander; Van de Wouwer, Dorien; Zažímalová, Eva

    2016-01-01

    The phenylpropanoid 3,4-(methylenedioxy)cinnamic acid (MDCA) is a plant-derived compound first extracted from roots of Asparagus officinalis and further characterized as an allelochemical. Later on, MDCA was identified as an efficient inhibitor of 4-COUMARATE-CoA LIGASE (4CL), a key enzyme of the general phenylpropanoid pathway. By blocking 4CL, MDCA affects the biosynthesis of many important metabolites, which might explain its phytotoxicity. To decipher the molecular basis of the allelochemical activity of MDCA, we evaluated the effect of this compound on Arabidopsis thaliana seedlings. Metabolic profiling revealed that MDCA is converted in planta into piperonylic acid (PA), an inhibitor of CINNAMATE-4-HYDROXYLASE (C4H), the enzyme directly upstream of 4CL. The inhibition of C4H was also reflected in the phenolic profile of MDCA-treated plants. Treatment of in vitro grown plants resulted in an inhibition of primary root growth and a proliferation of lateral and adventitious roots. These observed growth defects were not the consequence of lignin perturbation, but rather the result of disturbing auxin homeostasis. Based on DII-VENUS quantification and direct measurement of cellular auxin transport, we concluded that MDCA disturbs auxin gradients by interfering with auxin efflux. In addition, mass spectrometry was used to show that MDCA triggers auxin biosynthesis, conjugation, and catabolism. A similar shift in auxin homeostasis was found in the c4h mutant ref3-2, indicating that MDCA triggers a cross talk between the phenylpropanoid and auxin biosynthetic pathways independent from the observed auxin efflux inhibition. Altogether, our data provide, to our knowledge, a novel molecular explanation for the phytotoxic properties of MDCA. PMID:27506238

  1. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians

    USDA-ARS?s Scientific Manuscript database

    Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. We investigated the associations of meat intake and the intera...

  2. Soy Leaf Extract Containing Kaempferol Glycosides and Pheophorbides Improves Glucose Homeostasis by Enhancing Pancreatic β-Cell Function and Suppressing Hepatic Lipid Accumulation in db/db Mice.

    PubMed

    Li, Hua; Ji, Hyeon-Seon; Kang, Ji-Hyun; Shin, Dong-Ha; Park, Ho-Yong; Choi, Myung-Sook; Lee, Chul-Ho; Lee, In-Kyung; Yun, Bong-Sik; Jeong, Tae-Sook

    2015-08-19

    This study investigated the molecular mechanisms underlying the antidiabetic effect of an ethanol extract of soy leaves (ESL) in db/db mice. Control groups (db/+ and db/db) were fed a normal diet (ND), whereas the db/db-ESL group was fed ND with 1% ESL for 8 weeks. Dietary ESL improved glucose tolerance and lowered plasma glucose, glycated hemoglobin, HOMA-IR, and triglyceride levels. The pancreatic insulin content of the db/db-ESL group was significantly greater than that of the db/db group. ESL supplementation altered pancreatic IRS1, IRS2, Pdx1, Ngn3, Pax4, Ins1, Ins2, and FoxO1 expression. Furthermore, ESL suppressed lipid accumulation and increased glucokinase activity in the liver. ESL primarily contained kaempferol glycosides and pheophorbides. Kaempferol, an aglycone of kaempferol glycosides, improved β-cell proliferation through IRS2-related FoxO1 signaling, whereas pheophorbide a, a product of chlorophyll breakdown, improved insulin secretion and β-cell proliferation through IRS1-related signaling with protein kinase A in MIN6 cells. ESL effectively regulates glucose homeostasis by enhancing IRS-mediated β-cell insulin signaling and suppressing SREBP-1-mediated hepatic lipid accumulation in db/db mice.

  3. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting.

    PubMed

    Liang, Qingning; Zhong, Ling; Zhang, Jialiang; Wang, Yu; Bornstein, Stefan R; Triggle, Chris R; Ding, Hong; Lam, Karen S L; Xu, Aimin

    2014-12-01

    Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocyte-secreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor α (PPARα) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARα KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARα KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  4. Genetic deletion of the EGFR ligand epigen does not affect mouse embryonic development and tissue homeostasis.

    PubMed

    Dahlhoff, Maik; Schäfer, Matthias; Wolf, Eckhard; Schneider, Marlon R

    2013-02-15

    The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor with manifold functions during development, tissue homeostasis and disease. EGFR activation, the formation of homodimers or heterodimers (with the related ERBB2-4 receptors) and downstream signaling is initiated by the binding of a family of structurally related growth factors, the EGFR ligands. Genetic deletion experiments clarified the biological function of all family members except for the last characterized ligand, epigen. We employed gene targeting in mouse embryonic stem cells to generate mice lacking epigen expression. Loss of epigen did not affect mouse development, fertility, or organ physiology. Quantitative RT-PCR analysis revealed increased expression of betacellulin and EGF in a few organs of epigen-deficient mice, suggesting a functional compensation by these ligands. In conclusion, we completed the genetic analysis of EGFR ligands and show that epigen has non-essential functions or functions that can be compensated by other EGFR ligands during growth and tissue homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Subchronic arsenic exposure through drinking water alters vascular redox homeostasis and affects physical health in rats.

    PubMed

    Waghe, Prashantkumar; Sarath, Thengumpallil Sasindran; Gupta, Priyanka; Kutty, Harikumar Sankaran; Kandasamy, Kannan; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

    2014-12-01

    We evaluated whether arsenic can alter vascular redox homeostasis and modulate antioxidant status, taking rat thoracic aorta as a model vascular tissue. In addition, we evaluated whether the altered vascular biochemical homeostasis could be associated with alterations in the physical indicators of toxicity development. Rats were exposed to arsenic as 25, 50, and 100 ppm of sodium arsenite through drinking water for 90 consecutive days. Body weight, food intake, and water consumption were recorded weekly. On the 91st day, rats were sacrificed; vital organs and thoracic aorta were collected. Lipid peroxidation, reactive oxygen species generation, and antioxidants were assessed in the thoracic aorta. Arsenic increased aortic lipid peroxidation and hydrogen peroxide generation while decreased reduced glutathione content in a dose-dependent manner. The activities of the enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were decreased. Further, arsenic at 100 ppm decreased feed intake, water consumption, and body weight from the 11th week onward. At this concentration, arsenic increased the relative weights of the liver and kidney. The results suggest that arsenic causes dose-dependent oxidative stress, reduction in antioxidative defense systems, and body weight loss with alteration in hepato-renal organosomatic indices. Overall, subchronic arsenic exposure through drinking water causes alteration in vascular redox homeostasis and at high concentration affects physical health.

  6. Performance of homeostasis model assessment and serum high-sensitivity C-reactive protein for prediction of isolated post-load hyperglycaemia.

    PubMed

    Lai, Y-C; Li, H-Y; Hung, C-S; Lin, M-S; Shih, S-R; Ma, W-Y; Hua, C-H; Chuang, L-M; Sung, F-C; Wei, J-N

    2013-03-01

    To evaluate whether homeostasis model assessment and high-sensitivity C-reactive protein improve the prediction of isolated post-load hyperglycaemia. The subjects were 1458 adults without self-reported diabetes recruited between 2006 and 2010. Isolated post-load hyperglycaemia was defined as fasting plasma glucose < 7 mmol/l and 2-h post-load plasma glucose ≥ 11.1 mmol/l. Risk scores of isolated post-load hyperglycaemia were constructed by multivariate logistic regression. An independent group (n = 154) was enrolled from 2010 to 2011 to validate the models' performance. One hundred and twenty-three subjects (8.28%) were newly diagnosed as having diabetes mellitus. Among those with undiagnosed diabetes, 64 subjects (52%) had isolated post-load hyperglycaemia. Subjects with isolated post-load hyperglycaemia were older, more centrally obese and had higher blood pressure, HbA(1c), fasting plasma glucose, triglycerides, LDL cholesterol, high-sensitivity C-reactive protein and homeostasis model assessment of insulin resistance and lower homeostasis model assessment of β-cell function than those without diabetes. The risk scores included age, gender, BMI, homeostasis model assessment, high-sensitivity C-reactive protein and HbA(1c). The full model had high sensitivity (84%) and specificity (87%) and area under the receiver operating characteristic curve (0.91), with a cut-off point of 23.81; validation in an independent data set showed 88% sensitivity, 77% specificity and an area under curve of 0.89. Over half of those with undiagnosed diabetes had isolated post-load hyperglycaemia. Homeostasis model assessment and high-sensitivity C-reactive protein are useful to identify subjects with isolated post-load hyperglycaemia, with improved performance over fasting plasma glucose or HbA(1c) alone. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  7. Central insulin-mediated regulation of hepatic glucose production [Review].

    PubMed

    Inoue, Hiroshi

    2016-01-01

    Insulin controls hepatic glucose production (HGP) and maintains glucose homeostasis through the direct action of hepatic insulin receptors, as well as the indirect action of insulin receptors in the central nervous system. Insulin acts on insulin receptors in the hypothalamic arcuate nucleus, activates ATP-sensitive potassium channels in a phosphoinositide 3-kinase (PI3K)-dependent manner, induces hyperpolarization of the hypothalamic neurons, and regulates HGP via the vagus nerve. In the liver, central insulin action augments IL-6 expression in Kupffer cells and activates STAT3 transcription factors in hepatocytes. Activated STAT3 suppresses the gene expression of gluconeogenic enzymes, thereby reducing HGP. It has become evident that nutrients such as glucose, fatty acids, and amino acids act upon the hypothalamus together with insulin, affecting HGP. On the other hand, HGP control by central insulin action is impeded in obesity and impeded by insulin resistance due to disturbance of PI3K signaling and inflammation in the hypothalamus or inhibition of STAT3 signaling in the liver. Although the mechanism of control of hepatic gluconeogenic gene expression by central insulin action is conserved across species, its importance in human glucose metabolism has not been made entirely clear and its elucidation is anticipated in the future.

  8. Synaptic Activity and Bioenergy Homeostasis: Implications in Brain Trauma and Neurodegenerative Diseases

    PubMed Central

    Khatri, Natasha; Man, Heng-Ye

    2013-01-01

    Powered by glucose metabolism, the brain is the most energy-demanding organ in our body. Adequate ATP production and regulation of the metabolic processes are essential for the maintenance of synaptic transmission and neuronal function. Glutamatergic synaptic activity utilizes the largest portion of bioenergy for synaptic events including neurotransmitter synthesis, vesicle recycling, and most importantly, the postsynaptic activities leading to channel activation and rebalancing of ionic gradients. Bioenergy homeostasis is coupled with synaptic function via activities of the sodium pumps, glutamate transporters, glucose transport, and mitochondria translocation. Energy insufficiency is sensed by the AMP-activated protein kinase (AMPK), a master metabolic regulator that stimulates the catalytic process to enhance energy production. A decline in energy supply and a disruption in bioenergy homeostasis play a critical role in multiple neuropathological conditions including ischemia, stroke, and neurodegenerative diseases including Alzheimer’s disease and traumatic brain injuries. PMID:24376435

  9. Impaired Glucose Metabolism in Mice Lacking the Tas1r3 Taste Receptor Gene.

    PubMed

    Murovets, Vladimir O; Bachmanov, Alexander A; Zolotarev, Vasiliy A

    2015-01-01

    The G-protein-coupled sweet taste receptor dimer T1R2/T1R3 is expressed in taste bud cells in the oral cavity. In recent years, its involvement in membrane glucose sensing was discovered in endocrine cells regulating glucose homeostasis. We investigated importance of extraorally expressed T1R3 taste receptor protein in age-dependent control of blood glucose homeostasis in vivo, using nonfasted mice with a targeted mutation of the Tas1r3 gene that encodes the T1R3 protein. Glucose and insulin tolerance tests, as well as behavioral tests measuring taste responses to sucrose solutions, were performed with C57BL/6ByJ (Tas1r3+/+) inbred mice bearing the wild-type allele and C57BL/6J-Tas1r3tm1Rfm mice lacking the entire Tas1r3 coding region and devoid of the T1R3 protein (Tas1r3-/-). Compared with Tas1r3+/+ mice, Tas1r3-/- mice lacked attraction to sucrose in brief-access licking tests, had diminished taste preferences for sucrose solutions in the two-bottle tests, and had reduced insulin sensitivity and tolerance to glucose administered intraperitoneally or intragastrically, which suggests that these effects are due to absence of T1R3. Impairment of glucose clearance in Tas1r3-/- mice was exacerbated with age after intraperitoneal but not intragastric administration of glucose, pointing to a compensatory role of extraoral T1R3-dependent mechanisms in offsetting age-dependent decline in regulation of glucose homeostasis. Incretin effects were similar in Tas1r3+/+ and Tas1r3-/- mice, which suggests that control of blood glucose clearance is associated with effects of extraoral T1R3 in tissues other than the gastrointestinal tract. Collectively, the obtained data demonstrate that the T1R3 receptor protein plays an important role in control of glucose homeostasis not only by regulating sugar intake but also via its extraoral function, probably in the pancreas and brain.

  10. A novel insulin receptor-binding protein from Momordica charantia enhances glucose uptake and glucose clearance in vitro and in vivo through triggering insulin receptor signaling pathway.

    PubMed

    Lo, Hsin-Yi; Ho, Tin-Yun; Li, Chia-Cheng; Chen, Jaw-Chyun; Liu, Jau-Jin; Hsiang, Chien-Yun

    2014-09-10

    Diabetes, a common metabolic disorder, is characterized by hyperglycemia. Insulin is the principal mediator of glucose homeostasis. In a previous study, we identified a trypsin inhibitor, named Momordica charantia insulin receptor (IR)-binding protein (mcIRBP) in this study, that might interact with IR. The physical and functional interactions between mcIRBP and IR were clearly analyzed in the present study. Photo-cross-linking coupled with mass spectrometry showed that three regions (17-21, 34-40, and 59-66 residues) located on mcIRBP physically interacted with leucine-rich repeat domain and cysteine-rich region of IR. IR-binding assay showed that the binding behavior of mcIRBP and insulin displayed a cooperative manner. After binding to IR, mcIRBP activated the kinase activity of IR by (5.87 ± 0.45)-fold, increased the amount of phospho-IR protein by (1.31 ± 0.03)-fold, affected phosphoinositide-3-kinase/Akt pathways, and consequently stimulated the uptake of glucose in 3T3-L1 cells by (1.36 ± 0.12)-fold. Intraperitoneal injection of 2.5 nmol/kg mcIRBP significantly decreased the blood glucose levels by 20.9 ± 3.2% and 10.8 ± 3.6% in normal and diabetic mice, respectively. Microarray analysis showed that mcIRBP affected genes involved in insulin signaling transduction pathway in mice. In conclusion, our findings suggest that mcIRBP is a novel IRBP that binds to sites different from the insulin-binding sites on IR and stimulates both the glucose uptake in cells and the glucose clearance in mice.

  11. The Destiny of Glucose from a MicroRNA Perspective

    PubMed Central

    Mirra, Paola; Nigro, Cecilia; Prevenzano, Immacolata; Leone, Alessia; Raciti, Gregory Alexander; Formisano, Pietro; Beguinot, Francesco; Miele, Claudia

    2018-01-01

    Glucose serves as a primary, and for some tissues the unique, fuel source in order to generate and maintain the biological functions. Hyperglycemia is a hallmark of type 2 diabetes and is the direct consequence of perturbations in the glucose homeostasis. Insulin resistance, referred to as a reduced response of target tissues to the hormone, contributes to the development of hyperglycemia. The molecular mechanisms responsible for the altered glucose homeostasis are numerous and not completely understood. MicroRNAs (miRNAs) are now recognized as regulators of the lipid and glucose metabolism and are involved in the onset of metabolic diseases. Indeed, these small non-coding RNA molecules operate in the RNA silencing and posttranscriptional regulation of gene expression and may modulate the levels of kinases and enzymes in the glucose metabolism. Therefore, a better characterization of the function of miRNAs and a deeper understanding of their role in disease may represent a fundamental step toward innovative treatments addressing the causes, not only the symptoms, of hyperglycemia, using approaches aimed at restoring either miRNAs or their specific targets. In this review, we outline the current understanding regarding the impact of miRNAs in the glucose metabolism and highlight the need for further research focused on altered key kinases and enzymes in metabolic diseases. PMID:29535681

  12. SIRT1 enhances glucose tolerance by potentiating brown adipose tissue function

    PubMed Central

    Boutant, Marie; Joffraud, Magali; Kulkarni, Sameer S.; García-Casarrubios, Ester; García-Roves, Pablo M.; Ratajczak, Joanna; Fernández-Marcos, Pablo J.; Valverde, Angela M.; Serrano, Manuel; Cantó, Carles

    2014-01-01

    Objective SIRT1 has been proposed to be a key signaling node linking changes in energy metabolism to transcriptional adaptations. Although SIRT1 overexpression is protective against diverse metabolic complications, especially in response to high-fat diets, studies aiming to understand the etiology of such benefits are scarce. Here, we aimed to identify the key tissues and mechanisms implicated in the beneficial effects of SIRT1 on glucose homeostasis. Methods We have used a mouse model of moderate SIRT1 overexpression, under the control of its natural promoter, to evaluate glucose homeostasis and thoroughly characterize how different tissues could influence insulin sensitivity. Results Mice with moderate overexpression of SIRT1 exhibit better glucose tolerance and insulin sensitivity even on a low fat diet. Euglycemic-hyperinsulinemic clamps and in-depth tissue analyses revealed that enhanced insulin sensitivity was achieved through a higher brown adipose tissue activity and was fully reversed by housing the mice at thermoneutrality. SIRT1 did not influence brown adipocyte differentiation, but dramatically enhanced the metabolic transcriptional responses to β3-adrenergic stimuli in differentiated adipocytes. Conclusions Our work demonstrates that SIRT1 improves glucose homeostasis by enhancing BAT function. This is not consequent to an alteration in the brown adipocyte differentiation process, but as a result of potentiating the response to β3-adrenergic stimuli. PMID:25685699

  13. Hypothalamic vitamin D improves glucose homeostasis and reduces weight

    USDA-ARS?s Scientific Manuscript database

    Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weigh...

  14. ATM Regulates Adipocyte Differentiation and Contributes to Glucose Homeostasis.

    PubMed

    Takagi, Masatoshi; Uno, Hatsume; Nishi, Rina; Sugimoto, Masataka; Hasegawa, Setsuko; Piao, Jinhua; Ihara, Norimasa; Kanai, Sayaka; Kakei, Saori; Tamura, Yoshifumi; Suganami, Takayoshi; Kamei, Yasutomi; Shimizu, Toshiaki; Yasuda, Akio; Ogawa, Yoshihiro; Mizutani, Shuki

    2015-02-11

    Ataxia-telangiectasia (A-T) patients occasionally develop diabetes mellitus. However, only limited attempts have been made to gain insight into the molecular mechanism of diabetes mellitus development in A-T patients. We found that Atm -/- mice were insulin resistant and possessed less subcutaneous adipose tissue as well as a lower level of serum adiponectin than Atm +/+ mice. Furthermore, in vitro studies revealed impaired adipocyte differentiation in Atm -/- cells caused by the lack of induction of C/EBPα and PPARγ, crucial transcription factors involved in adipocyte differentiation. Interestingly, ATM was activated by stimuli that induced differentiation, and the binding of ATM to C/EBPβ and p300 was involved in the transcriptional regulation of C/EBPα and adipocyte differentiation. Thus, our study sheds light on the poorly understood role of ATM in the pathogenesis of glucose intolerance in A-T patients and provides insight into the role of ATM in glucose metabolism. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Interferon beta overexpression attenuates adipose tissue inflammation and high-fat diet-induced obesity and maintains glucose homeostasis.

    PubMed

    Alsaggar, M; Mills, M; Liu, D

    2017-01-01

    The worldwide prevalence of obesity is increasing, raising health concerns regarding obesity-related complications. Chronic inflammation has been characterized as a major contributor to the development of obesity and obesity-associated metabolic disorders. The purpose of the current study is to assess whether the overexpression of interferon beta (IFNβ1), an immune-modulating cytokine, will attenuate high-fat diet-induced adipose inflammation and protect animals against obesity development. Using hydrodynamic gene transfer to elevate and sustain blood concentration of IFNβ1 in mice fed a high-fat diet, we showed that the overexpression of Ifnβ1 gene markedly suppressed immune cell infiltration into adipose tissue, and attenuated production of pro-inflammatory cytokines. Systemically, IFNβ1 blocked adipose tissue expansion and body weight gain, independent of food intake. Possible browning of white adipose tissue might also contribute to blockade of weight gain. More importantly, IFNβ1 improved insulin sensitivity and glucose homeostasis. These results suggest that targeting inflammation represents a practical strategy to block the development of obesity and its related pathologies. In addition, IFNβ1-based therapies have promising potential for clinical applications for the prevention and treatment of various inflammation-driven pathologies.

  16. Effects of exercise training alone vs a combined exercise and nutritional lifestyle intervention on glucose homeostasis in prediabetic individuals: a randomised controlled trial.

    PubMed

    Slentz, Cris A; Bateman, Lori A; Willis, Leslie H; Granville, Esther O; Piner, Lucy W; Samsa, Gregory P; Setji, Tracy L; Muehlbauer, Michael J; Huffman, Kim M; Bales, Connie W; Kraus, William E

    2016-10-01

    Although the Diabetes Prevention Program (DPP) established lifestyle changes (diet, exercise and weight loss) as the 'gold standard' preventive therapy for diabetes, the relative contribution of exercise alone to the overall utility of the combined diet and exercise effect of DPP is unknown; furthermore, the optimal intensity of exercise for preventing progression to diabetes remains very controversial. To establish clinical efficacy, we undertook a study (2009 to 2013) to determine: how much of the effect on measures of glucose homeostasis of a 6 month programme modelled after the first 6 months of the DPP is due to exercise alone; whether moderate- or vigorous-intensity exercise is better for improving glucose homeostasis; and to what extent amount of exercise is a contributor to improving glucose control. The primary outcome was improvement in fasting plasma glucose, with improvement in plasma glucose AUC response to an OGTT as the major secondary outcome. The trial was a parallel clinical trial. Sedentary, non-smokers who were 45-75 year old adults (n = 237) with elevated fasting glucose (5.28-6.94 mmol/l) but without cardiovascular disease, uncontrolled hypertension, or diabetes, from the Durham area, were studied at Duke University. They were randomised into one of four 6 month interventions: (1) low amount (42 kJ kg body weight(-1) week(-1) [KKW])/moderate intensity: equivalent of expending 42 KKW (e.g. walking ∼16 km [8.6 miles] per week) with moderate-intensity (50% [Formula: see text]) exercise; (2) high amount (67 KKW)/moderate intensity: equivalent of expending 67 KKW (∼22.3 km [13.8 miles] per week) with moderate-intensity exercise; (3) high amount (67 KKW)/vigorous intensity: equivalent to group 2, but with vigorous-intensity exercise (75% [Formula: see text]); and (4) diet + 42 KKW moderate intensity: same as group 1 but with diet and weight loss (7%) to mimic the first 6 months of the DPP. Computer-generated randomisation lists

  17. Effects of the Soluble Fiber Complex PolyGlycopleX on Glucose Homeostasis and Body Weight in Young Zucker Diabetic Rats.

    PubMed

    Grover, Gary James; Koetzner, Lee; Wicks, Joan; Gahler, Roland J; Lyon, Michael R; Reimer, Raylene A; Wood, Simon

    2011-01-01

    Dietary fiber can reduce insulin resistance, body weight, and hyperlipidemia depending on fiber type, water solubility, and viscosity. PolyGlycopleX(®) (PGX(®)) is a natural, novel water soluble, non-starch polysaccharide complex that with water forms a highly viscous gel compared to other naturally occurring dietary fiber. We determined the effect of dietary PGX(®) vs. cellulose and inulin on the early development of insulin resistance, body weight, hyperlipidemia, and glycemia-induced tissue damage in young Zucker diabetic rats (ZDFs) in fasted and non-fasted states. ZDFs (5 weeks old) were fed a diet containing 5% (wgt/wgt) cellulose, inulin, or PGX(®) for 8 weeks. Body weight, lipids, insulin, and glucose levels were determined throughout the study and homeostasis model assessment (HOMA) was used to measure insulin sensitivity throughout the study in fasted animals. At study termination, insulin sensitivity (oral glucose tolerance test, OGTT) and kidney, liver, and pancreatic histopathology were determined. Body weight and food intake were significantly reduced by PGX(®) vs. inulin and cellulose. Serum insulin in fasted and non-fasted states was significantly reduced by PGX(®) as was non-fasted blood glucose. Insulin resistance, measured as a HOMA score, was significantly reduced by PGX(®) in weeks 5 through 8 as well as terminal OGTT scores in fed and fasted states. Serum total cholesterol was also significantly reduced by PGX(®). PGX(®) significantly reduced histological kidney and hepatic damage in addition to reduced hepatic steatosis and cholestasis. A greater mass of pancreatic β-cells was found in the PGX(®) group. PGX(®) therefore may be a useful dietary additive in the control of the development of the early development of the metabolic syndrome.

