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Sample records for affects glucose homeostasis

  1. Loss of Sugar Detection by GLUT2 Affects Glucose Homeostasis in Mice

    PubMed Central

    Stolarczyk, Emilie; Le Gall, Maude; Even, Patrick; Houllier, Anne; Serradas, Patricia; Brot-Laroche, Edith; Leturque, Armelle

    2007-01-01

    Background Mammals must sense the amount of sugar available to them and respond appropriately. For many years attention has focused on intracellular glucose sensing derived from glucose metabolism. Here, we studied the detection of extracellular glucose concentrations in vivo by invalidating the transduction pathway downstream from the transporter-detector GLUT2 and measured the physiological impact of this pathway. Methodology/Principal Findings We produced mice that ubiquitously express the largest cytoplasmic loop of GLUT2, blocking glucose-mediated gene expression in vitro without affecting glucose metabolism. Impairment of GLUT2-mediated sugar detection transiently protected transgenic mice against starvation and streptozotocin-induced diabetes, suggesting that both low- and high-glucose concentrations were not detected. Transgenic mice favored lipid oxidation, and oral glucose was slowly cleared from blood due to low insulin production, despite massive urinary glucose excretion. Kidney adaptation was characterized by a lower rate of glucose reabsorption, whereas pancreatic adaptation was associated with a larger number of small islets. Conclusions/Significance Molecular invalidation of sugar sensing in GLUT2-loop transgenic mice changed multiple aspects of glucose homeostasis, highlighting by a top-down approach, the role of membrane glucose receptors as potential therapeutic targets. PMID:18074013

  2. Neuroscience of glucose homeostasis.

    PubMed

    La Fleur, S E; Fliers, E; Kalsbeek, A

    2014-01-01

    Plasma glucose concentrations are homeostatically regulated and maintained within strict boundaries. Several mechanisms are in place to increase glucose output when glucose levels in the circulation drop as a result of glucose utilization, or to decrease glucose output and increase tissue glucose uptake to prevent hyperglycemia. Although the term homeostasis mostly refers to stable levels, the blood glucose concentrations fluctuate over the day/night cycle, with the highest concentrations occurring just prior to the activity period in anticipation of increased caloric need. In this chapter we describe how the brain, particularly the hypothalamus, is involved in both the daily rhythm of plasma glucose concentrations and acute glucose challenges.

  3. 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.

  4. Orally administered glucagon-like peptide-1 affects glucose homeostasis following an oral glucose tolerance test in healthy male subjects.

    PubMed

    Steinert, R E; Poller, B; Castelli, M C; Friedman, K; Huber, A R; Drewe, J; Beglinger, C

    2009-12-01

    Glucagon-like peptide-1 (GLP-1) exerts several effects on glucose homeostasis and reduces food intake. After its release from intestinal L cells, GLP-1 is subject to (i) rapid breakdown by dipeptidyl peptidase IV and (ii) high liver extraction. The highest concentrations of GLP-1 are found in the splanchnic blood rather than in the systemic circulation. An oral delivery system would mimic endogenous secretion. Here we investigated the pharmacokinetic/pharmacodynamic (PK/PD) effects of a single dose (2 mg) of oral GLP-1 administered prior to an oral glucose tolerance test (OGTT) in 16 healthy males. GLP-1 was rapidly absorbed from the gut, leading to tenfold higher plasma concentrations compared with controls. The PD profile was consistent with reported pharmacology; GLP-1 significantly stimulated basal insulin release (P < 0.027), with marked effects on glucose levels. The postprandial glucose peak was delayed with GLP-1, suggesting an effect on gastric emptying.

  5. Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight.

    PubMed

    Zhang, Ren; Dhillon, Harveen; Yin, Huali; Yoshimura, Akihiko; Lowell, Bradford B; Maratos-Flier, Eleftheria; Flier, Jeffrey S

    2008-11-01

    Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure.

  6. Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling.

    PubMed

    Vauthier, Virginie; Roujeau, Clara; Chen, Patty; Sarkis, Chamsy; Migrenne, Stéphanie; Hosoi, Toru; Ozawa, Koichiro; Rouillé, Yves; Foretz, Marc; Mallet, Jacques; Launay, Jean-Marie; Magnan, Christophe; Jockers, Ralf; Dam, Julie

    2017-01-01

    The hypothalamic arcuate nucleus (ARC) is a major integration center for energy and glucose homeostasis that responds to leptin. Resistance to leptin in the ARC is an important component of the development of obesity and type 2 diabetes. Recently, we showed that Endospanin1 (Endo1) is a negative regulator of the leptin receptor (OBR) that interacts with OBR and retains the receptor inside the cell, leading to a decreased activation of the anorectic STAT3 pathway. Endo1 is up-regulated in the ARC of high fat diet (HFD)-fed mice, and its silencing in the ARC of lean and obese mice prevents and reverses the development of obesity.

  7. Modulation of polyamine metabolic flux in adipose tissue alters the accumulation of body fat by affecting glucose homeostasis

    PubMed Central

    Liu, Chunli; Perez-Leal, Oscar; Barrero, Carlos; Zahedi, Kamyar; Soleimani, Manoocher; Porter, Carl

    2013-01-01

    The continued rise in obesity despite public education, awareness and policies indicates the need for mechanism-based therapeutic approaches to help control the disease. Our data, in conjunction with other studies, suggest an unexpected role for the polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT) in fat homeostasis. Our previous studies showed that deletion of SSAT greatly exaggerates weight gain and that the transgenic overexpression suppresses weight gain in mice on a high-fat diet. This discovery is substantial but the underlying molecular linkages are only vaguely understood. Here, we used a comprehensive systems biology approach, on white adipose tissue (WAT), to discover that the partition of acetyl-CoA towards polyamine catabolism alters glucose homeostasis and hence, fat accumulation. Comparative proteomics and antibody-based expression studies of WAT in SSAT knockout, wild type and transgenic mice identified nine proteins with an increasing gradient across the genotypes, all of which correlate with acetyl-CoA consumption in polyamine acetylation. Adipose-specific SSAT knockout mice and global SSAT knockout mice on a high-fat diet exhibited similar growth curves and proteomic patterns in their WAT, confirming that attenuated consumption of acetyl-CoA in acetylation of polyamines in adipose tissue drives the obese phenotype of these mice. Analysis of protein expression indicated that the identified changes in the levels of proteins regulating acetyl-CoA consumption occur via the AMP-activated protein kinase pathway. Together, our data suggest that differential expression of SSAT markedly alters acetyl-CoA levels, which in turn trigger a global shift in glucose metabolism in adipose tissue, thus affecting the accumulation of body fat. PMID:23881108

  8. 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

  9. [Contribution of the kidney to glucose homeostasis].

    PubMed

    Segura, Julián; Ruilope, Luis Miguel

    2013-09-01

    The kidney is involved in glucose homeostasis through three major mechanisms: renal gluconeogenesis, renal glucose consumption, and glucose reabsorption in the proximal tubule. Glucose reabsorption is one of the most important physiological functions of the kidney, allowing full recovery of filtered glucose, elimination of glucose from the urine, and prevention of calorie loss. Approximately 90% of the glucose is reabsorbed in the S1 segment of the proximal tubule, where glucose transporter-2 (GLUT2) and sodium-glucose transporter-2 (SGLT2) are located, while the remaining 10% is reabsorbed in the S3 segment by SGLT1 and GLUT1 transporters. In patients with hyperglycemia, the kidney continues to reabsorb glucose, thus maintaining hyperglycemia. Most of the renal glucose reabsorption is mediated by SGLT2. Several experimental and clinical studies suggest that pharmacological blockade of this transporter might be beneficial in the management of hyperglycemia in patients with type 2 diabetes.

  10. 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

  11. 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.

  12. GLUT2, glucose sensing and glucose homeostasis.

    PubMed

    Thorens, Bernard

    2015-02-01

    The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In humans, inactivating mutations in GLUT2 cause Fanconi-Bickel syndrome, which is characterised by hepatomegaly and kidney disease; defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology.

  13. Leucine supplementation does not affect protein turnover and impairs the beneficial effects of endurance training on glucose homeostasis in healthy mice.

    PubMed

    Costa Júnior, José M; Rosa, Morgana R; Protzek, André O; de Paula, Flávia M; Ferreira, Sandra M; Rezende, Luiz F; Vanzela, Emerielle C; Zoppi, Cláudio C; Silveira, Leonardo R; Kettelhut, Isis C; Boschero, Antonio C; de Oliveira, Camila A M; Carneiro, Everardo M

    2015-04-01

    Endurance exercise training as well as leucine supplementation modulates glucose homeostasis and protein turnover in mammals. Here, we analyze whether leucine supplementation alters the effects of endurance exercise on these parameters in healthy mice. Mice were distributed into sedentary (C) and exercise (T) groups. The exercise group performed a 12-week swimming protocol. Half of the C and T mice, designated as the CL and TL groups, were supplemented with leucine (1.5 % dissolved in the drinking water) throughout the experiment. As well known, endurance exercise training reduced body weight and the retroperitoneal fat pad, increased soleus mass, increased VO2max, decreased muscle proteolysis, and ameliorated peripheral insulin sensitivity. Leucine supplementation had no effect on any of these parameters and worsened glucose tolerance in both CL and TL mice. In the soleus muscle of the T group, AS-160(Thr-642) (AKT substrate of 160 kDa) and AMPK(Thr-172) (AMP-Activated Protein Kinase) phosphorylation was increased by exercise in both basal and insulin-stimulated conditions, but it was reduced in TL mice with insulin stimulation compared with the T group. Akt phosphorylation was not affected by exercise but was lower in the CL group compared with the other groups. Leucine supplementation increased mTOR phosphorylation at basal conditions, whereas exercise reduced it in the presence of insulin, despite no alterations in protein synthesis. In trained groups, the total FoxO3a protein content and the mRNA for the specific isoforms E2 and E3 ligases were reduced. In conclusion, leucine supplementation did not potentiate the effects of endurance training on protein turnover, and it also reduced its positive effects on glucose homeostasis.

  14. Hepatocytes: critical for glucose homeostasis.

    PubMed

    Klover, Peter J; Mooney, Robert A

    2004-05-01

    Maintaining blood glucose levels within a narrow range is a critical physiological function requiring multiple metabolic pathways and involving several cell types, including a prominent role for hepatocytes. Under hormonal control, hepatocytes can respond to either feeding or fasting conditions by storing or producing glucose as necessary. In the fasting state, the effects of glucagon avoid hypoglycemia by stimulating glucogenesis and glycogenolysis and initiating hepatic glucose release. Postprandially, insulin prevents hyperglycemia, in part, by suppressing hepatic gluconeogenesis and glycogenolysis and facilitating hepatic glycogen synthesis. Both transcriptional regulation of rate limiting enzymes and modulation of enzyme activity through phosphorylation and allosteric regulation are involved. Type 2 diabetes mellitus is the most common serious metabolic condition in the world, and results from a subnormal response of tissues to insulin (insulin resistance) and a failure of the insulin-secreting beta cells to compensate. In type 2 diabetes, glucose is overproduced by the hepatocyte and is ineffectively metabolized by other organs. Impairments in the insulin signal transduction pathway appear to be critical lesions contributing to insulin resistance and type 2 diabetes.

  15. Taurine supplementation modulates glucose homeostasis and islet function.

    PubMed

    Carneiro, Everardo M; Latorraca, Marcia Q; Araujo, Eliana; Beltrá, Marta; Oliveras, Maria J; Navarro, Mónica; Berná, Genoveva; Bedoya, Francisco J; Velloso, Licio A; Soria, Bernat; Martín, Franz

    2009-07-01

    Taurine is a conditionally essential amino acid for human that is involved in the control of glucose homeostasis; however, the mechanisms by which the amino acid affects blood glucose levels are unknown. Using an animal model, we have studied these mechanisms. Mice were supplemented with taurine for 30 d. Blood glucose homeostasis was assessed by intraperitoneal glucose tolerance tests (IPGTT). Islet cell function was determined by insulin secretion, cytosolic Ca2+ measurements and glucose metabolism from isolated islets. Islet cell gene expression and translocation was examined via immunohistochemistry and quantitative real-time polymerase chain reaction. Insulin signaling was studied by Western blot. Islets from taurine-supplemented mice had: (i) significantly higher insulin content, (ii) increased insulin secretion at stimulatory glucose concentrations, (iii) significantly displaced the dose-response curve for glucose-induced insulin release to the left, (iv) increased glucose metabolism at 5.6 and 11.1-mmol/L concentrations; (v) slowed cytosolic Ca2+ concentration ([Ca2+]i) oscillations in response to stimulatory glucose concentrations; (vi) increased insulin, sulfonylurea receptor-1, glucokinase, Glut-2, proconvertase and pancreas duodenum homeobox-1 (PDX-1) gene expression and (vii) increased PDX-1 expression in the nucleus. Moreover, taurine supplementation significantly increased both basal and insulin stimulated tyrosine phosphorylation of the insulin receptor in skeletal muscle and liver tissues. Finally, taurine supplemented mice showed an improved IPGTT. These results indicate that taurine controls glucose homeostasis by regulating the expression of genes required for glucose-stimulated insulin secretion. In addition, taurine enhances peripheral insulin sensitivity.

  16. Regulation of glucose homeostasis by GLP-1.

    PubMed

    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 homeostasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics.

  17. 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

  18. Stable and flexible system for glucose homeostasis

    NASA Astrophysics Data System (ADS)

    Hong, Hyunsuk; Jo, Junghyo; Sin, Sang-Jin

    2013-09-01

    Pancreatic islets, controlling glucose homeostasis, consist of α, β, and δ cells. It has been observed that α and β cells generate out-of-phase synchronization in the release of glucagon and insulin, counter-regulatory hormones for increasing and decreasing glucose levels, while β and δ cells produce in-phase synchronization in the release of the insulin and somatostatin. Pieces of interactions between the islet cells have been observed for a long time, although their physiological role as a whole has not been explored yet. We model the synchronized hormone pulses of islets with coupled phase oscillators that incorporate the observed cellular interactions. The integrated model shows that the interaction from β to δ cells, of which sign is a subject of controversy, should be positive to reproduce the in-phase synchronization between β and δ cells. The model also suggests that δ cells help the islet system flexibly respond to changes of glucose environment.

  19. [Glucose homeostasis in children. I. Regulation of blood glucose].

    PubMed

    Otto Buczkowska, E; Szirer, G; Jarosz-Chobot, P

    2001-01-01

    The amount of glucose in the circulation depends on its absorption from the intestine, uptake by and release from the liver and uptake by peripheral tissues. Insulin and glucagon together control the metabolities required by peripheral tissues and both are involved in maintaining glucose homeostasis. Insulin is considered to be an anabolic hormone in that it promotes the synthesis of protein, lipid and glycogen. The key target tissues for insulin are liver, muscles and adipose tissue. Glucagon acts largely to increase catabolic processes. Between meals or during fast, the most tightly regulated process is the release of glucose from the liver. During fasting glucose is produced from glycogen and is formed by enzymes on the gluconeogenic pathway. Fetal metabolism is directed to ensure anabolism with formation of glycogen, fat and protein. Glucogen is stored in the liver and serves as the immediate source of new glucose during first few hours after birth. Glucose is the most important substrate for brain metabolism. Due to the large size of neonatal brain in relation to body weight cerebral glucose consumption is particularly high. Postnatal hormonal changes have a central role in regulating glucose mobilization through glycogenolysis and gluconeogenesis. The initial glucagon surge is the key adaptive change which triggers the switch to glucose production. The control of insulin and glucagon secretion is of fundamental importance during first hours after birth. Children have a decreased tolerance to starvation when compared with adults, they are more prone to develop hypoglycaemia after short fasting. The faster rate in the fall of blood glucose and gluconeogenic substrates and rapid rate of ketogenesis are characteristic features of fasting adaptation in children.

  20. 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

  1. The endocannabinoid system and the control of glucose homeostasis.

    PubMed

    Nogueiras, R; Rohner-Jeanrenaud, F; Woods, S C; Tschöp, M H

    2008-05-01

    Blockade of the CB(1) receptor is one of the promising strategies for the treatment of obesity. The first selective CB(1) receptor antagonist, rimonabant, which has already successfully completed phase III clinical trials, led to sustained weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Currently, one of the most discussed aspects of endocannabinoid system function is to what extent the endocannabinoid system might affect metabolism independently of its control over body weight and food intake. Specifically, a food-intake- and body-weight-independent role in the regulation of glucose homeostasis and insulin sensitivity could have major impact on the potential of drug candidates targeting the endocannabinoid system for the prevention and treatment of metabolic syndrome. This review summarises the effects of the endocannabinoid system on glucose homeostasis and insulin sensitivity.

  2. Insulin Signaling in the Control of Glucose and Lipid Homeostasis.

    PubMed

    Saltiel, Alan R

    2016-01-01

    A continuous supply of glucose is necessary to ensure proper function and survival of all organs. Plasma glucose levels are thus maintained in a narrow range around 5 mM, which is considered the physiological set point. Glucose homeostasis is controlled primarily by the liver, fat, and skeletal muscle. Following a meal, most glucose disposals occur in the skeletal muscle, whereas fasting plasma glucose levels are determined primarily by glucose output from the liver. The balance between the utilization and production of glucose is primarily maintained at equilibrium by two opposing hormones, insulin and glucagon. In response to an elevation in plasma glucose and amino acids (after consumption of a meal), insulin is released from the beta cells of the islets of Langerhans in the pancreas. When plasma glucose falls (during fasting or exercise), glucagon is secreted by α cells, which surround the beta cells in the pancreas. Both cell types are extremely sensitive to glucose concentrations, can regulate hormone synthesis, and are released in response to small changes in plasma glucose levels. At the same time, insulin serves as the major physiological anabolic agent, promoting the synthesis and storage of glucose, lipids, and proteins and inhibiting their degradation and release back into the circulation. This chapter will focus mainly on signal transduction mechanisms by which insulin exerts its plethora of effects in liver, muscle, and fat cells, focusing on those pathways that are crucial in the control of glucose and lipid homeostasis.

  3. Breast Milk Hormones and Regulation of Glucose Homeostasis

    PubMed Central

    Savino, Francesco; Liguori, Stefania Alfonsina; Sorrenti, Miriam; Fissore, Maria Francesca; Oggero, Roberto

    2011-01-01

    Growing evidence suggests that a complex relationship exists between the central nervous system and peripheral organs involved in energy homeostasis. It consists in the balance between food intake and energy expenditure and includes the regulation of nutrient levels in storage organs, as well as in blood, in particular blood glucose. Therefore, food intake, energy expenditure, and glucose homeostasis are strictly connected to each other. Several hormones, such as leptin, adiponectin, resistin, and ghrelin, are involved in this complex regulation. These hormones play a role in the regulation of glucose metabolism and are involved in the development of obesity, diabetes, and metabolic syndrome. Recently, their presence in breast milk has been detected, suggesting that they may be involved in the regulation of growth in early infancy and could influence the programming of energy balance later in life. This paper focuses on hormones present in breast milk and their role in glucose homeostasis. PMID:21760816

  4. Melatonin modulates glucose homeostasis during winter dormancy in a vespertilionid bat, Scotophilus heathi.

    PubMed

    Srivastava, Raj Kamal; Krishna, Amitabh

    2010-03-01

    The role for melatonin in glucose homeostasis and insulin resistance is not very clear and has recently been an active area of investigation. The present study investigated the role of melatonin in seasonal accumulation of adipose tissue in Scotophilus heathi, with particular reference to its role in glucose homeostasis and development of insulin resistance. The circulating melatonin levels correlated positively (p<0.05) with the changes in body mass due to fat accumulation and circulating insulin level, but correlated negatively with the blood glucose level in S. heathi. The bats showed high circulating blood glucose levels and impaired glucose tolerance during the period of fat deposition suggesting insulin resistance condition which improves after winter when most of the fat has been utilized as a metabolic fuel. The high circulating melatonin levels during the period of maximum body fat at the beginning of winter prepare the bats for winter dormancy by modulating the glucose homeostasis through affecting blood glucose levels, muscle and liver glycogen stores, insulin receptor and glucose transporter 4 (GLUT 4) expression. This is also confirmed by in vivo study in which melatonin injection improves the glucose tolerance, increases muscle insulin receptor and GLUT 4 expression, and enhances glucose clearance from the blood. The results of present study further showed that the effect of melatonin injection on the blood glucose levels is determined by the metabolic state of the bats and may protect from decrease in blood glucose level during extreme starvation, however, melatonin when injected during fed state increases glucose clearance from the blood. In summary, the present study suggested that melatonin interferes with the glucose homeostasis through modulating intracellular glucose transport and may protect bats from hypoglycemia during winter dormancy.

  5. Does microbiota composition affect thyroid homeostasis?

    PubMed

    Virili, Camilla; Centanni, Marco

    2015-08-01

    The intestinal microbiota is essential for the host to ensure digestive and immunologic homeostasis. When microbiota homeostasis is impaired and dysbiosis occurs, the malfunction of epithelial barrier leads to intestinal and systemic disorders, chiefly immunologic and metabolic. The role of the intestinal tract is crucial in the metabolism of nutrients, drugs, and hormones, including exogenous and endogenous iodothyronines as well as micronutrients involved in thyroid homeostasis. However, the link between thyroid homeostasis and microbiota composition is not yet completely ascertained. A pathogenetic link with dysbiosis has been described in different autoimmune disorders but not yet fully elucidated in autoimmune thyroid disease which represents the most frequent of them. Anyway, it has been suggested that intestinal dysbiosis may trigger autoimmune thyroiditis. Furthermore, hypo- and hyper-thyroidism, often of autoimmune origin, were respectively associated to small intestinal bacterial overgrowth and to changes in microbiota composition. Whether some steps of this thyroid network may be affected by intestinal microbiota composition is briefly discussed below.

  6. Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity

    PubMed Central

    Prawitt, Janne; Abdelkarim, Mouaadh; Stroeve, Johanna H.M.; Popescu, Iuliana; Duez, Helene; Velagapudi, Vidya R.; Dumont, Julie; Bouchaert, Emmanuel; van Dijk, Theo H.; Lucas, Anthony; Dorchies, Emilie; Daoudi, Mehdi; Lestavel, Sophie; Gonzalez, Frank J.; Oresic, Matej; Cariou, Bertrand; Kuipers, Folkert; Caron, Sandrine; Staels, Bart

    2011-01-01

    OBJECTIVE Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed. RESEARCH DESIGN AND METHODS Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity. RESULTS FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism. CONCLUSIONS Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis. PMID:21593203

  7. Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes.

    PubMed

    Rafacho, Alex; Ortsäter, Henrik; Nadal, Angel; Quesada, Ivan

    2014-12-01

    Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic β-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of β-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic β-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

  8. Nutrients other than carbohydrates: their effects on glucose homeostasis in humans.

    PubMed

    Heer, Martina; Egert, Sarah

    2015-01-01

    Besides carbohydrates, other nutrients, such as dietary protein and amino acids; the supply of fat, vitamin D, and vitamin K; and sodium intake seem to affect glucose homeostasis. Although their effect is less pronounced than that of the amount and composition of carbohydrates, it seems reasonable to consider how nutrient intake habits may be modified to support an improved glucose homeostasis. For instance, taking into account the effect of some nutrients to lower blood glucose concentration on a day-by-day basis might support improvement of glucose homeostasis in the long run. On the other hand, lowering sodium intake too much, as recommended to avoid the development of hypertension, particularly in sodium-sensitive people, might lead to insulin resistance and thereby might risk increasing fasting as well as postprandial blood glucose concentrations. This review summarizes the state of our knowledge of how several nutrients other than carbohydrates, such as protein, fatty acids, vitamin D, vitamin K, magnesium, zinc, chromium, and sodium, affect blood glucose concentrations. Sufficient evidence exists to show that, in prospective studies based on randomized controlled trials, these selected nutrients affect blood glucose regulation. The review describes potential mechanisms leading to the observed effect. As much as is possible from the available data, the extent of the effect, is considered.

  9. Metabolic phenotyping guidelines: assessing glucose homeostasis in rodent models.

    PubMed

    Bowe, James E; Franklin, Zara J; Hauge-Evans, Astrid C; King, Aileen J; Persaud, Shanta J; Jones, Peter M

    2014-09-01

    The pathophysiology of diabetes as a disease is characterised by an inability to maintain normal glucose homeostasis. In type 1 diabetes, this is due to autoimmune destruction of the pancreatic β-cells and subsequent lack of insulin production, and in type 2 diabetes it is due to a combination of both insulin resistance and an inability of the β-cells to compensate adequately with increased insulin release. Animal models, in particular genetically modified mice, are increasingly being used to elucidate the mechanisms underlying both type 1 and type 2 diabetes, and as such the ability to study glucose homeostasis in vivo has become an essential tool. Several techniques exist for measuring different aspects of glucose tolerance and each of these methods has distinct advantages and disadvantages. Thus the appropriate methodology may vary from study to study depending on the desired end-points, the animal model, and other practical considerations. This review outlines the most commonly used techniques for assessing glucose tolerance in rodents and details the factors that should be taken into account in their use. Representative scenarios illustrating some of the practical considerations of designing in vivo experiments for the measurement of glucose homeostasis are also discussed.

  10. Glucosensing and glucose homeostasis: from fish to mammals.

    PubMed

    Polakof, Sergio; Mommsen, Thomas P; Soengas, José L

    2011-12-01

    This review is focused on two topics related to glucose in vertebrates. In a first section devoted to glucose homeostasis we describe how glucose levels fluctuate and are regulated in different classes of vertebrates. The detection of these fluctuations is essential for homeostasis and for other physiological processes such as regulation of food intake. The capacity of that detection is known as glucosensing, and the different mechanisms through which it occurs are known as glucosensors. Different glucosensor mechanisms have been demonstrated in different tissues and organs of rodents and humans whereas the information obtained for other vertebrates is scarce. In the second section of the review we describe the present knowledge regarding glucosensor mechanisms in different groups of vertebrates, with special emphasis in fish.

  11. Dopaminergic drugs in type 2 diabetes and glucose homeostasis.

    PubMed

    Lopez Vicchi, Felicitas; Luque, Guillermina Maria; Brie, Belen; Nogueira, Juan Patricio; Garcia Tornadu, Isabel; Becu-Villalobos, Damasia

    2016-07-01

    The importance of dopamine in central nervous system function is well known, but its effects on glucose homeostasis and pancreatic β cell function are beginning to be unraveled. Mutant mice lacking dopamine type 2 receptors (D2R) are glucose intolerant and have abnormal insulin secretion. In humans, administration of neuroleptic drugs, which block dopamine receptors, may cause hyperinsulinemia, increased weight gain and glucose intolerance. Conversely, treatment with the dopamine precursor l-DOPA in patients with Parkinson's disease reduces insulin secretion upon oral glucose tolerance test, and bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients as well as in non diabetic obese animals and humans. The actions of dopamine on glucose homeostasis and food intake impact both the autonomic nervous system and the endocrine system. Different central actions of the dopamine system may mediate its metabolic effects such as: (i) regulation of hypothalamic noradrenaline output, (ii) participation in appetite control, and (iii) maintenance of the biological clock in the suprachiasmatic nucleus. On the other hand, dopamine inhibits prolactin, which has metabolic functions; and, at the pancreatic beta cell dopamine D2 receptors inhibit insulin secretion. We review the evidence obtained in animal models and clinical studies that posited dopamine receptors as key elements in glucose homeostasis and ultimately led to the FDA approval of bromocriptine in adults with type 2 diabetes to improve glycemic control. Furthermore, we discuss the metabolic consequences of treatment with neuroleptics which target the D2R, that should be monitored in psychiatric patients to prevent the development in diabetes, weight gain, and hypertriglyceridemia.

  12. 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.

  13. PAS kinase: a nutrient sensing regulator of glucose homeostasis.

    PubMed

    DeMille, Desiree; Grose, Julianne H

    2013-11-01

    Per-Arnt-Sim (PAS) kinase (PASK, PASKIN, and PSK) is a member of the group of nutrient sensing protein kinases. These protein kinases sense the energy or nutrient status of the cell and regulate cellular metabolism appropriately. PAS kinase responds to glucose availability and regulates glucose homeostasis in yeast, mice, and man. Despite this pivotal role, the molecular mechanisms of PAS kinase regulation and function are largely unknown. This review focuses on what is known about PAS kinase, including its conservation from yeast to man, identified substrates, associated phenotypes and role in metabolic disease.

  14. The novel GLP-1-gastrin dual agonist ZP3022 improves glucose homeostasis and increases β-cell mass without affecting islet number in db/db mice.

    PubMed

    Dalbøge, Louise S; Almholt, Dorthe L C; Neerup, Trine S R; Vrang, Niels; Jelsing, Jacob; Fosgerau, Keld

    2014-08-01

    Antidiabetic treatments aiming to preserve or even to increase β-cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist ZP3022 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2) on glycemic control, β-cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks, with terminal assessment of hemoglobin A1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of β-cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in β-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in β-cell mass observed in the ZP3022-treated mice appeared to be driven by increased β-cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased but the number of islets remained constant. Our data demonstrate that the GLP-1-gastrin dual agonist ZP3022 causes a sustained improvement in glycemic control accompanied by an increase in β-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases β-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments.

  15. 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

  16. 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.

  17. p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity

    PubMed Central

    Baeza-Raja, Bernat; Li, Pingping; Le Moan, Natacha; Sachs, Benjamin D.; Schachtrup, Christian; Davalos, Dimitrios; Vagena, Eirini; Bridges, Dave; Kim, Choel; Saltiel, Alan R.; Olefsky, Jerrold M.; Akassoglou, Katerina

    2012-01-01

    Insulin resistance is a key factor in the etiology of type 2 diabetes. Insulin-stimulated glucose uptake is mediated by the glucose transporter 4 (GLUT4), which is expressed mainly in skeletal muscle and adipose tissue. Insulin-stimulated translocation of GLUT4 from its intracellular compartment to the plasma membrane is regulated by small guanosine triphosphate hydrolases (GTPases) and is essential for the maintenance of normal glucose homeostasis. Here we show that the p75 neurotrophin receptor (p75NTR) is a regulator of glucose uptake and insulin resistance. p75NTR knockout mice show increased insulin sensitivity on normal chow diet, independent of changes in body weight. Euglycemic-hyperinsulinemic clamp studies demonstrate that deletion of the p75NTR gene increases the insulin-stimulated glucose disposal rate and suppression of hepatic glucose production. Genetic depletion or shRNA knockdown of p75NTR in adipocytes or myoblasts increases insulin-stimulated glucose uptake and GLUT4 translocation. Conversely, overexpression of p75NTR in adipocytes decreases insulin-stimulated glucose transport. In adipocytes, p75NTR forms a complex with the Rab5 family GTPases Rab5 and Rab31 that regulate GLUT4 trafficking. Rab5 and Rab31 directly interact with p75NTR primarily via helix 4 of the p75NTR death domain. Adipocytes from p75NTR knockout mice show increased Rab5 and decreased Rab31 activities, and dominant negative Rab5 rescues the increase in glucose uptake seen in p75NTR knockout adipocytes. Our results identify p75NTR as a unique player in glucose metabolism and suggest that signaling from p75NTR to Rab5 family GTPases may represent a unique therapeutic target for insulin resistance and diabetes. PMID:22460790

  18. A role of the adaptive immune system in glucose homeostasis

    PubMed Central

    Bronsart, Laura L; Contag, Christopher H

    2016-01-01

    Objective The immune system, including the adaptive immune response, has recently been recognized as having a significant role in diet-induced insulin resistance. In this study, we aimed to determine if the adaptive immune system also functions in maintaining physiological glucose homeostasis in the absence of diet-induced disease. Research design and methods SCID mice and immunocompetent control animals were phenotypically assessed for variations in metabolic parameters and cytokine profiles. Additionally, the glucose tolerance of SCID and immunocompetent control animals was assessed following introduction of a high-fat diet. Results SCID mice on a normal chow diet were significantly insulin resistant relative to control animals despite having less fat mass. This was associated with a significant increase in the innate immunity-stimulating cytokines granulocyte colony-stimulating factor, monocyte chemoattractant protein 1 (MCP1), and MCP3. Additionally, the SCID mouse phenotype was exacerbated in response to a high-fat diet as evidenced by the further significant progression of glucose intolerance. Conclusions These results support the notion that the adaptive immune system plays a fundamental biological role in glucose homeostasis, and that the absence of functional B and T cells results in disruption in the concentrations of various cytokines associated with macrophage proliferation and recruitment. Additionally, the absence of functional B and T cells is not protective against diet-induced pathology. PMID:27026807

  19. Physiology and role of irisin in glucose homeostasis.

    PubMed

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

    2017-02-17

    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.

  20. Prediabetes Phenotype Influences Improvements in Glucose Homeostasis with Resistance Training

    PubMed Central

    Eikenberg, Joshua D.; Savla, Jyoti; Marinik, Elaina L.; Davy, Kevin P.; Pownall, John; Baugh, Mary E.; Flack, Kyle D.; Boshra, Soheir; Winett, Richard A.; Davy, Brenda M.

    2016-01-01

    Purpose To determine if prediabetes phenotype influences improvements in glucose homeostasis with resistance training (RT). Methods Older, overweight individuals with prediabetes (n = 159; aged 60±5 yrs; BMI 33±4 kg/m2) completed a supervised RT program twice per week for 12 weeks. Body weight and composition, strength, fasting plasma glucose, 2-hr oral glucose tolerance, and Matsuda-Defronza estimated insulin sensitivity index (ISI) were assessed before and after the intervention. Participants were categorized according to their baseline prediabetes phenotype as impaired fasting glucose only (IFG) (n = 73), impaired glucose tolerance only (IGT) (n = 21), or combined IFG and IGT (IFG/IGT) (n = 65). Results Chest press and leg press strength increased 27% and 18%, respectively, following the 12-week RT program (both p<0.05). Waist circumference (-1.0%; pre 109.3±10.3 cm, post 108.2±10.6 cm) and body fat (-0.6%; pre 43.7±6.8%, post 43.1±6.8%) declined, and lean body mass (+1.3%; pre 52.0±10.4 kg, post 52.7±10.7 kg) increased following the intervention. Fasting glucose concentrations did not change (p>0.05) following the intervention. However, 2-hr oral glucose tolerance improved in those with IGT (pre 8.94±0.72 mmol/l, post 7.83±1.11 mmol/l, p<0.05) and IFG/IGT (pre 9.66±1.11mmol/l, post 8.60±2.00 mmol/l) but not in those with IFG (pre 6.27±1.28mmol/l, post 6.33± 1.55 mmol/l). There were no significant changes in ISI or glucose area under the curve following the RT program. Conclusions RT without dietary intervention improves 2-hr oral glucose tolerance in individuals with prediabetes. However, the improvements in glucose homeostasis with RT appear limited to those with IGT or combined IFG and IGT. Trial Registration ClinicalTrials.gov: NCT01112709 PMID:26840904

  1. Melatonin improves glucose homeostasis in young Zucker diabetic fatty rats.

    PubMed

    Agil, Ahmad; Rosado, Isaac; Ruiz, Rosario; Figueroa, Adriana; Zen, Nourahouda; Fernández-Vázquez, Gumersindo

    2012-03-01

    The aim of this study was to investigate the effects of melatonin on glucose homeostasis in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n=30) and lean littermates (ZL) (n=30) were used. At 6wk of age, both lean and fatty animals were subdivided into three groups, each composed of ten rats: naive (N), vehicle treated (V), and melatonin treated (M) (10mg/kg/day) for 6wk. Vehicle and melatonin were added to the drinking water. ZDF rats developed DM (fasting hyperglycemia, 460±39.8mg/dL; HbA(1) c 8.3±0.5%) with both insulin resistance (HOMA-IR 9.28±0.9 versus 1.2±0.1 in ZL) and decreased β-cell function (HOMA1-%B) by 75%, compared with ZL rats. Melatonin reduced fasting hyperglycemia by 18.6% (P<0.05) and HbA(1) c by 11% (P<0.05) in ZDF rats. Also, melatonin lowered insulinemia by 15.9% (P<0.05) and HOMA-IR by 31% (P<0.01) and increased HOMA1-%B by 14.4% (P<0.05). In addition, melatonin decreased hyperleptinemia by 34% (P<0.001) and raised hypoadiponectinemia by 40% (P<0.001) in ZDF rats. Moreover, melatonin reduced serum free fatty acid levels by 13.5% (P<0.05). These data demonstrate that oral melatonin administration ameliorates glucose homeostasis in young ZDF rats by improving both insulin action and β-cell function. These observations have implications on melatonin's possible use as a new pharmacologic therapy for improving glucose homeostasis and of obesity-related T2DM, in young subjects.

  2. Adipocytes as regulators of energy balance and glucose homeostasis

    PubMed Central

    Rosen, Evan D.; Spiegelman, Bruce M.

    2011-01-01

    Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions. PMID:17167472

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

    PubMed Central

    Pal, M; Gupta, S

    2016-01-01

    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. PMID:27941939

  4. IL-1 resets glucose homeostasis at central levels

    PubMed Central

    del Rey, Adriana; Roggero, Eduardo; Randolf, Anke; Mahuad, Carolina; McCann, Samuel; Rettori, Valeria; Besedovsky, Hugo O.

    2006-01-01

    Administration of IL-1β results in a profound and long-lasting hypoglycemia. Here, we show that this effect can be elicited by endogenous IL-1 and is related to not only the capacity of the cytokine to increase glucose uptake in peripheral tissues but also to mechanisms integrated in the brain. We show that (i) blockade of IL-1 receptors in the brain partially counteracted IL-1-induced hypoglycemia; (ii) peripheral administration or induction of IL-1 production resulted in IL-1β gene expression in the hypothalamus of normal and insulin-resistant, leptin receptor-deficient, diabetic db/db mice; (iii) IL-1-treated normal and db/db mice challenged with glucose did not return to their initial glucose levels but remained hypoglycemic for several hours. This effect was largely antagonized by blockade of IL-1 receptors in the brain; and (iv) when animals with an advanced Type II diabetes were treated with IL-1 and challenged with glucose, they died in hypoglycemia. However, when IL-1 receptors in the brains of these diabetic mice were blocked, they survived, and glucose blood levels approached those that these mice had before IL-1 administration. The prolonged hypoglycemic effect of IL-1 is insulin-independent and develops against increased levels of glucocorticoids, catecholamines, and glucagon. These findings, together with the present demonstration that this effect is integrated in the brain and is paralleled by IL-1β expression in the hypothalamus, indicate that this cytokine can reset glucose homeostasis at central levels. Such reset, along with the peripheral actions of the cytokine, would favor glucose uptake by immune cells during inflammatory/immune processes. PMID:17035503

  5. 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

  6. Perinatal exercise improves glucose homeostasis in adult offspring.

    PubMed

    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; Pearson, Kevin J

    2012-10-15

    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.

  7. 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.

  8. Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

    PubMed Central

    Fan, Fan; Ji, Chen; Wu, Yumei; Ferguson, Shawn M.; Tamarina, Natalia; Philipson, Louis H.; Lou, Xuelin

    2015-01-01

    Alterations in insulin granule exocytosis and endocytosis are paramount to pancreatic β cell dysfunction in diabetes mellitus. Here, using temporally controlled gene ablation specifically in β cells in mice, we identified an essential role of dynamin 2 GTPase in preserving normal biphasic insulin secretion and blood glucose homeostasis. Dynamin 2 deletion in β cells caused glucose intolerance and substantial reduction of the second phase of glucose-stimulated insulin secretion (GSIS); however, mutant β cells still maintained abundant insulin granules, with no signs of cell surface expansion. Compared with control β cells, real-time capacitance measurements demonstrated that exocytosis-endocytosis coupling was less efficient but not abolished; clathrin-mediated endocytosis (CME) was severely impaired at the step of membrane fission, which resulted in accumulation of clathrin-coated endocytic intermediates on the plasma membrane. Moreover, dynamin 2 ablation in β cells led to striking reorganization and enhancement of actin filaments, and insulin granule recruitment and mobilization were impaired at the later stage of GSIS. Together, our results demonstrate that dynamin 2 regulates insulin secretory capacity and dynamics in vivo through a mechanism depending on CME and F-actin remodeling. Moreover, this study indicates a potential pathophysiological link between endocytosis and diabetes mellitus. PMID:26413867

  9. 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.

  10. Epoxyeicosatrienoic acids and glucose homeostasis in mice and men.

    PubMed

    Luther, James M; Brown, Nancy J

    2016-09-01

    Epoxyeicosatrienoic acids (EETs) are formed from arachidonic acid by the action of P450 epoxygenases (CYP2C and CYP2J). Effects of EETs are limited by hydrolysis by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. Studies in rodent models provide compelling evidence that epoxyeicosatrienoic acids exert favorable effects on glucose homeostasis, either by enhancing pancreatic islet cell function or by increasing insulin sensitivity in peripheral tissues. Specifically, the tissue expression of soluble epoxide hydrolase appears to be increased in rodent models of obesity and diabetes. Pharmacological inhibition of epoxide hydrolase or deletion of the gene encoding soluble epoxide hydrolase (Ephx2) preserves islet cells in rodent models of type 1 diabetes and enhances insulin sensitivity in models of type 2 diabetes, as does administration of epoxyeicosatrienoic acids or their stable analogues. In humans, circulating concentrations of epoxyeicosatrienoic acids correlate with insulin sensitivity, and a loss-of-function genetic polymorphism in EPHX2 is associated with insulin sensitivity.