  18. Plasma Insulin Levels and Hypoglycemia Affect Subcutaneous Interstitial Glucose Concentration.

    PubMed

    Moscardó, Vanessa; Bondia, Jorge; Ampudia-Blasco, Francisco J; Fanelli, Carmine G; Lucidi, Paola; Rossetti, Paolo

    2018-04-01

    Continuous glucose monitoring (CGM) accuracy during hypoglycemia is suboptimal. This might be partly explained by insulin or hypoglycemia-induced changes in the plasma interstitial subcutaneous (SC) fluid glucose gradient. The aim of the present study was to assess the role of plasma insulin (PI) and hypoglycemia itself in the plasma and interstitial SC fluid glucose concentration in patients with type 1 diabetes mellitus. Eleven subjects with type 1 diabetes (age 36.5 ± 9.1 years, HbA 1c 7.9 ± 0.4% [62.8 ± 2.02 mmol/mol]; mean ± standard deviation) were evaluated under hyperinsulinemic euglycemia and hypoglycemia. Each subject underwent two randomized crossover clamps with either a primed 0.3 (low insulin) or 1 mU/(kg·min) (high insulin) insulin infusion. The raw CGM signal was normalized with median preclamp values to obtain a standardized measure of the interstitial glucose (IG) concentration before statistical analysis. The mean PI concentration was greater in high insulin studies (HISs) versus low insulin studies (LISs) (412.89 ± 13.63 vs. 177.22 ± 10.05 pmol/L). During hypoglycemia, glucagon, adrenaline, free fatty acids, glycerol, and beta-OH-butyrate were higher in the LIS (P < 0.0001). Likewise, the IG concentration was significantly different (P < 0.0001). This was due to lower IG concentration than plasma glucose (PG) concentration during the euglycemic hyperinsulinemic phases in the HIS. In contrast, no difference was observed during hypoglycemia. This was the result of an unchanged PG/IG gradient during the entire LIS, while in the HIS, this gradient increased during the hyperinsulinemic euglycemia phase. Both PI levels and hypoglycemia affect the relationship between IG and PG concentration. ClinicalTrials.gov Identifier: NCT01714895.

  19. NO3-/NH4+ ratios affect nutritional homeostasis and production of Tanzania guinea grass under Cu toxicity.

    PubMed

    de Souza Junior, João Cardoso; Nogueirol, Roberta Corrêa; Monteiro, Francisco Antonio

    2018-05-01

    Nitrogen (N) can alleviate metal toxicity. However, as of yet, there have been no studies showing the efficacy of NO 3 - /NH 4 + in mitigating Cu toxicity. The objective of this study was to evaluate the Cu toxicity on the nutritional and productive attributes of Panicum maximum cv. Tanzania as well as the role of NO 3 - and NH 4 + ratios in nutritional homeostasis. The experiment was conducted using 3 × 4 factorial treatments arranged in a randomized complete block design with three replicates. The treatments were three NO 3 - /NH 4 + ratios (100/0, 70/30, and 50/50) and four Cu rates (0.3, 250, 500, and 1000 μmol L -1 ) in nutrient solution. Copper concentrations in the diagnostic leaves (DL) were highest in plants grown under 70/30 NO 3 - /NH 4 + ratios and a Cu rate of 1000 μmol L -1 . In this combination, it was observed that DL had higher concentrations of NH 4 + , greater glutamine synthetase activity, lower chlorophyll concentration (SPAD value), and lower shoot dry mass, suggesting high disorders of nutritional homeostasis. Plants receiving N in the form of NO 3 - and 1000 Cu μmol L -1 showed that DL had lower concentrations of Cu, higher concentration of chlorophyll, higher NO 3 - concentration, higher nitrate reductase activity, and higher NO 3 - accumulation in the roots, suggesting a reduction in disorders of nutritional homeostasis. The disorders on mineral uptake, N assimilation, and biomass production caused by Cu toxicity are shown to be affected by NO 3 - /NH 4 + ratios, and N supply via NO 3 - allowed for better homeostasis of the forage grass.

  20. Evaluation of the Genetic and Nutritional Control of Obesity and Type 2 Diabetes in a Novel Mouse Model on Chromosome 7: An Insight into Insulin Signaling and Glucose Homeostasis

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

    Nelson, S.; Dhar, M.

    Obesity is the main cause of type 2 diabetes, accounting for 90-95% of all diabetes cases in the US. Human obesity is a complex trait and can be studied using appropriate mouse models. A novel polygenic mouse model for studying the genetic and environmental contributions to and the physiological ramifications of obesity and related phenotypes is found in specific lines of mice bred and maintained at Oak Ridge National Laboratory. Heterozygous mice with a maternally inherited copy of two radiation-induced deletions in the p region of mouse chromosome 7, p23DFioD and p30PUb, have significantly greater body fat and show hyperinsulinemiamore » compared to the wild-type. A single gene, Atp10c, maps to this critical region and codes for a putative aminophospholipid translocase. Biochemical and molecular studies were initiated to gain insight into obesity and glucose homeostasis in these animals and to study the biological role of Atp10c in creating these phenotypes. Glucose and insulin tolerance tests were standardized for the heterozygous p23DFioD and control mice on a custom-made diet containing 20% protein, 70% carbohydrate, and 10% fat (kcal). Atp10c expression profiles were also generated using Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR). Heterozygous p23DFioD animals showed insulin resistance after receiving a dose of either 0.375 or 0.75 U/kg Illetin R insulin. RT-PCR data also shows differences in Atp10c expression in the mutants versus control mice. Using these standardized biochemical assays, future studies will further the understanding of genetic and nutritional controls of glucose homeostasis and obesity in animal models and subsequently in human populations.« less

  1. Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children.

    PubMed

    Butte, Nancy F; Voruganti, V Saroja; Cole, Shelley A; Haack, Karin; Comuzzie, Anthony G; Muzny, Donna M; Wheeler, David A; Chang, Kyle; Hawes, Alicia; Gibbs, Richard A

    2011-09-22

    Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5' and 3' flanking regions of IRS2 (∼14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3'-UTR, and 2 in the 5'-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001-0.009) were associated with obesity-related traits (P = 0.01-0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P = 0.77-0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children.

  2. Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children

    PubMed Central

    Voruganti, V. Saroja; Cole, Shelley A.; Haack, Karin; Comuzzie, Anthony G.; Muzny, Donna M.; Wheeler, David A.; Chang, Kyle; Hawes, Alicia; Gibbs, Richard A.

    2011-01-01

    Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5′ and 3′ flanking regions of IRS2 (∼14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3′-UTR, and 2 in the 5′-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001–0.009) were associated with obesity-related traits (P = 0.01–0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P = 0.77–0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children. PMID:21771880

  3. Olanzapine and aripiprazole differentially affect glucose uptake and energy metabolism in human mononuclear blood cells.

    PubMed

    Stapel, Britta; Kotsiari, Alexandra; Scherr, Michaela; Hilfiker-Kleiner, Denise; Bleich, Stefan; Frieling, Helge; Kahl, Kai G

    2017-05-01

    The use of antipsychotics carries the risk of metabolic side effects, such as weight gain and new onset type-2 diabetes mellitus. The mechanisms of the observed metabolic alterations are not fully understood. We compared the effects of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (aripiprazole), on glucose metabolism. Primary human peripheral blood mononuclear cells (PBMC) were isolated and stimulated with olanzapine or aripiprazole for 72 h. Cellular glucose uptake was analyzed in vitro by 18F-FDG uptake. Further measurements comprised mRNA expression of glucose transporter (GLUT) 1 and 3, GLUT1 protein expression, DNA methylation of GLUT1 promoter region, and proteins involved in downstream glucometabolic processes. We observed a 2-fold increase in glucose uptake after stimulation with aripiprazole. In contrast, olanzapine stimulation decreased glucose uptake by 40%, accompanied by downregulation of the cellular energy sensor AMP activated protein kinase (AMPK). GLUT1 protein expression increased, GLUT1 mRNA expression decreased, and GLUT1 promoter was hypermethylated with both antipsychotics. Pyruvat-dehydrogenase (PDH) complex activity decreased with olanzapine only. Our findings suggest that the atypical antipsychotics olanzapine and aripiprazole differentially affect energy metabolism in PBMC. The observed decrease in glucose uptake in olanzapine stimulated PBMC, accompanied by decreased PDH point to a worsening in cellular energy metabolism not compensated by AMKP upregulation. In contrast, aripiprazole stimulation lead to increased glucose uptake, while not affecting PDH complex expression. The observed differences may be involved in the different metabolic profiles observed in aripiprazole and olanzapine treated patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Perinatal Exposure to Perfluorooctane Sulfonate Affects Glucose Metabolism in Adult Offspring

    PubMed Central

    Wan, Hin T.; Zhao, Yin G.; Leung, Pik Y.; Wong, Chris K. C.

    2014-01-01

    Perfluoroalkyl acids (PFAAs) are globally present in the environment and are widely distributed in human populations and wildlife. The chemicals are ubiquitous in human body fluids and have a long serum elimination half-life. The notorious member of PFAAs, perfluorooctane sulfonate (PFOS) is prioritized as a global concerning chemical at the Stockholm Convention in 2009, due to its harmful effects in mammals and aquatic organisms. PFOS is known to affect lipid metabolism in adults and was found to be able to cross human placenta. However the effects of in utero exposure to the susceptibility of metabolic disorders in offspring have not yet been elucidated. In this study, pregnant CD-1 mice (F0) were fed with 0, 0.3 or 3 mg PFOS/kg body weight/day in corn oil by oral gavage daily throughout gestational and lactation periods. We investigated the immediate effects of perinatal exposure to PFOS on glucose metabolism in both maternal and offspring after weaning (PND 21). To determine if the perinatal exposure predisposes the risk for metabolic disorder to the offspring, weaned animals without further PFOS exposure, were fed with either standard or high-fat diet until PND 63. Fasting glucose and insulin levels were measured while HOMA-IR index and glucose AUCs were reported. Our data illustrated the first time the effects of the environmental equivalent dose of PFOS exposure on the disturbance of glucose metabolism in F1 pups and F1 adults at PND 21 and 63, respectively. Although the biological effects of PFOS on the elevated levels of fasting serum glucose and insulin levels were observed in both pups and adults of F1, the phenotypes of insulin resistance and glucose intolerance were only evident in the F1 adults. The effects were exacerbated under HFD, highlighting the synergistic action at postnatal growth on the development of metabolic disorders. PMID:24498028

  5. Brain-lung crosstalk in critical care: how protective mechanical ventilation can affect the brain homeostasis.

    PubMed

    Mazzeo, A T; Fanelli, V; Mascia, L

    2013-03-01

    The maintenance of brain homeostasis against multiple internal and external challenges occurring during the acute phase of acute brain injury may be influenced by critical care management, especially in its respiratory, hemodynamic and metabolic components. The occurrence of acute lung injury represents the most frequent extracranial complication after brain injury and deserves special attention in daily practice as optimal ventilatory strategy for patients with acute brain and lung injury are potentially in conflict. Protecting the lung while protecting the brain is thus a new target in the modern neurointensive care. This article discusses the essentials of brain-lung crosstalk and focuses on how mechanical ventilation may exert an active role in the process of maintaining or treatening brain homeostasis after acute brain injury, highlighting the following points: 1) the role of inflammation as common pathomechanism of both acute lung and brain injury; 2) the recognition of ventilatory induced lung injury as determinant of systemic inflammation affecting distal organs, included the brain; 3) the possible implication of protective mechanical ventilation strategy on the patient with an acute brain injury as an undiscovered area of research in both experimental and clinical settings.

  6. Emodin Regulates Glucose Utilization by Activating AMP-activated Protein Kinase*

    PubMed Central

    Song, Parkyong; Kim, Jong Hyun; Ghim, Jaewang; Yoon, Jong Hyuk; Lee, Areum; Kwon, Yonghoon; Hyun, Hyunjung; Moon, Hyo-Youl; Choi, Hueng-Sik; Berggren, Per-Olof; Suh, Pann-Ghill; Ryu, Sung Ho

    2013-01-01

    AMP-activated protein kinase has been described as a key signaling protein that can regulate energy homeostasis. Here, we aimed to characterize novel AMP-activated kinase (AMPK)-activating compounds that have a much lower effective concentration than metformin. As a result, emodin, a natural anthraquinone derivative, was shown to stimulate AMPK activity in skeletal muscle and liver cells. Emodin enhanced GLUT4 translocation and [14C]glucose uptake into the myotube in an AMPK-dependent manner. Also, emodin inhibited glucose production by suppressing the expression of key gluconeogenic genes, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, in hepatocytes. Furthermore, we found that emodin can activate AMPK by inhibiting mitochondrial respiratory complex I activity, leading to increased reactive oxygen species and Ca2+/calmodulin-dependent protein kinase kinase activity. Finally, we confirmed that a single dose administration of emodin significantly decreased the fasting plasma glucose levels and improved glucose tolerance in C57Bl/6J mice. Increased insulin sensitivity was also confirmed after daily injection of emodin for 8 days using an insulin tolerance test and insulin-stimulated PI3K phosphorylation in wild type and high fat diet-induced diabetic mouse models. Our study suggests that emodin regulates glucose homeostasis in vivo by AMPK activation and that this may represent a novel therapeutic principle in the treatment of type 2 diabetic models. PMID:23303186

  7. Double blockade of angiotensin II (AT1)-receptors and ACE does not improve weight gain and glucose homeostasis better than single-drug treatments in obese rats

    PubMed Central

    Miesel, Anja; Müller-Fielitz, Helge; Jöhren, Olaf; Vogt, Florian M; Raasch, Walter

    2012-01-01

    BACKGROUND AND PURPOSE Combination therapies are becoming increasingly important for the treatment of high blood pressure. Little is known about whether double blockade of angiotensin II (AT1) receptors and angiotensin-converting enzyme (ACE) exert synergistic metabolic effects. EXPERIMENTAL APPROACH Spontaneously hypertensive rats were allowed to choose between palatable chocolate bars and standard chow and were simultaneously treated with the AT1 blocker telmisartan (8 mg·kgbw−1·day−1), the ACE inhibitor ramipril (4 mg·kgbw−1·day−1) or a combination of the two (8 + 4 mg·kgbw−1·day−1) for 12 weeks. KEY RESULTS Although food-dependent energy intake was increased by telmisartan and telmisartan + ramipril compared with ramipril or controls, body weight gain, abundance of fat and plasma leptin levels were decreased. Increased insulin levels in response to an oral glucose tolerance test were comparably attenuated by telmisartan and telmisartan + ramipril, but not by ramipril. During an insulin tolerance test, glucose utilization was equally as effectively improved by telmisartan and telmisartan + ramipril. In response to a stress test, ACTH, corticosterone and glucose increased in controls. These stress reactions were attenuated by telmisartan and telmisartan + ramipril. CONCLUSIONS AND IMPLICATIONS The combination of telmisartan + ramipril was no more efficacious in regulating body weight and glucose homeostasis than telmisartan alone. However, telmisartan was more effective than ramipril in improving metabolic parameters and in reducing body weight. The association between the decrease in stress responses and the diminished glucose levels after stress supports our hypothesis that the ability of telmisartan, as an AT1 receptor blocker, to alleviate stress reactions may contribute to its hypoglycaemic actions. PMID:22014027

  8. Effect of blood glucose level on acute stress response of grass carp Ctenopharyngodon idella.

    PubMed

    Jiang, Danli; Wu, Yubo; Huang, Di; Ren, Xing; Wang, Yan

    2017-10-01

    Stress has a considerable impact on welfare and productivity of fish, and blood glucose level of fish may be a factor modulating stress response. This study evaluated the effect of blood glucose level and handling on acute stress response of grass carp Ctenopharyngodon idella. Fish were intraperitoneally injected with glucose at 0, 0.2, 0.5, and 1.0 mg g -1 body mass (BM) and then were exposed to handling for 5 min. Glucose injection resulted in increase of plasma glucose level and liver glycogen content and decrease of plasma lactate level. Handling resulted in increase of plasma levels of cortisol, glucose, and lactate and plasma lactic dehydrogenase (LDH) activity and decrease of liver glycogen content. At 1 h post-stress, the plasma cortisol level was lower in the stressed fish injected with glucose at 0.5 mg g -1 BM than the stressed fish injected with glucose at 0, 0.2, and 1.0 mg g -1 BM. No significant differences were found in the activities of phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate kinase (PK) in the liver between the stressed and unstressed fish, regardless of the dose of glucose injection. At 1 h post-stress, the liver glucose-6-phosphatase (G6Pase) activity was higher in the fish without glucose injection than in the fish injected with glucose. This study reveals that blood glucose level can affect stress response of grass carp by modulating cortisol release and glucose homeostasis through glycogen metabolism and gluconeogenesis in the liver.

  9. Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism

    PubMed Central

    Dirckx, Naomi; Tower, Robert J.; Mercken, Evi M.; Moreau-Triby, Caroline; Breugelmans, Tom; Nefyodova, Elena; Cardoen, Ruben; Mathieu, Chantal; Van der Schueren, Bart; Confavreux, Cyrille B.; Clemens, Thomas L.

    2018-01-01

    The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel–Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin. In vitro and in vivo data indicated that Vhl-deficient osteoblasts displayed massively increased glucose uptake and glycolysis associated with upregulated HIF-target gene expression, resembling the Warburg effect that typifies cancer cells. Overall, the glucose consumption by the skeleton was increased in the mutant mice, as revealed by 18F-FDG radioactive tracer experiments. Moreover, the glycemia levels correlated inversely with the level of skeletal glucose uptake, and pharmacological treatment with the glycolysis inhibitor dichloroacetate (DCA), which restored glucose metabolism in Vhl-deficient osteogenic cells in vitro, prevented the development of the systemic metabolic phenotype in the mutant mice. Altogether, these findings reveal a novel link between cellular glucose metabolism in osteoblasts and whole-body glucose homeostasis, controlled by local hypoxia signaling in the skeleton. PMID:29431735

  10. Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats.

    PubMed

    Lubaczeuski, C; Balbo, S L; Ribeiro, R A; Vettorazzi, J F; Santos-Silva, J C; Carneiro, E M; Bonfleur, M L

    2015-05-01

    The parasympathetic nervous system is important for β-cell secretion and mass regulation. Here, we characterized involvement of the vagus nerve in pancreatic β-cell morphofunctional regulation and body nutrient homeostasis in 90-day-old monosodium glutamate (MSG)-obese rats. Male newborn Wistar rats received MSG (4 g/kg body weight) or saline [control (CTL) group] during the first 5 days of life. At 30 days of age, both groups of rats were submitted to sham-surgery (CTL and MSG groups) or subdiaphragmatic vagotomy (Cvag and Mvag groups). The 90-day-old MSG rats presented obesity, hyperinsulinemia, insulin resistance, and hypertriglyceridemia. Their pancreatic islets hypersecreted insulin in response to glucose but did not increase insulin release upon carbachol (Cch) stimulus, despite a higher intracellular Ca(2+) mobilization. Furthermore, while the pancreas weight was 34% lower in MSG rats, no alteration in islet and β-cell mass was observed. However, in the MSG pancreas, increases of 51% and 55% were observed in the total islet and β-cell area/pancreas section, respectively. Also, the β-cell number per β-cell area was 19% higher in MSG rat pancreas than in CTL pancreas. Vagotomy prevented obesity, reducing 25% of body fat stores and ameliorated glucose homeostasis in Mvag rats. Mvag islets demonstrated partially reduced insulin secretion in response to 11.1 mM glucose and presented normalization of Cch-induced Ca(2+) mobilization and insulin release. All morphometric parameters were similar among Mvag and CTL rat pancreases. Therefore, the higher insulin release in MSG rats was associated with greater β-cell/islet numbers and not due to hypertrophy. Vagotomy improved whole body nutrient homeostasis and endocrine pancreatic morphofunction in Mvag rats.

  11. Oocyte aging-induced Neuronatin (NNAT) hypermethylation affects oocyte quality by impairing glucose transport in porcine.

    PubMed

    Gao, Ying-Ying; Chen, Li; Wang, Tao; Nie, Zheng-Wen; Zhang, Xia; Miao, Yi-Liang

    2016-10-26

    DNA methylation plays important roles in regulating many physiological behaviors; however, few studies were focused on the changes of DNA methylation during oocyte aging. Early studies showed that some imprinted genes' DNA methylation had been changed in aged mouse oocytes. In this study, we used porcine oocytes to test the hypothesis that oocyte aging would alter DNA methylation pattern of genes and disturb their expression in age oocytes, which affected the developmental potential of oocytes. We compared several different types of genes and found that the expression and DNA methylation of Neuronatin (NNAT) were disturbed in aged oocytes significantly. Additional experiments demonstrated that glucose transport was impaired in aged oocytes and injection of NNAT antibody into fresh oocytes led to the same effects on glucose transport. These results suggest that the expression of NNAT was declined by elevating DNA methylation, which affected oocyte quality by decreasing the ability of glucose transport in aged oocytes.

  12. Variants in glucose- and circadian rhythm-related genes affect the response of energy expenditure to weight-loss diets: the POUNDS LOST Trial.

    PubMed

    Mirzaei, Khadijeh; Xu, Min; Qi, Qibin; de Jonge, Lilian; Bray, George A; Sacks, Frank; Qi, Lu

    2014-02-01

    Circadian rhythm has been shown to be related to glucose metabolism and risk of diabetes, probably through effects on energy balance. Recent genome-wide association studies identified variants in circadian rhythm-related genes (CRY2 and MTNR1B) associated with glucose homeostasis. We tested whether CRY2 and MTNR1B genotypes affected changes in measures of energy expenditure in response to a weight-loss diet intervention in a 2-y randomized clinical trial, the POUNDS (Preventing Overweight Using Novel Dietary Strategies) LOST Trial. The variants CRY2 rs11605924 (n = 721) and MTNR1B rs10830963 (n = 722) were genotyped in overweight or obese adults who were randomly assigned to 1 of 4 weight-loss diets that differed in their proportions of macronutrients. Respiratory quotient (RQ) and resting metabolic rate (RMR) were measured. By 2 y of diet intervention, the A allele of CRY2 rs11605924 was significantly associated with a greater reduction in RQ (P = 0.03) and a greater increase in RMR and RMR/kg (both P = 0.04). The G allele of MTNR1B rs10830963 was significantly associated with a greater increase in RQ (P = 0.01) but was not related to changes in RMR and RMR/kg. In addition, we found significant gene-diet fat interactions for both CRY2 (P-interaction = 0.02) and MTNR1B (P-interaction < 0.001) in relation to 2-y changes in RQ. Our data indicate that variants in the circadian-related genes CRY2 and MTNR1B may affect long-term changes in energy expenditure, and dietary fat intake may modify the genetic effects. This trial was registered at www.clinicaltrials.gov as NCT00072995.

  13. Lower Maternal Body Condition During Pregnancy Affects Skeletal Muscle Structure and Glut-4 Protein Levels But Not Glucose Tolerance in Mature Adult Sheep

    PubMed Central

    Costello, Paula M.; Hollis, Lisa J.; Cripps, Roselle L.; Bearpark, Natasha; Patel, Harnish P.; Sayer, Avan Aihie; Cooper, Cyrus; Hanson, Mark A.; Ozanne, Susan E.