  11. Coplanar Polychlorinated Biphenyls Impair Glucose Homeostasis in Lean C57BL/6 Mice and Mitigate Beneficial Effects of Weight Loss on Glucose Homeostasis in Obese Mice

    PubMed Central

    Baker, Nicki A.; Karounos, Michael; English, Victoria; Fang, Jun; Wei, Yinan; Stromberg, Arnold; Sunkara, Manjula; Morris, Andrew J.; Swanson, Hollie I.

    2012-01-01

    Background: Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote proinflammatory gene expression in adipocytes. PCBs are highly lipophilic and accumulate in adipose tissue, a site of insulin resistance in persons with type 2 diabetes. Objectives: We investigated the in vitro and in vivo effects of coplanar PCBs on adipose expression of tumor necrosis factor α (TNF-α) and on glucose and insulin homeostasis in lean and obese mice. Methods: We quantified glucose and insulin tolerance, as well as TNF-α levels, in liver, muscle, and adipose tissue of male C57BL/6 mice administered vehicle, PCB-77, or PCB-126 and fed a low fat (LF) diet. Another group of mice administered vehicle or PCB-77 were fed a high fat (HF) diet for 12 weeks; the diet was then switched from HF to LF for 4 weeks to induce weight loss. We quantified glucose and insulin tolerance and adipose TNF-α expression in these mice. In addition, we used in vitro and in vivo studies to quantify aryl hydrocarbon receptor (AhR)-dependent effects of PCB-77 on parameters of glucose homeostasis. Results: Treatment with coplanar PCBs resulted in sustained impairment of glucose and insulin tolerance in mice fed the LF diet. In PCB-77–treated mice, TNF-α expression was increased in adipose tissue but not in liver or muscle. PCB-77 levels were strikingly higher in adipose tissue than in liver or serum. Antagonism of AhR abolished both in vitro and in vivo effects of PCB-77. In obese mice, PCB-77 had no effect on glucose homeostasis, but glucose homeostasis was impaired after weight loss. Conclusions: Coplanar PCBs impaired glucose homeostasis in lean mice and in obese mice following weight loss. Adipose-specific elevations in TNF-α expression by PCBs may contribute to impaired glucose homeostasis. PMID:23099484

  12. Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model.

    PubMed

    Zou, JiangHuan; Xiong, XiWen; Lai, BeiBei; Sun, Min; Tu, Xin; Gao, Xiang

    2015-04-01

    Bone was reported as a crucial organ for regulating glucose homeostasis. In this study, we found that Phex mutant mice (PUG), a model of human X-linked hypophosphatemic rickets (XLH), displayed metabolic abnormality in addition to abnormal phosphate homeostasis, skeletal deformity and growth retardation. Glucose tolerance was elevated with enhanced insulin sensitivity in PUG, though circulating insulin level decreased. Interestingly, bone mineral density defects and glucose metabolic abnormality were both rescued by adding phosphorus- and calcium-enriched supplements in daily diet. Serum insulin level, glucose tolerance and insulin sensitivity showed no differences between PUG and wild-type mice with rescued osteocalcin (OCN) following treatment. Our study suggested that OCN is a potential mediator between mineral homeostasis and glucose metabolism. This investigation brings a new perspective on glucose metabolism regulation through skeleton triggered mineral homeostasis and provides new clues in clinical therapeutics of potential metabolic disorders in XLH patients.

  13. Effect of fluoridated water on plasma insulin levels and glucose homeostasis in rats with renal deficiency.

    PubMed

    Lupo, Maela; Buzalaf, Marília Afonso Rabelo; Rigalli, Alfredo

    2011-05-01

    Glucose intolerance in fluorosis areas and when fluoride is administered for the treatment of osteoporosis has been reported. Controlled fluoridation of drinking water is regarded as a safe and effective measure to control dental caries. However, the effect on glucose homeostasis was not studied so far. The aim of this study was to evaluate the effect of the intake of fluoridated water supply on glucose metabolism in rats with normal and deficient renal function. Male Sprague-Dawley rats were divided into eight groups of four rats. Renal insufficiency was induced in four groups (NX) which received drinking water containing 0, 1, 5, and 15 ppm F (NaF) for 60 days. Four groups with simulated surgery acted as controls. There were no differences in plasma glucose concentration after a glucose tolerance test between controls and NX rats and among rats with different intakes of fluoride. However, plasma insulin level increased as a function of fluoride concentration in drinking water, both in controls and in NX rats. It is concluded that the consumption of fluoridated water from water supply did not affect plasma glucose levels even in cases of animals with renal disease. However, a resistance to insulin action was demonstrated.

  14. 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.

  15. Glucose homeostasis and cardiovascular disease biomarkers in older alpine skiers.

    PubMed

    Dela, F; Niederseer, D; Patsch, W; Pirich, C; Müller, E; Niebauer, J

    2011-08-01

    Alpine skiing and ski training involves elements of static and dynamic training, and may therefore improve insulin sensitivity. Healthy men and women who where beginners/intermediate level of alpine skiing, were studied before (Pre) and immediately after (Post) 12 weeks of alpine ski training. After an additional 8 weeks a third test (retention study, Ret) was performed. The subjects were randomized into an intervention group (IG, n=22, age=66.6 ± 0.4 years) or a control group (CG, n=20, age=67.0 ± 1.0 years). Plasma glucose decreased (P<0.05) in CG, but increased (P<0.05) again at Ret, while a continued decrease was seen in IG (Ret vs Post, P<0.05). Plasma insulin decreased (P<0.05) with training in IG, while no effect was seen in CG. HOMA2 index for insulin resistance decreased (P<0.05) from 0.80 ± 0.08 to 0.71 ± 0.09 in IG. The value at Ret (0.57 ± 0.08) tended (P=0.067) to be different from Post. In CG the corresponding values were 0.84 ± 0.09, 0.81 ± 0.12 and 0.70 ± 0.09, respectively. Total cholesterol and LDL decreased in both IC and CG, a result, interpreted as seasonal variation. Biomarkers for endothelial function and low-grade inflammation were not elevated and similar in IG and CG, and did not change. Alpine ski training improves glucose homeostasis and insulin sensitivity in healthy, elderly individuals.

  16. Transcriptional activation of glutathione pathways and role of glucose homeostasis during copper imbalance.

    PubMed

    Quiroz, Natalia; Rivas, Nicole; del Pozo, Talía; Burkhead, Jason; Suazo, Miriam; González, Mauricio; Latorre, Mauricio

    2015-04-01

    Copper is an essential micronutrient for organism health. Dietary changes or pathologies linked to this metal induce changes in intracellular glutathione concentrations. Here, we studied the transcriptional activation of glutathione pathways in Jurkat cell lines, analyzing the effect of change in glucose homeostasis during a physiological and supra-physiological copper exposure. An immortalized line of human T lymphocyte cell line (Jurkat) was exposed to different copper and glucose conditions to mimic concentrations present in human blood. We applied treatments for 6 (acute) and 24 h (sustained) to 2 µM (physiological) or 20 µM (supra-physiological, Wilson disease scenario) of CuSO4 in combination with 25 mg/dL (hypoglycemia), 100 mg/dL (normal) and 200 mg/dL (hyperglycemia, diabetes scenario) of glucose. The results indicate that a physiological concentration of copper exposure does not induce transcriptional changes in the glutathione synthesis pathway after 6 or 24 h. The G6PDH gene (regeneration pathway), however, is induced during a supra-physiological copper condition. This data was correlated with the viability assays, where fluctuation in both glucose conditions (hypo and hyperglycemia scenario) affected Jurkat proliferation when 20 µM of CuSO4 was added to the culture media. Under a copper overload condition, the transcription of a component of glutathione regeneration pathway (G6PDH gene) is activated in cells chronically exposed to a hyperglycemia scenario, indicating that fluctuations in glucose concentration impact the resistance against the metal. Our findings illustrate the importance of glucose homeostasis during copper excess.

  17. 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.

  18. Multivitamin restriction increases adiposity and disrupts glucose homeostasis in mice.

    PubMed

    Amara, Nisserine Ben; Marcotorchino, Julie; Tourniaire, Franck; Astier, Julien; Amiot, Marie-Josèphe; Darmon, Patrice; Landrier, Jean-François

    2014-07-01

    A strong association between obesity and low plasma concentrations of vitamins has been widely reported; however, the causality of this relationship is still not established. Our goal was to evaluate the impact of a multivitamin restriction diet (MRD) on body weight, adiposity and glucose homeostasis in mice. The mice were given a standard diet or a diet containing 50 % of the recommended vitamin intake (MRD) for 12 weeks. At the end of the experiment, total body weight was 6 % higher in MRD animals than in the control group, and the adiposity of the MRD animals more than doubled. The HOMA-IR index of the MRD animals was significantly increased. The adipose tissue of MRD animals had lower expression of mRNA encoding adiponectin and Pnpla2 (47 and 32 %, respectively) and 43 % higher leptin mRNA levels. In the liver, the mRNA levels of Pparα and Pgc1α were reduced (29 and 69 %, respectively) in MRD mice. Finally, the level of β-hydroxybutyrate, a ketonic body reflecting fatty acid oxidation, was decreased by 45 % in MRD mice. Our results suggest that MRD promotes adiposity, possibly by decreasing adipose tissue lipolysis and hepatic β-oxidation. These results could highlight a possible role of vitamin deficiency in the etiology of obesity and associated disorders.

  19. Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism.

    PubMed

    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.

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

    PubMed

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

    2012-07-15

    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.

  1. Roles of dorsomedial hypothalamic cholecystokinin signaling in the controls of meal patterns and glucose homeostasis.

    PubMed

    Zhu, Guangjing; Yan, Jianqun; Smith, Wanli W; Moran, Timothy H; Bi, Sheng

    2012-01-18

    A role for dorsomedial hypothalamus (DMH) cholecystokinin (CCK) signaling in feeding control has been proposed. Administration of CCK into the DMH reduces food intake and OLETF rats lacking CCK1 receptors (CCK1R) become hyperphagic and obese. We hypothesized that site specific replenishment of CCK1R in the DMH of OLETF rats would attenuate aspects of their feeding deficits. Recombinant vectors of adeno-associated viral (AAV)-mediated expression of CCK1R (AAVCCK1R) were bilaterally delivered into the DMH of OLETF. OLETF rats with AAVCCK1R injections demonstrated a 65% replenishment of Cck1r mRNA expression in the DMH relative to lean LETO control rats. Although this level of replenishment did not significantly affect overall food intake or body weight through 14 weeks following viral injections, meal patterns were partially normalized in OLETF rats receiving AAVCCK1R with a significant decrease in dark cycle meal size and a small but significant decrease in daily food intake in the meal analysis chambers. Importantly, the elevation in blood glucose level of OLETF rats was attenuated by the AAVCCK1R injections (p=0.03), suggesting a role for DMH CCK signaling in glucose homeostasis. In support of this role, administration of CCK into the DMH of intact rats enhanced glucose tolerance, as this occurred through activation of CCK1R but not CCK2R signaling. In conclusion, partial replenishment of CCK1R in the DMH of OLETF rats, although insufficient for altering overall food intake and body weight, normalizes meal pattern changes and reduces blood glucose levels. Our study also shows a novel role of DMH CCK signaling in glucose homeostasis.

  2. High glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway

    PubMed Central

    Wu, Yu-Fu; Wang, Hsing-Kuo; Chang, Hong-Wei; Sun, Jingyu; Sun, Jui-Sheng; Chao, Yuan-Hung

    2017-01-01

    Diabetes mellitus (DM) is associated with higher risk of tendinopathy, which reduces tolerance to exercise and functional activities and affects lifestyle and glycemic control. Expression of tendon-related genes and matrix metabolism in tenocytes are essential for maintaining physiological functions of tendon. However, the molecular mechanisms involved in diabetic tendinopathy remain unclear. We hypothesized that high glucose (HG) alters the characteristics of tenocyte. Using in vitro 2-week culture of tenocytes, we found that expression of tendon-related genes, including Egr1, Mkx, TGF-β1, Col1a2, and Bgn, was significantly decreased in HG culture and that higher glucose consumption occurred. Down-regulation of Egr1 by siRNA decreased Scx, Mkx, TGF-β1, Col1a1, Col1a2, and Bgn expression. Blocking AMPK activation with Compound C reduced the expression of Egr1, Scx, TGF-β1, Col1a1, Col1a2, and Bgn in the low glucose condition. In addition, histological examination of tendons from diabetic mice displayed larger interfibrillar space and uneven glycoprotein deposition. Thus, we concluded that high glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway and the expression of downstream tendon-related genes in tenocytes. The findings render a molecular basis of the mechanism of diabetic tendinopathy and may help develop preventive and therapeutic strategies for the pathology. PMID:28266660

  3. Implications of Hydrogen Sulfide in Glucose Regulation: How H2S Can Alter Glucose Homeostasis through Metabolic Hormones.

    PubMed

    Pichette, Jennifer; Gagnon, Jeffrey

    2016-01-01

    Diabetes and its comorbidities continue to be a major health problem worldwide. Understanding the precise mechanisms that control glucose homeostasis and their dysregulation during diabetes are a major research focus. Hydrogen sulfide (H2S) has emerged as an important regulator of glucose homeostasis. This is achieved through its production and action in several metabolic and hormone producing organs including the pancreas, liver, and adipose. Of importance, H2S production and signaling in these tissues are altered during both type 1 and type 2 diabetes mellitus. This review first examines how H2S is produced both endogenously and by gastrointestinal microbes, with a particular focus on the altered production that occurs during obesity and diabetes. Next, the action of H2S on the metabolic organs with key roles in glucose homeostasis, with a particular focus on insulin, is described. Recent work has also suggested that the effects of H2S on glucose homeostasis goes beyond its role in insulin secretion. Several studies have demonstrated important roles for H2S in hepatic glucose output and adipose glucose uptake. The mechanism of H2S action on these metabolic organs is described. In the final part of this review, future directions examining the roles of H2S in other metabolic and glucoregulatory hormone secreting tissues are proposed.

  4. Implications of Hydrogen Sulfide in Glucose Regulation: How H2S Can Alter Glucose Homeostasis through Metabolic Hormones

    PubMed Central

    Pichette, Jennifer

    2016-01-01

    Diabetes and its comorbidities continue to be a major health problem worldwide. Understanding the precise mechanisms that control glucose homeostasis and their dysregulation during diabetes are a major research focus. Hydrogen sulfide (H2S) has emerged as an important regulator of glucose homeostasis. This is achieved through its production and action in several metabolic and hormone producing organs including the pancreas, liver, and adipose. Of importance, H2S production and signaling in these tissues are altered during both type 1 and type 2 diabetes mellitus. This review first examines how H2S is produced both endogenously and by gastrointestinal microbes, with a particular focus on the altered production that occurs during obesity and diabetes. Next, the action of H2S on the metabolic organs with key roles in glucose homeostasis, with a particular focus on insulin, is described. Recent work has also suggested that the effects of H2S on glucose homeostasis goes beyond its role in insulin secretion. Several studies have demonstrated important roles for H2S in hepatic glucose output and adipose glucose uptake. The mechanism of H2S action on these metabolic organs is described. In the final part of this review, future directions examining the roles of H2S in other metabolic and glucoregulatory hormone secreting tissues are proposed. PMID:27478532

  5. 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.

  6. 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

  7. Utility of Childhood Glucose Homeostasis Variables in Predicting Adult Diabetes and Related Cardiometabolic Risk Factors

    PubMed Central

    Nguyen, Quoc Manh; Srinivasan, Sathanur R.; Xu, Ji-Hua; Chen, Wei; Kieltyka, Lyn; Berenson, Gerald S.

    2010-01-01

    OBJECTIVE This study examines the usefulness of childhood glucose homeostasis variables (glucose, insulin, and insulin resistance index [homeostasis model assessment of insulin resistance {HOMA-IR}]) in predicting pre-diabetes and type 2 diabetes and related cardiometabolic risk factors in adulthood. RESEARCH DESIGN AND METHODS This retrospective cohort study consisted of normoglycemic (n = 1,058), pre-diabetic (n = 37), and type 2 diabetic (n = 25) adults aged 19–39 years who were followed on average for 17 years since childhood. RESULTS At least 50% of the individuals who ranked highest (top quintile) in childhood for glucose homeostasis variables maintained their high rank by being above the 60th percentile in adulthood. In a multivariate model, the best predictors of adulthood glucose homeostasis variables were the change in BMI Z score from childhood to adulthood and childhood BMI Z score, followed by the corresponding childhood levels of glucose, insulin, and HOMA-IR. Further, children in the top decile versus the rest for insulin and HOMA-IR were 2.85 and 2.55 times, respectively, more likely to develop pre-diabetes; children in the top decile versus the rest for glucose, insulin, and HOMA-IR were 3.28, 5.54, and 5.84 times, respectively, more likely to develop diabetes, independent of change in BMI Z score, baseline BMI Z score, and total-to-HDL cholesterol ratio. In addition, children with adverse levels (top quintile versus the rest) of glucose homeostasis variables displayed significantly higher prevalences of, among others, hyperglycemia, hypertriglyceridemia, and metabolic syndrome. CONCLUSIONS Adverse levels of glucose homeostasis variables in childhood not only persist into adulthood but also predict adult pre-diabetes and type 2 diabetes and relate to cardiometabolic risk factors. PMID:20009096

  8. Contribution of galactose and fructose to glucose homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  9. GPR17 gene disruption does not alter food intake or glucose homeostasis in mice

    PubMed Central

    Mastaitis, Jason; Min, Soo; Elvert, Ralf; Kannt, Aimo; Xin, Yurong; Ochoa, Francisca; Gale, Nicholas W.; Valenzuela, David M.; Murphy, Andrew J.; Yancopoulos, George D.; Gromada, Jesper

    2015-01-01

    G protein-coupled receptor 17 (GPR17) was recently reported to be a Foxo1 target in agouti-related peptide (AGRP) neurons. Intracerebroventricular injection of GPR17 agonists induced food intake, whereas administration of an antagonist to the receptor reduced feeding. These data lead to the conclusion that pharmacological modulation of GPR17 has therapeutic potential to treat obesity. Here we report that mice deficient in Gpr17 (Gpr17−/−) have similar food intake and body weight compared with their wild-type littermates. Gpr17−/− mice have normal hypothalamic Agrp mRNA expression, AGRP plasma levels, and metabolic rate. GPR17 deficiency in mice did not affect glucose homeostasis or prevent fat-induced insulin resistance. These data do not support a role for GPR17 in the control of food intake, body weight, or glycemic control. PMID:25624481

  10. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response.

    PubMed

    Moreau, Amélie; Vilarem, Marie José; Maurel, Patrick; Pascussi, Jean Marc

    2008-01-01

    Xenobiotic and drug metabolism and transport are managed by a large number of genes coordinately regulated by at least three nuclear receptors or xenosensors: aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR, NR1I3), and pregnane X receptor (PXR, NR1I2). Initially characterized as xenosensors, it is now evident that CAR and PXR also trigger pleiotropic effects on liver function. Recent studies have shown the existence of crosstalk between xenosensors and other nuclear receptors or transcription factors controlling endogenous signaling pathways which regulate physiological functions. This review is focused on recent observations showing that activation of CAR and PXR alters lipid metabolism, glucose homeostasis, and inflammation by interfering with HNF4alpha, FoxO1, FoxA2, PGC1alpha, or NFkB p65. Such crosstalks explain clinical observations and provide molecular mechanisms allowing understanding how xenobiotics and drugs may affect physiological functions and provoke endocrine disruptions.

  11. 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

  12. Cholecystokinin impact on rainbow trout glucose homeostasis: possible involvement of central glucosensors.

    PubMed

    Polakof, Sergio; Míguez, Jesus M; Soengas, José L

    2011-12-10

    Although the role of cholecystokinin (CCK) on fish appetite regulation has been widely studied, its involvement in the regulation of glucose metabolism had been little explored to date. In the present study we have carried out different experimental approaches to study CCK effects in rainbow trout (a so-called 'glucose intolerant' fish species) glucose homeostasis. We have found that for the first time in a vertebrate species, systemic or central CCK administration causes hyperglycemia, which is at least in part related to the presence of an ancestral gut-brain axis in which CCK is involved. By using capsaicin we have found that part of the action of CCK on glucose homeostasis is mediated by vagal and splanchnic afferents. Changes in hepatic metabolism after systemic CCK administration suggest that the effects are not directly taking place on the liver, but probably in other tissues, while after the central CCK administration, the glycogenolytic response observed in liver could be mediated by the activation of the sympathetic system. In hypothalamus and hindbrain changes elicited by CCK-8 treatment are likely related to the glucosensor response to the increased glycemia and/or vagal/splanchnic afferences whereas in hindbrain a possible action through specific CCK-1 receptors cannot be excluded. All these processes result in changes in metabolic parameters related with glucose homeostasis control. Further studies are needed to fully understand the role of this peptide on glucose homeostasis control in fish.

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

    PubMed

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

    2017-02-20

    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.

  14. Hepatic overexpression of a constitutively active form of liver glycogen synthase improves glucose homeostasis.

    PubMed

    Ros, Susana; Zafra, Delia; Valles-Ortega, Jordi; García-Rocha, Mar; Forrow, Stephen; Domínguez, Jorge; Calbó, Joaquim; Guinovart, Joan J

    2010-11-26

    In this study, we tested the efficacy of increasing liver glycogen synthase to improve blood glucose homeostasis. The overexpression of wild-type liver glycogen synthase in rats had no effect on blood glucose homeostasis in either the fed or the fasted state. In contrast, the expression of a constitutively active mutant form of the enzyme caused a significant lowering of blood glucose in the former but not the latter state. Moreover, it markedly enhanced the clearance of blood glucose when fasted rats were challenged with a glucose load. Hepatic glycogen stores in rats overexpressing the activated mutant form of liver glycogen synthase were enhanced in the fed state and in response to an oral glucose load but showed a net decline during fasting. In order to test whether these effects were maintained during long term activation of liver glycogen synthase, we generated liver-specific transgenic mice expressing the constitutively active LGS form. These mice also showed an enhanced capacity to store glycogen in the fed state and an improved glucose tolerance when challenged with a glucose load. Thus, we conclude that the activation of liver glycogen synthase improves glucose tolerance in the fed state without compromising glycogenolysis in the postabsorptive state. On the basis of these findings, we propose that the activation of liver glycogen synthase may provide a potential strategy for improvement of glucose tolerance in the postprandial state.

  15. Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice.

    PubMed

    Van Sinderen, Michelle L; Steinberg, Gregory R; Jørgensen, Sebastian B; Honeyman, Jane; Chow, Jenny D; Herridge, Kerrie A; Winship, Amy L; Dimitriadis, Evdokia; Jones, Margaret E E; Simpson, Evan R; Boon, Wah Chin

    2015-01-01

    The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2) treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental) adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule) in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα) and interleukin 6 (IL6). Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.

  16. Resveratrol protects against polychlorinated biphenyl-mediated impairment of glucose homeostasis in adipocytes

    PubMed Central

    Baker, Nicki A.; English, Victoria; Sunkara, Manjula; Morris, Andrew J.; Pearson, Kevin J.; Cassis, Lisa A.

    2014-01-01

    Resveratrol (RSV) is a plant polyphenol that exhibits several favorable effects on glucose homeostasis in adipocytes. Recent studies from our laboratory demonstrated that coplanar polychlorinated biphenyls (PCBs) that are ligands of the aryl hydrocarbon receptor (AhR) impair glucose homeostasis in mice. PCB-induced impairment of glucose homeostasis was associated with augmented expression of inflammatory cytokines in adipose tissue, a site for accumulation of lipophilic PCBs. This study determined if RSV protects against PCB-77 induced impairment of glucose disposal in vitro and in vivo, and if these beneficial effects are associated with enhanced nuclear factor erythoid 2-related factor 2 (Nrf2) signaling in adipose tissue. PCB-77 increased oxidative stress and abolished insulin stimulated 2-deoxy-D-glucose (2DG) uptake in 3T3-L1 adipocytes. These effects were restored by RSV, which resulted in a concentration-dependent increase in NAD(P)H:quinone oxidoreductase 1 (NQO1), the downstream target of Nrf2 signaling. We quantified glucose and insulin tolerance and components of Nrf2 and insulin signaling cascades in adipose tissue of male C57BL/6 mice administered vehicle or PCB-77 (50 mg/kg) and fed a diet with or without resVida® (0.1%, or 160 mg/kg/day). PCB-77 impaired glucose and insulin tolerance, and these effects were reversed by RSV. PCB-77 induced reductions in insulin signaling in adipose tissue were also abolished by RSV, which increased NQO1 expression. These results demonstrate that coplanar PCB-induced impairment of glucose homeostasis in mice can be prevented by RSV, potentially through stimulation of Nrf2 signaling and enhanced insulin stimulated glucose disposal in adipose tissue. PMID:24231106

  17. Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice

    PubMed Central

    Van Sinderen, Michelle L.; Steinberg, Gregory R.; Jørgensen, Sebastian B.; Honeyman, Jane; Chow, Jenny D.; Herridge, Kerrie A.; Winship, Amy L.; Dimitriadis, Evdokia; Jones, Margaret E. E.; Simpson, Evan R.; Boon, Wah Chin

    2015-01-01

    The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2) treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental) adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule) in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα) and interleukin 6 (IL6). Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile. PMID:26317527

  18. Effects of ethanol ingestion on maternal and fetal glucose homeostasis

    SciTech Connect

    Singh, S.P.; Snyder, A.K.; Singh, S.K.

    1984-08-01

    Carbohydrate metabolism has been studied in the offspring of rats fed liqiud diet containing ethanol during gestation (EF group). Weight-matched control dams were given liquid diet either by the pair-fed technique (PF group) or ad libitum (AF group). EF and PF dams showed reduced food consumption and attenuated gain in body weight during the gestation period compared with the AF group. Blood glucose, liver glycogen, and plasma insulin levels were significantly reduced in EF and PF dams. Ethanol ingestion resulted in a significant decrease in litter survival and fetal body weight. At term, EF pups on average showed a 30% decrease in blood glucose levels and 40% decrease in plasma insulin levels compared with AF pups. One hour after birth, EF pups exhibited a marked increase in blood sugar level compared with either control group. Fetal hyperinsulinemia disappeared shortly after delivery in control pups, as expected; however, in EF pups, the fall in plasma insulin level was gradual. Fetal and neonatal plasma glucagon levels were not altered by ethanol exposure in utero. Blood glucose levels remained significantly low at 2 days of age in EF pups, but reached near control values at 4 days of age. Plasma insulin and glucagon were nearly equal in EF and control pups at 2 and 4 days of age. These results show aberrations in blood glucose, plasma insulin, and liver glycogen levels in offspring exposed to ethanol in utero.

  19. Hypothalamic vitamin D improves glucose homeostasis and reduces weight

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  20. Glucose homeostasis during spontaneous labor in normal human pregnancy.

    PubMed

    Maheux, P C; Bonin, B; Dizazo, A; Guimond, P; Monier, D; Bourque, J; Chiasson, J L

    1996-01-01

    Using stable isotope, glucose turnover was measured in six normal pregnant women during the various stages of labor; during the latent (A1) and active (A2) phases of cervical dilatation, during fetal expulsion (B), and during placental expulsion (C). These data were compared to measurements made in five postpartum women. Pancreatic hormones and cortisol were also measured. In four other normal women undergoing spontaneous labor, catecholamines and free fatty acids were measured. Plasma glucose increased throughout labor from 4.0 +/- 0.2 (A1) to 5.5 +/- 0.5 mmol/L (C) (P < 0.01), compared to 4.7 +/- 0.1 in the postpartum women. Glucose utilization and production were increased throughout labor at 33.4 +/- 3.1 and 32.8 +/- 3.1 mumol/kg min, respectively, compared to 8.2 +/- 0.9 in postpartum women. Glucose metabolic clearance was also increased to 7.5 +/- 0.8 mL/kg.min compared to that in nonpregnant women (1.8 +/- 0.3). Plasma insulin remained at 59 +/- 5 pmol/L during stages A1, A2, and B, but increased to 115 +/- 15 pmol/L during stage C. Plasma glucagon was increased throughout labor at 127 +/- 7 pg/mL, compared to 90 +/- 4 pg/mL in control postpartum women. Plasma cortisol increased during labor from 921 +/- 136 to 2018 +/- 160 nmol/L, compared to 645 +/- 355 during the postpartum period. Epinephrine and norepinephrine also increased during labor from 218 +/- 132 pmol/L and 1.09 +/- 0.16 nmol/L to 1119 +/- 158 and 3.61 +/- 1.04, respectively. It is concluded that labor is associated with a marked increase in glucose utilization and production. These findings suggest that muscle contraction (uterus and skeletal) independent of insulin is a major regulator of glucose utilization during labor. Furthermore, the increase in hepatic glucose production could be favored by an increase in glucagon, catecholamines, and cortisol.

  1. Berberine Improves Glucose Homeostasis in Streptozotocin-Induced Diabetic Rats in Association with Multiple Factors of Insulin Resistance

    PubMed Central

    Chen, Yanfeng; Wang, Yanwen; Zhang, Junzeng; Sun, Changhao; Lopez, Alfonso

    2011-01-01

    The present study was carried out to determine the effect of berberine on glucose homeostasis and several biomarkers associated with insulin sensitivity in male Wistar rats with intraperitoneal injection of streptozotocin (STZ)-induced diabetes. Rats with fasting blood glucose 16.7 mmol/L after 2 weeks of STZ injection were divided into two groups. One group was used as the diabetic control and another treated by gavage feeding with 100 mg/kg/d of berberine in water containing 0.5% carboxymethyl cellulose. A group of rats without receiving STZ was used as the normal control. After 7 weeks, berberine supplementation moderately but significantly lowered fasting blood glucose levels and improved oral glucose tolerance. Berberine lowered plasma free fatty acids and C-reactive protein levels without affecting plasma insulin levels. Diabetic rats treated with berberine showed significantly lower plasma triacylglycerol and cholesterol levels. Furthermore, berberine inhibited dipeptidyl peptidase-4 and protein tyrosine phosphatase-1B activities. In conclusion, berberine showed a dramatic effect of lowering blood cholesterol and triacylglycerols and improved moderately glucose homeostasis in STZ-induced diabetic rats in association with multiple factors related to insulin resistance. PMID:22363882

  2. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia.

    PubMed

    DeFronzo, R A; Davidson, J A; Del Prato, S

    2012-01-01

    The maintenance of normal glucose homeostasis requires a complex, highly integrated interaction among the liver, muscle, adipocytes, pancreas and neuroendocrine system. Recent studies have showed that the kidneys also play a central role in glucose homeostasis by reabsorbing all the filtered glucose, an adaptive mechanism that ensures sufficient energy is available during fasting periods. This mechanism becomes maladaptive in diabetes, however, as hyperglycaemia augments the expression and activity of the sodium-glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney. As a result, glucose reabsorption may be increased by as much as 20% in individuals with poorly controlled diabetes. SGLT2 is a low-affinity, high-capacity glucose transport protein that reabsorbs 90% of filtered glucose, while the high-affinity, low-capacity SGLT1 transporter reabsorbs the remaining 10%. SGLT2 represents a novel target for the treatment of diabetes. In animal studies, SGLT2 inhibition reduces plasma glucose levels, resulting in improved β-cell function and enhanced insulin sensitivity in liver and muscle. Human studies have confirmed the efficacy of SLGT2 inhibitors in improving glucose control and reducing the A1c. Because the mechanism of SGLT2 inhibition is independent of circulating insulin levels or insulin sensitivity, these agents can be combined with all other antidiabetic classes, including exogenous insulin. Although the long-term efficacy and safety of SGLT2 inhibitors remain under study, the class represents a novel therapeutic approach with potential for the treatment of both type 2 and 1 diabetes.

  3. 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

  4. Impact of low dose prenatal ethanol exposure on glucose homeostasis in Sprague-Dawley rats aged up to eight months.

    PubMed

    Probyn, Megan E; Parsonson, Kylie R; Gårdebjer, Emelie M; Ward, Leigh C; Wlodek, Mary E; Anderson, Stephen T; Moritz, Karen M

    2013-01-01

    Excessive exposure to alcohol prenatally has a myriad of detrimental effects on the health and well-being of the offspring. It is unknown whether chronic low-moderate exposure of alcohol prenatally has similar and lasting effects on the adult offspring's health. Using our recently developed Sprague-Dawley rat model of 6% chronic prenatal ethanol exposure, this study aimed to determine if this modest level of exposure adversely affects glucose homeostasis in male and female offspring aged up to eight months. Plasma glucose concentrations were measured in late fetal and postnatal life. The pancreas of 30 day old offspring was analysed for β-cell mass. Glucose handling and insulin action was measured at four months using an intraperitoneal glucose tolerance test and insulin challenge, respectively. Body composition and metabolic gene expression were measured at eight months. Despite normoglycaemia in ethanol consuming dams, ethanol-exposed fetuses were hypoglycaemic at embryonic day 20. Ethanol-exposed offspring were normoglycaemic and normoinsulinaemic under basal fasting conditions and had normal pancreatic β-cell mass at postnatal day 30. However, during a glucose tolerance test, male ethanol-exposed offspring were hyperinsulinaemic with increased first phase insulin secretion. Female ethanol-exposed offspring displayed enhanced glucose clearance during an insulin challenge. Body composition and hepatic, muscle and adipose tissue metabolic gene expression levels at eight months were not altered by prenatal ethanol exposure. Low-moderate chronic prenatal ethanol exposure has subtle, sex specific effects on glucose homeostasis in the young adult rat. As aging is associated with glucose dysregulation, further studies will clarify the long lasting effects of prenatal ethanol exposure.

  5. Inflammatory Properties of Diet and Glucose-Insulin Homeostasis in a Cohort of Iranian Adults

    PubMed Central

    Moslehi, Nazanin; Ehsani, Behnaz; Mirmiran, Parvin; Shivappa, Nitin; Tohidi, Maryam; Hébert, James R.; Azizi, Fereidoun

    2016-01-01

    We aimed to investigate associations of the dietary inflammatory index (DII) with glucose-insulin homeostasis markers, and the risk of glucose intolerance. This cross-sectional study included 2975 adults from the Tehran Lipid and Glucose Study. Fasting plasma glucose (FPG), 2-h post-load glucose (2h-PG), and fasting serum insulin were measured. Homeostatic model assessment of insulin resistance index (HOMA-IR) and β-cell function (HOMA-B), and the quantitative insulin sensitivity check index (QUICKI) were calculated. Glucose tolerance abnormalities included impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM). DII scores were positively associated with 2h-PG (β = 0.04; p = 0.05). There was no significant linear trend across quartiles of DII for adjusted means of glucose-insulin homeostasis markers. Participants in the highest quartile of DII score tended to have higher FPG compared to those in the second quartile of DII score (5.46 vs. 5.38 mmol/L, p = 0.07) and higher fasting insulin and HOMA-IR compared to those in the lowest quartile (8.52 vs. 8.12 µU/mL for fasting insulin, p = 0.07; 2.06 vs. 1.96 for HOMA-IR, p = 0.08). No significant associations were observed between DII and risk of IFG, IGT, T2DM, and insulin resistance. Among glucose-insulin homeostasis markers, DII had a positive weak association only with 2h-PG. PMID:27869717

  6. Acyl ghrelin acts in the brain to control liver function and peripheral glucose homeostasis in male mice.

    PubMed

    Stark, Romana; Reichenbach, Alex; Lockie, Sarah H; Pracht, Corinna; Wu, Qunli; Tups, Alexander; Andrews, Zane B

    2015-03-01

    Recent evidence suggests that peripheral ghrelin regulates glucose metabolism. Here, we designed experiments to examine how central acyl ghrelin infusion affects peripheral glucose metabolism under pair-fed or ad libitum feeding conditions. Mice received intracerebroventricular (icv) infusion of artificial cerebrospinal fluid (aCSF), ghrelin, and allowed to eat ad libitum (icv ghrelin ad lib) or ghrelin and pair-fed to the aCSF group (icv ghrelin pf). Minipumps delivered acyl ghrelin at a dose of 0.25 μg/h at 0.5 μL/h for 7 days. There was no difference in daily blood glucose, insulin, glucagon, triglycerides, or nonesterified fatty acids. Body weight gain and food intake was significantly higher in icv ghrelin ad lib mice. However, both icv ghrelin ad lib and icv ghrelin pf groups exhibited heavier white adipose mass. Icv ghrelin pf mice exhibited better glucose tolerance than aCSF or icv ghrelin ad lib mice during a glucose tolerance test, although both icv ghrelin ad lib and icv ghrelin pf increased insulin release during the glucose tolerance test. Central acyl ghrelin infusion and pair feeding also increased breakdown of liver glycogen and triglyceride, and regulated genes involved in hepatic lipid and glucose metabolism. Icv ghrelin pf mice had an increase in plasma blood glucose during a pyruvate tolerance test relative to icv ghrelin ad lib or aCSF mice. Our results suggest that under conditions of negative energy (icv ghrelin pf), central acyl ghrelin engages a neural circuit that influences hepatic glucose function. Metabolic status affects the ability of central acyl ghrelin to regulate peripheral glucose homeostasis.

  7. Petalonia improves glucose homeostasis in streptozotocin-induced diabetic mice

    SciTech Connect

    Kang, Seong-Il; Jin, Young-Jun; Ko, Hee-Chul; Choi, Soo-Youn; Hwang, Joon-Ho; Whang, Ilson; Kim, Moo-Han; Shin, Hye-Sun; Jeong, Hyung-Bok; Kim, Se-Jae

    2008-08-22

    The anti-diabetic potential of Petalonia binghamiae extract (PBE) was evaluated in vivo. Dietary administration of PBE to streptozotocin (STZ)-induced diabetic mice significantly lowered blood glucose levels and improved glucose tolerance. The mode of action by which PBE attenuated diabetes was investigated in vitro using 3T3-L1 cells. PBE treatment stimulated 3T3-L1 adipocyte differentiation as evidenced by increased triglyceride accumulation. At the molecular level, peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and terminal marker protein aP2, as well as the mRNA of GLUT4 were up-regulated by PBE. In mature adipocytes, PBE significantly stimulated the uptake of glucose and the expression of insulin receptor substrate-1 (IRS-1). Furthermore, PBE increased PPAR{gamma} luciferase reporter gene activity in COS-1 cells. Taken together, these results suggest that the in vivo anti-diabetic effect of PBE is mediated by both insulin-like and insulin-sensitizing actions in adipocytes.

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

    PubMed Central

    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.

    2014-01-01

    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. PMID:24944899

  9. Time-dependent homeostasis between glucose uptake and consumption in astrocytes exposed to CoCl₂ treatment.

    PubMed

    Wang, Peng; Li, Ling; Zhang, Zhenxiang; Kan, Quancheng; Chen, Suyan; Gao, Feng

    2016-03-01

    Hypoxia has been implicated in the pathology of the central nervous system during stroke. It also has a significant effect on the regulation of glucose transporters (GLUTs), and homeostasis between glucose uptake and consumption. CoCl2 is a hypoxia‑mimetic agent, and thus stabilizes the hypoxia‑inducible factor 1α (HIF‑1α) subunit and regulates GLUT genes. GLUT‑1 and GLUT‑3 are the most common isoforms of the GLUT family present in the brain, with the former primarily expressed in astrocytes and the latter in neurons under physiological conditions. However, it remains controversial whether GLUT‑3 is expressed in astrocytes. Additionally, it is unclear whether the regulation of GLUT‑1 and GLUT‑3, and glucose homeostasis, are affected by CoCl2 treatment in a time‑dependent manner. In the present study, mRNA and protein levels of GLUT‑1, GLUT‑3 and HIF‑1α in astrocytes were examined by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. The intracellular glucose concentration, glycogen storage, ATP content, pyruvate concentration, lactate dehydrogenase (LDH) release activity and cell viability in astrocytes were also investigated. The observations of the current study confirmed that both protein and mRNA levels of GLUT‑1 and GLUT‑3 were elevated in a time‑dependent manner induced by CoCl2 treatment, followed by accumulation of HIF‑1α. Furthermore, in the early period of CoCl2 treatment (≤8 h at 100 µM), LDH release, ATP content, glycogen storage and cell viability remained unchanged, whereas intracellular pyruvate concentration increased and glucose concentration was reduced. However, in the later period of CoCl2 treatment (>8 h at 100 µM), LDH release and intracellular pyruvate concentration increased, while intracellular glucose concentration, ATP content and glycogen storage were reduced. This may be due to disruption of homeostasis and reduced cell viability. In conclusion

  10. Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice

    PubMed Central

    Missios, Pavlos; Zhou, Yuan; Guachalla, Luis Miguel; von Figura, Guido; Wegner, Andre; Chakkarappan, Sundaram Reddy; Binz, Tina; Gompf, Anne; Hartleben, Götz; Burkhalter, Martin D.; Wulff, Veronika; Günes, Cagatay; Sattler, Rui Wang; Song, Zhangfa; Illig, Thomas; Klaus, Susanne; Böhm, Bernhard O.; Wenz, Tina; Hiller, Karsten; Rudolph, K. Lenhard

    2014-01-01

    DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues. PMID:25233189

  11. Caffeine and glucose homeostasis during rest and exercise in diabetes mellitus.

    PubMed

    Zaharieva, Dessi P; Riddell, Michael C

    2013-08-01

    Caffeine is a substance that has been used in our society for generations, primarily for its effects on the central nervous system that causes wakefulness. Caffeine supplementation has become increasingly more popular as an ergogenic aid for athletes and considerable scientific evidence supports its effectiveness. Because of their potential to alter energy metabolism, the effects of coffee and caffeine on glucose metabolism in diabetes have also been studied both epidemiologically and experimentally. Predominantly targeting the adenosine receptors, caffeine causes alterations in glucose homeostasis by decreasing glucose uptake into skeletal muscle, thereby causing elevations in blood glucose concentration. Caffeine intake has also been proposed to increase symptomatic warning signs of hypoglycemia in patients with type 1 diabetes and elevate blood glucose levels in patients with type 2 diabetes. Other effects include potential increases in glucose counterregulatory hormones such as epinephrine, which can also decrease peripheral glucose disposal. Despite these established physiological effects, increased coffee intake has been associated with reduced risk of developing type 2 diabetes in large-scale epidemiological studies. This review paper highlights the known effects of caffeine on glucose homeostasis and diabetes metabolism during rest and exercise.