    2013-01-01

    Suboptimal maternal nutrition and body composition are implicated in metabolic disease risk in adult offspring. We hypothesized that modest disruption of glucose homeostasis previously observed in young adult sheep offspring from ewes of a lower body condition score (BCS) would deteriorate with age, due to changes in skeletal muscle structure and insulin signaling mechanisms. Ewes were fed to achieve a lower (LBCS, n = 10) or higher (HBCS, n = 14) BCS before and during pregnancy. Baseline plasma glucose, glucose tolerance and basal glucose uptake into isolated muscle strips were similar in male offspring at 210 ± 4 weeks. Vastus total myofiber density (HBCS, 343 ± 15; LBCS, 294 ± 14 fibers/mm2, P < .05) and fast myofiber density (HBCS, 226 ± 10; LBCS 194 ± 10 fibers/mm2, P < .05), capillary to myofiber ratio (HBCS, 1.5 ± 0.1; LBCS 1.2 ± 0.1 capillary:myofiber, P < .05) were lower in LBCS offspring. Vastus protein levels of Akt1 were lower (83% ± 7% of HBCS, P < .05), and total glucose transporter 4 was increased (157% ± 6% of HBCS, P < .001) in LBCS offspring, Despite the reduction in total myofiber density in LBCS offspring, glucose tolerance was normal in mature adult life. However, such adaptations may lead to complications in metabolic control in an overabundant postnatal nutrient environment. PMID:23420826

  14. Maternal Nutrition during Pregnancy Affects Testicular and Bone Development, Glucose Metabolism and Response to Overnutrition in Weaned Horses Up to Two Years

    PubMed Central

    Mendoza, Luis; Peugnet, Pauline; Dubois, Cédric; Dahirel, Michèle; Lejeune, Jean-Philippe; Caudron, Isabelle; Guenon, Isabelle; Camous, Sylvaine; Tarrade, Anne; Wimel, Laurence; Serteyn, Didier; Bouraima-Lelong, Hélène; Chavatte-Palmer, Pascale

    2017-01-01

    Introduction Pregnant mares and post-weaning foals are often fed concentrates rich in soluble carbohydrates, together with forage. Recent studies suggest that the use of concentrates is linked to alterations of metabolism and the development of osteochondrosis in foals. The aim of this study was to determine if broodmare diet during gestation affects metabolism, osteoarticular status and growth of yearlings overfed from 20 to 24 months of age and/or sexual maturity in prepubertal colts. Material and methods Twenty-four saddlebred mares were fed forage only (n = 12, group F) or cracked barley and forage (n = 12, group B) from mid-gestation until foaling. Colts were gelded at 12 months of age. Between 20 and 24 months of age, all yearlings were overfed (+140% of requirements) using an automatic concentrate feeder. Offspring were monitored for growth between 6 and 24 months of age, glucose homeostasis was evaluated via modified frequently sampled intra veinous glucose tolerance test (FSIGT) at 19 and 24 months of age and osteoarticular status was investigated using radiographic examinations at 24 months of age. The structure and function of testicles from prepubertal colts were analyzed using stereology and RT-qPCR. Results Post-weaning weight growth was not different between groups. Testicular maturation was delayed in F colts compared to B colts at 12 months of age. From 19 months of age, the cannon bone was wider in B vs F yearlings. F yearlings were more insulin resistant at 19 months compared to B yearlings but B yearlings were affected more severely by overnutrition with reduced insulin sensitivity. The osteoarticular status at 24 months of age was not different between groups. Conclusion In conclusion, nutritional management of the pregnant broodmare and the growing foal may affect sexual maturity of colts and the metabolism of foals until 24 months of age. These effects may be deleterious for reproductive and sportive performances in older horses. PMID

  15. Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model

    PubMed Central

    Kim, Chea-Ha

    2015-01-01

    We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA-pretreated group was higher than in the saline-pretreated group. The up-regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up-regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level. PMID:25792867

  16. Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model.

    PubMed

    Kim, Chea-Ha; Hong, Jae-Seung

    2015-03-01

    We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA-pretreated group was higher than in the saline-pretreated group. The up-regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up-regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level.

  17. Apelin targets gut contraction to control glucose metabolism via the brain

    PubMed Central

    Fournel, Audren; Drougard, Anne; Duparc, Thibaut; Marlin, Alysson; Brierley, Stuart M; Castro, Joel; Le-Gonidec, Sophie; Masri, Bernard; Colom, André; Lucas, Alexandre; Rousset, Perrine; Cenac, Nicolas; Vergnolle, Nathalie; Valet, Philippe; Cani, Patrice D; Knauf, Claude

    2017-01-01

    Objective The gut–brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. Design We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. Results In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. Conclusions Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders. PMID:26565000

  18. Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice.

    PubMed

    Ma, Xiaojun; Lin, Yuezhen; Lin, Ligen; Qin, Guijun; Pereira, Fred A; Haymond, Morey W; Butte, Nancy F; Sun, Yuxiang

    2012-08-01

    The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ob mice (Ghsr(-/-):ob/ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ob mice upregulated negative β-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive β-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic β-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ob mice did not affect the islet size; the average islet size of Ghsr(-/-):ob/ob mice is similar to that of ob/ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway.

  19. CCCTC-binding Factor Mediates Effects of Glucose On Beta Cell Survival

    PubMed Central

    Tsui, Shanli; Dai, Wei; Lu, Luo

    2013-01-01

    Objectives Pancreatic islet β-cell survival is important in regulating insulin activities and maintaining glucose homeostasis. Recently, Pax6 has been shown to be essential for many vital functions in β-cells, though the molecular mechanisms of its regulation in β-cells remain unclear. The present study investigates the novel effects of glucose- and insulin-induced CTCF activity on Pax6 gene expression as well as the subsequent effects of insulin-activated signaling pathways on β-cell proliferation. Material and methods Pancreatic β-TC-1-6 cells were cultured in DMEM medium and stimulated with high concentrations of glucose (5 to 125 mM) and cell viability was assessed by MTT assays. The effect of CTCF on Pax6 was evaluated in high glucose-induced and CCCTC-binding Factor (CTCF)/Erk suppressed cells by promoter reporter and Western analyses. Results Increases in glucose and insulin concentrations up-regulated CTCF and consequently down-regulated Pax6 in β-cell survival and proliferation. Knocking-down CTCF directly affected Pax6 transcription through CTCF binding and blocked the response to glucose. Altered Erk activity mediated the effects of CTCF on controlling Pax6 expression, which partially regulates β-cell proliferation. Conclusions CTCF functions as a molecular mediator between insulin-induced upstream Erk signaling and Pax6 expression in pancreatic β-cells. This pathway may contribute to regulation of β-cell survival and proliferation. PMID:24354619

  20. Titanium dioxide nanoparticle exposure alters metabolic homeostasis in a cell culture model of the intestinal epithelium and Drosophila melanogaster.

    PubMed

    Richter, Jonathan W; Shull, Gabriella M; Fountain, John H; Guo, Zhongyuan; Musselman, Laura P; Fiumera, Anthony C; Mahler, Gretchen J

    2018-06-01

    Nanosized titanium dioxide (TiO 2 ) is a common additive in food and cosmetic products. The goal of this study was to investigate if TiO 2 nanoparticles affect intestinal epithelial tissues, normal intestinal function, or metabolic homeostasis using in vitro and in vivo methods. An in vitro model of intestinal epithelial tissue was created by seeding co-cultures of Caco-2 and HT29-MTX cells on a Transwell permeable support. These experiments were repeated with monolayers that had been cultured with the beneficial commensal bacteria Lactobacillus rhamnosus GG (L. rhamnosus). Glucose uptake and transport in the presence of TiO 2 nanoparticles was assessed using fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG). When the cell monolayers were exposed to physiologically relevant doses of TiO 2 , a statistically significant reduction in glucose transport was observed. These differences in glucose absorption were eliminated in the presence of beneficial bacteria. The decrease in glucose absorption was caused by damage to intestinal microvilli, which decreased the surface area available for absorption. Damage to microvilli was ameliorated in the presence of L. rhamnosus. Complimentary studies in Drosophila melanogaster showed that TiO 2 ingestion resulted in decreased body size and glucose content. The results suggest that TiO 2 nanoparticles alter glucose transport across the intestinal epithelium, and that TiO 2 nanoparticle ingestion may have physiological consequences.

  1. Basic Fibroblast Growth Factor Influences Epidermal Homeostasis of Living Skin Equivalents through Affecting Fibroblast Phenotypes and Functions.

    PubMed

    Yang, Lujun; Zhang, Dangui; Wu, Hongjuan; Xie, Sitian; Zhang, Mingjun; Zhang, Bingna; Tang, Shijie

    2018-05-30

    To elucidate the possible mechanisms of how basic fibroblast growth factor (bFGF) influences epidermal homeostasis in a living skin equivalent (LSE) model. Several wound healing-related growth factors were analyzed at protein and mRNA levels for dermal fibroblasts of induced alpha-smooth muscle actin (α-SMA)-positive or α-SMA-negative phenotypes. During culturing an LSE model by seeding normal human keratinocytes on a fibroblast-populated type I collagen gel, bFGF or neutralizing antibody for keratinocyte growth factor (KGF) was added to investigate its effects on fibroblast phenotypes and, subsequently, epidermal homeostasis by histology and immunohistochemistry. The α-SMA-positive phenotype of fibroblasts induced by transforming growth factor beta-1 (TGF-β1) markedly suppressed the expression of KGF and hepatocyte growth factor (HGF), and slightly upregulated vascular endothelial growth factor (VEGF) and TGF-β1 at mRNA and protein levels, compared with α-SMA-negative fibroblasts treated with bFGF. α-SMA expression of fibroblasts at the epidermal-mesenchymal junction of the LSEs was suppressed by the addition of bFGF, and a better-differentiated epidermis was presented. The abrogation of KGF from fibroblasts by the addition of the KGF neutralizing antibody disenabled the LSE culturing system to develop an epidermis. bFGF, through affecting the phenotypes and functions of fibroblasts, especially KGF expression, influenced epidermal homeostasis in an LSE model. © 2018 S. Karger AG, Basel.

  2. Mean Levels and Variability in Affect, Diabetes Self-Care Behaviors, and Continuously Monitored Glucose: A Daily Study of Latinos With Type 2 Diabetes.

    PubMed

    Wagner, Julie; Armeli, Stephen; Tennen, Howard; Bermudez-Millan, Angela; Wolpert, Howard; Pérez-Escamilla, Rafael

    2017-09-01

    This study investigated between- and within-person associations among mean levels and variability in affect, diabetes self-care behaviors, and continuously monitored glucose in Latinos with type 2 diabetes. Fifty participants (M [SD] age = 57.8 [11.7] years, 74% women, mean [SD] glycosylated hemoglobin A1c = 8.3% [1.5%]) wore a "blinded" continuous glucose monitor for 7 days, and they responded to twice daily automated phone surveys regarding positive affect, negative affect, and self-care behaviors. Higher mean levels of NA were associated with higher mean glucose (r = .30), greater percent hyperglycemia (r = .34) and greater percentage of out-of-range glucose (r = .34). Higher NA variability was also related to higher mean glucose (r = .34), greater percent of hyperglycemia (r = .44) and greater percentage of out-of-range glucose (r = .43). Higher positive affect variability was related to lower percentage of hypoglycemia (r = -.33). Higher mean levels of self-care behaviors were related to lower glucose variability (r = -.35). Finally, higher self-care behavior variability was related to greater percentage of hyperglycemia (r = .31) and greater percentage of out-of-range glucose (r = -.28). In multilevel regression models, within-person increases from mean levels of self-care were associated with lower mean levels of glucose (b = -7.4, 95% confidence interval [CI] = -12.8 to -1.9), lower percentage of hyperglycemia (b = -0.04, 95% CI = -0.07 to -0.01), and higher percentage of hypoglycemia (b = 0.02, 95% CI = 0.01 to 0.03) in the subsequent 10-hour period. Near-to-real time sampling documented associations of glucose with affect and diabetes self-care that are not detectable with traditional measures.

  3. Solutes transport characteristics in peritoneal dialysis: variations in glucose and insulin serum levels.

    PubMed

    da Silva, Dirceu R; Figueiredo, Ana E; Antonello, Ivan C; Poli de Figueiredo, Carlos E; d'Avila, Domingos O

    2008-01-01

    Differences in small solutes transport rate (SSTR) during peritoneal dialysis (PD) may affect water and solutes removal. Patients with high SSTR must rely on shorter dwell times and increased dialysate glucose concentrations to keep fluid balance. Glucose absorption during peritoneal dialysis (PD), besides affecting glucose and insulin metabolism, may induce weight gain. The study aimed at examining acute glucose and insulin serum level changes and other potential relationships in PD patients with diverse SSTR. This cross-sectional study used a modified peritoneal equilibration test (PET) that enrolled 34 prevalent PD patients. Zero, 15, 30, 60, 120, 180, and 240-minute glucose and insulin serum levels were measured. Insulin resistance index was assessed by the homeostasis model assessment (HOMA-IR) formula. SSTR categories were classified by quartiles of the four-hour dialysate/serum creatinine ratio (D(4)/P(Cr)). Demographic and clinical variables were evaluated, and the body mass index (BMI) was estimated. Correlations among variables of interest and categories of SSTR were explored. Glucose serum levels were significantly different at 15, 30, and 60 minutes between high and low SSTR categories (p = 0.014, 0.009, and 0.022). Increased BMI (25.5 +/- 5.1) and insulin resistance [HOMA-IR = 2.60 (1.40-4.23)] were evidenced overall. Very strong to moderate correlations between insulin levels along the PET and HOMA-IR (r = 0.973, 0.834, 0.766, 0.728, 0.843, 0.857, 0.882) and BMI (r = 0.562, 0.459, 0.417, 0.370, 0.508, 0.514, 0.483) were disclosed. CONCLUSIONS; Early glucose serum levels were associated with SSTR during a PET. Overweight or obesity and insulin resistance were prevalent. An association between insulin serum levels and BMI was demonstrated.

  4. Central insulin and leptin-mediated autonomic control of glucose homeostasis

    USDA-ARS?s Scientific Manuscript database

    Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucos...

  5. T3 supplementation affects ventilatory timing & glucose levels in type 2 diabetes mellitus model.

    PubMed

    Bollinger, Stephen S; Weltman, Nathen Y; Gerdes, A Martin; Schlenker, Evelyn H

    2015-01-01

    Type II diabetes mellitus (T2DM) can affect ventilation, metabolism, and fasting blood glucose levels. Hypothyroidism may be a comorbidity of T2DM. In this study T2DM was induced in 20 female Sprague Dawley rats using Streptozotocin (STZ) and Nicotinamide (N). One of experimental STZ/N groups (N=10 per group) was treated with a low dose of triiodothyronine (T3). Blood glucose levels, metabolism and ventilation (in air and in response to hypoxia) were measured in the 3 groups. STZ/N-treated rats increased fasting blood glucose compared to control rats eight days and 2 months post-STZ/N injections indicating stable induction of T2DM state. Treatments had no effects on ventilation, metabolism or body weight. After one month of T3 supplementation, there were no physiological indications of hyperthyroidism, but T3 supplementation altered ventilatory timing and decreased blood glucose levels compared to STZ/N rats. These results suggest that low levels of T3 supplementation could offer modest effects on blood glucose and ventilatory timing in this T2M model. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats

    PubMed Central

    Lubaczeuski, C.; Balbo, S.L.; Ribeiro, R.A.; Vettorazzi, J.F.; Santos-Silva, J.C.; Carneiro, E.M.; Bonfleur, M.L.

    2015-01-01

    The parasympathetic nervous system is important for β-cell secretion and mass regulation. Here, we characterized involvement of the vagus nerve in pancreatic β-cell morphofunctional regulation and body nutrient homeostasis in 90-day-old monosodium glutamate (MSG)-obese rats. Male newborn Wistar rats received MSG (4 g/kg body weight) or saline [control (CTL) group] during the first 5 days of life. At 30 days of age, both groups of rats were submitted to sham-surgery (CTL and MSG groups) or subdiaphragmatic vagotomy (Cvag and Mvag groups). The 90-day-old MSG rats presented obesity, hyperinsulinemia, insulin resistance, and hypertriglyceridemia. Their pancreatic islets hypersecreted insulin in response to glucose but did not increase insulin release upon carbachol (Cch) stimulus, despite a higher intracellular Ca2+ mobilization. Furthermore, while the pancreas weight was 34% lower in MSG rats, no alteration in islet and β-cell mass was observed. However, in the MSG pancreas, increases of 51% and 55% were observed in the total islet and β-cell area/pancreas section, respectively. Also, the β-cell number per β-cell area was 19% higher in MSG rat pancreas than in CTL pancreas. Vagotomy prevented obesity, reducing 25% of body fat stores and ameliorated glucose homeostasis in Mvag rats. Mvag islets demonstrated partially reduced insulin secretion in response to 11.1 mM glucose and presented normalization of Cch-induced Ca2+ mobilization and insulin release. All morphometric parameters were similar among Mvag and CTL rat pancreases. Therefore, the higher insulin release in MSG rats was associated with greater β-cell/islet numbers and not due to hypertrophy. Vagotomy improved whole body nutrient homeostasis and endocrine pancreatic morphofunction in Mvag rats. PMID:25714886

  7. Variants in glucose- and circadian rhythm–related genes affect the response of energy expenditure to weight-loss diets: the POUNDS LOST Trial123

    PubMed Central

    Mirzaei, Khadijeh; Xu, Min; Qi, Qibin; de Jonge, Lilian; Bray, George A; Sacks, Frank; Qi, Lu

    2014-01-01

    Background: Circadian rhythm has been shown to be related to glucose metabolism and risk of diabetes, probably through effects on energy balance. Recent genome-wide association studies identified variants in circadian rhythm–related genes (CRY2 and MTNR1B) associated with glucose homeostasis. Objective: We tested whether CRY2 and MTNR1B genotypes affected changes in measures of energy expenditure in response to a weight-loss diet intervention in a 2-y randomized clinical trial, the POUNDS (Preventing Overweight Using Novel Dietary Strategies) LOST Trial. Design: The variants CRY2 rs11605924 (n = 721) and MTNR1B rs10830963 (n = 722) were genotyped in overweight or obese adults who were randomly assigned to 1 of 4 weight-loss diets that differed in their proportions of macronutrients. Respiratory quotient (RQ) and resting metabolic rate (RMR) were measured. Results: By 2 y of diet intervention, the A allele of CRY2 rs11605924 was significantly associated with a greater reduction in RQ (P = 0.03) and a greater increase in RMR and RMR/kg (both P = 0.04). The G allele of MTNR1B rs10830963 was significantly associated with a greater increase in RQ (P = 0.01) but was not related to changes in RMR and RMR/kg. In addition, we found significant gene-diet fat interactions for both CRY2 (P-interaction = 0.02) and MTNR1B (P-interaction < 0.001) in relation to 2-y changes in RQ. Conclusions: Our data indicate that variants in the circadian-related genes CRY2 and MTNR1B may affect long-term changes in energy expenditure, and dietary fat intake may modify the genetic effects. This trial was registered at www.clinicaltrials.gov as NCT00072995. PMID:24335056

  8. Dietary iron controls circadian hepatic glucose metabolism through heme synthesis.

    PubMed

    Simcox, Judith A; Mitchell, Thomas Creighton; Gao, Yan; Just, Steven F; Cooksey, Robert; Cox, James; Ajioka, Richard; Jones, Deborah; Lee, Soh-Hyun; King, Daniel; Huang, Jingyu; McClain, Donald A

    2015-04-01

    The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling. © 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.

  9. The effects of abnormalities of glucose homeostasis on the expression and binding of muscarinic receptors in cerebral cortex of rats.

    PubMed

    Sherin, Antony; Peeyush, Kumar T; Naijil, George; Nandhu, Mohan Sobhana; Jayanarayanan, Sadanandan; Jes, Paul; Paulose, Cheramadathikudiyil Skaria

    2011-01-25

    Glucose homeostasis in humans is an important factor for the functioning of nervous system. Both hypo and hyperglycemia contributes to neuronal functional deficit. In the present study, effect of insulin induced hypoglycemia and streptozotocin induced diabetes on muscarinic receptor binding, cholinergic enzymes; AChE, ChAT expression and GLUT3 in the cerebral cortex of experimental rats were analysed. Total muscarinic, muscarinic M(1) receptor showed a significant decrease and muscarinic M(3) receptor subtype showed a significant increased binding in the cerebral cortex of hypoglycemic rats compared to diabetic and control. Real-Time PCR analysis of muscarinic M(1), M(3) receptor subtypes confirmed the receptor binding studies. Immunohistochemistry of muscarinic M(1), M(3) receptors using specific antibodies were also carried out. AChE and GLUT3 expression up regulated and ChAT expression down regulated in hypoglycemic rats compared to diabetic and control rats. Our results showed that hypo/hyperglycemia caused impaired glucose transport in neuronal cells as shown by altered expression of GLUT3. Increased AChE and decreased ChAT expression is suggested to alter cortical acetylcholine metabolism in experimental rats along with altered muscarinic receptor binding in hypo/hyperglycemic rats, impair cholinergic transmission, which subsequently lead to cholinergic dysfunction thereby causing learning and memory deficits. We observed a prominent cholinergic functional disturbance in hypoglycemic condition than in hyperglycemia. Hypoglycemia exacerbated the neurochemical changes in cerebral cortex induced by hyperglycemia. These findings have implications for both therapy and identification of causes contributing to neuronal dysfunction in diabetes. Copyright © 2010 Elsevier B.V. All rights reserved.

  10. Glucose and hypothalamic astrocytes: More than a fueling role?

    PubMed

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

    2016-05-26

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

  11. Apelin targets gut contraction to control glucose metabolism via the brain.

    PubMed

    Fournel, Audren; Drougard, Anne; Duparc, Thibaut; Marlin, Alysson; Brierley, Stuart M; Castro, Joel; Le-Gonidec, Sophie; Masri, Bernard; Colom, André; Lucas, Alexandre; Rousset, Perrine; Cenac, Nicolas; Vergnolle, Nathalie; Valet, Philippe; Cani, Patrice D; Knauf, Claude

    2017-02-01

    The gut-brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  12. Redox Homeostasis in Pancreatic β Cells

    PubMed Central

    Ježek, Petr; Dlasková, Andrea; Plecitá-Hlavatá, Lydie

    2012-01-01

    We reviewed mechanisms that determine reactive oxygen species (redox) homeostasis, redox information signaling and metabolic/regulatory function of autocrine insulin signaling in pancreatic β cells, and consequences of oxidative stress and dysregulation of redox/information signaling for their dysfunction. We emphasize the role of mitochondrion in β cell molecular physiology and pathology, including the antioxidant role of mitochondrial uncoupling protein UCP2. Since in pancreatic β cells pyruvate cannot be easily diverted towards lactate dehydrogenase for lactate formation, the respiration and oxidative phosphorylation intensity are governed by the availability of glucose, leading to a certain ATP/ADP ratio, whereas in other cell types, cell demand dictates respiration/metabolism rates. Moreover, we examine the possibility that type 2 diabetes mellitus might be considered as an inevitable result of progressive self-accelerating oxidative stress and concomitantly dysregulated information signaling in peripheral tissues as well as in pancreatic β cells. It is because the redox signaling is inherent to the insulin receptor signaling mechanism and its impairment leads to the oxidative and nitrosative stress. Also emerging concepts, admiting participation of redox signaling even in glucose sensing and insulin release in pancreatic β cells, fit in this view. For example, NADPH has been firmly established to be a modulator of glucose-stimulated insulin release. PMID:23304259

  13. Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

    PubMed

    Nordström, Viola; Willershäuser, Monja; Herzer, Silke; Rozman, Jan; von Bohlen Und Halbach, Oliver; Meldner, Sascha; Rothermel, Ulrike; Kaden, Sylvia; Roth, Fabian C; Waldeck, Clemens; Gretz, Norbert; de Angelis, Martin Hrabě; Draguhn, Andreas; Klingenspor, Martin; Gröne, Hermann-Josef; Jennemann, Richard

    2013-01-01

    Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.

  14. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans

    USDA-ARS?s Scientific Manuscript database

    Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. T...

  15. Skeleton and Glucose Metabolism: A Bone-Pancreas Loop

    PubMed Central

    Luce, Vincenza; Ventura, Annamaria; Colucci, Silvia; Cavallo, Luciano; Grano, Maria

    2015-01-01

    Bone has been considered a structure essential for mobility, calcium homeostasis, and hematopoietic function. Recent advances in bone biology have highlighted the importance of skeleton as an endocrine organ which regulates some metabolic pathways, in particular, insulin signaling and glucose tolerance. This review will point out the role of bone as an endocrine “gland” and, specifically, of bone-specific proteins, as the osteocalcin (Ocn), and proteins involved in bone remodeling, as osteoprotegerin, in the regulation of insulin function and glucose metabolism. PMID:25873957

  16. Homeostasis in a feed forward loop gene regulatory motif.

    PubMed

    Antoneli, Fernando; Golubitsky, Martin; Stewart, Ian

    2018-05-14

    The internal state of a cell is affected by inputs from the extra-cellular environment such as external temperature. If some output, such as the concentration of a target protein, remains approximately constant as inputs vary, the system exhibits homeostasis. Special sub-networks called motifs are unusually common in gene regulatory networks (GRNs), suggesting that they may have a significant biological function. Potentially, one such function is homeostasis. In support of this hypothesis, we show that the feed-forward loop GRN produces homeostasis. Here the inputs are subsumed into a single parameter that affects only the first node in the motif, and the output is the concentration of a target protein. The analysis uses the notion of infinitesimal homeostasis, which occurs when the input-output map has a critical point (zero derivative). In model equations such points can be located using implicit differentiation. If the second derivative of the input-output map also vanishes, the critical point is a chair: the output rises roughly linearly, then flattens out (the homeostasis region or plateau), and then starts to rise again. Chair points are a common cause of homeostasis. In more complicated equations or networks, numerical exploration would have to augment analysis. Thus, in terms of finding chairs, this paper presents a proof of concept. We apply this method to a standard family of differential equations modeling the feed-forward loop GRN, and deduce that chair points occur. This function determines the production of a particular mRNA and the resulting chair points are found analytically. The same method can potentially be used to find homeostasis regions in other GRNs. In the discussion and conclusion section, we also discuss why homeostasis in the motif may persist even when the rest of the network is taken into account. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. The Resist Diabetes trial: Rationale, design, and methods of a hybrid efficacy/effectiveness intervention trial for resistance training maintenance to improve glucose homeostasis in older prediabetic adults

    PubMed Central

    Marinik, Elaina L.; Kelleher, Sarah; Savla, Jyoti; Winett, Richard A.; Davy, Brenda M.