  12. Impact of chronic diuretic treatment on glucose homeostasis

    PubMed Central

    2013-01-01

    Background The use of diuretics for hypertension has been associated with unfavorable changes in cardiovascular risk factors, such as uric acid and glucose tolerance, though the findings in the literature are contradictory. Methods This study investigated whether diuretic use is associated with markers of metabolic and cardiovascular risk, such as insulin-resistance and uric acid, in a cohort of adults without known diabetes and/or atherosclerotic cardiovascular disease. Nine hundred sixty-nine randomly selected participants answered a questionnaire on clinical history and dietary habits. Laboratory blood measurements were obtained in 507 participants. Results Previously undiagnosed type 2 diabetes was recognized in 4.2% of participants who were on diuretics (n = 71), and in 2% of those who were not (n = 890; P = 0.53). Pre-diabetes was diagnosed in 38% of patients who were on diuretics, and in 17.4% (P < 0.001) of those who were not. Multivariate analysis showed that insulin-resistance (HOMA-IR) was associated with the use of diuretics (P = 0.002) independent of other well-known predisposing factors, such as diet, physical activity, body mass index, and waist circumference. The use of diuretics was also independently associated with fasting plasma glucose concentrations (P = 0.001) and uric acid concentrations (P = 0.01). Conclusions The use of diuretics is associated with insulin-resistance and serum uric acid levels and may contribute to abnormal glucose tolerance. PMID:24330854

  13. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  15. 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...

  16. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis.

    PubMed

    Elmquist, Joel K; Coppari, Roberto; Balthasar, Nina; Ichinose, Masumi; Lowell, Bradford B

    2005-12-05

    The past decade has greatly increased our understanding and appreciation of the ability of the central nervous system (CNS) to regulate food intake and body weight. This was spearheaded by the discovery of key molecules regulating body weight homeostasis. It is now also apparent that the CNS, especially the hypothalamus, plays a primary role in directly regulating glucose homeostasis, independently of effects on body weight. These discoveries are important given the increasing incidences of obesity and type II diabetes in Western societies. In this article, we will highlight recent data from genetically modified mice. These data and other models have helped to dissect the CNS pathways regulating body weight and glucose homeostasis. Finally, although these studies have been illustrative, they also underscore our relative lack of knowledge and highlight the need for more definitive approaches to unravel the functional significance of these pathways.

  17. Affect development as a need to preserve homeostasis.

    PubMed

    Dönmez, Aslıhan; Ceylan, Mehmet Emin; Ünsalver, Barış Önen

    2016-03-01

    In this review, we aim to present our hypothesis about the neural development of affect. According to this view, affect develops at a multi-layered process, and as a mediator between drives, emotion and cognition. This development is parallel to the evolution of the brain from reptiles to mammals. There are five steps in this process: (1) Because of the various environmental challenges, changes in the autonomic nervous system occur and homeostasis becomes destabilized; (2) Drives arise from the destabilized homeostasis; (3) Drives trigger the neural basis of the basic emotional systems; (4) These basic emotions evolve into affect to find the particular object to invest the emotional energy; and (5) In the final stage, cognition is added to increase the possibility of identifying a particular object. In this paper, we will summarize the rationale behind this view, which is based on neuroscientific proofs, such as evolution of autonomic nervous system, neural basis the raw affective states, the interaction between affect and cognition, related brain areas, related neurotransmitters, as well as some clinical examples.

  18. Mucosal maltase-glucoamylase plays a crucial role in starch digestion and prandial glucose homeostasis of mice.

    PubMed

    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

    2009-04-01

    Starch is the major source of food glucose and its digestion requires small intestinal alpha-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 alpha-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 alpha-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 (13)C-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 alpha-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 alpha-glucogenic activity of Mgam plays a crucial role in the regulation of prandial glucose homeostasis.

  19. Intermittent cold exposure improves glucose homeostasis associated with brown and white adipose tissues in mice

    PubMed Central

    Wang, Tse-Yao; Liu, Cuiqing; Wang, Aixia; Sun, Qinghua

    2015-01-01

    Aims The discovery of different shades of fat has been implicated in the pathogenesis of obesity-related metabolic disorders. However, the effects of early and intermittent exposure to cold temperature on systemic metabolic changes in adult life remain unclear. Main methods To elucidate the impact of cold temperature exposure on metabolic function of adipose tissues, we investigated the glucose homeostasis, activation of brown adipose tissue (BAT) and “browning” of white adipose tissue (WAT) in mice in response to intermittent cold exposure. Mice were exposed to 4 °C, 2 hours per day and 5 days per week, for 14 weeks. Glucose homeostasis was tested via intraperitoneal glucose tolerance test and insulin tolerance test; body fat mass was evaluated using in vivo magnetic resonance imaging; BAT activity was detected primarily by positron emission tomography/computed tomography; and WAT “browning” was evaluated using immunohistochemistry. Key findings Our results showed that 14-week cold exposure improved glucose tolerance and enhanced insulin sensitivity, reduced the relative weights of epididymal and retroperitoneal WAT, increased expressions of UCP1 and PGC1α in subcutaneous adipose tissue. Significance Intermittent exposure to cold temperature in early life may improve systemic glucose homeostasis and induce WAT “browning”, suggesting that ambient cold temperature exposure may serve as a promising intervention to metabolic disorders. PMID:26281919

  20. Glucose homeostasis can be differentially modulated by varying individual components of a western diet.

    PubMed

    Forbes, Josephine M; Cowan, Samantha P; Andrikopoulos, Sofianos; Morley, Amy L; Ward, Leigh C; Walker, Karen Z; Cooper, Mark E; Coughlan, Melinda T

    2013-07-01

    Chronic overconsumption of a Western diet has been identified as a major risk factor for diabetes, yet precisely how each individual component contributes to defects in glucose homeostasis independent of consumption of other macronutrients remains unclear. Eight-week-old male Sprague Dawley rats were randomized to feeding with one of six semi-pure diets: control, processed (high advanced glycation end products/AGE), high protein, high dextrose (glucose polymer), high in saturated fat (plant origin), or high in saturated fat (animal origin). After chronic feeding for 24 weeks, body composition was determined by bioelectrical impedance spectroscopy and glucose homeostasis was assessed. When compared to the control and high AGE diets, excess consumption of the diet high in saturated fat (animal source) increased body weight and adiposity, and decreased insulin sensitivity, as defined by HOMA IR, impaired skeletal muscle insulin signaling and insulin hypersecretion in the context of increased circulating glucagon-like peptide (GLP-1). Compared to the control diet, chronic consumption of the high AGE, protein or dextrose diet increased fasting plasma glucose, decreased fasting plasma insulin and insulin secretion. These diets also reduced circulating GLP-1 concentrations. These data suggest that individual components of a western diet have differential effects in modulating glucose homeostasis and adiposity. These data provide clear evidence of a link between over-consumption of a western diet and the development of diabetes.

  1. 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

  2. Acute elevation of endogenous prolactin does not influence glucose homeostasis in healthy men.

    PubMed

    Vigas, M; Klimes, I; Jurcovicová, J; Jezová, D

    1993-01-01

    The diabetogenic effect of prolactin observed in patients with pathological hyperprolactinaemia was verified in healthy subjects. Plasma prolactin elevation was induced by administration of a dopamine antagonist drug domperidone (Motilium 10 mg orally, 9 subjects) and 2 h later the oral glucose tolerance test was performed. The influence of dopamine receptor stimulation on glucose homeostasis was tested by dopamine infusion (0.3 mg in saline or 20% glucose, 1 g/min for 60 min, 11 subjects). After the blockade of dopamine receptors, a significant and prolonged increase of prolactin concentration was found. However, the levels of glucose, insulin, and C-peptide either before or after the glucose load were not different from control ones. The decreased number of insulin receptors (1.97 +/- 0.41 vs 0.51 +/- 0.14 pmol per 2.10(9) red blood cells) was compensated by increased affinity (0.51 +/- 0.17 vs 1.00 +/- 0.22 Ke 10(8) mol.-1 per l]) of insulin receptors. The stimulation of dopamine receptors showed a negligible effect on glucose regulation. It may be suggested that an endogenous increase of prolactin concentration in the physiological range does not participate in the regulation of glucose homeostasis in healthy subjects.

  3. Glucocorticoid regulation of the circadian clock modulates glucose homeostasis.

    PubMed

    So, Alex Y -L; Bernal, Teresita U; Pillsbury, Marlisa L; Yamamoto, Keith R; Feldman, Brian J

    2009-10-13

    Circadian clock genes are regulated by glucocorticoids; however, whether this regulation is a direct or secondary effect and the physiological consequences of this regulation were unknown. Here, we identified glucocorticoid response elements (GREs) at multiple clock genes and showed that 3 were directly regulated by the glucocorticoid receptor. We determined that a GRE within the core clock gene Per2 was continuously occupied during rhythmic expression and essential for glucocorticoid regulation of that gene in vivo. We further demonstrated that mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. We conclude that Per2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.

  4. Fermentable dietary fiber increases GLP-1 secretion and improves glucose homeostasis despite increased intestinal glucose transport capacity in healthy dogs.

    PubMed

    Massimino, S P; McBurney, M I; Field, C J; Thomson, A B; Keelan, M; Hayek, M G; Sunvold, G D

    1998-10-01

    Ileal proglucagon gene expression and postprandial plasma concentrations of proglucagon-derived peptides are reported to change with the type and quantity of dietary fiber ingested by rats. Within the intestine, proglucagon encodes several proglucagon-derived peptides known to modulate intestinal absorption capacity and pancreatic insulin secretion. To determine whether the chronic ingestion of fermentable dietary fiber regulates the expression and synthesis of proglucagon-derived peptides in the distal intestine to modulate glucose homeostasis, the following study was conducted: 16 adult dogs (23 +/- 2 kg) were fed isoenergetic, isonitrogenous diets containing a mixture of high fermentable dietary fibers (HFF) or low fermentable (LFF) wood cellulose for 14 d in a randomized cross-over design. Food was withheld for 16 h before an oral glucose tolerance test was conducted supplying 2 g of glucose/kg body wt, and peripheral blood was collected via a hind-leg catheter at 0, 15, 30, 45, 60, 90 and 120 min for plasma glucose, insulin and glucagon-like peptide-1(7-36)NH2 (GLP-1) analyses. Intestinal samples were collected after the second dietary treatment. Ileal proglucagon mRNA, intestinal (GLP-1) concentrations and the integrated area under the curves (AUC) for plasma GLP-1 and insulin were greater and plasma glucose AUC was reduced when dogs were fed the HFF diet compared to the LFF diet (P < 0.05). Intestinal villi heights, brush border and basolateral glucose transporter protein abundance and jejunal transport capacities were significantly greater when dogs were fed the HFF diet than when fed the LFF diet. In conclusion, improvements in glucose homeostasis are observed in healthy dogs when they ingest fermentable fibers.

  5. Central effects of beta-endorphins on glucose homeostasis in the conscious dog

    SciTech Connect

    Radosevich, P.M.; Lacy, D.B.; Brown, L.L.; Williams, P.E.; Abumrad, N.N.

    1989-02-01

    The effects of centrally administered beta-endorphins on glucose homeostasis in the conscious dog were studied. Intracerebroventricular administration of beta-endorphin (0.2 mg/h) caused a 70% increase in plasma glucose. The mechanism of the hyperglycemia was twofold: there was an early increase in glucose production and a late inhibition of glucose clearance. These changes are explained by marked increases in plasma epinephrine (30-fold) and norepinephrine (6-fold) that occurred during infusion of beta-endorphin. Central administration of beta-endorphin also resulted in increased levels of adrenocorticotropic hormone and cortisol. In addition there was an increase in plasma insulin but no increase in plasma glucagon. Intravenous administration of beta-endorphin did not alter glucose homeostasis. Intracerebroventricular administration of acetylated beta-endorphin did not perturb glucose kinetics or any of the hormones that changed during infusion of the unacetylated peptide. We conclude that beta-endorphin acts centrally to cause hyperglycemia by stimulating sympathetic outflow and the pituitary-adrenal axis. Acetylation of beta-endorphin abolishes the in vivo activity of the peptide.

  6. Exercise, Energy Intake, Glucose Homeostasis, and the Brain

    PubMed Central

    van Praag, Henriette; Fleshner, Monika; Schwartz, Michael W.

    2014-01-01

    Here we summarize topics covered in an SFN symposium that considered how and why exercise and energy intake affect neuroplasticity and, conversely, how the brain regulates peripheral energy metabolism. This article is not a comprehensive review of the subject, but rather a view of how the authors' findings fit into a broader context. Emerging findings elucidate cellular and molecular mechanisms by which exercise and energy intake modify the plasticity of neural circuits in ways that affect brain health. By enhancing neurogenesis, synaptic plasticity and neuronal stress robustness, exercise and intermittent energy restriction/fasting may optimize brain function and forestall metabolic and neurodegenerative diseases. Moreover, brain-centered glucoregulatory and immunomodulating systems that mediate peripheral health benefits of intermittent energetic challenges have recently been described. A better understanding of adaptive neural response pathways activated by energetic challenges will enable the development and optimization of interventions to reduce the burden of disease in our communities. PMID:25392482

  7. Exercise, energy intake, glucose homeostasis, and the brain.

    PubMed

    van Praag, Henriette; Fleshner, Monika; Schwartz, Michael W; Mattson, Mark P

    2014-11-12

    Here we summarize topics covered in an SFN symposium that considered how and why exercise and energy intake affect neuroplasticity and, conversely, how the brain regulates peripheral energy metabolism. This article is not a comprehensive review of the subject, but rather a view of how the authors' findings fit into a broader context. Emerging findings elucidate cellular and molecular mechanisms by which exercise and energy intake modify the plasticity of neural circuits in ways that affect brain health. By enhancing neurogenesis, synaptic plasticity and neuronal stress robustness, exercise and intermittent energy restriction/fasting may optimize brain function and forestall metabolic and neurodegenerative diseases. Moreover, brain-centered glucoregulatory and immunomodulating systems that mediate peripheral health benefits of intermittent energetic challenges have recently been described. A better understanding of adaptive neural response pathways activated by energetic challenges will enable the development and optimization of interventions to reduce the burden of disease in our communities.

  8. Effect of acacia polyphenol on glucose homeostasis in subjects with impaired glucose tolerance: A randomized multicenter feeding trial

    PubMed Central

    OGAWA, SOSUKE; MATSUMAE, TOMOYUKI; KATAOKA, TAKESHI; YAZAKI, YOSHIKAZU; YAMAGUCHI, HIDEYO

    2013-01-01

    Numerous in vitro and animal studies, as well as clinical trials have indicated that plant-derived polyphenols exert beneficial effects on glucose intolerance or type 2 diabetes. This clinical study aimed to investigate the effects of acacia polyphenol (AP) on glucose and insulin responses to an oral glucose tolerance test (OGTT) in non-diabetic subjects with impaired glucose tolerance (IGT). A randomized, double-blind, placebo-controlled trial was conducted in a total of 34 enrolled subjects. The subjects were randomly assigned to the AP-containing dietary supplement (AP supplement; in a daily dose of 250 mg as AP; n=17) or placebo (n=17) and the intervention was continued for 8 weeks. Prior to the start of the intervention (baseline) and after 4 and 8 weeks of intervention, plasma glucose and insulin were measured during a two-hour OGTT. Compared with the baseline, plasma glucose and insulin levels at 90 and/or 120 min, as well as the total area under the curve values during the OGTT (AUC0→2h) for glucose and insulin, were significantly reduced in the AP group, but not in the placebo group after intervention for 8 weeks. The decline from baseline in plasma glucose and insulin at 90 or 120 min of the OGTT for the AP group was significantly greater compared with that of the placebo group after 8 weeks of intervention. No AP supplement-related adverse side-effects nor any abnormal changes in routine laboratory tests and anthropometric parameters were observed throughout the study period. The AP supplement may have the potential to improve glucose homeostasis in subjects with IGT. PMID:23837032

  9. 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.

  10. Iron overload alters glucose homeostasis, causes liver steatosis, and increases serum triacylglycerols in rats.

    PubMed

    Silva, Maísa; Silva, Marcelo E; de Paula, Heberth; Carneiro, Cláudia Martins; Pedrosa, Maria Lucia

    2008-06-01

    The objective of this study was to investigate the effect of iron overload with a hyperlipidemic diet on the histologic feature of hepatic tissue, the lipid and glycemic serum profiles, and the markers of oxidative damage and stress in a rat model. Twenty-four male Fischer rats, purchased from Experimental Nutrition Laboratory, Federal University of Ouro Preto, were assigned to 4 equal groups, 2 were fed a standard cholesterol-free diet (group C or control and CI or control with iron) containing 8.0% soybean oil and 2 were fed a hyperlipidemic diet (group H or hyperlipidemic and HI or hyperlipidemic with iron) containing 1.0% cholesterol and 25.0% soybean oil. A total of 50 mg of iron was administered to rats in groups CI and HI in 5 equal doses (1 every 3 weeks for a 16-week period) by intraperitoneal injections of 0.1 mL of iron dextran solution (100 g Fe(2+)/L; Sigma, St Louis, Mo). The other rats in groups C and H were treated in a similar manner but with sterile saline (0.1 mL). Irrespective of the diet, iron excess enhanced serum triacylglycerols (P < .05) and reduced serum glucose and glycated hemoglobin levels (P < .05) but did not affect serum cholesterol concentration. Histologic analysis showed steatosis in groups H and to a lesser extent in HI. No significant differences (P > .05) were observed in paraoxonase activities or in serum levels of free or total sulfhydryl radicals, malondialdehyde, or total antioxidants. The findings suggest that iron excess in the rat probably modifies lipid metabolism and, as a consequence, alters glucose homeostasis and increases the level of serum triacylglycerols but not of cholesterol.

  11. 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) expression ismore » 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

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

    SciTech Connect

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

    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) 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. 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.

  13. Dual Effect of Rosuvastatin on Glucose Homeostasis Through Improved Insulin Sensitivity and Reduced Insulin Secretion.

    PubMed

    Salunkhe, Vishal A; Mollet, Inês G; Ofori, Jones K; Malm, Helena A; Esguerra, Jonathan L S; Reinbothe, Thomas M; Stenkula, Karin G; Wendt, Anna; Eliasson, Lena; Vikman, Jenny

    2016-08-01

    Statins are beneficial in the treatment of cardiovascular disease (CVD), but these lipid-lowering drugs are associated with increased incidence of new on-set diabetes. The cellular mechanisms behind the development of diabetes by statins are elusive. Here we have treated mice on normal diet (ND) and high fat diet (HFD) with rosuvastatin. Under ND rosuvastatin lowered blood glucose through improved insulin sensitivity and increased glucose uptake in adipose tissue. In vitro rosuvastatin reduced insulin secretion and insulin content in islets. In the beta cell Ca(2+) signaling was impaired and the density of granules at the plasma membrane was increased by rosuvastatin treatment. HFD mice developed insulin resistance and increased insulin secretion prior to administration of rosuvastatin. Treatment with rosuvastatin decreased the compensatory insulin secretion and increased glucose uptake. In conclusion, our data shows dual effects on glucose homeostasis by rosuvastatin where insulin sensitivity is improved, but beta cell function is impaired.

  14. Cardiovascular Therapies and Associated Glucose Homeostasis: Implications across the Dysglycemia Continuum

    PubMed Central

    Cooper-DeHoff, Rhonda M.; Pacanowski, Michael A.; Pepine, Carl J.