    2014-01-01

    Advancing age is associated with reduced levels of physical activity, increased body weight and fat, decreased lean body mass, and a high prevalence of type 2 diabetes (T2D). Resistance training (RT) increases muscle strength and lean body mass, and reduces risk of T2D among older adults. The Resist Diabetes trial will determine if a social cognitive theory (SCT)-based intervention improves RT maintenance in older, prediabetic adults, using a hybrid efficacy/effectiveness approach. Sedentary, overweight/obese (BMI 25-39.9 kg/m2) adults aged 50-69 (N=170) with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) completed a supervised 3-month RT (2x/wk) Initiation Phase and were then randomly assigned (n=159; 94% retention) to one of two 6-month maintenance conditions: SCT or Standard care. The SCT intervention consisted of faded contacts compared to Standard care. Participants continue RT at an approved, self-selected community facility during maintenance. A subsequent 6-month period involves no contact for both conditions. Assessments occur at baseline and months 3 (post-initiation), 9 (post-intervention), and 15 (six months after no contact). Primary outcomes are prediabetes indices (i.e., impaired fasting and 2-hour glucose concentration) and strength. Secondary measures include insulin sensitivity, beta-cell responsiveness, and disposition index (oral glucose and C-peptide minimal model); adherence; body composition; and SCT measures. Resist Diabetes is the first trial to examine the effectiveness of a high fidelity SCT-based intervention for maintaining RT in older adults with prediabetes to improve glucose homeostasis. Successful application of SCT constructs for RT maintenance may support translation of our RT program for diabetes prevention into community settings. PMID:24252311

  18. The resist diabetes trial: Rationale, design, and methods of a hybrid efficacy/effectiveness intervention trial for resistance training maintenance to improve glucose homeostasis in older prediabetic adults.

    PubMed

    Marinik, Elaina L; Kelleher, Sarah; Savla, Jyoti; Winett, Richard A; Davy, Brenda M

    2014-01-01

    Advancing age is associated with reduced levels of physical activity, increased body weight and fat, decreased lean body mass, and a high prevalence of type 2 diabetes (T2D). Resistance training (RT) increases muscle strength and lean body mass, and reduces risk of T2D among older adults. The Resist Diabetes trial will determine if a social cognitive theory (SCT)-based intervention improves RT maintenance in older, prediabetic adults, using a hybrid efficacy/effectiveness approach. Sedentary, overweight/obese (BMI: 25-39.9 kg/m(2)) adults aged 50-69 (N = 170) with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) completed a supervised 3-month RT (2×/wk) initiation phase and were then randomly assigned (N = 159; 94% retention) to one of two 6-month maintenance conditions: SCT or standard care. The SCT intervention consisted of faded contacts compared to standard care. Participants continue RT at an approved, self-selected community facility during maintenance. A subsequent 6-month period involves no contact for both conditions. Assessments occur at baseline and months 3 (post-initiation), 9 (post-intervention), and 15 (six months after no contact). Primary outcomes are prediabetes indices (i.e., impaired fasting and 2-hour glucose concentration) and strength. Secondary measures include insulin sensitivity, beta-cell responsiveness, and disposition index (oral glucose and C-peptide minimal model); adherence; body composition; and SCT measures. Resist Diabetes is the first trial to examine the effectiveness of a high fidelity SCT-based intervention for maintaining RT in older adults with prediabetes to improve glucose homeostasis. Successful application of SCT constructs for RT maintenance may support translation of our RT program for diabetes prevention into community settings. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Reducing Liver Fat by Low Carbohydrate Caloric Restriction Targets Hepatic Glucose Production in Non-Diabetic Obese Adults with Non-Alcoholic Fatty Liver Disease.

    PubMed

    Yu, Haoyong; Jia, Weiping; Guo, ZengKui

    2014-09-01

    Non-alcoholic fatty liver disease (NAFLD) impairs liver functions, the organ responsible for the regulation of endogenous glucose production and thus plays a key role in glycemic homeostasis. Therefore, interventions designed to normalize liver fat content are needed to improve glucose metabolism in patients affected by NAFLD such as obesity. this investigation is designed to determine the effects of caloric restriction on hepatic and peripheral glucose metabolism in obese humans with NAFLD. eight non-diabetic obese adults were restricted for daily energy intake (800 kcal) and low carbohydrate (<10%) for 8 weeks. Body compositions, liver fat and hepatic glucose production (HGP) and peripheral glucose disposal before and after the intervention were determined. the caloric restriction reduced liver fat content by 2/3 (p = 0.004). Abdominal subcutaneous and visceral fat, body weight, BMI, waist circumference and fasting plasma triglyceride and free fatty acid concentrations all significantly decreased (p < 0.05). The suppression of post-load HGP was improved by 22% (p = 0.002) whereas glucose disposal was not affected (p = 0.3). Fasting glucose remained unchanged and the changes in the 2-hour plasma glucose and insulin concentration were modest and statistically insignificant (p > 0.05). Liver fat is the only independent variable highly correlated to HGP after the removal of confounders. NAFLD impairs HGP but not peripheral glucose disposal; low carbohydrate caloric restriction effectively lowers liver fat which appears to directly correct the HGP impairment.

  20. Compound- and sex-specific effects on programming of energy and immune homeostasis in adult C57BL/6JxFVB mice after perinatal TCDD and PCB 153.

    PubMed

    van Esterik, J C J; Verharen, H W; Hodemaekers, H M; Gremmer, E R; Nagarajah, B; Kamstra, J H; Dollé, M E T; Legler, J; van der Ven, L T M

    2015-12-01

    Early life exposure to endocrine disrupting compounds has been linked to chronic diseases later in life, like obesity and related metabolic disorders. We exposed C57BL/6JxFVB hybrid mice to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the constitutive androstane receptor/pregnane X receptor agonist polychlorinated biphenyl 153 (PCB 153) in an experimental design relevant for human exposure. Exposure occurred during gestation and lactation via maternal feed to a wide dose range (TCDD: 10-10,000 pg/kg body weight/day; PCB 153: 0.09-1406 μg/kg body weight/d). Then exposure was ceased and offspring were followed up to 1 year of age. Metabolic parameters like body weight, fat pad weights, glucose tolerance, endocrine serum profile, and neurobehavioral and immunological parameters were determined. Body weight was transiently affected by both compounds throughout the follow-up. TCDD-exposed males showed decreased fat pad and spleen weights and an increase in IL-4 production of splenic immune cells. In contrast, females showed increased fat pad weights and production of IFNγ. PCB 153-exposed males showed an increase in glucose, whereas females showed an increase in glucagon, a decrease in pancreas weight, and an increase in thymus weight. In conclusion, early life exposure to TCDD appears to affect programming of energy and immune homeostasis in offspring, whereas the effects of perinatal PCB 153 were mainly on programming of glucose homeostasis. Both compounds act sex-specifically. Lowest derived BMDLs (lower bounds of the (two sided) 90%-confidence interval for the benchmark dose) for both compounds are not lower than current tolerable daily intakes.

  1. Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice.

    PubMed

    Min, So Yun; Kady, Jamie; Nam, Minwoo; Rojas-Rodriguez, Raziel; Berkenwald, Aaron; Kim, Jong Hun; Noh, Hye-Lim; Kim, Jason K; Cooper, Marcus P; Fitzgibbons, Timothy; Brehm, Michael A; Corvera, Silvia

    2016-03-01

    Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'. In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear. Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks. Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration. When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance. These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity. Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism.

  2. Brain glucose sensing in homeostatic and hedonic regulation.

    PubMed

    Steinbusch, Laura; Labouèbe, Gwenaël; Thorens, Bernard

    2015-09-01

    Glucose homeostasis as well as homeostatic and hedonic control of feeding is regulated by hormonal, neuronal, and nutrient-related cues. Glucose, besides its role as a source of metabolic energy, is an important signal controlling hormone secretion and neuronal activity, hence contributing to whole-body metabolic integration in coordination with feeding control. Brain glucose sensing plays a key, but insufficiently explored, role in these metabolic and behavioral controls, which when deregulated may contribute to the development of obesity and diabetes. The recent introduction of innovative transgenic, pharmacogenetic, and optogenetic techniques allows unprecedented analysis of the complexity of central glucose sensing at the molecular, cellular, and neuronal circuit levels, which will lead to a new understanding of the pathogenesis of metabolic diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Beyond the morphology of the glucose curve following an oral glucose tolerance test in obese youth.

    PubMed

    Nolfe, Giuseppe; Spreghini, Maria Rita; Sforza, Rita Wietrzycowska; Morino, Giuseppe; Manco, Melania

    2012-01-01

    To describe the morphology of glucose curve during the oral glucose tolerance test (OGTT) and any association with glucose tolerance, insulin action and secretion in obese youth. Cross-sectional. OGTT data of 553 patients were analysed. Subjects were divided in groups based on the morphology (i.e. monophasic, biphasic, triphasic and upward monotonous) of glucose curve. Insulin action was estimated by the homeostasis model assessment of insulin resistance, the insulin sensitivity, the muscle insulin sensitivity and the hepatic insulin resistance indexes (HIRI), and the oral glucose insulin sensitivity (OGIS). Insulin secretion was estimated by the insulinogenic index (IGI). Disposition index, including the insulin secretion-sensitivity index-2, and areas under glucose (AUC(G)) and insulin (AUC(I)) curves were computed. In patients with normal glucose tolerance (n=522), prevalent morphology of the glucose curve was monophasic (n=285, 54%). Monophasic morphology was associated with the highest concentration of 1 h plasma glucose (P<0.0001) and AUC(G) (P<0.0001); biphasic morphology with better insulin sensitivity as estimated by OGIS (P<0.03) and lower AUC(I) (P<0.0001); triphasic morphology with the highest values of HIRI (P<0.02) and IGI (P<0.007). By combining morphologies of glucose and insulin curves or time of the glucose peak, a deeper characterisation of different phenotypes of glucose metabolism emerged. Morphologies of the glucose curve seem reflecting different metabolic phenotypes of insulin action and secretion, particularly when combined with morphologies of insulin curve or time of glucose peak. Such findings may deserve validation in cohort study, in which glucose metabolism would be estimated by using gold standard techniques.

  4. Rapid changes in local extracellular rat brain glucose observed with an in vivo glucose sensor.

    PubMed

    Hu, Y; Wilson, G S

    1997-04-01

    A needle-type electrochemically based microsensor for glucose (110 microns o.d.) is described. This sensor, designed for monitoring transient glucose content changes in response to neural stimuli, has a response time of approximately 5 s and has been shown to be free of interference from endogenous electroactive species such as ascorbate, urate, and various neurotransmitters. It exhibits linear response to glucose up to 10 mM. The usefulness of the sensor has been demonstrated by examining the time-dependent interstitial glucose concentration in the rat hippocampus in response to KCl depolarization and by stimulation of glutamate neurons through a perforant pathway. Simultaneous monitoring of oxygen is also carried out and demonstrates that for both oxygen and glucose there is substantial local depletion of both species and that their pools are replenished by increased regional cerebral blood flow. The transient initial rapid (10-13 s) decrease up to 20-34%, observed on a time scale comparable to that for neurotransmitter release, may be involved in a recently suggested astrocytic uptake for glutamate-stimulated aerobic glycolysis possibly needed to meet energy homeostasis in brain. These studies demonstrate the importance of microsensors in monitoring transient events linked to neuronal stimulation.

  5. Olfactory stimulation modulates the blood glucose level in rats.

    PubMed

    Tsuji, Tadataka; Tanaka, Susumu; Bakhshishayan, Sanam; Kogo, Mikihiko; Yamamoto, Takashi

    2018-01-01

    In both humans and animals, chemosensory stimuli, including odors and tastes, induce a variety of physiologic and mental responses related to energy homeostasis, such as glucose kinetics. The present study examined the importance of olfactory function in glucose kinetics following ingestion behavior in a simplified experimental scenario. We applied a conventional glucose tolerance test to rats with and without olfactory function and analyzed subsequent blood glucose (BG) curves in detail. The loss of olfactory input due to experimental damage to the olfactory mucosa induced a marked decrease in the area under the BG curve. Exposure to grapefruit odor and its main component, limonene, both of which activate the sympathetic nerves, before glucose loading also greatly depressed the BG curve. Pre-loading exposure to lavender odor, a parasympathetic activator, stabilized the BG level. These results suggest that olfactory function is important for proper glucose kinetics after glucose intake and that certain fragrances could be utilized as tools for controlling BG levels.

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

    PubMed

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

    2015-10-05

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

  7. Quantitative approaches to energy and glucose homeostasis: machine learning and modelling for precision understanding and prediction

    PubMed Central

    Murphy, Kevin G.; Jones, Nick S.

    2018-01-01

    Obesity is a major global public health problem. Understanding how energy homeostasis is regulated, and can become dysregulated, is crucial for developing new treatments for obesity. Detailed recording of individual behaviour and new imaging modalities offer the prospect of medically relevant models of energy homeostasis that are both understandable and individually predictive. The profusion of data from these sources has led to an interest in applying machine learning techniques to gain insight from these large, relatively unstructured datasets. We review both physiological models and machine learning results across a diverse range of applications in energy homeostasis, and highlight how modelling and machine learning can work together to improve predictive ability. We collect quantitative details in a comprehensive mathematical supplement. We also discuss the prospects of forecasting homeostatic behaviour and stress the importance of characterizing stochasticity within and between individuals in order to provide practical, tailored forecasts and guidance to combat the spread of obesity. PMID:29367240

  8. Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis.

    PubMed

    Sadagurski, Marianna; Dong, X Charlie; Myers, Martin G; White, Morris F

    2014-02-01

    Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although Irs4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because Irs4-null mice barely distinguishable from controls. We postulated that Irs2 and Irs4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body Irs4(-/y) mice that lacked Irs2 in the CNS (bIrs2(-/-)·Irs4(-/y)) or only in LepRb-neurons (Lepr (∆Irs2) ·Irs4 (-/y) ). bIrs2(-/-)·Irs4(-/y) mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr (∆Irs2) ·Irs4 (-/y) mice were not different from Lepr (∆Irs2) mice, suggesting that the functions of Irs2 and Irs4 converge upon neurons that are distinct from those expressing LepRb.

  9. Cellular Links between Neuronal Activity and Energy Homeostasis.

    PubMed

    Shetty, Pavan K; Galeffi, Francesca; Turner, Dennis A

    2012-01-01

    Neuronal activity, astrocytic responses to this activity, and energy homeostasis are linked together during baseline, conscious conditions, and short-term rapid activation (as occurs with sensory or motor function). Nervous system energy homeostasis also varies during long-term physiological conditions (i.e., development and aging) and with adaptation to pathological conditions, such as ischemia or low glucose. Neuronal activation requires increased metabolism (i.e., ATP generation) which leads initially to substrate depletion, induction of a variety of signals for enhanced astrocytic function, and increased local blood flow and substrate delivery. Energy generation (particularly in mitochondria) and use during ATP hydrolysis also lead to considerable heat generation. The local increases in blood flow noted following neuronal activation can both enhance local substrate delivery but also provides a heat sink to help cool the brain and removal of waste by-products. In this review we highlight the interactions between short-term neuronal activity and energy metabolism with an emphasis on signals and factors regulating astrocyte function and substrate supply.

  10. β-Hydroxybutyrate is the preferred substrate for GABA and glutamate synthesis while glucose is indispensable during depolarization in cultured GABAergic neurons.

    PubMed

    Lund, Trine M; Obel, Linea F; Risa, Øystein; Sonnewald, Ursula

    2011-08-01

    The ketogenic diet has multiple beneficial effects not only in treatment of epilepsy, but also in that of glucose transporter 1 deficiency, cancer, Parkinson's disease, obesity and pain. Thus, there is an increasing interest in understanding the mechanism behind this metabolic therapy. Patients on a ketogenic diet reach high plasma levels of ketone bodies, which are used by the brain as energy substrates. The interaction between glucose and ketone bodies is complex and there is still controversy as to what extent it affects the homeostasis of the neurotransmitters glutamate, aspartate and GABA. The present study was conducted to study this metabolic interaction in cultured GABAergic neurons exposed to different combinations of (13)C-labeled and unlabeled glucose and β-hydroxybutyrate. Depolarization was induced and the incorporation of (13)C into glutamate, GABA and aspartate was analyzed. The presence of β-hydroxybutyrate together with glucose did not affect the total GABA content but did, however, decrease the aspartate content to a lower value than when either glucose or β-hydroxybutyrate was employed alone. When combinations of the two substrates were used (13)C-atoms from β-hydroxybutyrate were found in all three amino acids to a greater extent than (13)C-atoms from glucose, but only the (13)C contribution from [1,6-(13)C]glucose increased upon depolarization. In conclusion, β-hydroxybutyrate was preferred over glucose as substrate for amino acid synthesis but the total content of aspartate decreased when both substrates were present. Furthermore only the use of glucose increased upon depolarization. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Effect of one time high dose "stoss therapy" of vitamin D on glucose homeostasis in high risk obese adolescents.

    PubMed

    Brar, Preneet Cheema; Contreras, Maria; Fan, Xiaozhou; Visavachaipan, Nipapat

    2018-04-05

    To study the effect of using a one time high dose "stoss therapy" of vitamin D2 (ergocalciferol: VD2) on indices of insulin sensitivity {whole body sensitivity index: WBISI} and secretion {insulinogenic index: IGI} measured during an oral glucose tolerance test (OGTT) in obese adolescents with VDD (25 OHD; serum metabolite of vit D: < 30 ng/dL). In a randomized placebo controlled cross over design 20 obese adolescents with vitamin D deficiency (VDD) had baseline OGTT. Arm A received one time high dose 300,000 IU of ergocalciferol and Arm B received placebo. After 6 weeks the adolescents were reassigned to Arm A if they were in Arm B and vice versa. 25OHD, calcium, parathyroid hormone, comprehensive metabolic panel, urine calcium creatinine ratio were measured at each study visit. OGTTs to assess indices of sensitivity and secretion were done at baseline, 6 weeks and 12 weeks respectively. Adolescents were obese and insulin resistant (mean ± SD: mean age = 15.1 ± 1.9 years; BMI: 32.7 ± 9.8; homeostatic model of insulin resistance: HOMA-IR: 4.2 ± 2.8). Stoss therapy with VD2 increased 25OHD from baseline (16.7 ± 2.9 to 19.5 ± 4.5; p = 0.0029) when compared to the placebo. WBISI (2.8 ± 1.9) showed a trend towards improvement in Rx group (p = 0.0577) after adjustment for covariates. IGI (3 ± 2.2) showed an improvement in both Rx and placebo groups. Our study demonstrated that using a high dose of VD2 (300,000 IU) did not have any beneficial effect on insulin sensitivity (whole body sensitivity index {WBISI}) and secretory indices (insulinogenic index {IGI}) in obese adolescents. High dose "stoss therapy" of VD2 did not appear to have any beneficial effect on glucose homeostasis on obese adolescents.

  12. 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.

  13. Effect of Cinnamon Tea on Postprandial Glucose Concentration.

    PubMed

    Bernardo, Maria Alexandra; Silva, Maria Leonor; Santos, Elisabeth; Moncada, Margarida Maria; Brito, José; Proença, Luis; Singh, Jaipaul; de Mesquita, Maria Fernanda

    2015-01-01

    Glycaemic control, in particular at postprandial period, has a key role in prevention of different diseases, including diabetes and cardiovascular events. Previous studies suggest that postprandial high blood glucose levels (BGL) can lead to an oxidative stress status, which is associated with metabolic alterations. Cinnamon powder has demonstrated a beneficial effect on postprandial glucose homeostasis in animals and human models. The purpose of this study is to investigate the effect of cinnamon tea (C. burmannii) on postprandial capillary blood glucose level on nondiabetic adults. Participants were given oral glucose tolerance test either with or without cinnamon tea in a randomized clinical trial. The data revealed that cinnamon tea administration slightly decreased postprandial BGL. Cinnamon tea ingestion also results in a significantly lower postprandial maximum glucose concentration and variation of maximum glucose concentration (p < 0.05). Chemical analysis showed that cinnamon tea has a high antioxidant capacity, which may be due to its polyphenol content. The present study provides evidence that cinnamon tea, obtained from C. burmannii, could be beneficial for controlling glucose metabolism in nondiabetic adults during postprandial period.

  14. O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response in Caenorhabditis elegans

    PubMed Central

    Mondoux, Michelle A.; Love, Dona C.; Ghosh, Salil K.; Fukushige, Tetsunari; Bond, Michelle; Weerasinghe, Gayani R.; Hanover, John A.; Krause, Michael W.

    2011-01-01

    In a variety of organisms, including worms, flies, and mammals, glucose homeostasis is maintained by insulin-like signaling in a robust network of opposing and complementary signaling pathways. The hexosamine signaling pathway, terminating in O-linked-N-acetylglucosamine (O-GlcNAc) cycling, is a key sensor of nutrient status and has been genetically linked to the regulation of insulin signaling in Caenorhabditis elegans. Here we demonstrate that O-GlcNAc cycling and insulin signaling are both essential components of the C. elegans response to glucose stress. A number of insulin-dependent processes were found to be sensitive to glucose stress, including fertility, reproductive timing, and dauer formation, yet each of these differed in their threshold of sensitivity to glucose excess. Our findings suggest that O-GlcNAc cycling and insulin signaling are both required for a robust and adaptable response to glucose stress, but these two pathways show complex and interdependent roles in the maintenance of glucose–insulin homeostasis. PMID:21441213

  15. Glucose regulates hypothalamic long-chain fatty acid metabolism via AMP-activated kinase (AMPK) in neurons and astrocytes.

    PubMed

    Taïb, Bouchra; Bouyakdan, Khalil; Hryhorczuk, Cécile; Rodaros, Demetra; Fulton, Stephanie; Alquier, Thierry

    2013-12-27

    Hypothalamic controls of energy balance rely on the detection of circulating nutrients such as glucose and long-chain fatty acids (LCFA) by the mediobasal hypothalamus (MBH). LCFA metabolism in the MBH plays a key role in the control of food intake and glucose homeostasis, yet it is not known if glucose regulates LCFA oxidation and esterification in the MBH and, if so, which hypothalamic cell type(s) and intracellular signaling mechanisms are involved. The aim of this study was to determine the impact of glucose on LCFA metabolism, assess the role of AMP-activated Kinase (AMPK), and to establish if changes in LCFA metabolism and its regulation by glucose vary as a function of the kind of LCFA, cell type, and brain region. We show that glucose inhibits palmitate oxidation via AMPK in hypothalamic neuronal cell lines, primary hypothalamic astrocyte cultures, and MBH slices ex vivo but not in cortical astrocytes and slice preparations. In contrast, oleate oxidation was not affected by glucose or AMPK inhibition in MBH slices. In addition, our results show that glucose increases palmitate, but not oleate, esterification into neutral lipids in neurons and MBH slices but not in hypothalamic astrocytes. These findings reveal for the first time the metabolic fate of different LCFA in the MBH, demonstrate AMPK-dependent glucose regulation of LCFA oxidation in both astrocytes and neurons, and establish metabolic coupling of glucose and LCFA as a distinguishing feature of hypothalamic nuclei critical for the control of energy balance.

  16. Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

    PubMed

    Tudurí, Eva; Beiroa, Daniel; Stegbauer, Johannes; Fernø, Johan; López, Miguel; Diéguez, Carlos; Nogueiras, Rubén

    2016-11-01

    Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Neuronal redox imbalance results in altered energy homeostasis and early postnatal lethality.

    PubMed

    Maity-Kumar, Gandhari; Thal, Dietmar R; Baumann, Bernd; Scharffetter-Kochanek, Karin; Wirth, Thomas

    2015-07-01

    Redox imbalance is believed to contribute to the development and progression of several neurodegenerative disorders. Our aim was to develop an animal model that exhibits neuron-specific oxidative stress in the CNS to study the consequences and eventually find clues regarding the pathomechanisms of oxidative insults in neuronal homeostasis. We therefore generated a novel neuron-specific superoxide dismutase 2 (SOD2)-deficient mouse by deleting exon 3 of the SOD2 gene using CamKIIα promoter-driven Cre expression. These neuron-specific SOD2 knockout (SOD2(nko)) mice, although born at normal frequencies, died at the age of 4 weeks with critical growth retardation, severe energy failure, and several neurologic phenotypes. In addition, SOD2(nko) mice exhibited severe neuronal alterations such as reactive astrogliosis, neuronal cell cycle inhibition, and induction of apoptosis. JNK activation and stabilization of p53, as a result of reactive oxygen species accumulation, are most likely the inducers of neuronal apoptosis in SOD2(nko) mice. It is remarkable that hypothalamic regulation of glucose metabolism was affected, which in turn induced necrotic brain lesions in SOD2(nko) mice. Taken together, our findings suggest that exclusive deficiency of SOD2 in neurons results in an impaired central regulation of energy homeostasis that leads to persistent hypoglycemia, hypoglycemia-related neuropathology, and an early lethality of the mutant mice. © FASEB.

  18. Genetic ablation of phosphatidylcholine transfer protein/StarD2 in ob/ob mice improves glucose tolerance without increasing energy expenditure.

    PubMed

    Krisko, Tibor I; LeClair, Katherine B; Cohen, David E

    2017-03-01

    Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is highly expressed in liver and oxidative tissues. PC-TP promotes hepatic glucose production during fasting and aggravates glucose intolerance in high fat fed mice. However, because PC-TP also suppresses thermogenesis in brown adipose tissue (BAT), its direct contribution to obesity-associated diabetes in mice remains unclear. Here we examined the effects of genetic PC-TP ablation on glucose homeostasis in leptin-deficient ob/ob mice, which exhibit both diabetes and altered thermoregulation. Mice lacking both PC-TP and leptin (Pctp -/- ;ob/ob) were prepared by crossing Pctp -/- with ob/+ mice. Glucose homeostasis was assessed by standard assays, and energy expenditure was determined by indirect calorimetry using a comprehensive laboratory animal monitoring system, which also recorded physical activity and food intake. Body composition was determined by NMR and hepatic lipids by enzymatic assays. Core body temperature was measured using a rectal thermocouple probe. Pctp -/- ;ob/ob mice demonstrated improved glucose homeostasis, as evidenced by markedly improved glucose and pyruvate tolerance tests, without changes in insulin tolerance. However, there were no differences in EE at any ambient temperature. There were also no effects of PC-TP expression on physical activity, food intake or core body temperature. Improved glucose tolerance in Pctp -/- ;ob/ob mice in the absence of increases in energy expenditure or core body temperature indicates a direct pathogenic role for PC-TP in diabetes in leptin deficient mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Sweat glucose and GLUT2 expression in atopic dermatitis: Implication for clinical manifestation and treatment

    PubMed Central

    Ono, Emi; Mori, Yuki; Yoshioka, Yoshichika; Nomura, Yuko; Munetsugu, Takichi; Yokozeki, Hiroo; Katayama, Ichiro

    2018-01-01

    Sweat includes active components and metabolites, which are needed to maintain skin homeostasis. Component changes in sweat derived from atopic dermatitis (AD) have been reported. To investigate the influence of sweat components on the pathogenesis of AD, we performed a multifaceted assessment, including nuclear magnetic resonance spectroscopy-based metabolomic analysis, and linked these features to clinical features of AD. Distinctive properties of AD sweat are the quite-variation in protein, anti-microbial peptides and glucose concentrations. pH, sodium, and other salt levels in sweat of AD were comparable to that of healthy subjects. Sweat from AD patients with acute inflammation had a more prominent increase in glucose concentration than sweat from healthy individuals or those with AD with chronic inflammation. Topical glucose application delayed recovery of transepidermal water loss in barrier-disrupted mice. Furthermore, the glucose transporter GLUT2 was highly expressed in the lumen of sweat glands from AD patients. AD patients with chronic inflammation had significantly increased GLUT2 mRNA expression and near normal sweat glucose levels. Despite the small sample size in our study, we speculate that the increased glucose levels might be affected by AD severity and phenotype. We hope that this report will bring novel insight into the impact of sweat components on the clinical manifestation of AD. PMID:29677207

  20. The Drosophila HNF4 nuclear receptor promotes glucose-stimulated insulin secretion and mitochondrial function in adults

    PubMed Central

    Barry, William E; Thummel, Carl S

    2016-01-01

    Although mutations in HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) two decades ago, the mechanisms by which this nuclear receptor regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to a role for dHNF4 in promoting mitochondrial function as well as the expression of Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative phosphorylation and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal. DOI: http://dx.doi.org/10.7554/eLife.11183.001 PMID:27185732

  1. Activation of innate immunity modulates insulin sensitivity, glucose effectiveness and pancreatic β-cell function in both African ancestry and European ancestry healthy humans.

    PubMed

    Ferguson, Jane F; Shah, Rhia Y; Shah, Rachana; Mehta, Nehal N; Rickels, Michael R; Reilly, Muredach P

    2015-04-01

    Insulin resistance is a risk factor for type 2 diabetes, and is associated with inflammatory cardiometabolic disease. Given differences between African ancestry (AA) and European ancestry (EA) in the epidemiology of type 2 diabetes as well as in response to inflammatory stress, we investigated potential race differences in glucose homeostasis responses during experimental endotoxemia in humans. Healthy volunteers (age 18-45 years, BMI 18-30 kg/m(2), 47% female, African-ancestry (AA, n=42) and European-ancestry (EA, n=106)) were recruited as part of the Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) Study. Subjects underwent an inpatient endotoxin challenge (1 ng/kg LPS) and two frequently-sampled intravenous glucose tolerance tests (FSIGTT). Insulin and glucose values obtained during FSIGTT pre- and 24-hours post-LPS were analyzed using the minimal model. FSIGTT derived insulin sensitivity index (SI), disposition index (DI) and glucose effectiveness (SG) decreased significantly following LPS (p<0.0001) while the acute insulin response to glucose (AIR(g)) increased (p<0.0001). Although expected race differences were observed in glucose homeostasis parameters at baseline prior to LPS e.g., lower SI (2.5 vs. 4.1 μU/L/min, p<0.0001) but higher AIR(g) (median 848 vs. 290 μU/L/min, p<0.0001) in AA vs. EA, the changes in glucose homeostasis responses to LPS were directionally and proportionally consistent across race e.g., SI median -35% in EA and -29% in AA and AIR(g) median +17% in EA and +26% in AA. Both EA and AA samples modulated glucose and insulin homeostasis similarly during endotoxemia. Race differences in response to environmental inflammatory stress are unlikely to be a substantial contributor to the observed difference in diabetes incidence and complications between EA and AA. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Substantial replacement of lactose with fat in a high-lactose milk replacer diet increases liver fat accumulation but does not affect insulin sensitivity in veal calves.

    PubMed

    Pantophlet, A J; Gerrits, W J J; Vonk, R J; van den Borne, J J G C

    2016-12-01

    In veal calves, the major portion of digestible energy intake originates from milk replacer (MR), with lactose and fat contributing approximately 45 and 35%, respectively. In veal calves older than 4 mo, prolonged high intakes of MR may lead to problems with glucose homeostasis and insulin sensitivity, ultimately resulting in sustained insulin resistance, hepatic steatosis, and impaired animal performance. The contribution of each of the dietary energy sources (lactose and fat) to deteriorated glucose homeostasis and insulin resistance is currently unknown. Therefore, an experiment was designed to compare the effects of a high-lactose and a high-fat MR on glucose homeostasis and insulin sensitivity in veal calves. Sixteen male Holstein-Friesian calves (120±2.8kg of BW) were assigned to either a high-lactose (HL) or a high-fat (HF) MR for 13 consecutive weeks. After at least 7 wk of adaptation, whole-body insulin sensitivity and insulin secretion were assessed by euglycemic-hyperinsulinemic and hyperglycemic clamps, respectively. Postprandial blood samples were collected to assess glucose, insulin, and triglyceride responses to feeding, and 24-h urine was collected to quantify urinary glucose excretion. At the end of the trial, liver and muscle biopsies were taken to assess triglyceride contents in these tissues. Long-term exposure of calves to HF or HL MR did not affect whole-body insulin sensitivity (averaging 4.2±0.5×10 -2 [(mg/kg∙min)/(μU/mL)]) and insulin secretion. Responses to feeding were greater for plasma glucose and tended to be greater for plasma insulin in HL calves than in HF calves. Urinary glucose excretion was substantially higher in HL calves (75±13g/d) than in HF calves (21±6g/d). Muscle triglyceride content was not affected by treatment and averaged 4.5±0.6g/kg, but liver triglyceride content was higher in HF calves (16.4±0.9g/kg) than in HL calves (11.2±0.7g/kg), indicating increased hepatic fat accumulation. We conclude that

  3. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

    PubMed Central

    Duparc, Thibaut; Plovier, Hubert; Marrachelli, Vannina G; Van Hul, Matthias; Essaghir, Ahmed; Ståhlman, Marcus; Matamoros, Sébastien; Geurts, Lucie; Pardo-Tendero, Mercedes M; Druart, Céline; Delzenne, Nathalie M; Demoulin, Jean-Baptiste; van der Merwe, Schalk W; van Pelt, Jos; Bäckhed, Fredrik; Monleon, Daniel; Everard, Amandine; Cani, Patrice D

    2017-01-01

    Objective To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism. Design To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH). Results Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis. Conclusions Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans. PMID

  4. Human ‘brite / beige’ adipocytes develop from capillary networks and their implantation improves metabolic homeostasis in mice

    PubMed Central

    Min, So Yun; Kady, Jamie; Nam, Minwoo; Rojas-Rodriguez, Raziel; Berkenwald, Aaron; Kim, Jong Hun; Noh, Hye-Lim; Kim, Jason K.; Cooper, Marcus P.; Fitzgibbons, Timothy; Brehm, Michael A.; Corvera, Silvia

    2015-01-01

    The uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outside classical brown adipose tissue depots1–4, in adipocytes termed ‘brite’ (brown-in-white) or ‘beige’. In humans, the presence of ‘brite/beige’ adipocytes correlates with a lean, metabolically healthy phenotype5–8, but whether a causal relationship exists is not clear. Here we report that human ‘brite/beige’ adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks. Adipocytes formed from these progenitors transform from being UCP1-negative to UCP1-positive in response to adenylate cyclase activation, a defining feature of the ‘beige/brite’ phenotype, and display uncoupled respiration. When implanted into normal or high fat diet-fed, glucose intolerant NOD-scid IL2rgnull mice, activated ‘brite/beige’ adipocytes enhance systemic glucose tolerance. These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity. Thus, pro-angiogenic conditions drive proliferation of human ‘beige/brite’ adipocyte progenitors, and activated ‘beige/brite’ adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism. PMID:26808348

  5. Brain to bone: What is the contribution of the brain to skeletal homeostasis?

    PubMed

    Idelevich, Anna; Baron, Roland

    2018-05-16

    The brain, which governs most, if not all, physiological functions in the body, from the complexities of cognition, learning and memory, to the regulation of basal body temperature, heart rate and breathing, has long been known to affect skeletal health. In particular, the hypothalamus - located at the base of the brain in close proximity to the medial eminence, where the blood-brain-barrier is not as tight as in other regions of the brain but rather "leaky", due to fenestrated capillaries - is exposed to a variety of circulating body cues, such as nutrients (glucose, fatty acids, amino acids), and hormones (insulin, glucagon, leptin, adiponectin) [1-3].Information collected from the body via these peripheral cues is integrated by hypothalamic sensing neurons and glial cells [4-7], which express receptors for these nutrients and hormones, transforming these cues into physiological outputs. Interestingly, many of the same molecules, including leptin, adiponectin and insulin, regulate both energy and skeletal homeostasis. Moreover, they act on a common set of hypothalamic nuclei and their residing neurons, activating endocrine and neuronal systems, which ultimately fine-tune the body to new physiological states. This review will focus exclusively on the brain-to-bone pathway, highlighting the most important anatomical sites within the brain, which are known to affect bone, but not covering the input pathways and molecules informing the brain of the energy and bone metabolic status, covered elsewhere [8-10]. The discussion in each section will present side by side the metabolic and bone-related functions of hypothalamic nuclei, in an attempt to answer some of the long-standing questions of whether energy is affected by bone remodeling and homeostasis and vice versa. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Renal glucose metabolism in normal physiological conditions and in diabetes.

    PubMed

    Alsahli, Mazen; Gerich, John E

    2017-11-01

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

  7. The redox-sensing gene Nrf2 affects intestinal homeostasis, insecticide resistance, and Zika virus susceptibility in the mosquito Aedes aegypti.

    PubMed

    Bottino-Rojas, Vanessa; Talyuli, Octavio A C; Carrara, Luana; Martins, Ademir J; James, Anthony A; Oliveira, Pedro L; Paiva-Silva, Gabriela O

    2018-06-08

    Production and degradation of reactive oxygen species (ROS) are extensively regulated to ensure proper cellular responses to various environmental stimuli and stresses. Moreover, physiologically generated ROS function as secondary messengers that can influence tissue homeostasis. The cap'n'collar transcription factor known as nuclear factor erythroid-derived factor 2 (Nrf2) coordinates an evolutionarily conserved transcriptional activation pathway that mediates antioxidant and detoxification responses in many animal species, including insects and mammals. Here, we show that Nrf2-mediated signaling affects embryo survival, midgut homeostasis, and redox biology in Aedes aegypti , a mosquito species vector of dengue, Zika, and other disease-causing viruses. We observed that AeNrf2 silencing increases ROS levels and stimulates intestinal stem cell proliferation. Because ROS production is a major aspect of innate immunity in mosquito gut, we found that a decrease in Nrf2 signaling results in reduced microbiota growth and Zika virus infection. Moreover, we provide evidence that AeNrf2 signaling also controls transcriptional adaptation of A. aegypti to insecticide challenge. Therefore, we conclude that Nrf2-mediated response regulates assorted gene clusters in A. aegypti that determine cellular and midgut redox balance, affecting overall xenobiotic resistance and vectorial adaptation of the mosquito. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Influence of abdominal surgical trauma and intra-operative infusion of glucose on splanchnic glucose metabolism in man.

    PubMed

    Stjernström, H; Jorfeldt, L; Wiklund, L

    1981-10-01

    Abdominal surgery increases blood glucose concentration and peripheral release and splanchnic uptake of gluconeogenic substrates, including alanine. During trauma or sepsis, infusion of glucose fails to depress alanine conversion to glucose. The effect of intra-operative glucose infusion on splanchnic metabolism was examined in the present study. In eight patients undergoing elective cholecystectomy, splanchnic glucose metabolism was investigated before, during and immediately after surgery. Glucose was infused at a constant rate of 1 mmol/min. Splanchnic blood flow and arterio-hepatic venous differences of oxygen, glucose, lactate, glycerol, 3-hydroxybutyrate and alanine were measured. Eight other patients, who received saline instead of glucose, served as a control group. Infusion of glucose resulted in total inhibition of splanchnic glucose release before as well as during and immediately after surgery. This was observed, even before surgery, at an arterial glucose level which was lower than that in the control group at the end of and immediately after surgery, at which no decrease of the splanchnic glucose release was recorded. changes in neuronal and hormonal factors due to the surgical trauma are considered responsible for this difference in glucose homeostasis. Splanchnic alanine uptake increased during surgery in both groups, but tended to be somewhat lower in the glucose group. The arterial glycerol concentration and splanchnic uptake, as well as the arterial concentration and splanchnic release of 3-hydroxybutyrate, were reduced. It is concluded that an intravenous infusion of glucose at the rate of 1 mmol/min during abdominal surgery (a) increases the arterial blood glucose level and abolishes splanchnic glucose release, (b) reduces, but does not totally prevent the increase in splanchnic uptake of gluconeogenic substrates, and (c) diminishes lipolysis and the formation of 3-hydroxybutyrate.

  9. [Cardiac risk profile in diabetes mellitus and impaired fasting glucose].

    PubMed

    Schaan, Beatriz D'Agord; Harzheim, Erno; Gus, Iseu

    2004-08-01

    Mortality of diabetic patients is higher than that of the population at large, and mainly results from cardiovascular diseases. The purpose of the present study was to identify the prevalence of cardiovascular risk factors in subjects with diabetes mellitus (DM) or abnormal fasting glucose (FG) in order to guide health actions. A population-based cross-sectional study was carried out in a representative random cluster sampling of 1,066 adult urban population (> or =20 years) in the state of Rio Grande do Sul between 1999 and 2000. A structured questionnaire on coronary risk factors was applied and sociodemographic characteristics of all adults older than 20 years living in the same dwelling were collected. Subjects were clinically evaluated and blood samples were obtained for measuring total cholesterol and fasting glycemia. Statistical analysis was performed using Stata 7 and a 5% significance level was set. Categorical variables were compared by Pearson's chi-square and continuous variables were compared using Student's t-test or Anova and multivariate analysis, all controlled for the cluster effect. Of 992 subjects, 12.4% were diabetic and 7.4% had impaired fasting glucose. Among the risk factors evaluated, subjects who presented any kind of glucose homeostasis abnormality were at a higher prevalence of obesity (17.8, 29.2 and 35.3% in healthy subjects, impaired fasting glucose and DM respectively, p<0.001), hypertension (30.1, 56.3 and 50.5% in healthy subjects, impaired fasting glucose and DM, respectively, p<0.001), and hypercholesterolemia (23.2, 35.1 and 39.5 in healthy subjects, impaired fasting glucose and DM respectively, p=0.01). Subjects with any kind of glucose homeostasis abnormality represent a group, which preventive individual and population health policies should target since they have higher prevalence of coronary artery disease risk factors.

  10. FAT/CD36: a major regulator of neuronal fatty acid sensing and energy homeostasis in rats and mice.

    PubMed

    Le Foll, Christelle; Dunn-Meynell, Ambrose; Musatov, Serguei; Magnan, Christophe; Levin, Barry E

    2013-08-01

    Hypothalamic "metabolic-sensing" neurons sense glucose and fatty acids (FAs) and play an integral role in the regulation of glucose, energy homeostasis, and the development of obesity and diabetes. Using pharmacologic agents, we previously found that ~50% of these neurons responded to oleic acid (OA) by using the FA translocator/receptor FAT/CD36 (CD36). For further elucidation of the role of CD36 in neuronal FA sensing, ventromedial hypothalamus (VMH) CD36 was depleted using adeno-associated viral (AAV) vector expressing CD36 short hairpin RNA (shRNA) in rats. Whereas their neuronal glucosensing was unaffected by CD36 depletion, the percent of neurons that responded to OA was decreased specifically in glucosensing neurons. A similar effect was seen in total-body CD36-knockout mice. Next, weanling rats were injected in the VMH with CD36 AAV shRNA. Despite significant VMH CD36 depletion, there was no effect on food intake, body weight gain, or total carcass adiposity on chow or 45% fat diets. However, VMH CD36-depleted rats did have increased plasma leptin and subcutaneous fat deposition and markedly abnormal glucose tolerance. These results demonstrate that CD36 is a critical factor in both VMH neuronal FA sensing and the regulation of energy and glucose homeostasis.

  11. Visualizing Sweetness: Increasingly Diverse Applications for Fluorescent-Tagged Glucose Bioprobes and Their Recent Structural Modifications

    PubMed Central

    Kim, Woong Hee; Lee, Jinho; Jung, Da-Woon; Williams, Darren R.

    2012-01-01

    Glucose homeostasis is a fundamental aspect of life and its dysregulation is associated with important diseases, such as cancer and diabetes. Traditionally, glucose radioisotopes have been used to monitor glucose utilization in biological systems. Fluorescent-tagged glucose analogues were initially developed in the 1980s, but it is only in the past decade that their use as a glucose sensor has increased significantly. These analogues were developed for monitoring glucose uptake in blood cells, but their recent applications include tracking glucose uptake by tumor cells and imaging brain cell metabolism. This review outlines the development of fluorescent-tagged glucose analogues, describes their recent structural modifications and discusses their increasingly diverse biological applications. PMID:22666073

  12. Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

    PubMed Central

    Song, Panai; Onishi, Akira; Koepsell, Hermann; Vallon, Volker

    2016-01-01

    Introduction Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium–glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential. Areas covered This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart. Expert opinion SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition. PMID:26998950

  13. Phloretin Prevents High-Fat Diet-Induced Obesity and Improves Metabolic Homeostasis.

    PubMed

    Alsanea, Sary; Gao, Mingming; Liu, Dexi

    2017-05-01

    Reactive oxygen species generated as a by-product in metabolism play a central role in the development of obesity and obesity-related metabolic complications. The objective of the current study is to explore the possibility to block obesity and improve metabolic homeostasis via phloretin, a natural antioxidant product from apple tree leaves and Manchurian apricot. Both preventive and therapeutic activities of phloretin were assessed using a high-fat diet-induced obesity mouse model. Phloretin was injected intraperitoneally twice weekly into regular and obese mice fed a high-fat diet. The effects of phloretin treatment on body weight and composition, fat content in the liver, glucose and lipid metabolism, and insulin resistance were monitored and compared to the control animals. Phloretin treatment significantly blocks high-fat diet-induced weight gain but did not induce weight loss in obese animals. Phloretin improved glucose homeostasis and insulin sensitivity and alleviated hepatic lipid accumulation. RT-PCR analysis showed that phloretin treatment suppresses expression of macrophage markers (F4/80 and Cd68) and pro-inflammatory genes (Mcp-1 and Ccr2) and enhances adiponectin gene expression in white adipose tissue. In addition, phloretin treatment elevated the expression of fatty acid oxidation genes such as carnitine palmitoyltransferase 1a and 1b (Cpt1a and Cpt1b) and reduced expression of monocyte chemoattractant protein-1 (Mcp-1), de novo lipogenesis transcriptional factor peroxisome proliferator-activated receptor-γ 2 (Pparγ2), and its target monoacylglycerol O-acyltransferase (Mgat-1) genes. These results provide direct evidence to support a possible use of phloretin for mitigation of obesity and maintenance of metabolic homeostasis.

  14. 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

  15. Transporters involved in pH and K + homeostasis affect pollen wall formation, male fertility, and embryo development

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

    Padmanaban, Senthilkumar; Czerny, Daniel D.; Levin, Kara A.

    Flowering plant genomes encode multiple cation/H + exchangers (CHXs) whose functions are largely unknown. AtCHX17, AtCHX18, and AtCHX19 are membrane transporters that modulate K+ and pH homeostasis and are localized in the dynamic endomembrane system. Loss of function reduced seed set, but the particular phase(s) of reproduction affected was not determined. Pollen tube growth and ovule targeting of chx17chx18chx19 mutant pollen appeared normal, but reciprocal cross experiments indicate a largely male defect. Although triple mutant pollen tubes reach ovules of a wild-type pistil and a synergid cell degenerated, half of those ovules were unfertilized or showed fertilization of the eggmore » or central cell, but not both female gametes. Fertility could be partially compromised by impaired pollen tube and/or sperm function as CHX19 and CHX18 are expressed in the pollen tube and sperm cell, respectively. When fertilization was successful in self-pollinated mutants, early embryo formation was retarded compared with embryos from wild-type ovules receiving mutant pollen. Thus CHX17 and CHX18 proteins may promote embryo development possibly through the endosperm where these genes are expressed. The reticulate pattern of the pollen wall was disorganized in triple mutants, indicating perturbation of wall formation during male gametophyte development. Lastly, as pH and cation homeostasis mediated by AtCHX17 affect membrane trafficking and cargo delivery, these results suggest that male fertility, sperm function, and embryo development are dependent on proper cargo sorting and secretion that remodel cell walls, plasma membranes, and extracellular factors.« less

  16. Transporters involved in pH and K + homeostasis affect pollen wall formation, male fertility, and embryo development

    DOE PAGES

    Padmanaban, Senthilkumar; Czerny, Daniel D.; Levin, Kara A.; ...

    2017-02-23

    Flowering plant genomes encode multiple cation/H + exchangers (CHXs) whose functions are largely unknown. AtCHX17, AtCHX18, and AtCHX19 are membrane transporters that modulate K+ and pH homeostasis and are localized in the dynamic endomembrane system. Loss of function reduced seed set, but the particular phase(s) of reproduction affected was not determined. Pollen tube growth and ovule targeting of chx17chx18chx19 mutant pollen appeared normal, but reciprocal cross experiments indicate a largely male defect. Although triple mutant pollen tubes reach ovules of a wild-type pistil and a synergid cell degenerated, half of those ovules were unfertilized or showed fertilization of the eggmore » or central cell, but not both female gametes. Fertility could be partially compromised by impaired pollen tube and/or sperm function as CHX19 and CHX18 are expressed in the pollen tube and sperm cell, respectively. When fertilization was successful in self-pollinated mutants, early embryo formation was retarded compared with embryos from wild-type ovules receiving mutant pollen. Thus CHX17 and CHX18 proteins may promote embryo development possibly through the endosperm where these genes are expressed. The reticulate pattern of the pollen wall was disorganized in triple mutants, indicating perturbation of wall formation during male gametophyte development. Lastly, as pH and cation homeostasis mediated by AtCHX17 affect membrane trafficking and cargo delivery, these results suggest that male fertility, sperm function, and embryo development are dependent on proper cargo sorting and secretion that remodel cell walls, plasma membranes, and extracellular factors.« less

  17. Ubiquitin-Specific Protease 2 Regulates Hepatic Gluconeogenesis and Diurnal Glucose Metabolism Through 11β-Hydroxysteroid Dehydrogenase 1

    PubMed Central

    Molusky, Matthew M.; Li, Siming; Ma, Di; Yu, Lei; Lin, Jiandie D.