    2009-01-01

    Certain cardiovascular drugs have adverse effects on glucose homeostasis which may lead to important long-term implications for increased risks for adverse outcomes. Thiazide diuretics, niacin, and β-adrenergic blockers impair glucose homeostasis. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated beneficial metabolic effects. The newer vasodilating β-blocking agents and calcium antagonists appear to be metabolically neutral. These considerations, in addition to meticulous attention to blood pressure control and lifestyle changes, have the potential to beneficially modify glycemia and long-term risks. These considerations have particular importance in younger patients who may also have prediabetes or the metabolic syndrome and who are likely to require therapy over the course of decades. PMID:19179214

  15. The hypothalamus and metabolism: integrating signals to control energy and glucose homeostasis.

    PubMed

    Coll, Anthony P; Yeo, Giles S H

    2013-12-01

    Molecules acting in the central nervous system play a critical role in the control of both energy and glucose homeostasis. The hypothalamus consists of a highly diverse collection of interconnected neurons and supporting glial cells that allow this region of the brain to sense and respond to a diverse range of hormonal and metabolic signals. We review recent advances in our understanding of the anatomical architecture and molecular mechanisms within the hypothalamus and how these facilitate the orchestration of systemic metabolic processes.

  16. Effects of insulin infusion on glucose homeostasis and glucose metabolism in rainbow trout fed a high-carbohydrate diet.

    PubMed

    Polakof, S; Moon, T W; Aguirre, P; Skiba-Cassy, S; Panserat, S

    2010-12-15

    The origin for the poor glucose utilization in carnivorous fish species fed high carbohydrate diets remains under debate. In the present study, we have fed rainbow trout a diet containing 30% carbohydrate for 1 or 5 days. In both cases, fish were implanted with mini-osmotic pumps releasing 0.7 i.u. kg(-1) day(-1) bovine insulin, and mRNA transcripts and the protein phosphorylation status of proteins controlling glycemia and glucose-related metabolism were studied in fish killed 6 h after the last meal. We demonstrate that when the exposure occurs over a short term (30 h), insulin exerts beneficial actions on trout glucose homeostasis, including a lowered glycemia and increased hepatic lipogenic and glycogenic potentials. However, when trout were fed for 5 days, these beneficial actions of insulin infusion were no longer observed. Thus, the increased lipogenic potential observed after one single meal was not present, and this together with the increased glycogenesis and the decreased glucose exported to the blood from the liver explains the lack of hypoglycemic action of insulin. The fact that insulin improved glucose homeostasis when administrated over a short time period implies that endogenous insulin secretion is inadequate in trout to deal with this amount of dietary carbohydrates. Moreover, the fact that a longer exposure to insulin resulted in a reduced response indicates that the rainbow trout is sensitive to insulin, re-enforcing the hypothesis that the hyperglycemia observed following a high carbohydrate meal is an insulin secretion issue rather an insulin action issue.

  17. Anthropometry, glucose homeostasis, and lipid profile in prepubertal children born early, full, or late term.

    PubMed

    Derraik, José G B; Savage, Tim; Miles, Harriet L; Mouat, Fran; Hofman, Paul L; Cutfield, Wayne S

    2014-09-29

    To examine differences in growth and metabolism in prepubertal children born early term, full term, and late term. We retrospectively studied 294 prepubertal children aged 7.3 years (range 3.0-12.1 years). Children were separated into those born early term (37 0/7-38 6/7 weeks of gestation; n = 68), full term (39 0/7-40 6/7 weeks; n = 179), and late term (41 0/7-41 6/7 weeks; n = 47). Clinical assessments included anthropometry, DXA-derived body composition, fasting lipids, and glucose homeostasis. Statistical models accounted for important confounding factors, such as gender, age, birth weight SDS, birth order, and parental variables. When birth weight was adjusted for sex and gestational age (birth weight SDS), late terms were heavier than both early (p = 0.034) and full (p = 0.020) terms. Early term children were shorter than both full (p = 0.010) and late (p = 0.049) term children, but differences in height disappeared following correction for parents' heights. There were no differences in glucose homeostasis, BMI SDS, adiposity, or fat distribution between groups. Lipid profiles were also similar. When important confounding factors were accounted for, there were no meaningful differences in anthropometry, glucose homeostasis, and lipid profile among children born early term, full term, or late term.

  18. 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

  19. Indices of Glucose Homeostasis in Cord Blood in Term and Preterm Newborns

    PubMed Central

    Ahmad, Afzal; Rukmini, M. S.; Yadav, Charu; Agarwal, Ashish; Manjrekar, Poornima A.; Hegde, Anupama

    2016-01-01

    Objective: According to the thrifty phenotype hypothesis, intrauterine malnutrition has a role in the etiology of type 2 diabetes. This study was planned to determine the early alterations in indices of glucose homeostasis (glucose, insulin, and cortisol) in term and preterm newborns and the correlations of glucose, insulin, and cortisol levels with insulin resistance indices. Methods: A descriptive study comprising 35 term and 35 preterm newborns was carried out from December 2013 to June 2015. Venous cord blood was collected and plasma glucose was analyzed by the glucose oxidase-peroxidase method in an auto analyzer. Serum insulin and cortisol levels were assessed by the enzyme-linked immunosorbent assay. Homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index and glucose insulin ratio were calculated to assess insulin resistance. The data on physical and metabolic parameters were analyzed using standard tests for statistical significance. Results: In term newborns, mean glucose and cortisol levels (83.6±17.4 mg/dL and 11.88±5.78 µg/dL, respectively) were significantly higher than those in preterm infants (70.4±15.8 mg/dL and 8.9±4.6 µg/dL, respectively). Insulin and HOMA-IR levels were found higher in preterm newborns (10.8±4.8 µIU/mL and 1.52±0.66, respectively) than in term newborns (7.9±2.7 µIU/mL and 1.19±0.29, respectively). Insulin was found to positively correlate with HOMA-IR, whereas cortisol was negatively correlated with HOMA-IR in both term and preterm newborns. Conclusion: Higher insulin levels and HOMA-IR values in the cord blood of preterm newborns support the theory of intrauterine origin of metabolic diseases. PMID:27087404

  20. Contrasting effects of puerarin and daidzin on glucose homeostasis in mice.

    PubMed

    Meezan, Elias; Meezan, Elisabeth M; Jones, Kenneth; Moore, Ray; Barnes, Stephen; Prasain, Jeevan K

    2005-11-02

    Puerarin and daidzin are the major isoflavone glucosides found in kudzu dietary supplements. In this study, we demonstrated that puerarin significantly improves glucose tolerance in C57BL/6J-ob/ob mice, an animal model of type 2 diabetes mellitus, blunting the rise in blood glucose levels after i.p. administration of glucose. In contrast, daidzin, the O-glucoside, had a significant but opposite effect, impairing glucose tolerance as compared to saline-treated controls. When they were administered i.p. with (14)C-glucose to C57BL/6J lean mice, puerarin inhibited glucose uptake into tissues and incorporation into glycogen, while daidzin stimulated glucose uptake, showing an opposite effect to puerarin. Puerarin also antagonized the stimulatory effect of decyl-beta-D-thiomaltoside, an artificial primer of glycogen synthesis, which increases (14)C-glucose uptake and incorporation into glycogen in mouse liver and heart. A liquid chromatography-tandem mass spectrometry procedure was used to investigate the metabolism and bioavailability of puerarin and daidzin. The blood puerarin concentration-time curve by i.p. and oral administration indicated that puerarin was four times more bioavailable via i.p. injection than via the oral route of administration. This may account for the increased hypoglycemic effect seen in the i.p. glucose tolerance test vs that seen orally. Our results suggest that puerarin is rapidly absorbed from the intestine without metabolism, while daidzin is hydrolyzed to the aglycone daidzein. The opposing effects of puerarin and daidzin on glucose homeostasis may have implications for the activity of dietary supplements that contain both of these isoflavonoids.

  1. Administration of olanzapine as an antiemetic agent changes glucose homeostasis in cisplatin-treated rats.

    PubMed

    Machida, Maiko; Miyamura, Yuki; Machida, Takuji; Koyama, Kinuko; Iizuka, Kenji; Hirafuji, Masahiko

    2015-01-01

    We investigated the effects of olanzapine on cisplatin-induced pica (the consumption of non-nutrient materials such as kaolin) and glucose homeostasis in rats to clarify the effects of olanzapine when used as an anti-emetic drug. Rats were injected intraperitoneally (i.p.) with either 5 mg/kg cisplatin or saline. Additionally, 2 or 10 mg/kg olanzapine were administered i.p. to the rats 10 min before the administration of cisplatin and subsequently administered every 24 h for 3 d. Kaolin and food intake was measured using an automatic monitoring apparatus. Plasma glucose levels were measured by an enzyme electrode method. The plasma levels of insulin and intact proinsulin were measured by enzyme-linked immunosorbent assay (ELISA). The proinsulin-to-insulin (P/I) ratio was calculated. Cisplatin significantly increased kaolin intake, but decreased food intake and body weight up to 72 h. Olanzapine had no effect on these parameters. Neither olanzapine nor cisplatin alone had a significant effect on the plasma levels of glucose, insulin, or proinsulin. However, a combination of olanzapine and cisplatin significantly decreased plasma insulin levels, but increased plasma intact proinsulin levels and the P/I ratio. Our results suggest that an additive deterioration of insulin-secreting beta-cell function and disturbance of glucose homeostasis should be considered during treatment of patients with olanzapine for cisplatin-induced nausea and vomiting.

  2. 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.

  3. 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

  4. Yuzu extract prevents cognitive decline and impaired glucose homeostasis in β-amyloid-infused rats.

    PubMed

    Yang, Hye Jeong; Hwang, Jin Taek; Kwon, Dae Young; Kim, Min Jung; Kang, Suna; Moon, Na Rang; Park, Sunmin

    2013-07-01

    Our preliminary study revealed that dementia induced by β-amyloid accumulation impairs peripheral glucose homeostasis (unpublished). We therefore evaluated whether long-term oral consumption of yuzu (Citrus junos Tanaka) extract improves cognitive dysfunction and glucose homeostasis in β-amyloid-induced rats. Male rats received hippocampal CA1 infusions of β-amyloid (25-35) [plaque forming β-amyloid; Alzheimer disease (AD)] or β-amyloid (35-25) [non-plaque forming β-amyloid; C (non-Alzheimer disease control)] at a rate of 3.6 nmol/d for 14 d. AD rats were divided into 2 dietary groups that received either 3% lyophilized 70% ethanol extracts of yuzu (AD-Y) or 3% dextrin (AD-C) in high-fat diets (43% energy as fat). The AD-C group exhibited greater hippocampal β-amyloid deposition, which was not detected in the C group, and attenuated hippocampal insulin signaling. Yuzu treatment prevented β-amyloid accumulation, increased tau phosphorylation, and attenuated hippocampal insulin signaling observed in AD-C rats. Consistent with β-amyloid accumulation, the AD-C rats experienced cognitive dysfunction, which was prevented by yuzu. AD-C rats gained less weight than did C rats due to decreased feed consumption, and yuzu treatment prevented the decrease in feed consumption. Serum glucose concentrations were higher in AD-C than in C rats at 40-120 min after glucose loading during an oral-glucose-tolerance test, but not at 0-40 min. Serum insulin concentrations were highly elevated in AD-C rats but not enough to lower serum glucose to normal concentrations, indicating that rats in the AD-C group had insulin resistance and a borderline diabetic state. Although AD-C rats were profoundly insulin resistant, AD-Y rats exhibited normal first and second phases of glucose tolerance and insulin sensitivity and secretion. In conclusion, yuzu treatment prevented the cognitive dysfunction and impaired energy and glucose homeostasis induced by β-amyloid infusion.

  5. 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.

  6. Bis-Pyrano Prenyl Isoflavone Improves Glucose Homeostasis by Inhibiting Dipeptidyl Peptidase-4 in Hyperglycemic Rats.

    PubMed

    Altenhofen, Delsi; da Luz, Gabrielle; Frederico, Marisa Jádna Silva; Venzke, Dalila; Brich, Mayara; Vigil, Silvana; Fröde, Tania Silvia; Linares, Carlos Eduardo Blanco; Pizzolatti, Moacir Geraldo; Silva, Fátima Regina Mena Barreto

    2017-01-01

    Isoflavones widely distributed in plants prevent diabetes. This study investigated the in vivo and in vitro effect of 3',4'-dihydroxy-6″,6″,6″',6″'-tetramethylbis(pyrano[2″,3″:5,6::2″',3″':7,8]isoflavone (bis-pyrano prenyl isoflavone) on glucose homeostasis in hyperglycemic rats. The ethyl acetate fraction from aerial parts of Polygala molluginifolia that contain isoflavones was assayed on glucose tolerance, on in vitro maltase activity and on protein glycation. The isoflavone bis-pyrano prenyl isolated from this fraction was investigated on glucose homeostasis. The in vivo action of the isoflavone exhibits an anti-hyperglycemic effect by improving glucose tolerance, augmenting the liver glycogen, inhibiting maltase activity, and stimulating glucagon-like peptide-1 (GLP-1) and insulin secretion. The in vitro isoflavone inhibits dipeptidyl peptidase-4 (DPP-4) activity since the glucose tolerance was improved in the presence of the isoflavone as much as sitagliptin, an inhibitor of DPP-4. However, the co-incubation with isoflavone and sitagliptin exhibited an additive anti-hyperglycemic action. The isoflavone increased the GLP-1 faster than the positive hyperglycemic group, which shows that the intestine is a potential target. Thus, to clarify the main site of action in which isoflavone improves glucose balance, the in vitro mechanism of action of this compound was tested in intestine using calcium influx as a trigger for the signal pathways for GLP-1 secretion. The isoflavone stimulates calcium influx in intestine and its mechanism involves voltage-dependent calcium channels, phospholipase C, protein kinase C, and stored calcium contributing for GLP-1 secretion. In conclusion, the isoflavone regulates glycaemia by acting mainly in a serum target, the DPP-4 inhibitor. Furthermore, the long-term effect of isoflavone prevents protein glycation. J. Cell. Biochem. 118: 92-103, 2017. © 2016 Wiley Periodicals, Inc.

  7. 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

  8. Iron regulates glucose homeostasis in liver and muscle via AMP-activated protein kinase in mice

    PubMed Central

    Huang, Jingyu; Simcox, Judith; Mitchell, T. Creighton; Jones, Deborah; Cox, James; Luo, Bai; Cooksey, Robert C.; Boros, Laszlo G.; McClain, Donald A.

    2013-01-01

    Excess iron is associated with hepatic damage and diabetes in humans, although the detailed molecular mechanisms are not known. To investigate how iron regulates glucose homeostasis, we fed C57BL/6J male mice with high-iron (HI) diets (2 or 20 g Fe/kg chow). Mice fed an HI diet exhibited elevated AMP-activated protein kinase (AMPK) activity and impaired insulin signaling in skeletal muscle and liver. Consistent with the increased AMPK activity, glucose uptake was enhanced in mice fed an HI diet. The effects of improved glucose tolerance induced by HI feeding were abolished in transgenic mice with expression of muscle specific dominant-negative AMPK. Glucose output was suppressed in the liver of wild-type mice fed an HI diet, due to decreased expression of gluconeogenic genes and decreased substrate (lactate) from peripheral glycolysis. Iron activated AMPK by increasing deacetylase and decreasing LKB1 acetylation, in turn stimulating the phosphorylation of LKB1 and AMPK. The effects of HI diet were abrogated by treatment of the mice with N-acetyl cysteine, suggesting a redox-dependent mechanism for increasing deacetylase activity. In addition, tissue from iron-fed mice exhibited an elevated AMP/ATP ratio, further contributing to AMPK activation. In summary, a diet high in iron improves glucose tolerance by activating AMPK through mechanisms that include deacetylation.—Huang J., Simcox, J., Mitchell, T. C., Jones, D., Cox, J., Luo, B., Cooksey, R. C., Boros, L. G., McClain, D. A. Iron regulates glucose homeostasis in liver and muscle via AMP-activated protein kinase in mice. PMID:23515442

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

    PubMed

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

    2015-05-22

    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.

  10. 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

  11. SGLT2 Deletion Improves Glucose Homeostasis and Preserves Pancreatic β-Cell Function

    PubMed Central

    Jurczak, Michael J.; Lee, Hui-Young; Birkenfeld, Andreas L.; Jornayvaz, Francois R.; Frederick, David W.; Pongratz, Rebecca L.; Zhao, Xiaoxian; Moeckel, Gilbert W.; Samuel, Varman T.; Whaley, Jean M.; Shulman, Gerald I.; Kibbey, Richard G.

    2011-01-01

    OBJECTIVE Inhibition of the Na+-glucose cotransporter type 2 (SGLT2) is currently being pursued as an insulin-independent treatment for diabetes; however, the behavioral and metabolic consequences of SGLT2 deletion are unknown. Here, we used a SGLT2 knockout mouse to investigate the effect of increased renal glucose excretion on glucose homeostasis, insulin sensitivity, and pancreatic β-cell function. RESEARCH DESIGN AND METHODS SGLT2 knockout mice were fed regular chow or a high-fat diet (HFD) for 4 weeks, or backcrossed onto the db/db background. The analysis used metabolic cages, glucose tolerance tests, euglycemic and hyperglycemic clamps, as well as isolated islet and perifusion studies. RESULTS SGLT2 deletion resulted in a threefold increase in urine output and a 500-fold increase in glucosuria, as well as compensatory increases in feeding, drinking, and activity. SGLT2 knockout mice were protected from HFD-induced hyperglycemia and glucose intolerance and had reduced plasma insulin concentrations compared with controls. On the db/db background, SGLT2 deletion prevented fasting hyperglycemia, and plasma insulin levels were also dramatically improved. Strikingly, prevention of hyperglycemia by SGLT2 knockout in db/db mice preserved pancreatic β-cell function in vivo, which was associated with a 60% increase in β-cell mass and reduced incidence of β-cell death. CONCLUSIONS Prevention of renal glucose reabsorption by SGLT2 deletion reduced HFD- and obesity-associated hyperglycemia, improved glucose intolerance, and increased glucose-stimulated insulin secretion in vivo. Taken together, these data support SGLT2 inhibition as a viable insulin-independent treatment of type 2 diabetes. PMID:21357472

  12. PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis

    PubMed Central

    Cheng, Yong-Sheng; Seibert, Oksana; Klöting, Nora; Dietrich, Arne; Straßburger, Katrin; Fernández-Veledo, Sonia; Vendrell, Joan J.; Zorzano, Antonio; Blüher, Matthias; Herzig, Stephan; Berriel Diaz, Mauricio; Teleman, Aurelio A.

    2015-01-01

    In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state. PMID:26440364

  13. High-fat diet aggravates glucose homeostasis disorder caused by chronic exposure to bisphenol A.

    PubMed

    Ding, Shibin; Fan, Ying; Zhao, Nana; Yang, Huiqin; Ye, Xiaolei; He, Dongliang; Jin, Xin; Liu, Jian; Tian, Chong; Li, Hongyu; Xu, Shunqing; Ying, Chenjiang

    2014-04-01

    Epidemiological findings on the association between bisphenol A (BPA, 2,2-bis-(4-hydroxyphenyl)propane) exposure and type 2 diabetes mellitus (T2DM) are paradoxical. In animal studies, BPA has been shown to disrupt pancreatic function and blood glucose homeostasis even at a reference 'safe' level during perinatal period. In this study, we explored the effects of long-term paternal exposure to a 'safe' level of BPA on parents themselves and their offspring. Adult male genitor rats fed with either standard chow diet (STD) or high-fat diet (HFD) were treated respectively with either vehicle or BPA (50 μg/kg per day) for 35 weeks. The male rats treated with vehicle or BPA for 21 weeks were then used as sires, and the adult female rats were fed with STD during the gestation and lactation. Offspring rats were weaned on postnatal day 21 and fed with STD in later life. Metabolic parameters were recorded on the adult male rats and their adult offspring. BPA exposure disrupted glucose homeostasis and pancreatic function, and HFD aggravated these adverse effects. However, BPA exposure did not alter body weight, body fat percentage, or serum lipid. In addition, the paternal BPA exposure did not cause adverse reproductive consequence or metabolic disorder in the adult offspring. Our findings indicate that chronic exposure to a predicted 'safe' dose of BPA contributes to glucose metabolic disorders, and that HFD aggravates these adverse effects in paternal rats.

  14. DJ-1 maintains energy and glucose homeostasis by regulating the function of brown adipose tissue

    PubMed Central

    Wu, Rong; Liu, Xiao-meng; Sun, Jian-guang; Chen, Hong; Ma, Jun; Dong, Meng; Peng, Shengyi; Wang, Ji-qiu; Ding, Jian-qing; Li, Dong-hao; Speakman, John R; Ning, Guang; Jin, Wanzhu; Yuan, Zengqiang

    2017-01-01

    DJ-1 protein is involved in multiple physiological processes, including Parkinson’s disease. However, the role of DJ-1 in the metabolism is largely unknown. Here we found that DJ-1 maintained energy balance and glucose homeostasis via regulating brown adipose tissue (BAT) activity. DJ-1-deficient mice reduced body mass, increased energy expenditure and improved insulin sensitivity. DJ-1 deletion also resisted high-fat-diet (HFD) induced obesity and insulin resistance. Accordingly, DJ-1 transgene triggered autonomous obesity and glucose intolerance. Further BAT transplantation experiments clarified DJ-1 regulates energy and glucose homeostasis by modulating BAT function. Mechanistically, we found that DJ-1 promoted PTEN proteasomal degradation via an E3 ligase, mind bomb-2 (Mib2), which led to Akt activation and inhibited FoxO1-dependent Ucp1 (Uncoupling protein-1) expression in BAT. Consistently, ablation of Akt1 mitigated the obesity and BAT dysfunction induced by DJ-1 transgene. These findings define a new biological role of DJ-1 protein in regulating BAT function, with an implication of the therapeutic target in the treatment of metabolic disorders. PMID:28224045

  15. Vitamin D Deficiency in Obese Children and Its Relationship to Glucose Homeostasis

    PubMed Central

    Olson, Micah L.; Maalouf, Naim M.; Oden, Jon D.; White, Perrin C.