    2012-01-01

    Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral-mediated expression of USP2 in the liver promotes hepatic glucose production and exacerbates glucose intolerance in diet-induced obese mice. In contrast, in vivo RNA interference (RNAi) knockdown of this factor improves systemic glycemic control. USP2 is a target gene of peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), a coactivator that integrates clock and energy metabolism, and is required for maintaining diurnal glucose homeostasis during restricted feeding. At the mechanistic level, USP2 regulates hepatic glucose metabolism through its induction of 11β-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling in the liver. Pharmacological inhibition and liver-specific RNAi knockdown of HSD1 significantly impair the stimulation of hepatic gluconeogenesis by USP2. Together, these studies delineate a novel pathway that links hormonal and circadian signals to gluconeogenesis and glucose homeostasis. PMID:22447855

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

    PubMed Central

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

    2015-01-01

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

  19. Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes*

    PubMed Central

    Taïb, Bouchra; Bouyakdan, Khalil; Hryhorczuk, Cécile; Rodaros, Demetra; Fulton, Stephanie; Alquier, Thierry

    2013-01-01

    Hypothalamic controls of energy balance rely on the detection of circulating nutrients such as glucose and long-chain fatty acids (LCFA) by the mediobasal hypothalamus (MBH). LCFA metabolism in the MBH plays a key role in the control of food intake and glucose homeostasis, yet it is not known if glucose regulates LCFA oxidation and esterification in the MBH and, if so, which hypothalamic cell type(s) and intracellular signaling mechanisms are involved. The aim of this study was to determine the impact of glucose on LCFA metabolism, assess the role of AMP-activated Kinase (AMPK), and to establish if changes in LCFA metabolism and its regulation by glucose vary as a function of the kind of LCFA, cell type, and brain region. We show that glucose inhibits palmitate oxidation via AMPK in hypothalamic neuronal cell lines, primary hypothalamic astrocyte cultures, and MBH slices ex vivo but not in cortical astrocytes and slice preparations. In contrast, oleate oxidation was not affected by glucose or AMPK inhibition in MBH slices. In addition, our results show that glucose increases palmitate, but not oleate, esterification into neutral lipids in neurons and MBH slices but not in hypothalamic astrocytes. These findings reveal for the first time the metabolic fate of different LCFA in the MBH, demonstrate AMPK-dependent glucose regulation of LCFA oxidation in both astrocytes and neurons, and establish metabolic coupling of glucose and LCFA as a distinguishing feature of hypothalamic nuclei critical for the control of energy balance. PMID:24240094

  20. Diabetes and kidney disease: the role of sodium-glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes.

    PubMed

    Mende, Christian W

    2017-03-01

    Patients with type 2 diabetes (T2D) often have coexisting chronic kidney disease (CKD). However, healthy renal function is crucial in maintaining glucose homeostasis, assuring that almost all of the filtered glucose is reabsorbed by the sodium glucose cotransporters (SGLTs) SGLT-1 and SGLT-2. In diabetes, an increased amount of glucose is filtered by the kidneys and SGLT-2 is upregulated, leading to increased glucose absorption and worsening hyperglycemia. Prolonged hyperglycemia contributes to the development of CKD by inducing metabolic and hemodynamic changes in the kidneys. Due to the importance of SGLT-2 in regulating glucose levels, investigation into SGLT-2 inhibitors was initiated as a glucose-dependent mechanism to control hyperglycemia, and there are three agents currently approved for use in the United States: dapagliflozin, canagliflozin, and empagliflozin. SGLT-2 inhibitors have been shown to reduce glycated hemoglobin (A1C), weight, and blood pressure, which not only affects glycemic control, but may also help slow the progression of renal disease by impacting the underlying mechanisms of kidney injury. In addition, SGLT-2 inhibitors have shown reductions in albuminuria, uric acid, and an increase in magnesium. Caution is advised when prescribing SGLT-2 inhibitors to patients with moderately impaired renal function and those at risk for volume depletion and hypotension. Published data on slowing of the development, as well as progression of CKD, is a hopeful indicator for the possible renal protection potential of this drug class. This narrative review provides an in-depth discussion of the interplay between diabetes, SGLT-2 inhibitors, and factors that affect kidney function.

  1. Physical activity and hypocaloric diet recovers osteoblasts homeostasis in women affected by abdominal obesity.

    PubMed

    Bimonte, Viviana M; Fittipaldi, Simona; Marocco, Chiara; Emerenziani, Gian Pietro; Fornari, Rachele; Guidetti, Laura; Poggiogalle, Eleonora; Nicolai, Emanuele; Di Luigi, Luigi; Donini, Lorenzo M; Baldari, Carlo; Lenzi, Andrea; Greco, Emanuela A; Migliaccio, Silvia

    2017-11-01

    Obesity is a multifactorial disease linked to metabolic chronic disorders such as diabetes, and hypertension. Also, it has recently been associated with skeletal alterations and low bone mineral density. We previously demonstrated that exposure of osteoblasts to sera of sedentary subjects affected by obesity alters cell homeostasis in vitro, leading to disruption of intracellular differentiation pathways and cellular activity. Thus, the purpose of the present study has been to evaluate whether sera of sedentary obese women, subjected to physical activity and hypocaloric diet, could recover osteoblast homeostasis in vitro as compared to the sera of same patients before intervention protocol. To this aim, obese women were evaluated at time 0 and after 4, 6, and 12 months of individualized prescribed physical activity and hypocaloric diet. Dual-energy-X-ray absorptiometry measurements were performed at each time point, as well as blood was collected at the same points. Cells were incubated with sera of subjects before and after physical activity as described: obese at baseline and after for 4, 6, and 12 months of physical activity and nutritional protocol intervention. Osteoblasts exposed to sera of patients, who displayed increased lean and decreased fat mass (from 55.5 ± 6.5 to 57.1 ± 5.6% p ≤ 0.05; from 44.5 ± 1.1 to 40.9 ± 2.6% p ≤ 0.01 respectively), showed a time-dependent increase of Wnt/β-catenin signaling, versus cells exposed to sera of obese patients before intervention protocol, suggesting recovery of osteoblast homeostasis upon improvement of body composition. An increase in β-catenin nuclear accumulation and nuclear translocation was also observed, accompanied by an increase in Adiponectin receptor 1 protein expression, suggesting positive effect on cell differentiation program. Furthermore, a decrease in sclerostin amount and an increase of type 1 procollagen amino-terminal-propeptide were depicted as compared to

  2. Novel association between the nonsynonymous A803G polymorphism of the N-acetyltransferase 2 gene and impaired glucose homeostasis in obese children and adolescents.

    PubMed

    Marzuillo, Pierluigi; Di Sessa, Anna; Umano, Giuseppina Rosaria; Nunziata, Luigia; Cirillo, Grazia; Perrone, Laura; Miraglia Del Giudice, Emanuele; Grandone, Anna

    2017-09-01

    The N-acetyltransferase 2 ( NAT2 ) A803G polymorphism has been associated with decreased insulin sensitivity in a large adult population with the A allele associated with insulin-resistance-related traits. Evaluate the association of this polymorphism with anthropometric and metabolic parameters in obese children and adolescents. A total of 748 obese children and adolescents were enrolled. Anthropometric and laboratory data were collected. During oral glucose tolerance test, the presence of a possible exaggerated plasma glucose excursion at 1 h (1HPG) or impaired glucose tolerance (IGT) was considered. Homeostasis model assessment, oral disposition index (oDI) and insulinogenic index (IDI) were calculated. Patients were genotyped for the NAT2 A803G polymorphism. The prevalence of both IGT and elevated-1HPG was higher in children carrying the A803 allele (P = .02 and P = .03). Moreover, this allele was associated with both oDI and IGI reduction (P = .01). No differences among the NAT2 A803G genotypes for the other parameters were shown. Children homozygous for the A allele presented an odds ratio (OR), to show IGT of 4.9 (P = .01). Children both homozygous and heterozygous for the A allele had higher risk to show elevated-1HPG (OR of 2.7, P = .005; and OR = 2.3, P = .005) compared with patients homozygous for the NAT2 803G allele. NAT2 A803 allele seems to play a role in worsening the destiny of obese children carrying it, predisposing them to elevated-1HPG and IGT and then to a possible future type 2 diabetes mellitus throughout an impairment of pancreatic β-cellular insulin secretion as suggested by oDI and IGI reduction. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. The Identification of Novel Protein-Protein Interactions in Liver that Affect Glucagon Receptor Activity

    PubMed Central

    Froese, Sean; Dai, Feihan F.; Robitaille, Mélanie; Bhattacharjee, Alpana; Huang, Xinyi; Jia, Weiping; Angers, Stéphane; Wheeler, Michael B.; Wei, Li

    2015-01-01

    Glucagon regulates glucose homeostasis by controlling glycogenolysis and gluconeogenesis in the liver. Exaggerated and dysregulated glucagon secretion can exacerbate hyperglycemia contributing to type 2 diabetes (T2D). Thus, it is important to understand how glucagon receptor (GCGR) activity and signaling is controlled in hepatocytes. To better understand this, we sought to identify proteins that interact with the GCGR to affect ligand-dependent receptor activation. A Flag-tagged human GCGR was recombinantly expressed in Chinese hamster ovary (CHO) cells, and GCGR complexes were isolated by affinity purification (AP). Complexes were then analyzed by mass spectrometry (MS), and protein-GCGR interactions were validated by co-immunoprecipitation (Co-IP) and Western blot. This was followed by studies in primary hepatocytes to assess the effects of each interactor on glucagon-dependent glucose production and intracellular cAMP accumulation, and then in immortalized CHO and liver cell lines to further examine cell signaling. Thirty-three unique interactors were identified from the AP-MS screening of GCGR expressing CHO cells in both glucagon liganded and unliganded states. These studies revealed a particularly robust interaction between GCGR and 5 proteins, further validated by Co-IP, Western blot and qPCR. Overexpression of selected interactors in mouse hepatocytes indicated that two interactors, LDLR and TMED2, significantly enhanced glucagon-stimulated glucose production, while YWHAB inhibited glucose production. This was mirrored with glucagon-stimulated cAMP production, with LDLR and TMED2 enhancing and YWHAB inhibiting cAMP accumulation. To further link these interactors to glucose production, key gluconeogenic genes were assessed. Both LDLR and TMED2 stimulated while YWHAB inhibited PEPCK and G6Pase gene expression. In the present study, we have probed the GCGR interactome and found three novel GCGR interactors that control glucagon-stimulated glucose production

  4. Microbial Regulation of Glucose Metabolism and Cell-Cycle Progression in Mammalian Colonocytes

    PubMed Central

    Donohoe, Dallas R.; Wali, Aminah; Brylawski, Bruna P.; Bultman, Scott J.

    2012-01-01

    A prodigious number of microbes inhabit the human body, especially in the lumen of the gastrointestinal (GI) tract, yet our knowledge of how they regulate metabolic pathways within our cells is rather limited. To investigate the role of microbiota in host energy metabolism, we analyzed ATP levels and AMPK phosphorylation in tissues isolated from germfree and conventionally-raised C57BL/6 mice. These experiments demonstrated that microbiota are required for energy homeostasis in the proximal colon to a greater extent than other segments of the GI tract that also harbor high densities of bacteria. This tissue-specific effect is consistent with colonocytes utilizing bacterially-produced butyrate as their primary energy source, whereas most other cell types utilize glucose. However, it was surprising that glucose did not compensate for butyrate deficiency. We measured a 3.5-fold increase in glucose uptake in germfree colonocytes. However, 13C-glucose metabolic-flux experiments and biochemical assays demonstrated that they shifted their glucose metabolism away from mitochondrial oxidation/CO2 production and toward increased glycolysis/lactate production, which does not yield enough ATPs to compensate. The mechanism responsible for this metabolic shift is diminished pyruvate dehydrogenase (PDH) levels and activity. Consistent with perturbed PDH function, the addition of butyrate, but not glucose, to germfree colonocytes ex vivo stimulated oxidative metabolism. As a result of this energetic defect, germfree colonocytes exhibited a partial block in the G1-to-S-phase transition that was rescued by a butyrate-fortified diet. These data reveal a mechanism by which microbiota regulate glucose utilization to influence energy homeostasis and cell-cycle progression of mammalian host cells. PMID:23029553

  5. Hypothalamic glucose-sensing: role of Glia-to-neuron signaling.

    PubMed

    Tonon, M C; Lanfray, D; Castel, H; Vaudry, H; Morin, F

    2013-12-01

    The hypothalamus senses hormones and nutrients in order to regulate energy balance. In particular, detection of hypothalamic glucose levels has been shown to regulate both feeding behavior and peripheral glucose homeostasis, and impairment of this regulatory system is believed to be involved in the development of obesity and diabetes. Several data clearly demonstrate that glial cells are key elements in the perception of glucose, constituting with neurons a "glucose-sensing unit". Characterization of this interplay between glia and neurons represents an exciting challenge, and will undoubtedly contribute to identify new candidates for therapeutic intervention. The purpose of this review is to summarize the current data that stress the importance of glia in central glucose-sensing. The nature of the glia-to-neuron signaling is discussed, with a special focus on the endozepine ODN, a potent anorexigenic peptide that is highly expressed in hypothalamic glia. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice.

    PubMed

    Tudurí, E; Beiroa, D; Porteiro, B; López, M; Diéguez, C; Nogueiras, R

    2015-08-01

    To investigate the role of brain glucagon-like peptide-1 (GLP-1) in pancreatic β-cell function. To determine the role of brain GLP-1 receptor (GLP-1R) on β-cell function, we administered intracerebroventricular (i.c.v.) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), in both an acute and a chronic setting. We observed that acute i.c.v. GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired glucose excursion after a glucose load. Sustained activation of central nervous system GLP-1R, however, did not produce any effect on either GSIS or glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with i.c.v. GLP-1 resulted in no differences compared with controls. In addition, in mice fed a high-fat diet we observed that acute i.c.v. GLP-1 infusion improved glucose tolerance without changes in GSIS, while chronic GLP-1R activation had no effect on glucose homeostasis. Our results indicate that, under non-clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents. © 2015 John Wiley & Sons Ltd.

  7. pH homeostasis links the nutrient sensing PKA/TORC1/Sch9 ménage-à-trois to stress tolerance and longevity.

    PubMed

    Deprez, Marie-Anne; Eskes, Elja; Wilms, Tobias; Ludovico, Paula; Winderickx, Joris

    2018-01-12

    The plasma membrane H + -ATPase Pma1 and the vacuolar V-ATPase act in close harmony to tightly control pH homeostasis, which is essential for a vast number of physiological processes. As these main two regulators of pH are responsive to the nutritional status of the cell, it seems evident that pH homeostasis acts in conjunction with nutrient-induced signalling pathways. Indeed, both PKA and the TORC1-Sch9 axis influence the proton pumping activity of the V-ATPase and possibly also of Pma1. In addition, it recently became clear that the proton acts as a second messenger to signal glucose availability via the V-ATPase to PKA and TORC1-Sch9. Given the prominent role of nutrient signalling in longevity, it is not surprising that pH homeostasis has been linked to ageing and longevity as well. A first indication is provided by acetic acid, whose uptake by the cell induces toxicity and affects longevity. Secondly, vacuolar acidity has been linked to autophagic processes, including mitophagy. In agreement with this, a decline in vacuolar acidity was shown to induce mitochondrial dysfunction and shorten lifespan. In addition, the asymmetric inheritance of Pma1 has been associated with replicative ageing and this again links to repercussions on vacuolar pH. Taken together, accumulating evidence indicates that pH homeostasis plays a prominent role in the determination of ageing and longevity, thereby providing new perspectives and avenues to explore the underlying molecular mechanisms.

  8. Pak3 promotes cell cycle exit and differentiation of β-cells in the embryonic pancreas and is necessary to maintain glucose homeostasis in adult mice.

    PubMed

    Piccand, Julie; Meunier, Aline; Merle, Carole; Jia, Zhengping; Barnier, Jean-Vianney; Gradwohl, Gérard

    2014-01-01

    The transcription factor neurogenin3 (Ngn3) triggers islet cell differentiation in the developing pancreas. However, little is known about the molecular mechanisms coupling cell cycle exit and differentiation in Ngn3(+) islet progenitors. We identified a novel effector of Ngn3 endocrinogenic function, the p21 protein-activated kinase Pak3, known to control neuronal differentiation and implicated in X-linked intellectual disability in humans. We show that Pak3 expression is initiated in Ngn3(+) endocrine progenitor cells and next maintained in maturing hormone-expressing cells during pancreas development as well as in adult islet cells. In Pak3-deficient embryos, the proliferation of Ngn3(+) progenitors and β-cells is transiently increased concomitantly with an upregulation of Ccnd1. β-Cell differentiation is impaired at E15.5 but resumes at later stages. Pak3-deficient mice do not develop overt diabetes but are glucose intolerant under high-fat diet (HFD). In the intestine, Pak3 is expressed in enteroendocrine cells but is not necessary for their differentiation. Our results indicate that Pak3 is a novel regulator of β-cell differentiation and function. Pak3 acts downstream of Ngn3 to promote cell cycle exit and differentiation in the embryo by a mechanism that might involve repression of Ccnd1. In the adult, Pak3 is required for the proper control of glucose homeostasis under challenging HFD.

  9. [Effects of barley flake on metabolism of glucose and lipids in the patients with impaired fasting glucose].

    PubMed

    Bi, Mingxin; Niu, Yucun; Li, Xue; Li, Ying; Sun, Changhao

    2013-09-01

    To investigate the effects of barley flake (BF) on the glucose-lipid metabolism in patients with impaired fasting glucose (IFG). 100 patients with IFG were divided into the oat meal (OM) control group and barley flake experimental group for three months intervention according to randomized controlled trail (RCT). Biochemical indicators, glucose-lipid metabolism related enzymes, the area under curve (AUC) of blood glucose and insulin after oral glucose tolerance test (OGTT) were assessed before and after intervention. In addition, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated by FBG (mmol/L) x INS (microU/L)/ 22.5. At the end of the three month active intervention, the mean fasting blood glucose (FBG) and insulin (INS) in the patients with BF treatment decreased by 9.26% (P < 0.001) and 13.37% (P = 0.001) separately compared with that in patients with OM treatment; meanwhile, total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in patients with BF treatment also decreased by 7.20% (P < 0.001) and 9.42% (P = 0. 002), respectively. Glycosylated hemoglobin (HbA1c), HOMA-IR, total glyceride (TG), Apo-B, the AUC of blood glucose and insulin after OGTT were also significantly decreased separately (P < 0.01 or < 0.05 ). However, statistically significant differences failed to be found in HDL-C, Apo-A, ALP and SOD between these two groups. BF had favorable effect on improvement of glucose-lipid metabolism in the patients with impaired fasting glucose.

  10. The flavonoid-rich fraction of Coreopsis tinctoria promotes glucose tolerance regain through pancreatic function recovery in streptozotocin-induced glucose-intolerant rats.

    PubMed

    Dias, Teresa; Bronze, Maria Rosário; Houghton, Peter J; Mota-Filipe, Hélder; Paulo, Alexandra

    2010-11-11

    (8.35 ± 0.69 U/L) demonstrating recovery of pancreatic function. On the other hand, treatment with standard antioxidant Trolox had no effect on glucose homeostasis of glucose-intolerant rats. The oral treatment with Coreopsis tinctoria fraction caused no hepatotoxicity, as determined by blood alanine and aspartate transaminases, and had also no effect on glucose homeostasis and pancreatic function of normal rats. AcOEt fraction, containing the same amount of marein as the infusion, promoted glucose tolerance regain in the rats more quickly, which means that the bioactivity is probably due to the several flavonoids present in Coreopsis tinctoria extracts and not to marein alone. The results also strongly suggest that these compounds act by promoting pancreatic cell function recovery from STZ-induced injury, possibly through a mechanism of action other than merely antioxidant mediated. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  11. Activation of p38 in C2C12 myotubes following ATP depletion depends on extracellular glucose.

    PubMed

    Hsu, Chia George; Burkholder, Thomas J

    2015-06-01

    Muscle cells adjust their glucose metabolism in response to myriad stimuli, and particular attention has been paid to glucose metabolism after contraction, ATP depletion, and insulin stimulation. Each of these requires translocation of GLUT4 to the cell membrane, and may require activation of glucose transporters by p38. In contrast, AICAR stimulates glucose transport without activation of p38, suggesting that p38 activation may be an indirect consequence of accelerated glucose transport or metabolism. This study was designed to investigate the contribution of AMPK and p38 to ATP homeostasis and glucose metabolism to test the hypothesis that p38 reflects glycolytic activity rather than controls glucose uptake. Treating mature myotubes with rotenone caused transient ATP depletion in 15 min with recovery by 120 min, associated with increased lactate production. Both ACC and p38 were rapidly phosphorylated, but ACC remained phosphorylated while p38 phosphorylation declined as ATP recovered. AMPK inhibition blocked ATP recovery, lactate production, and phosphorylation of p38 and ACC. Inhibition of p38 had little effect. AICAR induced ACC phosphorylation, but not lactate production or p38 phosphorylation. Finally, removing extracellular glucose potentiated rotenone-induced AMPK activation, but reduced lactate generation, ATP recovery and p38 activation. Thus, glucose metabolism is highly sensitive to ATP homeostasis via AMPK activity, but p38 activity is dispensable. Although p38 is strongly phosphorylated during ATP depletion, this appears to be an indirect consequence of accelerated glycolysis.

  12. Regulation of hepatic glucose metabolism in health and disease

    PubMed Central

    Petersen, Max C.; Vatner, Daniel F.; Shulman, Gerald I.

    2017-01-01

    The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis. PMID:28731034

  13. Glucose Regulates Cyclin D2 Expression in Quiescent and Replicating Pancreatic β-Cells Through Glycolysis and Calcium Channels

    PubMed Central

    Salpeter, Seth J.; Klochendler, Agnes; Weinberg-Corem, Noa; Porat, Shay; Granot, Zvi; Shapiro, A. M. James; Magnuson, Mark A.; Eden, Amir; Grimsby, Joseph; Glaser, Benjamin

    2011-01-01

    Understanding the molecular triggers of pancreatic β-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in β-cell proliferation and mass homeostasis, but its specific function in β-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent β-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the β-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G2-M phases of each β-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent β-cells and modulates the down-regulation of cyclin D2 in replicating β-cells. These data challenge the standard model for regulation of cyclin D2 during the cell division cycle and suggest cyclin D2 as a molecular link between glucose levels and β-cell replication. PMID:21521747

  14. Targeting hepatic glucose output in the treatment of type 2 diabetes

    PubMed Central

    Rines, Amy K.; Sharabi, Kfir; Tavares, Clint D. J.; Puigserver, Pere

    2017-01-01

    Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis resulting in hyperglycemia. Although current diabetes treatments have exhibited some success in lowering blood glucose, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycemia. Novel diabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver in order to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes. PMID:27516169

  15. Osteopontin-a Alters Glucose Homeostasis in Anchorage-Independent Breast Cancer Cells*

    PubMed Central

    Wang, Bo; Kennedy, Michael A.; Weber, Georg F.

    2013-01-01

    Invasive breast tumor cells generate three splice variants of the metastasis gene osteopontin, while non-invasive breast cells express only the unspliced form or no osteopontin at all. One role for osteopontin in tumor progression is the support of anchorage-independence. Here we show that the full-length gene product, osteopontin-a, induces a gene expression profile that is associated with tissue remodeling and directed movement/sprouting. This occurs via signals through STAT1 and STAT3 to snglycero-3-phosphocholine. Osteopontin-a upregulates the levels of glucose in breast cancer cells, likely through STAT3 and its transcriptional targets apolipoprotein D and IGFBP5. The splice variants osteopontin-a and osteopontin-c may synergize, with each form activating signal transduction pathways that are distinct from the other. The elevated glucose is used by osteopontin-c dependent signals to generate chemical energy (Shi et al. manuscript submitted). The splice variant-specific metabolic effects of osteopontin add a novel aspect to the pro-metastatic functions of this molecule. PMID:24157812

  16. Bloodletting therapy in hemochromatosis: Does it affect trace element homeostasis?

    PubMed

    Bolann, Bjørn J; Distante, Sonia; Mørkrid, Lars; Ulvik, Rune J

    2015-01-01

    Hemochromatosis is the most common hereditary disorder in the Nordic population, if left untreated it can result in severe parenchymal iron accumulation. Bloodletting is mainstay treatment. Iron and trace elements partially share cellular uptake and transport mechanisms, and the aim of the present study was to see if bloodletting for hemochromatosis affects trace elements homeostasis. We recruited patients referred for diagnosis and treatment of hemochromatosis, four women and 22 men 23-68 years of age. Thirteen were C282Y homozygote, one was C282Y heterozygote, three were H63D homozygote, seven were compound heterozygote and two had none of the mutations above. Iron and liver function tests were performed; serum levels of trace elements were measured using inductively coupled plasma mass spectrometry. Results before the start of treatment and after normalization of iron parameters were compared. On completion of the bloodlettings the following average serum concentrations increased: Co from 5.6 to 11.5 nmol/L, serum Cu 16.2-17.6 μmol/L, Ni increased from 50.0 to 52.6 nmol/L and Sb from 13.2 to 16.3 nmol/L. Average serum Mn concentration declined from 30.2 to 28.3 nmol/L. All changes were statistically significant (by paired t-test). B, Ba, Cs, Mo, Se, Sr and Zn were not significantly changed. We conclude that bloodlettings in hemochromatosis lead to changes in trace element metabolism, including increased absorption of potentially toxic elements. Copyright © 2014 Elsevier GmbH. All rights reserved.

  17. Procyanidins improve some disrupted glucose homoeostatic situations: an analysis of doses and treatments according to different animal models.