    2012-01-01

    Objectives: The aim of the study was to compare the prevalence of vitamin D deficiency in obese and non-overweight children in North Texas, to examine relationships between dietary habits and 25-hydroxyvitamin D [25(OH)D] level in obese children, and to examine the relationship between 25(OH)D level and markers of abnormal glucose metabolism and blood pressure. Patients and Methods: Using a cross-sectional design, systolic and diastolic blood pressure, dietary information, serum 25(OH)D, fasting glucose and insulin, 2-h glucose from oral glucose tolerance test, hemoglobin A1c, and homeostasis model assessment of insulin resistance were recorded for 411 obese subjects (6–16 yr old) at an obesity referral clinic. 25(OH)D was also obtained from 87 control non-overweight subjects (6–16 yr old). Results: Ninety-two percent of obese subjects had a 25(OH)D level below 75 nmol/liter, and 50% were below 50 nmol/liter. Among non-overweight subjects, these frequencies were 68 and 22%, respectively (both P < 0.01 compared with obese subjects). 25(OH)D was negatively associated with soda intake (P < 0.001), juice intake (P = 0.009), and skipping breakfast (P < 0.001). 25(OH)D was negatively correlated with homeostasis model assessment of insulin resistance (r = −0.19; P = 0.001) and 2-h glucose (r = −0.12; P = 0.04) after adjustment for body mass index and age but was not correlated with hemoglobin A1c, systolic blood pressure Z score, or diastolic blood pressure Z score. Conclusions: Vitamin D deficiency is common in children in this southern United States location and is significantly more prevalent in obese children. Lower 25(OH)D level is associated with risk factors for type 2 diabetes in obese children. PMID:22072738

  16. ApoA-IV: current and emerging roles in intestinal lipid metabolism, glucose homeostasis, and satiety.

    PubMed

    Kohan, Alison B; Wang, Fei; Lo, Chun-Min; Liu, Min; Tso, Patrick

    2015-03-15

    Apolipoprotein A-IV (apoA-IV) is secreted by the small intestine on chylomicrons into intestinal lymph in response to fat absorption. Many physiological functions have been ascribed to apoA-IV, including a role in chylomicron assembly and lipid metabolism, a mediator of reverse-cholesterol transport, an acute satiety factor, a regulator of gastric function, and, finally, a modulator of blood glucose homeostasis. The purpose of this review is to update our current view of intestinal apoA-IV synthesis and secretion and the physiological roles of apoA-IV in lipid metabolism and energy homeostasis, and to underscore the potential for intestinal apoA-IV to serve as a therapeutic target for the treatment of diabetes and obesity-related disease.

  17. 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

  18. Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish.

    PubMed

    Michel, Maximilian; Page-McCaw, Patrick S; Chen, Wenbiao; Cone, Roger D

    2016-03-15

    Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals.

  19. Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish

    PubMed Central

    Michel, Maximilian; Page-McCaw, Patrick S.; Chen, Wenbiao; Cone, Roger D.

    2016-01-01

    Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals. PMID:26903647

  20. 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

  1. The Histone Deacetylase SIRT6 Regulates Glucose Homeostasis via Hif1α

    PubMed Central

    Zhong, Lei; D'Urso, Agustina; Toiber, Debra; Sebastian, Carlos; Henry, Ryan E.; Vadysirisack, Douangsone D.; Guimaraes, Alexander; Marinelli, Brett; Wikstrom, Jakob D.; Nir, Tomer; Clish, Clary B.; Vaitheesvaran, Bhavapriya; Iliopoulos, Othon; Kurland, Irwin; Dor, Yuval; Weissleder, Ralph; Shirihai, Orian S.; Ellisen, Leif W.; Espinosa, Joaquin M.; Mostoslavsky, Raul

    2010-01-01

    Summary SIRT6 is a member of a highly conserved family of NAD+-dependent deacetylases with various roles in metabolism, stress resistance and lifespan. SIRT6 deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a co-repressor of the transcription factor Hif1α, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6 deficient cells exhibit increased Hif1α activity and show increased glucose uptake with up-regulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a novel role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis, and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity. PMID:20141841

  2. Effects of Noise Exposure on Systemic and Tissue-Level Markers of Glucose Homeostasis and Insulin Resistance in Male Mice

    PubMed Central

    Liu, Lijie; Wang, Fanfan; Lu, Haiying; Cao, Shuangfeng; Du, Ziwei; Wang, Yongfang; Feng, Xian; Gao, Ye; Zha, Mingming; Guo, Min; Sun, Zilin; Wang, Jian

    2016-01-01

    Background: Epidemiological studies have indicated that noise exposure is associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the nature of the connection between noise exposure and T2DM remains to be explored. Objectives: We explored whether and how noise exposure affects glucose homeostasis in mice as the initial step toward T2DM development. Methods: Male ICR mice were randomly assigned to one of four groups: the control group and three noise groups (N20D, N10D, and N1D), in which the animals were exposed to white noise at 95 decibel sound pressure level (dB SPL) for 4 hr per day for 20 successive days, 10 successive days, or 1 day, respectively. Glucose tolerance and insulin sensitivity were evaluated 1 day, 1 week, and 1 month after the final noise exposure (1DPN, 1WPN, and 1MPN). Standard immunoblots, immunohistochemical methods, and enzyme-linked immunosorbent assays (ELISA) were performed to assess insulin signaling in skeletal muscle, the morphology of β cells, and plasma corticosterone levels. Results: Noise exposure for 1 day caused transient glucose intolerance and insulin resistance, whereas noise exposure for 10 and 20 days had no effect on glucose tolerance but did cause prolonged insulin resistance and an increased insulin response to glucose challenge. Akt phosphorylation and GLUT4 translocation in response to exogenous insulin were decreased in the skeletal muscle of noise-exposed animals. Conclusions: Noise exposure at 95 dB SPL caused insulin resistance in male ICR mice, which was prolonged with longer noise exposure and was likely related to the observed blunted insulin signaling in skeletal muscle. Citation: Liu L, Wang F, Lu H, Cao S, Du Z, Wang Y, Feng X, Gao Y, Zha M, Guo M, Sun Z, Wang J. 2016. Effects of noise exposure on systemic and tissue-level markers of glucose homeostasis and insulin resistance in male mice. Environ Health Perspect 124:1390–1398; http://dx.doi.org/10.1289/EHP162 PMID:27128844

  3. Impaired Lipid and Glucose Homeostasis in Hexabromocyclododecane-Exposed Mice Fed a High-Fat Diet

    PubMed Central

    Koike, Eiko; Win-Shwe, Tin-Tin; Yamamoto, Megumi; Takano, Hirohisa

    2014-01-01

    Background: Hexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear. Objectives: We investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD). Methods: Male C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 μg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue. Results: In HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 μg/kg) and medium (35 μg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice. Conclusions: Our findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity. Citation: Yanagisawa R, Koike E, Win-Shwe TT, Yamamoto M, Takano H. 2014. Impaired lipid and glucose homeostasis in hexabromocyclododecane-exposed mice fed a high-fat diet. Environ Health

  4. 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.

  5. Involvement of IL-1 in the Maintenance of Masseter Muscle Activity and Glucose Homeostasis

    PubMed Central

    Chiba, Ko; Tsuchiya, Masahiro; Koide, Masashi; Hagiwara, Yoshihiro; Sasaki, Keiichi; Hattori, Yoshinori; Watanabe, Makoto; Sugawara, Shunji; Kanzaki, Makoto; Endo, Yasuo

    2015-01-01

    Physical exercise reportedly stimulates IL-1 production within working skeletal muscles, but its physiological significance remains unknown due to the existence of two distinct IL-1 isoforms, IL-1α and IL-1β. The regulatory complexities of these two isoforms, in terms of which cells in muscles produce them and their distinct/redundant biological actions, have yet to be elucidated. Taking advantage of our masticatory behavior (Restrained/Gnawing) model, we herein show that IL-1α/1β-double-knockout (IL-1-KO) mice exhibit compromised masseter muscle (MM) activity which is at least partially attributable to abnormalities of glucose handling (rapid glycogen depletion along with impaired glucose uptake) and dysfunction of IL-6 upregulation in working MMs. In wild-type mice, masticatory behavior clearly increased IL-1β mRNA expression but no incremental protein abundance was detectable in whole MM homogenates, whereas immunohistochemical staining analysis revealed that both IL-1α- and IL-1β-immunopositive cells were recruited around blood vessels in the perimysium of MMs after masticatory behavior. In addition to the aforementioned phenotype of IL-1-KO mice, we found the IL-6 mRNA and protein levels in MMs after masticatory behavior to be significantly lower in IL-1-KO than in WT. Thus, our findings confirm that the locally-increased IL-1 elicited by masticatory behavior, although present small in amounts, contributes to supporting MM activity by maintaining normal glucose homeostasis in these muscles. Our data also underscore the importance of IL-1-mediated local interplay between autocrine myokines including IL-6 and paracrine cytokines in active skeletal muscles. This interplay is directly involved in MM performance and fatigability, perhaps mediated through maintaining muscular glucose homeostasis. PMID:26599867

  6. Role of the ENPP1 K121Q Polymorphism in Glucose Homeostasis

    PubMed Central

    Baratta, Roberto; Rossetti, Paola; Prudente, Sabrina; Barbetti, Fabrizio; Sudano, Dora; Nigro, Angela; Farina, Maria Grazia; Pellegrini, Fabio; Trischitta, Vincenzo; Frittitta, Lucia

    2008-01-01

    OBJECTIVE— To study the role of the ENPP1 Q121 variant on glucose homeostasis in whites from Italy. RESEARCH DESIGN AND METHODS— We conducted case-control studies in 764 adults (from two independent samples of 289 nonobese and 485 obese individuals) and 240 overweight/obese children undergoing oral glucose tolerance testing (OGTT). Early-phase insulin secretion and insulin sensitivity (the insulinogenic index and the insulin sensitivity index) and their interplay (the disposition index) were calculated. RESULTS— In adult subjects, glucose profiles during OGTT were significantly (P = 2 × 10−2) different across K121Q genotype groups and higher in QQ than KK individuals (P = 5 × 10−2). The insulinogenic index was significantly reduced in QQ (18.5 ± 3.4) compared with both KK (31.6 ± 1.0; P = 2.2 × 10−7) and KQ (30.5 ± 1.5; P = 3.2 × 10−6) individuals. KQ individuals also showed a reduced insulin sensitivity index compared with KK subjects (P = 3.6 × 10−2). The disposition index was lower in QQ carriers than in KQ and KK individuals (P = 8 × 10−3 and 4 × 10−4, respectively) and lower in KQ than in KK individuals (P = 3 × 10−2). Data obtained in overweight/obese children were very similar to those observed in adults, with QQ individuals showing (compared with KQ and KK subjects) a reduced insulinogenic index (P = 7 × 10−3 and 2 × 10−2, respectively) and disposition index (P = 2 × 10−2 and 7 × 10−3, respectively). CONCLUSIONS— Homozygous carriers of the ENPP1 Q121 variant are characterized by an altered glucose homeostasis. Reduced early-phase insulin secretion and inefficient interplay between insulin secretion and sensitivity, which occur at early ages, are major determinants of this defect. PMID:18776139

  7. Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis.

    PubMed

    Li, Jiehan; Papadopoulos, Vassilios

    2015-09-01

    As a major regulator in obesity and its associated metabolic complications, the proper functioning of adipocytes is crucial for health maintenance, thus serving as an important target for the development of anti-obese and anti-diabetic therapies. There is increasing evidence that mitochondrial malfunction is a pivotal event in disturbing adipocyte cell homeostasis. Among major mitochondrial structure components, the high-affinity drug- and cholesterol-binding outer mitochondrial membrane translocator protein (18 kDa; TSPO) has shown importance across a broad spectrum of mitochondrial functions. Recent studies demonstrated the presence of TSPO in white adipocyte mitochondria of mice, and administration of TSPO drug ligands to obese mice reduced weight gain and lowered glucose level. Therefore, it is of great interest to assess whether TSPO in adipocytes could serve as a drug target to regulate adipocyte activities with potential influence on weight control and glucose metabolism. Two structurally distinct TSPO drug ligands, PK 11195 and FGIN-1-27, improved the intracellular dynamics of 3T3-L1 adipocytes, such as the production and release of adipokines, glucose uptake, and adipogenesis. TSPO knockdown in either differentiated adipocytes or preadipocytes impaired these functions. Findings from 3T3-L1 cells were related to human primary cells, where TSPO expression was tightly associated with the metabolic state of primary adipocytes and the differentiation of primary preadipocytes. These results suggest that TSPO expression is essential to safeguard healthy adipocyte functions, and that TSPO activation in adipocytes improves their metabolic status in regulating glucose homeostasis. Adipocyte TSPO may serve as a pharmacologic target for the treatment of obesity and diabetes.

  8. Involvement of IL-1 in the Maintenance of Masseter Muscle Activity and Glucose Homeostasis.

    PubMed

    Chiba, Ko; Tsuchiya, Masahiro; Koide, Masashi; Hagiwara, Yoshihiro; Sasaki, Keiichi; Hattori, Yoshinori; Watanabe, Makoto; Sugawara, Shunji; Kanzaki, Makoto; Endo, Yasuo

    2015-01-01

    Physical exercise reportedly stimulates IL-1 production within working skeletal muscles, but its physiological significance remains unknown due to the existence of two distinct IL-1 isoforms, IL-1α and IL-1β. The regulatory complexities of these two isoforms, in terms of which cells in muscles produce them and their distinct/redundant biological actions, have yet to be elucidated. Taking advantage of our masticatory behavior (Restrained/Gnawing) model, we herein show that IL-1α/1β-double-knockout (IL-1-KO) mice exhibit compromised masseter muscle (MM) activity which is at least partially attributable to abnormalities of glucose handling (rapid glycogen depletion along with impaired glucose uptake) and dysfunction of IL-6 upregulation in working MMs. In wild-type mice, masticatory behavior clearly increased IL-1β mRNA expression but no incremental protein abundance was detectable in whole MM homogenates, whereas immunohistochemical staining analysis revealed that both IL-1α- and IL-1β-immunopositive cells were recruited around blood vessels in the perimysium of MMs after masticatory behavior. In addition to the aforementioned phenotype of IL-1-KO mice, we found the IL-6 mRNA and protein levels in MMs after masticatory behavior to be significantly lower in IL-1-KO than in WT. Thus, our findings confirm that the locally-increased IL-1 elicited by masticatory behavior, although present small in amounts, contributes to supporting MM activity by maintaining normal glucose homeostasis in these muscles. Our data also underscore the importance of IL-1-mediated local interplay between autocrine myokines including IL-6 and paracrine cytokines in active skeletal muscles. This interplay is directly involved in MM performance and fatigability, perhaps mediated through maintaining muscular glucose homeostasis.

  9. Effects of chronic noise on glucose metabolism and gut microbiota–host inflammatory homeostasis in rats

    PubMed Central

    Cui, Bo; Gai, Zhihui; She, Xiaojun; Wang, Rui; Xi, Zhuge

    2016-01-01

    Chronic noise exposure has been implicated in increased risk of diabetes. However, there is limited experimental evidence of the mechanisms linking chronic noise stress and glucose metabolism. We addressed this in the present study by examining glucose metabolism, immune response, and changes in gut microbiota/host inflammatory homeostasis in rats exposed to noise for 30 consecutive days. Chronic noise exposure increased blood glucose and corticosterone levels for at least 14 days after cessation of noise. Stressed rats also exhibited elevated levels of glycogen and triglyceride in the liver and impaired hepatic insulin production via insulin-induced insulin receptor/insulin receptor substrate 1/glycogen synthase kinase 3β signalling, which persisted for 3–14 days after cessation of noise exposure. Chronic noise altered the percentage of Proteobacteria and Actinobacteria in the gut, increasing Roseburia but decreasing Faecalibacterium levels in the cecum relative to controls. Immunoglobulin A, interleukin 1β, and tumor necrosis factor α levels were also elevated in the intestine of these animals, corresponding to noise-induced abnormalities in glucose regulation and insulin sensitivity. These results suggest that lifelong environmental noise exposure could have cumulative effects on diabetes onset and development resulting from alterations in gut microbiota composition and intestinal inflammation. PMID:27811997

  10. 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.

  11. Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism.

    PubMed

    Grgurevic, Lovorka; Christensen, Gitte Lund; Schulz, Tim J; Vukicevic, Slobodan

    2016-02-01

    Bore morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-β superfamily, a group of secreted proteins that regulate embryonic development. This review summarizes the effects of BMPs on physiological processes not exclusively linked to the musculoskeletal system. Specifically, we focus on the involvement of BMPs in inflammatory disorders, e.g. fibrosis, inflammatory bowel disease, anchylosing spondylitis, rheumatoid arthritis. Moreover, we discuss the role of BMPs in the context of vascular disorders, and explore the role of these signalling proteins in iron homeostasis (anaemia, hemochromatosis) and oxidative damage. The second and third parts of this review focus on BMPs in the development of metabolic pathologies such as type-2 diabetes mellitus and obesity. The pancreatic beta cells are the sole source of the hormone insulin and BMPs have recently been implicated in pancreas development as well as control of adult glucose homeostasis. Lastly, we review the recently recognized role of BMPs in brown adipose tissue formation and their consequences for energy expenditure and adiposity. In summary, BMPs play a pivotal role in metabolism beyond their role in skeletal homeostasis. However, increased understanding of these pleiotropic functions also highlights the necessity of tissue-specific strategies when harnessing BMP action as a therapeutic target.

  12. 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.

  13. GLP-2 as Beneficial Factor in the Glucose Homeostasis in Mice Fed a High Fat Diet.

    PubMed

    Baldassano, Sara; Rappa, Francesca; Amato, Antonella; Cappello, Francesco; Mulè, Flavia

    2015-12-01

    Glucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to dietary nutrients, which acts through a specific receptor, the GLP-2 receptor (GLP-2R). The physiological effects of GLP-2 are multiple, involving also the intestinal adaptation to high fat diet (HFD). In consideration of the well-known relationship between chronic HFD and impaired glucose metabolism, in the present study we examined if the blocking of the GLP-2 signaling by chronic treatment with the GLP-2R antagonist, GLP-2 (3-33), leads to functional consequences in the regulation of glucose metabolism in HFD-fed mice. Compared with animals fed standard diet (STD), mice at the 10th week of HFD showed hyperglycaemia, glucose intolerance, high plasma insulin level after glucose load, increased pancreas weight and β cell expansion, but not insulin resistance. In HFD fed mice, GLP-2 (3-33) treatment for 4 weeks (from the 6th to the 10th week of diet) did not affect fasting glycaemia, but it significantly increased the glucose intolerance, both fasting and glucose-induced insulin levels, and reduced the sensitivity to insulin leading to insulin-resistance. In GLP-2 (3-33)-treated HFD mice pancreas was significantly heavier and displayed a significant increase in β-cell mass in comparison with vehicle-treated HFD mice. In STD mice, the GLP-2 (3-33) treatment did not affect fasted or glucose-stimulated glycemia, insulin, insulin sensitivity, pancreas weight and beta cell mass. The present study suggests that endogenous GLP-2 may act as a protective factor against the dysregulation of the glucose metabolism that occurs in HFD mice, because GLP-2 (3-33) worsens glucose metabolism disorders.

  14. Vertical sleeve gastrectomy restores glucose homeostasis in apolipoprotein A-IV KO mice.

    PubMed

    Pressler, Josh W; Haller, April; Sorrell, Joyce; Wang, Fei; Seeley, Randy J; Tso, Patrick; Sandoval, Darleen A

    2015-02-01

    Bariatric surgery is the most successful strategy for treating obesity, yet the mechanisms for this success are not clearly understood. Clinical literature suggests that plasma levels of apolipoprotein A-IV (apoA-IV) rise with Roux-en-Y gastric bypass (RYGB). apoA-IV is secreted from the intestine postprandially and has demonstrated benefits for both glucose and lipid homeostasis. Because of the parallels in the metabolic improvements seen with surgery and the rise in apoA-IV levels, we hypothesized that apoA-IV was necessary for obtaining the metabolic benefits of bariatric surgery. To test this hypothesis, we performed vertical sleeve gastrectomy (VSG), a surgery with clinical efficacy very similar to that for RYGB, in whole-body apoA-IV knockout (KO) mice. We found that VSG reduced body mass and improved both glucose and lipid homeostasis similarly in wild-type mice compared with apoA-IV KO mice. In fact, VSG normalized the impairment in glucose tolerance and caused a significantly greater improvement in hepatic triglyceride storage in the apoA-IV KO mice. Last, independent of surgery, apoA-IV KO mice had a significantly reduced preference for a high-fat diet. Altogether, these data suggest that apoA-IV is not necessary for the metabolic improvements shown with VSG, but also suggest an interesting role for apoA-IV in regulating macronutrient preference and hepatic triglyceride levels. Future studies are necessary to determine whether this is the case for RYGB as well.