    PubMed

    Pinent, Montserrat; Cedó, Lidia; Montagut, Gemma; Blay, Mayte; Ardévol, Anna

    2012-01-01

    This review analyses the potential beneficial effects of procyanidins, the main class of flavonoids, in situations in which glucose homeostasis is disrupted. Because the disruption of glucose homeostasis can occur as a result of various causes, we critically review the effects of procyanidins based on the specific origin of each type of disruption. Where little or no insulin is present (Type I diabetic animals), summarized studies of procyanidin treatment suggest that procyanidins have a short-lived insulin-mimetic effect on the internal targets of the organism, an effect not reproduced in normoglycemic, normoinsulinemic healthy animals. Insulin resistance (usually linked to hyperinsulinemia) poses a very different situation. Preventive studies using fructose-fed models indicate that procyanidins may be useful in preventing the induction of damage and thus in limiting hyperglycemia. But the results of other studies using models such as high-fat diet treated rats or genetically obese animals are controversial. Although the effects on glucose parameters are hazy, it is known that procyanidins target key tissues involved in its homeostasis. Interestingly, all available data suggest that procyanidins are more effective when administered in one acute load than when mixed with food.

  18. Serum miRNA levels are related to glucose homeostasis and islet autoantibodies in children with high risk for type 1 diabetes.

    PubMed

    Åkerman, Linda; Casas, Rosaura; Ludvigsson, Johnny; Tavira, Beatriz; Skoglund, Camilla

    2018-01-01

    Micro RNAs (miRNAs) are promising disease biomarkers due to their high stability. Their expression in serum is altered in type 1 diabetes, but whether deviations exist in individuals with high risk for type 1 diabetes remains unexplored. We therefore assessed serum miRNAs in high-risk individuals (n = 21) positive for multiple islet autoantibodies, age-matched healthy children (n = 17) and recent-onset type 1 diabetes patients (n = 8), using Serum/Plasma Focus microRNA PCR Panels from Exiqon. The miRNA levels in the high-risk group were similar to healthy controls, and no specific miRNA profile was identified for the high-risk group. However, serum miRNAs appeared to reflect glycemic status and ongoing islet autoimmunity in high-risk individuals, since several miRNAs were associated to glucose homeostasis and autoantibody titers. High-risk individuals progressing to clinical disease after the sampling could not be clearly distinguished from non-progressors, while miRNA expression in the type 1 diabetes group deviated significantly from high-risk individuals and healthy controls, perhaps explained by major metabolic disturbances around the time of diagnosis.

  19. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism.

    PubMed

    Duparc, Thibaut; Plovier, Hubert; Marrachelli, Vannina G; Van Hul, Matthias; Essaghir, Ahmed; Ståhlman, Marcus; Matamoros, Sébastien; Geurts, Lucie; Pardo-Tendero, Mercedes M; Druart, Céline; Delzenne, Nathalie M; Demoulin, Jean-Baptiste; van der Merwe, Schalk W; van Pelt, Jos; Bäckhed, Fredrik; Monleon, Daniel; Everard, Amandine; Cani, Patrice D

    2017-04-01

    To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism. To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88 . We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH). Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis. Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans. Published by the BMJ Publishing Group Limited

  20. Phloretin promotes adipocyte differentiation in vitro and improves glucose homeostasis in vivo.

    PubMed

    Shu, Gang; Lu, Nai-Sheng; Zhu, Xiao-Tong; Xu, Yong; Du, Min-Qing; Xie, Qiu-Ping; Zhu, Can-Jun; Xu, Qi; Wang, Song-Bo; Wang, Li-Na; Gao, Ping; Xi, Qian-Yun; Zhang, Yong-Liang; Jiang, Qing-Yan

    2014-12-01

    Adipocyte dysfunction is associated with many metabolic diseases such as obesity, insulin resistance and diabetes. Previous studies found that phloretin promotes 3T3-L1 cells differentiation, but the underlying mechanisms for phloretin's effects on adipogenesis remain unclear. In this study, we demonstrated that phloretin enhanced the lipid accumulation in porcine primary adipocytes in a time-dependent manner. Furthermore, phloretin increased the utilization of glucose and nonesterified fatty acid, while it decreased the lactate output. Microarray analysis revealed that genes associated with peroxisome proliferator-activated receptor-γ (PPARγ), mitogen-activated protein kinase and insulin signaling pathways were altered in response to phloretin. We further confirmed that phloretin enhanced expression of PPARγ, CAAT enhancer binding protein-α (C/EBPα) and adipose-related genes, such as fatty acids translocase and fatty acid synthase. In addition, phloretin activated the Akt (Thr308) and extracellular signal-regulated kinase, and therefore, inactivated Akt targets protein. Wortmannin effectively blocked the effect of phloretin on Akt activity and the protein levels of PPARγ, C/EBPα and fatty acid binding protein-4 (FABP4/aP2). Oral administration of 5 or 10 mg/kg phloretin to C57BL BKS-DB mice significantly decreased the serum glucose level and improved glucose tolerance. In conclusion, phloretin promotes the adipogenesis of porcine primary preadipocytes through Akt-associated signaling pathway. These findings suggested that phloretin might be able to increase insulin sensitivity and alleviate the metabolic diseases. Copyright © 2014. Published by Elsevier Inc.

  1. Sensing of glucose in the brain.

    PubMed

    Thorens, Bernard

    2012-01-01

    The brain, and in particular the hypothalamus and brainstem, have been recognized for decades as important centers for the homeostatic control of feeding, energy expenditure, and glucose homeostasis. These structures contain neurons and neuronal circuits that may be directly or indirectly activated or inhibited by glucose, lipids, or amino acids. The detection by neurons of these nutrient cues may become deregulated, and possibly cause metabolic diseases such as obesity and diabetes. Thus, there is a major interest in identifying these neurons, how they respond to nutrients, the neuronal circuits they form, and the physiological function they control. Here I will review some aspects of glucose sensing by the brain. The brain is responsive to both hyperglycemia and hypoglycemia, and the glucose sensing cells involved are distributed in several anatomical sites that are connected to each other. These eventually control the activity of the sympathetic or parasympathetic nervous system, which regulates the function of peripheral organs such as liver, white and brown fat, muscle, and pancreatic islets alpha and beta cells. There is now evidence for an extreme diversity in the sensing mechanisms used, and these will be reviewed.

  2. Roles of Chlorogenic Acid on Regulating Glucose and Lipids Metabolism: A Review

    PubMed Central

    Meng, Shengxi; Cao, Jianmei; Feng, Qin; Peng, Jinghua; Hu, Yiyang

    2013-01-01

    Intracellular glucose and lipid metabolic homeostasis is vital for maintaining basic life activities of a cell or an organism. Glucose and lipid metabolic disorders are closely related with the occurrence and progression of diabetes, obesity, hepatic steatosis, cardiovascular disease, and cancer. Chlorogenic acid (CGA), one of the most abundant polyphenol compounds in the human diet, is a group of phenolic secondary metabolites produced by certain plant species and is an important component of coffee. Accumulating evidence has demonstrated that CGA exerts many biological properties, including antibacterial, antioxidant, and anticarcinogenic activities. Recently, the roles and applications of CGA, particularly in relation to glucose and lipid metabolism, have been highlighted. This review addresses current studies investigating the roles of CGA in glucose and lipid metabolism. PMID:24062792

  3. Minireview: Toward the Establishment of a Link between Melatonin and Glucose Homeostasis: Association of Melatonin MT2 Receptor Variants with Type 2 Diabetes

    PubMed Central

    Karamitri, Angeliki; Renault, Nicolas; Clement, Nathalie; Guillaume, Jean-Luc

    2013-01-01

    The existence of interindividual variations in G protein-coupled receptor sequences has been recognized early on. Recent advances in large-scale exon sequencing techniques are expected to dramatically increase the number of variants identified in G protein-coupled receptors, giving rise to new challenges regarding their functional characterization. The current minireview will illustrate these challenges based on the MTNR1B gene, which encodes the melatonin MT2 receptor, for which exon sequencing revealed 40 rare nonsynonymous variants in the general population and in type 2 diabetes (T2D) cohorts. Functional characterization of these MT2 mutants revealed 14 mutants with loss of Gi protein activation that associate with increased risk of T2D development. This repertoire of disease-associated mutants is a rich source for structure-activity studies and will help to define the still poorly understood role of melatonin in glucose homeostasis and T2D development in humans. Defining the functional defects in carriers of rare MT2 mutations will help to provide personalized therapies to these patients in the future. PMID:23798576

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

    PubMed

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

    2012-01-01

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

  5. Effects of Bisphenol A on glucose homeostasis and brain insulin signaling pathways in male mice.

    PubMed

    Fang, Fangfang; Chen, Donglong; Yu, Pan; Qian, Wenyi; Zhou, Jing; Liu, Jingli; Gao, Rong; Wang, Jun; Xiao, Hang

    2015-02-01

    The potential effects of Bisphenol A (BPA) on peripheral insulin resistance have recently gained more attention, however, its functions on brain insulin resistance are still unknown. The aim of the present study was to investigate the effects of BPA on insulin signaling and glucose transport in mouse brain. The male mice were administrated of 100 μg/kg/day BPA or vehicle for 15 days then challenged with glucose and insulin tolerance tests. The insulin levels were detected with radioimmunoassay (RIA), and the insulin signaling pathways were investigated by Western blot. Our results revealed that BPA significantly increased peripheral plasma insulin levels, and decreased the insulin signals including phosphorylated insulin receptor (p-IR), phosphorylated insulin receptor substrate 1 (p-IRS1), phosphorylated protein kinase B (p-AKT), phosphorylated glycogen synthase kinase 3β (p-GSK3β) and phosphorylated extracellular regulated protein kinases (p-ERK1/2) in the brain, though insulin expression in both hippocampus and profrontal cortex was increased. In parallel, BPA exposure might contribute to glucose transport disturbance in the brain since the expression of glucose transporters were markedly decreased. In conclusion, BPA exposure perturbs the insulin signaling and glucose transport in the brain, therefore, it might be a risk factor for brain insulin resistance. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs

    PubMed Central

    Frost, Robert J. A.; Olson, Eric N.

    2011-01-01

    Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. MicroRNAs are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. Here we show that the Let-7 family of microRNAs regulates glucose metabolism in multiple organs. Global and pancreas-specific overexpression of Let-7 in mice resulted in impaired glucose tolerance and reduced glucose-induced pancreatic insulin secretion. Mice overexpressing Let-7 also had decreased fat mass and body weight, as well as reduced body size. Global knockdown of the Let-7 family with an antimiR was sufficient to prevent and treat impaired glucose tolerance in mice with diet-induced obesity, at least in part by improving insulin sensitivity in liver and muscle. AntimiR treatment of mice on a high-fat diet also resulted in increased lean and muscle mass, but not increased fat mass, and prevented ectopic fat deposition in the liver. These findings demonstrate that Let-7 regulates multiple aspects of glucose metabolism and suggest antimiR-induced Let-7 knockdown as a potential treatment for type 2 diabetes mellitus. Furthermore, our Cre-inducible Let-7-transgenic mice provide a unique model for studying tissue-specific aspects of body growth and type 2 diabetes. PMID:22160727

  7. Pinitol Supplementation Does Not Affect Insulin-Mediated Glucose Metabolism and Muscle Insulin Receptor Content and Phosphorylation in Older Humans12

    PubMed Central

    Campbell, Wayne W.; Haub, Mark D.; Fluckey, James D.; Ostlund, Richard E.; Thyfault, John P.; Morse-Carrithers, Hannah; Hulver, Matthew W.; Birge, Zonda K.

    2008-01-01

    This study assessed the effect of oral pinitol supplementation on oral and intravenous glucose tolerances and on skeletal muscle insulin receptor content and phosphorylation in older people. Fifteen people (6 men, 9 women; age 66 ± 8 y; BMI 27.9 ± 3.3 kg/m2; hemoglobin A1c 5.39 ± 0.46%, mean ± SD) completed a 7-wk protocol. Subjects were randomly assigned to groups that during wk 2−7 consumed twice daily either a non-nutritive beverage (Placebo group, n = 8) or the same beverage with 1000 mg pinitol dissolved into it (Pinitol group, n = 7, total dose = 2000 mg pinitol/d). Testing was done at wk 1 and wk 7. In the Pinitol group with supplementation, 24-h urinary pinitol excretion increased 17-fold. The fasting concentrations of glucose, insulin, and C-peptide, and the 180-min area under the curve for these compounds, in response to oral (75 g) and intravenous (300 mg/kg) glucose tolerance challenges, were unchanged from wk 1 to wk 7 and were not influenced by pinitol. Also, pinitol did not affect indices of hepatic and whole-body insulin sensitivity from the oral glucose tolerance test and indices of insulin sensitivity, acute insulin response to glucose, and glucose effectiveness from the intravenous glucose tolerance test, estimated using minimal modeling. Pinitol did not differentially affect total insulin receptor content and insulin receptor phosphotyrosine 1158 and insulin receptor phosphotyrosine 1162/1163 activation in vastus lateralis samples taken during an oral-glucose–induced hyperglycemic and hyperinsulinemic state. These data suggest that pinitol supplementation does not influence whole-body insulin-mediated glucose metabolism and muscle insulin receptor content and phosphorylation in nondiabetic, older people. PMID:15514265

  8. Sodium-Glucose linked transporter 2 (SGLT2) inhibitors--fighting diabetes from a new perspective.

    PubMed

    Angelopoulos, Theodoros P; Doupis, John

    2014-06-01

    Sodium-Glucose linked transporter 2 (SGLT2) inhibitors are a new family of antidiabetic pharmaceutical agents whose action is based on the inhibition of the glucose reabsorption pathway, resulting in glucosuria and a consequent reduction of the blood glucose levels, in patients with type 2 diabetes mellitus. Apart from lowering both fasting and postprandial blood glucose levels, without causing hypoglycemia, SGLT2 inhibitors have also shown a reduction in body weight and the systolic blood pressure. This review paper explores the renal involvement in glucose homeostasis providing also the latest safety and efficacy data for the European Medicines Agency and U.S. Food and Drug Administration approved SGLT2 inhibitors, looking, finally, into the future of this novel antidiabetic category of pharmaceutical agents.

  9. Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis.

    PubMed

    Mehta, Minal B; Shewale, Swapnil V; Sequeira, Raymond N; Millar, John S; Hand, Nicholas J; Rader, Daniel J

    2017-06-23

    Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (G L ) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion ( Ppp1r3b Δ hep ) or liver-specific overexpression of Ppp1r3b The Ppp1r3b deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic Ppp1r3b had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in Ppp1r3b Δ hep mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of Ppp1r3b enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12-36 h) were protected from blood ketone-body accumulation, unlike control and Ppp1r3b Δ hep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion.

    PubMed

    Houtz, Jessica; Borden, Philip; Ceasrine, Alexis; Minichiello, Liliana; Kuruvilla, Rejji

    2016-11-07

    Insulin secretion by pancreatic islet β cells is critical for glucose homeostasis, and a blunted β cell secretory response is an early deficit in type 2 diabetes. Here, we uncover a regulatory mechanism by which glucose recruits vascular-derived neurotrophins to control insulin secretion. Nerve growth factor (NGF), a classical trophic factor for nerve cells, is expressed in pancreatic vasculature while its TrkA receptor is localized to islet β cells. High glucose rapidly enhances NGF secretion and increases TrkA phosphorylation in mouse and human islets. Tissue-specific deletion of NGF or TrkA, or acute disruption of TrkA signaling, impairs glucose tolerance and insulin secretion in mice. We show that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. Furthermore, NGF treatment augments glucose-induced insulin secretion in human islets. These findings reveal a non-neuronal role for neurotrophins and identify a new regulatory pathway in insulin secretion that can be targeted to ameliorate β cell dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Physical activity into the meal glucose-insulin model of type 1 diabetes: in silico studies.

    PubMed

    Man, Chiara Dalla; Breton, Marc D; Cobelli, Claudio

    2009-01-01

    A simulation model of a glucose-insulin system accounting for physical activity is needed to reliably simulate normal life conditions, thus accelerating the development of an artificial pancreas. In fact, exercise causes a transient increase of insulin action and may lead to hypoglycemia. However, physical activity is difficult to model. In the past, it was described indirectly as a rise in insulin. Recently, a new parsimonious model of exercise effect on glucose homeostasis has been proposed that links the change in insulin action and glucose effectiveness to heart rate (HR). The aim of this study was to plug this exercise model into our recently proposed large-scale simulation model of glucose metabolism in type 1 diabetes to better describe normal life conditions. The exercise model describes changes in glucose-insulin dynamics in two phases: a rapid on-and-off change in insulin-independent glucose clearance and a rapid-on/slow-off change in insulin sensitivity. Three candidate models of glucose effectiveness and insulin sensitivity as a function of HR have been considered, both during exercise and recovery after exercise. By incorporating these three models into the type 1 diabetes model, we simulated different levels (from mild to moderate) and duration of exercise (15 and 30 minutes), both in steady-state (e.g., during euglycemic-hyperinsulinemic clamp) and in nonsteady state (e.g., after a meal) conditions. One candidate exercise model was selected as the most reliable. A type 1 diabetes model also describing physical activity is proposed. The model represents a step forward to accurately describe glucose homeostasis in normal life conditions; however, further studies are needed to validate it against data. © Diabetes Technology Society

  12. Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota.

    PubMed

    Janssen, Aafke W F; Katiraei, Saeed; Bartosinska, Barbara; Eberhard, Daniel; Willems van Dijk, Ko; Kersten, Sander

    2018-06-01

    Angiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4 -/- mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity. We chronically fed wild-type (WT) and Angptl4 -/- mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests. Mice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4 -/- mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4

  13. Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.

    PubMed

    Akman, Cigdem I; Engelstad, Kristin; Hinton, Veronica J; Ullner, Paivi; Koenigsberger, Dorcas; Leary, Linda; Wang, Dong; De Vivo, Darryl C

    2010-01-01

    Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain. Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT. The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance. This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.

  14. Homeostasis Model Assessment-Adiponectin: the role of different types of physical exercise in obese adolescents.

    PubMed

    da Silveira Campos, Raquel M; Landi Masquio, Deborah C; Campos Corgosinho, Flávia; de Lima Sanches, Priscila; de Piano, Aline; Carnier, June; Leão da Silva, Patrícia; Grotti Clemente, Ana P; de Castro Ferreira Vicente, Sofia E; Oyama, Lila M; da Penha Oller do Nascimento, Claudia M; Tock, Lian; Tufik, Sergio; de Mello, Marco T; Dâmaso, Ana R

    2017-06-01

    Homeostasis Model Assessment-Adiponectin (HOMA-AD) is suggesting a new biomarker of insulin resistance in obese population. In this way, the purpose of this study was to investigate the effects of different kinds of exercise in the sensitive index predictor of insulin resistance. A total of 148 obese adolescents were enrolled in the program. They aged 15-19 y, with Body Mass Index (BMI) ≥P95th and were submitted to 1 year of interdisciplinary weight loss therapy, randomized in two groups, aerobic training (AT) (N.=51) and aerobic plus resistance training (N.=97). Blood samples were collected to analyze adiponectin, glucose and insulin concentrations. The insulin resistance was measured by HOMA-AD and Homeostasis Model Assessment Insulin Resistance Index (HOMA-IR). Both kinds of exercise training promoted a decrease in body mass, body mass index, fat mass, visceral and subcutaneous fat. However, only aerobic plus resistance training was effective to reduce HOMA-AD, insulin and glucose concentration; and increase insulin sensibility and adiponectin concentration. The aerobic plus resistance training was more effective than AT alone to improve the HOMA-AD, suggesting clinical application on obesity, diabetes, atherosclerosis and metabolic syndrome control in the pediatric population.

  15. Orexins control intestinal glucose transport by distinct neuronal, endocrine, and direct epithelial pathways.

    PubMed

    Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

    2007-10-01

    Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and orexin B (OxB) on intestinal glucose transport in the rat. Injection of orexins led to a decrease in the blood glucose level in oral glucose tolerance tests (OGTTs). Effects of orexins on glucose entry were analyzed in Ussing chambers using the Na(+)-dependent increase in short-circuit current (Isc) to quantify jejunal glucose transport. The rapid and marked increase in Isc induced by luminal glucose was inhibited by 10 nmol/l OxA or OxB (53 and 59%, respectively). Response curves to OxA and OxB were not significantly different with half-maximal inhibitory concentrations at 0.9 and 0.4 nmol/l, respectively. On the one hand, OxA-induced inhibition of Isc was reduced by the neuronal blocker tetrodotoxin (TTX) and by a cholecystokinin (CCK) 2R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX(1)R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX(2)R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX(1)R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX(1)R. These distinct effects of OxA and OxB are consistent with the expression of OX(1)R and OX(2)R mRNA in the epithelial and nonepithelial tissues, respectively. Our data delineate a new function for orexins as inhibitors of intestinal glucose absorption and provide a new basis for orexin-induced short-term control of energy homeostasis.

  16. Natural History of Impaired Glucose Tolerance in Japanese Americans: Change in Visceral Adiposity is Associated with Remission from Impaired Glucose Tolerance to Normal Glucose Tolerance.

    PubMed

    Onishi, Yukiko; Hayashi, Tomoshige; Sato, Kyoko K; Leonetti, Donna L; Kahn, Steven E; Fujimoto, Wilfred Y; Boyko, Edward J

    2018-05-30

    To describe the roles of intra-abdominal fat and its change in the remission of impaired glucose tolerance (IGT) to normal glucose tolerance (NGT). We followed 157 Japanese Americans with IGT at baseline for 10-11 years without external intervention. We measured intra-abdominal and abdominal subcutaneous fat area (IAFA and ASFA) by computed tomography at baseline and at 5-6 years of follow-up. Change in IAFA and ASFA (ΔIAFA and ΔASFA) were calculated by subtracting baseline fat area from 5-6 year follow-up fat area. Glucose and insulin at fasting and during a 75-g oral glucose tolerance test, insulinogenic index (IGI [Δinsulin/Δglucose (30-0 min)]) and homeostasis model assessment for insulin resistance (HOMA-IR) were measured at baseline. Fourty-four subjects remitted to NGT. Among those with lower IAFA (≤median 91.31 cm 2 ) and the lowest tertile of ΔIAFA, 45% remitted, while with higher IAFA (>91.31 cm 2 ) and the highest tertile of ΔIAFA, only 12.5% remitted. ΔIAFA was significantly associated with remission to NGT (multiple-adjusted odd ratio [1-SD decrease] 1.93, 95% CI 1.10-3.36) independent of IAFA, ASFA, ΔASFA, IGI, HOMA-IR, age, sex, and family history of diabetes. In the natural history of IGT, change in intra-abdominal fat was associated with remission to NGT. Copyright © 2018. Published by Elsevier B.V.

  17. ALTERATIONS OF FE HOMEOSTASIS IN RAT CARDIOVASCULAR DISEASE MODELS AND ITS CONTRIBUTION TO CARDIOPULMONARY TOXICITY

    EPA Science Inventory

    Introduction: Fe homeostasis can be disrupted in human cardiovascular diseases (CVD). We addressed how dysregulation of Fe homeostasis affected the pulmonary inflammation/oxidative stress response and disease progression after exposure to Libby amphibole (LA), an asbestifonn mine...

  18. Zinc stimulates glucose oxidation and glycemic control by modulating the insulin signaling pathway in human and mouse skeletal muscle cell lines.

    PubMed

    Norouzi, Shaghayegh; Adulcikas, John; Sohal, Sukhwinder Singh; Myers, Stephen

    2018-01-01

    Zinc is a metal ion that is an essential cell signaling molecule. Highlighting this, zinc is an insulin mimetic, activating cellular pathways that regulate cellular homeostasis and physiological responses. Previous studies have linked dysfunctional zinc signaling with several disease states including cancer, obesity, cardiovascular disease and type 2 diabetes. The present study evaluated the insulin-like effects of zinc on cell signaling molecules including tyrosine, PRSA40, Akt, ERK1/2, SHP-2, GSK-3β and p38, and glucose oxidation in human and mouse skeletal muscle cells. Insulin and zinc independently led to the phosphorylation of these proteins over a 60-minute time course in both mouse and human skeletal muscle cells. Similarly, utilizing a protein array we identified that zinc could active the phosphorylation of p38, ERK1/2 and GSK-3B in human and ERK1/2 and GSK-3B in mouse skeletal muscle cells. Glucose oxidation assays were performed on skeletal muscle cells treated with insulin, zinc, or a combination of both and resulted in a significant induction of glucose consumption in mouse (p<0.01) and human (p<0.05) skeletal muscle cells when treated with zinc alone. Insulin, as expected, increased glucose oxidation in mouse (p<0.001) and human (0.001) skeletal muscle cells, however the combination of zinc and insulin did not augment glucose consumption in these cells. Zinc acts as an insulin mimetic, activating key molecules implicated in cell signaling to maintain glucose homeostasis in mouse and human skeletal muscle cells. Zinc is an important metal ion implicated in several biological processes. The role of zinc as an insulin memetic in activating key signaling molecules involved in glucose homeostasis could provide opportunities to utilize this ion therapeutically in treating disorders associated with dysfunctional zinc signaling.

  19. Insulin resistance, β-cell dysfunction and differences in curves of plasma glucose and insulin in the intermediate points of the standard glucose tolerance test in adults with cystic fibrosis.

    PubMed

    Cano Megías, Marta; González Albarrán, Olga; Guisado Vasco, Pablo; Lamas Ferreiro, Adelaida; Máiz Carro, Luis

    2015-02-01

    diabetes has become a co-morbidity with a negative impact on nutritional status, lung function and survival in cystic fibrosis. To identify any changes in intermediate points after a 2-hour oral glucose tolerance test (OGTT), pancreatic β-cell dysfunction, and insulin resistance in cystic fibrosis-related diabetes. It was carried out a retrospective analysis in a cohort of 64 patients affected of cystic fibrosis, older than 14 years, using the first pathological OGTT. Peripheral insulin resistance was measured using the homeostasis model assessment for insulin resistance (HOMA- IR), and pancreatic β-cell function was calculated according to Wareham. Time to maximum plasma insulin and glucose levels and area under the curve (AUC0-120) were also measured. Twenty-eight women and 36 men with a mean age of 26.8 years were enrolled, of whom 26.7% had normal glucose tolerance (NGT), 18.3% cystic fibrosis-related diabetes without fasting hyperglycemia (CFRD w/o FPG), 10% indeterminate (INDET), and 45% impaired glucose tolerance (IGT). HOMA-IR values were not significantly different between the diagnostic categories. Patients with any pathological change had worse β cell function, with a significant delay in insulin secretion, although there were no differences in total insulin production (AUC0-120). Time to maximum glucose levels was significantly shorter in NGT patients as compared to other categories, with glucose AUC0-120 being higher in the different diagnostic categories as compared to NGT. In over half the cases, peak blood glucose levels during a standard OGTT are reached in the intermediate time points, rather than at the usual time of 120minutes. Patients with cystic fibrosis and impaired glucose metabolism have a delayed insulin secretion during the standard OGTT due to loss of first-phase insulin secretion, with no differences in total insulin production. Absence of significant changes in HOMA-IR suggests that β-cell dysfunction is the main pathogenetic

  20. Regulatory role of mucosal maltase-glucoamylase in starch digestion and glucose homeostasis

    USDA-ARS?s Scientific Manuscript database

    Slower rates of starch digestion by sucrase-isomaltase (Si) in Mgam null mice may fail to regulate gluconeogenesis (GNG). Mgam nulls have 40% reduction of glucose production from starch. The aim of this study was to measure glycemic index and rate of gluconeogenesis (fGNG) as fraction of total gluc...

  1. Glucose concentration alters dissolved oxygen levels in liquid cultures of Beauveria bassiana and affects formation and bioefficacy of blastospores.

    PubMed

    Mascarin, Gabriel Moura; Jackson, Mark A; Kobori, Nilce Naomi; Behle, Robert W; Dunlap, Christopher A; Delalibera Júnior, Ítalo

    2015-08-01

    The filamentous fungus Beauveria bassiana is an economically important pathogen of numerous arthropod pests and is able to grow in submerged culture as filaments (mycelia) or as budding yeast-like blastospores. In this study, we evaluated the effect of dissolved oxygen and high glucose concentrations on blastospore production by submerged cultures of two isolates of B. bassiana, ESALQ1432 and GHA. Results showed that maintaining adequate dissolved oxygen levels coupled with high glucose concentrations enhanced blastospore yields by both isolates. High glucose concentrations increased the osmotic pressure of the media and coincided with higher dissolved oxygen levels and increased production of significantly smaller blastospores compared with blastospores produced in media with lower concentrations of glucose. The desiccation tolerance of blastospores dried to less than 2.6 % moisture was not affected by the glucose concentration of the medium but was isolate dependent. Blastospores of isolate ESALQ1432 produced in media containing 140 g glucose L(-1) showed greater virulence toward whitefly nymphs (Bemisia tabaci) as compared with blastospores produced in media containing 40 g glucose L(-1). These results suggest a synergistic effect between glucose concentration and oxygen availability on changing morphology and enhancing the yield and efficacy of blastospores of B. bassiana, thereby facilitating the development of a cost-effective production method for this blastospore-based bioinsecticide.

  2. Dysregulated hepatic expression of glucose transporters in chronic disease: contribution of semicarbazide-sensitive amine oxidase to hepatic glucose uptake.

    PubMed

    Karim, Sumera; Liaskou, Evaggelia; Fear, Janine; Garg, Abhilok; Reynolds, Gary; Claridge, Lee; Adams, David H; Newsome, Philip N; Lalor, Patricia F

    2014-12-15

    Insulin resistance is common in patients with chronic liver disease (CLD). Serum levels of soluble vascular adhesion protein-1 (VAP-1) are also increased in these patients. The amine oxidase activity of VAP-1 stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. We aimed to document human hepatocellular expression of glucose transporters (GLUTs) and to determine if VAP-1 activity influences receptor expression and hepatic glucose uptake. Quantitative PCR and immunocytochemistry were used to study human liver tissue and cultured cells. We also used tissue slices from humans and VAP-1-deficient mice to assay glucose uptake and measure hepatocellular responses to stimulation. We report upregulation of GLUT1, -3, -5, -6, -7, -8, -9, -10, -11, -12, and -13 in CLD. VAP-1 expression and enzyme activity increased in disease, and provision of substrate to hepatic VAP-1 drives hepatic glucose uptake. This effect was sensitive to inhibition of VAP-1 and could be recapitulated by H2O2. VAP-1 activity also altered expression and subcellular localization of GLUT2, -4, -9, -10, and -13. Therefore, we show, for the first time, alterations in hepatocellular expression of glucose and fructose transporters in CLD and provide evidence that the semicarbazide-sensitive amine oxidase activity of VAP-1 modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease. Copyright © 2014 the American Physiological Society.

  3. Glucose metabolism and regulation in lactating mink (Mustela vison)--effects of low dietary protein supply.

    PubMed

    Fink, Rikke; Børsting, Chr F; Damgaard, Birthe Marie; Rosted, Anne Katrine Lundegård

    2002-04-01

    Eighteen lactating mink raising litters of 6 to 7 kits were fed ad libitum from parturition on diets with 32% of ME derived from protein and decreasing fat:carbohydrate ratios [high fat:low carbohydrate (HFLC): 67:1, medium fat:medium carbohydrate (MFMC): 52:16, low fat:high carbohydrate (LFHC): 37:31]. Four weeks post partum the dams were fitted with a jugular vein catheter, and the experiment started with a 3 hours fasting period, after which the dams were fed 210 kJ ME of the experimental diets. Blood samples were collected 10 and 5 min before feeding and 30, 60, 90, 120, 150 and 180 min postprandially. Two hours postprandially a single dose of 50 microCi U-14C-labelled glucose was administered to each dam and blood samples were collected 5, 10, 20, 30, 45 and 60 min after the tracer administration. Plasma concentrations of glucose and insulin 30 to 120 min postprandially were higher in dams fed the LFHC diet, than in dams fed the HFLC diet, values for dams fed the MFMC diet being intermediate. Plasma glucagon concentrations were not significantly affected by dietary treatment. The glucagon:insulin ratios decreased postprandially in all dams, the response being significant in dams fed the LFHC diet. Plasma concentrations of urea were not significantly affected by dietary treatment. Plasma FFA concentrations tended to increase postprandially in dams fed the HFLC diet. Glucose turnover rates were approximately 4.0% per min in all dams, irrespective of dietary treatment. However, the daily glucose flux was lower in dams fed the HFLC diet than in dams fed the LFHC diet, and tended to be lower than in dams fed the MFMC diet. In conclusion, a dietary protein supply of 32% of ME simultaneously with a carbohydrate supply of 16% or 31% of ME had no adverse effects on glucose homeostasis or glucose metabolism in lactating mink.

  4. Light at night acutely impairs glucose tolerance in a time-, intensity- and wavelength-dependent manner in rats.

    PubMed

    Opperhuizen, Anne-Loes; Stenvers, Dirk J; Jansen, Remi D; Foppen, Ewout; Fliers, Eric; Kalsbeek, Andries

    2017-07-01

    Exposure to light at night (LAN) has increased dramatically in recent decades. Animal studies have shown that chronic dim LAN induced obesity and glucose intolerance. Furthermore, several studies in humans have demonstrated that chronic exposure to artificial LAN may have adverse health effects with an increased risk of metabolic disorders, including type 2 diabetes. It is well-known that acute exposure to LAN affects biological clock function, hormone secretion and the activity of the autonomic nervous system, but data on the effects of LAN on glucose homeostasis are lacking. This study aimed to investigate the acute effects of LAN on glucose metabolism. Male Wistar rats were subjected to i.v. glucose or insulin tolerance tests while exposed to 2 h of LAN in the early or late dark phase. In subsequent experiments, different light intensities and wavelengths were used. LAN exposure early in the dark phase at ZT15 caused increased glucose responses during the first 20 min after glucose infusion (p < 0.001), whereas LAN exposure at the end of the dark phase, at ZT21, caused increased insulin responses during the first 10 min (p < 0.01), indicating that LAN immediately induces glucose intolerance in rats. Subsequent experiments demonstrated that the effect of LAN was both intensity- and wavelength-dependent. White light of 50 and 150 lx induced greater glucose responses than 5 and 20 lx, whereas all intensities other than 5 lx reduced locomotor activity. Green light induced glucose intolerance, but red and blue light did not, suggesting the involvement of a specific retina-brain pathway. Together, these data show that exposure to LAN has acute adverse effects on glucose metabolism in a time-, intensity- and wavelength-dependent manner.

  5. 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.

  6. Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates

    PubMed Central

    Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne

    2017-01-01

    Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus, spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (rs=0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (rs=0.56) and hippocampus (rs=−0.62) or septum (rs=−0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes. PMID:28039490

  7. Impaired fasting blood glucose is associated to cognitive impairment and cerebral atrophy in middle-aged non-human primates.

    PubMed

    Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne

    2016-12-28

    Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus , spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (r s =0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (r s =0.56) and hippocampus (r s =-0.62) or septum (r s =-0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes.

  8. Genetics of hereditary disorders of magnesium homeostasis.

    PubMed

    Schlingmann, Karl P; Konrad, Martin; Seyberth, Hannsjörg W

    2004-01-01

    Magnesium plays an essential role in many biochemical and physiological processes. Homeostasis of magnesium is tightly regulated and depends on the balance between intestinal absorption and renal excretion. During the last decades, various hereditary disorders of magnesium handling have been clinically characterized and genetic studies in affected individuals have led to the identification of some molecular components of cellular magnesium transport. In addition to these hereditary forms of magnesium deficiency, recent studies have revealed a high prevalence of latent hypomagnesemia in the general population. This finding is of special interest in view of the association between hypomagnesemia and common chronic diseases such as diabetes, coronary heart disease, hypertension, and asthma. However, valuable methods for the diagnosis of body and tissue magnesium deficiency are still lacking. This review focuses on clinical and genetic aspects of hereditary disorders of magnesium homeostasis. We will review primary defects of epithelial magnesium transport, disorders associated with defects in Ca(2+)/ Mg(2+) sensing, as well as diseases characterized by renal salt wasting and hypokalemic alkalosis, with special emphasis on disturbed magnesium homeostasis.

  9. Epinephrine deficiency results in intact glucose counter-regulation, severe hepatic steatosis and possible defective autophagy in fasting mice

    PubMed Central

    Sharara-Chami, Rana I.; Zhou, Yingjiang; Ebert, Steven; Pacak, Karel; Ozcan, Umut; Majzoub, Joseph A.

    2016-01-01

    Epinephrine is one of the major hormones involved in glucose counter-regulation and gluconeogenesis. However, little is known about its importance in energy homeostasis during fasting. Our objective is to study the specific role of epinephrine in glucose and lipid metabolism during starvation. In our experiment, we subject regular mice and epinephrine-deficient mice to a 48-h fast then we evaluate the different metabolic responses to fasting. Our results show that epinephrine is not required for glucose counter-regulation: epinephrine-deficient mice maintain their blood glucose at normal fasting levels via glycogenolysis and gluconeogenesis, with normal fasting-induced changes in the peroxisomal activators: peroxisome proliferator activated receptor γ coactivator α (PGC-1α), fibroblast growth factor 21 (FGF-21), peroxisome proliferator activated receptor α (PPAR-α), and sterol regulatory element binding protein (SREBP-1c). However, fasted epinephrine-deficient mice develop severe ketosis and hepatic steatosis, with evidence for inhibition of hepatic autophagy, a process that normally provides essential energy via degradation of hepatic triglycerides during starvation. We conclude that, during fasting, epinephrine is not required for glucose homeostasis, lipolysis or ketogenesis. Epinephrine may have an essential role in lipid handling, possibly via an autophagy-dependent mechanism. PMID:22405854

  10. Cortical firing and sleep homeostasis.

    PubMed

    Vyazovskiy, Vladyslav V; Olcese, Umberto; Lazimy, Yaniv M; Faraguna, Ugo; Esser, Steve K; Williams, Justin C; Cirelli, Chiara; Tononi, Giulio

    2009-09-24

    The need to sleep grows with the duration of wakefulness and dissipates with time spent asleep, a process called sleep homeostasis. What are the consequences of staying awake on brain cells, and why is sleep needed? Surprisingly, we do not know whether the firing of cortical neurons is affected by how long an animal has been awake or asleep. Here, we found that after sustained wakefulness cortical neurons fire at higher frequencies in all behavioral states. During early NREM sleep after sustained wakefulness, periods of population activity (ON) are short, frequent, and associated with synchronous firing, while periods of neuronal silence are long and frequent. After sustained sleep, firing rates and synchrony decrease, while the duration of ON periods increases. Changes in firing patterns in NREM sleep correlate with changes in slow-wave activity, a marker of sleep homeostasis. Thus, the systematic increase of firing during wakefulness is counterbalanced by staying asleep.

  11. Availability of neurotransmitter glutamate is diminished when beta-hydroxybutyrate replaces glucose in cultured neurons.

    PubMed

    Lund, Trine M; Risa, Oystein; Sonnewald, Ursula; Schousboe, Arne; Waagepetersen, Helle S

    2009-07-01

    Ketone bodies serve as alternative energy substrates for the brain in cases of low glucose availability such as during starvation or in patients treated with a ketogenic diet. The ketone bodies are metabolized via a distinct pathway confined to the mitochondria. We have compared metabolism of [2,4-(13)C]beta-hydroxybutyrate to that of [1,6-(13)C]glucose in cultured glutamatergic neurons and investigated the effect of neuronal activity focusing on the aspartate-glutamate homeostasis, an essential component of the excitatory activity in the brain. The amount of (13)C incorporation and cellular content was lower for glutamate and higher for aspartate in the presence of [2,4-(13)C]beta-hydroxybutyrate as opposed to [1,6-(13)C]glucose. Our results suggest that the change in aspartate-glutamate homeostasis is due to a decreased availability of NADH for cytosolic malate dehydrogenase and thus reduced malate-aspartate shuttle activity in neurons using beta-hydroxybutyrate. In the presence of glucose, the glutamate content decreased significantly upon activation of neurotransmitter release, whereas in the presence of only beta-hydroxybutyrate, no decrease in the glutamate content was observed. Thus, the fraction of the glutamate pool available for transmitter release was diminished when metabolizing beta-hydroxybutyrate, which is in line with the hypothesis of formation of transmitter glutamate via an obligatory involvement of the malate-aspartate shuttle.

  12. Alcohol disrupts sleep homeostasis.

    PubMed

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  13. Duodenum Exclusion Alone Is Sufficient to Improve Glucose Metabolism in STZ-Induced Diabetes Rats.

    PubMed

    Wu, Weihang; Lin, Li; Lin, Zhixiong; Yang, Weijin; Cai, Zhicong; Hong, Jie; Qiu, Jiandong; Lin, Chen; Lin, Nan; Wang, Yu

    2018-05-22

    Several studies have found that metabolic surgery can significantly improve glucose homeostasis; however, the intrinsic mechanisms remain unclear. Accumulating evidence suggests that duodenal bypass plays a crucial role in the treatment of type 2 diabetes mellitus (T2DM). Here, we aimed to evaluate the effect of duodenal reflux on glucose metabolism in T2DM. A high-fat diet and low-dose streptozotocin (STZ) administration were used to induce T2DM in male rats, which were assigned to three experimental groups: sham operation (SO; n = 10), new duodenal-jejunal bypass (NDJB; n = 10), and new duodenal-jejunal bypass with a tube (NDJBT; n = 10). Weight, food intake, oral glucose tolerance test (OGTT) results, glucagon-like peptide 1 (GLP-1) levels, and histopathology were assessed before or after surgery. Plain abdominal radiography was performed 1 week after the operation. Plain abdominal radiography indicated the occurrence of contrast agent reflux into the duodenum. The body weight and food intake in all three groups did not significantly differ before and after surgery. The NDJB and particularly the NDJBT groups exhibited better glucose tolerance, lower fasting blood glucose (FBG) levels, lower area under the curves for OGTT (AUC OGTT ) values, and higher GLP-1 levels, as compared with the sham group postoperatively. The villus height and crypt depth were both shorter in the biliopancreatic limb after NDJBT, as compared with those after SO and NDJB. Thus, exclusion of the duodenum alone and tube placement can effectively prevent duodenal reflux and improve glucose homeostasis, which further suggests that the duodenum plays an important role in T2DM.

  14. High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis.

    PubMed

    McClain, D A; Abraham, D; Rogers, J; Brady, R; Gault, P; Ajioka, R; Kushner, J P

    2006-07-01

    The prevalence and mechanisms of diabetes in hereditary haemochromatosis are not known. We therefore measured glucose tolerance, insulin secretory capacity and insulin sensitivity in adults with haemochromatosis. Subjects recruited from referrals to a haemochromatosis clinic underwent OGTT and frequently sampled IVGTT. A chart review of former clinic patients was also performed. The prevalence of diabetes (23%) and IGT (30%) was increased in haemochromatosis compared with matched control subjects (0% diabetes and 14% IGT). Subjects with haemochromatosis and diabetes were overweight (14%) or obese (86%). The prevalence of diabetes, as determined by chart review of fasting glucose values, in subjects who had haemochromatosis and were in the 40-79 years age range was 26%. Overall, patients with haemochromatosis and control subjects had similar values for acute insulin response to glucose and insulin sensitivity. However, patients with haemochromatosis and IGT had a 68% decrease in acute insulin response to glucose (p<0.02) compared with those with NGT. They were not insulin-resistant, exhibiting instead a 62% increase in insulin sensitivity (NS). Haemochromatosis subjects with diabetes exhibited further declines in acute insulin response to glucose, insulin resistance, or both. Diabetes and IGT are common in haemochromatosis, justifying screening for diabetes and therapeutic phlebotomy. The major abnormality associated with IGT is decreased insulin secretory capacity. Diabetes is usually associated with obesity and concomitant insulin resistance.

  15. Voltage-Gated Na+ Channels are Modulated by Glucose and Involved in Regulating Cellular Insulin Content of INS-1 Cells.

    PubMed

    Chen, Chong; Wang, Songhua; Hu, Qingjuan; Zeng, Lvming; Peng, Hailong; Liu, Chao; Huang, Li-Ping; Song, Hao; Li, Yuping; Yao, Li-Hua; Meng, Wei

    2018-01-01

    Islet beta cells (β-cells) are unique cells that play a critical role in glucose homeostasis by secreting insulin in response to increased glucose levels. Voltage-gated ion channels in β-cells, such as K+ and Ca2+ channels, contribute to insulin secretion. The response of voltage-gated Na+ channels (VGSCs) in β-cells to the changes in glucose levels remains unknown. This work aims to determine the role of extracellular glucose on the regulation of VGSC. The effect of glucose on VGSC currents (INa) was investigated in insulin-secreting β-cell line (INS-1) cells of rats using whole-cell patch clamp techniques, and the effects of glucose on insulin content and cell viability were determined using Enzyme-Linked Immunosorbent Assay (ELISA) and Methylthiazolyldiphenyl-tetrazolium Bromide (MTT) assay methods respectively. Our results show that extracellular glucose application can inhibit the peak of INa in a concentration-dependent manner. Glucose concentration of 18 mM reduced the amplitude of INa, suppressed the INa of steady-state activation, shifted the steady-state inactivation curves of INa to negative potentials, and prolonged the time course of INa recovery from inactivation. Glucose also enhanced the activity-dependent attenuation of INa and reduced the fraction of activated channels. Furthermore, 18 mM glucose or low concentration of tetrodotoxin (TTX, a VGSC-specific blocker) partially inhibited the activity of VGSC and also improved insulin synthesis. These results revealed that extracellular glucose application enhances the insulin synthesis in INS-1 cells and the mechanism through the partial inhibition on INa channel is involved. Our results innovatively suggest that VGSC plays a vital role in modulating glucose homeostasis. © 2018 The Author(s). Published by S. Karger AG, Basel.

  16. Influence of High Aspect Ratio Vessel Cell Culture on TNF-Alpha, Insulin Secretion and Glucose Homeostasis in Pancreatic Islets of Langerhans from Wistar Furth Rats

    NASA Technical Reports Server (NTRS)

    Tobin, Brian W.a; Leeper-Woodford, Sandra K.

    1999-01-01

    The present studies were carried out to determine the influence of a ground based microgravity paradigm, utilizing the High Aspect Ratio Vessel (HARV) cell culture upon lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha (TNF-alpha) production of pancreatic islets of Langerhans. An additional aim was to elucidate alterations in insulin secretion and glucose utilization using the HARV low shear, gravity averaged vector, cell culture technique. Islets were isolated (1726 +/- 117, 150 micron islet equivalent units) from Wistar Furth rats and assigned to four treatment groups: 1) HARV, 2) HARV plus LPS, 3) static culture, 4) static culture plus LPS. Following 48 hours of culture, insulin concentration was increased in both HARV and static cultures (p<0.05). Islet medium from HARV and static cultures were assayed for TNF-alpha (L929 cytotoxicity assay) and was measured at selected time points for 48 hours. TNF-alpha was significantly increased in LPS-induced HARV and static cultures, yet the increase was more pronounced in the static culture group (p<0.05). This is a novel observation and indicates that TNF producing cells are present in islets and that LPS stimulates TNF secretion in isolated islets. A decrease in insulin concentration was demonstrated in the islet medium of the LPS stimulated HARV culture (p<0.05). That TNF-alpha is associated with a decreased insulin secretion is intriguing, both as it relates to in-flight investigations, and as it may provide insight into the pathophysiology of Type I and Type 11 diabetes. Glucose concentration in islet medium was lesser throughout the experiment in static cultures, suggesting a decreased reliance upon glucose as a metabolic substrate in the islets cultured in HARVS. In conclusion, the present studies demonstrate alterations in LPS induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF production in the microgravity HARV paradigm. Additionally, alterations in fuel

  17. Brain glucose sensing, glucokinase and neural control of metabolism and islet function.

    PubMed

    Ogunnowo-Bada, E O; Heeley, N; Brochard, L; Evans, M L

    2014-09-01

    It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel--emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases. © 2014 John Wiley & Sons Ltd.

  18. Brain glucose sensing, glucokinase and neural control of metabolism and islet function

    PubMed Central

    Ogunnowo-Bada, E O; Heeley, N; Brochard, L; Evans, M L

    2014-01-01

    It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel – emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases. PMID:25200293

  19. Autonomic regulation of hepatic glucose production.

    PubMed

    Bisschop, Peter H; Fliers, Eric; Kalsbeek, Andries

    2015-01-01

    Glucose produced by the liver is a major energy source for the brain. Considering its critical dependence on glucose, it seems only natural that the brain is capable of monitoring and controlling glucose homeostasis. In addition to neuroendocrine pathways, the brain uses the autonomic nervous system to communicate with peripheral organs. Within the brain, the hypothalamus is the key region to integrate signals on energy status, including signals from lipid, glucose, and hormone sensing cells, with afferent neural signals from the internal and external milieu. In turn, the hypothalamus regulates metabolism in peripheral organs, including the liver, not only via the anterior pituitary gland but also via multiple neuropeptidergic pathways in the hypothalamus that have been identified as regulators of hepatic glucose metabolism. These pathways comprise preautonomic neurons projecting to nuclei in the brain stem and spinal cord, which relay signals from the hypothalamus to the liver via the autonomic nervous system. The neuroendocrine and neuronal outputs of the hypothalamus are not separate entities. They appear to act as a single integrated regulatory system, far more subtle, and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and neural influences. As a result, our endocrine-based understanding of diseases such as diabetes and obesity should be expanded by integration of neural inputs into our concept of the pathophysiological process. © 2014 American Physiological Society.

  20. Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism.

    PubMed

    Anandhan, Annadurai; Jacome, Maria S; Lei, Shulei; Hernandez-Franco, Pablo; Pappa, Aglaia; Panayiotidis, Mihalis I; Powers, Robert; Franco, Rodrigo

    2017-07-01

    The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.