  15. Calcium release channel RyR2 regulates insulin release and glucose homeostasis

    PubMed Central

    Santulli, Gaetano; Pagano, Gennaro; Sardu, Celestino; Xie, Wenjun; Reiken, Steven; D’Ascia, Salvatore Luca; Cannone, Michele; Marziliano, Nicola; Trimarco, Bruno; Guise, Theresa A.; Lacampagne, Alain; Marks, Andrew R.

    2015-01-01

    The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a “leaky” RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis. PMID:25844899

  16. Calcium release channel RyR2 regulates insulin release and glucose homeostasis.

    PubMed

    Santulli, Gaetano; Pagano, Gennaro; Sardu, Celestino; Xie, Wenjun; Reiken, Steven; D'Ascia, Salvatore Luca; Cannone, Michele; Marziliano, Nicola; Trimarco, Bruno; Guise, Theresa A; Lacampagne, Alain; Marks, Andrew R

    2015-05-01

    The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.

  17. DJ-1 maintains energy and glucose homeostasis by regulating the function of brown adipose tissue.

    PubMed

    Wu, Rong; Liu, Xiao-Meng; Sun, Jian-Guang; Chen, Hong; Ma, Jun; Dong, Meng; Peng, Shengyi; Wang, Ji-Qiu; Ding, Jian-Qing; Li, Dong-Hao; Speakman, John R; Ning, Guang; Jin, Wanzhu; Yuan, Zengqiang

    2017-01-01

    DJ-1 protein is involved in multiple physiological processes, including Parkinson's disease. However, the role of DJ-1 in the metabolism is largely unknown. Here we found that DJ-1 maintained energy balance and glucose homeostasisvia regulating brown adipose tissue (BAT) activity. DJ-1-deficient mice reduced body mass, increased energy expenditure and improved insulin sensitivity. DJ-1 deletion also resisted high-fat-diet (HFD) induced obesity and insulin resistance. Accordingly, DJ-1 transgene triggered autonomous obesity and glucose intolerance. Further BAT transplantation experiments clarified DJ-1 regulates energy and glucose homeostasis by modulating BAT function. Mechanistically, we found that DJ-1 promoted PTEN proteasomal degradation via an E3 ligase, mind bomb-2 (Mib2), which led to Akt activation and inhibited FoxO1-dependent Ucp1 (Uncoupling protein-1) expression in BAT. Consistently, ablation of Akt1 mitigated the obesity and BAT dysfunction induced by DJ-1 transgene. These findings define a new biological role of DJ-1 protein in regulating BAT function, with an implication of the therapeutic target in the treatment of metabolic disorders.

  18. 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.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27983572

  20. 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

  1. Ferulic acid improves lipid and glucose homeostasis in high-fat diet-induced obese mice.

    PubMed

    Naowaboot, Jarinyaporn; Piyabhan, Pritsana; Munkong, Narongsuk; Parklak, Wason; Pannangpetch, Patchareewan

    2016-02-01

    Ferulic acid (FA) is a plant phenolic acid that has several pharmacological effects including antihyperglycaemic activity. Thus, the objective of this study is to investigate the effect of FA on glucose and lipid metabolism in high-fat diet (HFD)-induced obese mice. Institute for Cancer Research (ICR) mice were fed a HFD (45 kcal% fat) for 16 weeks. At the ninth week of induction, the obese mice were orally administered with daily FA doses of 25 and 50 mg/kg for the next eight weeks. The results show that FA significantly reduced the elevated blood glucose and serum leptin levels, lowered the insulin resistance, and increased the serum adiponectin level. Moreover, serum lipid level, and liver cholesterol and triglyceride accumulations were also reduced. The histological examination showed clear evidence of a decrease in the lipid droplets in liver tissues and smaller size of fat cells in the adipose tissue in the obese mice treated with FA. Interestingly, FA reduced the expression of hepatic lipogenic genes such as sterol regulatory element-binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). It could also up-regulate hepatic carnitine palmitoyltransferase 1a (CPT1a) gene and peroxisome proliferator-activated receptor alpha (PPARα) proteins. The FA treatment was also found to suppress the protein expressions of hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxylase (PEPCK) and glucose-6-phosphatase (G6Pase). In conclusion, the findings of this study demonstrate that FA improves the glucose and lipid homeostasis in HFD-induced obese mice probably via modulating the expression of lipogenic and gluconeogenic genes in liver tissues.

  2. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  4. Utero-placental transfer of alternate energy substrates and glucose homeostasis in the newborn pig

    SciTech Connect

    Thulin, A.J.

    1985-01-01

    In the first experiment, three sows in late gestation were infused with (/sup 14/C)..beta..-hydroxybutyrate to evaluate utero-placental transfer of ketones. ..beta..-Hydroxy-butyrate (BOHB) concentrations were low in both the mother and fetus throughout the experiments (0.0189, 0.0197, 0.0054, and 0.0063 mmole/liter blood for UV, UA, FV, and FA, respectively). Radioactive BOHB was detected in fetal blood within two minutes post-injection. Lipid extracts of liver and adipose tissue exhibited the greatest relative incorporation of (/sup 14/C)..beta..-hydroxybutyrate followed by lung and heart tissues (3540, 3674, 1214, and 528 dpm/g wet weight, respectively). In a second study, five gravid gilts during late gestation were used to determine utero-placental transfer of maternal free fatty acids (FFA). Using similar techniques as Exp. 1, injections were given containing (/sup 14/C) linoleic acid and (/sup 3/H) palmitic acid or (/sup 14/C) octanoic acid. In a third experiment, gravid gilts were fed supplemental energy as starch (C), soybean oil (SO) or medium-chain triglycerides (MCT) during late gestation to determine the influence on colostrum composition and neonatal pig glucose homeostasis. Energy content of colostrum was increased (P = 0.05 by feeding SO and MCT. After a 36 h fast, mean piglet glucose concentrations were higher (P < 0.05) for MCT pigs. Glucose and creatinine levels showed quadratic effects, while FFA and blood urea nitrogen (BUN) exhibited cubic patterns during the fasting period. Although creatine levels were similar, BUN concentrations were higher (P < 0.01) for MCT progeny.

  5. Comparable Effects of Brief Resistance Exercise and Isotime Sprint Interval Exercise on Glucose Homeostasis in Men

    PubMed Central

    Tong, Tomas K.; Kong, Zhaowei; Shi, Xueying

    2017-01-01

    This study compared the effects of a single bout of resistance exercise (RES) on glycemic homeostasis to isotime sprint interval exercise (SIE) using a within-subjects design. Nineteen nondiabetic males (age: 23.3 ± 0.7 yrs; height: 173.1 ± 1.2 cm; weight: 79.1 ± 4.8 kg; % fat: 22.5 ± 2.5%) were studied. RES involved nine exercises of 10 repetitions at 75% 1-RM using a 2 : 2 s tempo and was interspersed with a one-minute recovery; SIE involved four 30 s' all-out cycling effort interspersed with four minutes of active recovery. Plasma glucose and insulin in response to a 75 g oral glucose tolerance test were assessed 12 h after exercise. In comparison to a no exercise control trial (CON), the area under curve (AUC) of plasma glucose was reduced with both RES and SIE (P < 0.05), while insulin AUC was only reduced with RES. Cederholm, Gutt, Matsuda, and HOMA indices were improved (P < 0.05) following RES compared to CON. Corresponding changes following SIE were only found in Cederholm and Gutt indices (P < 0.05). No difference was found in plasma variables and indices between RES and SIE (P > 0.05). Such findings suggest that the RES may represent a potential alternative to the SIE in the development of time-efficient lifestyle intervention strategies for improving diabetes risk factors in healthy populations. PMID:28349072

  6. 1,2-Dichloroethane impairs glucose and lipid homeostasis in the livers of NIH Swiss mice.

    PubMed

    Wang, Ting; Xu, Dandan; Fan, Qiming; Rong, Weifeng; Zheng, Jiewei; Gao, Chen; Li, Guoliang; Zeng, Ni; Guo, Tao; Zeng, Lihai; Wang, Fei; Xiao, Chen; Cai, Li; Tang, Shangqing; Deng, Xinlei; Yin, Xiao; Huang, Manqi; Lu, Fengrong; Hu, Qiansheng; Chen, Wen; Huang, Zhenlie; Wang, Qing

    2017-04-01

    Excessive exposure to 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to liver dysfunction. To fully explore the mechanism of 1,2-DCE-induced hepatic abnormalities, 30 male National Institutes of Health (NIH) Swiss mice were exposed to 0, 350, or 700mg/m(3) of 1,2-DCE, via inhalation, 6h/day for 28days. Increased liver/body weight ratios, as well as serum AST and serum ALT activity were observed in the 350 and 700mg/m(3) 1,2-DCE exposure group mice, compared with the control group mice. In addition, decreased body weights were observed in mice exposed to 700mg/m(3) 1,2-DCE, compared with control mice. Exposure to 350 and 700mg/m(3) 1,2-DCE also led to significant accumulation of hepatic glycogen, free fatty acids (FFA) and triglycerides, elevation of blood triglyceride and FFA levels, and decreases in blood glucose levels. Results from microarray analysis indicated that the decreases in glucose-6-phosphatase catalytic subunit (G6PC) and liver glycogen phosphorylase (PYGL) expression, mediated by the activation of AKT serine/threonine kinase 1 (Akt1), might be responsible for the hepatic glycogen accumulation and steatosis. Further in vitro study demonstrated that 2-chloroacetic acid (1,2-DCE metabolite), rather than 1,2-DCE, up-regulated Akt1 phosphorylation and suppressed G6PC and PYGL expression, resulting in hepatocellular glycogen accumulation. These results suggest that hepatic glucose and lipid homeostasis are impaired by 1,2-DCE exposure via down-regulation of PYGL and G6PC expression, which may be primarily mediated by the 2-chloroacetic acid-activated Akt1 pathway.

  7. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice

    PubMed Central

    Bermudez-Silva, Francisco J.; Romero-Zerbo, Silvana Y.; Haissaguerre, Magalie; Ruz-Maldonado, Inmaculada; Lhamyani, Said; El Bekay, Rajaa; Tabarin, Antoine; Marsicano, Giovanni; Cota, Daniela

    2016-01-01

    ABSTRACT The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases. PMID:26563389

  8. Molecules implicated in glucose homeostasis are differentially expressed in the trachea of lean and obese Zucker rats.

    PubMed

    Merigo, F; Boschi, F; Lasconi, C; Benati, D; Sbarbati, A

    2016-02-01

    Recent studies indicate that the processes mediated by the (T1R2/T1R3) glucose/sugar receptor of gustatory cells in the tongue, and hormones like leptin and ghrelin contribute to the regulation of glucose homeostasis. Altered plasma levels of leptin and ghrelin are associated with obesity both in humans and rodents. In the present study, we evaluated the ultrastructure of the mucosa, and the expression of molecules implicated in the regulation of glucose homeostasis (GLUT2, SGLT1, T1R3, ghrelin and its receptor) in the trachea of an animal model of obesity (Zucker rats). We found that the tracheal epithelium of obese animals was characterized by the presence of poorly differentiated cells. Ciliated and secretory cells were the cell lineages with greatest loss of differentiation. Severe epithelial alterations were associated with marked deposit of extracellular matrix in the lamina propria. The expression pattern of GLUT2 and SGLT1 glucose transporters was similar in the trachea of both the Zucker rat genotypes, whereas that of T1R3 was reduced in ciliated cells of obese rats. A different immunolocalization for ghrelin was also found in the trachea of obese rats. In conclusion, the tracheal morphological alterations in obese animals seem to compromise the expression of molecules involved in the homeostasis of glucose.

  9. 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.

  10. 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.

  11. 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.

  12. [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.

  13. Involvement of SIK3 in glucose and lipid homeostasis in mice.

    PubMed

    Uebi, Tatsuya; Itoh, Yumi; Hatano, Osamu; Kumagai, Ayako; Sanosaka, Masato; Sasaki, Tsutomu; Sasagawa, Satoru; Doi, Junko; Tatsumi, Keita; Mitamura, Kuniko; Morii, Eiichi; Aozasa, Katsuyuki; Kawamura, Tomohiro; Okumura, Meinoshin; Nakae, Jun; Takikawa, Hajime; Fukusato, Toshio; Koura, Minako; Nish, Mayumi; Hamsten, Anders; Silveira, Angela; Bertorello, Alejandro M; Kitagawa, Kazuo; Nagaoka, Yasuo; Kawahara, Hidehisa; Tomonaga, Takeshi; Naka, Tetsuji; Ikegawa, Shigeo; Tsumaki, Noriyuki; Matsuda, Junichiro; Takemori, Hiroshi

    2012-01-01

    Salt-inducible kinase 3 (SIK3), an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3(-/-) mice have a malnourished the phenotype (i.e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity) accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3(-/-) mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3(-/-) mice. Lipid metabolism disorders in Sik3(-/-) mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice.

  14. The islet circadian clock: entrainment mechanisms, function and role in glucose homeostasis.

    PubMed

    Rakshit, K; Qian, J; Colwell, C S; Matveyenko, A V

    2015-09-01

    Circadian regulation of glucose homeostasis and insulin secretion has long been appreciated as an important feature of metabolic control in humans. Circadian disruption is becoming increasingly prevalent in today's society and is likely responsible in part for the considerable rise in type 2 diabetes (T2DM) and metabolic syndrome worldwide. Thus, understanding molecular mechanisms driving the inter-relationship between circadian disruption and T2DM is important in context of disease prevention and therapeutics. In this regard, the goal of this article is to highlight the role of the circadian system, and islet circadian clocks in particular, as potential regulators of β-cell function and survival. To date, studies have shown that islet clocks respond to changes in feeding patterns, and regulate a multitude of critical cellular processes in insulin secreting β-cells (e.g. insulin exocytosis, mitochondrial function and response to oxidative stress). Subsequently, either genetic or environmental disruption of normal islet clock performance compromises β-cell function and leads to loss of glycaemic control. Future work is warranted to further unravel the role of circadian clocks in human islet function in health and contributions to pathogenesis of T2DM.

  15. Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice.

    PubMed

    Sartori, Claudio; Dessen, Pierre; Mathieu, Caroline; Monney, Anita; Bloch, Jonathan; Nicod, Pascal; Scherrer, Urs; Duplain, Hervé

    2009-12-01

    Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

  16. 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.

  17. Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.

    PubMed

    Hromatka, Bethann S; Tung, Joyce Y; Kiefer, Amy K; Do, Chuong B; Hinds, David A; Eriksson, Nicholas

    2015-05-01

    Roughly one in three individuals is highly susceptible to motion sickness and yet the underlying causes of this condition are not well understood. Despite high heritability, no associated genetic factors have been discovered. Here, we conducted the first genome-wide association study on motion sickness in 80 494 individuals from the 23andMe database who were surveyed about car sickness. Thirty-five single-nucleotide polymorphisms (SNPs) were associated with motion sickness at a genome-wide-significant level (P < 5 × 10(-8)). Many of these SNPs are near genes involved in balance, and eye, ear and cranial development (e.g. PVRL3, TSHZ1, MUTED, HOXB3, HOXD3). Other SNPs may affect motion sickness through nearby genes with roles in the nervous system, glucose homeostasis or hypoxia. We show that several of these SNPs display sex-specific effects, with up to three times stronger effects in women. We searched for comorbid phenotypes with motion sickness, confirming associations with known comorbidities including migraines, postoperative nausea and vomiting (PONV), vertigo and morning sickness and observing new associations with altitude sickness and many gastrointestinal conditions. We also show that two of these related phenotypes (PONV and migraines) share underlying genetic factors with motion sickness. These results point to the importance of the nervous system in motion sickness and suggest a role for glucose levels in motion-induced nausea and vomiting, a finding that may provide insight into other nausea-related phenotypes like PONV. They also highlight personal characteristics (e.g. being a poor sleeper) that correlate with motion sickness, findings that could help identify risk factors or treatments.

  18. 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.

  19. Lactose in milk replacer can partly be replaced by glucose, fructose, or glycerol without affecting insulin sensitivity in veal calves.

    PubMed

    Pantophlet, A J; Gilbert, M S; van den Borne, J J G C; Gerrits, W J J; Roelofsen, H; Priebe, M G; Vonk, R J

    2016-04-01

    Calf milk replacer (MR) contains 40 to 50% lactose. Lactose strongly fluctuates in price and alternatives are desired. Also, problems with glucose homeostasis and insulin sensitivity (i.e., high incidence of hyperglycemia and hyperinsulinemia) have been described for heavy veal calves (body weight >100 kg). Replacement of lactose by other dietary substrates can be economically attractive, and may also positively (or negatively) affect the risk of developing problems with glucose metabolism. An experiment was designed to study the effects of replacing one third of the dietary lactose by glucose, fructose, or glycerol on glucose homeostasis and insulin sensitivity in veal calves. Forty male Holstein-Friesian (body weight=114 ± 2.4 kg; age=97 ± 1.4 d) calves were fed an MR containing 462 g of lactose/kg (CON), or an MR in which 150 g of lactose/kg of MR was replaced by glucose (GLU), fructose (FRU), or glycerol (GLY). During the first 10d of the trial, all calves received CON. The CON group remained on this diet and the other groups received their experimental diets for a period of 8 wk. Measurements were conducted during the first (baseline) and last week of the trial. A frequently sampled intravenous glucose tolerance test was performed to assess insulin sensitivity and 24 h of urine was collected to measure glucose excretion. During the last week of the trial, a bolus of 1.5 g of [U-(13)C] substrates was added to their respective meals and plasma glucose, insulin, and (13)C-glucose responses were measured. Insulin sensitivity was low at the start of the trial and remained low [1.2 ± 0.1 and 1.0 ± 0.1 (mU/L)(-1) × min(-1)], and no treatment effect was noted. Glucose excretion was low at the start of the trial (3.4 ± 1.0 g/d), but increased in CON and GLU calves (26.9 ± 3.9 and 43.0 ± 10.6g/d) but not in FRU and GLY calves. Postprandial glucose was higher in GLU, lower in FRU, and similar in GLY compared with CON calves. Postprandial insulin was lower in FRU

  20. Loss-of-Function Mutations in the Cell-Cycle Control Gene CDKN2A Impact on Glucose Homeostasis in Humans

    PubMed Central

    Pal, Aparna; Potjer, Thomas P.; Thomsen, Soren K.; Ng, Hui Jin; Barrett, Amy; Scharfmann, Raphael; James, Tim J.; Bishop, D. T.; Karpe, Fredrik; Godsland, Ian F.; Vasen, Hans F.A.; Newton-Bishop, Julia; Pijl, Hanno; McCarthy, Mark I.; Gloyn, Anna L.

    2015-01-01

    At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a non-coding region near CDKN2A. The disease-associated alleles have been implicated in reduced β-cell function, but the underlying mechanism remains elusive. In mice, β-cell specific loss of Cdkn2a causes hyperplasia whilst overexpression leads to diabetes, highlighting CDKN2A as a candidate effector transcript. Rare CDKN2A loss-of-function mutations are a cause of familial melanoma and offer the opportunity to determine the impact of CDKN2A haploinsufficiency on glucose homeostasis in humans. To test the hypothesis that such individuals have improved β-cell function, we performed oral and intravenous glucose tolerance tests on mutation carriers and matched controls. Compared with controls, carriers displayed increased insulin secretion, impaired insulin sensitivity and reduced hepatic insulin clearance. These results are consistent with a model whereby CDKN2A-loss affects a range of different tissues, including pancreatic β-cells and liver. To test for direct effects of CDKN2A-loss on β-cell function, we performed knockdown in a human β-cell line, EndoC-bH1. This revealed increased insulin secretion independent of proliferation. Overall, we demonstrate that CDKN2A is an important regulator of glucose homeostasis in humans, thus supporting its candidacy as an effector transcript for type 2 diabetes-associated alleles in the region. PMID:26542317

  1. Diabetes-Related Ankyrin Repeat Protein (DARP/Ankrd23) Modifies Glucose Homeostasis by Modulating AMPK Activity in Skeletal Muscle.

    PubMed

    Shimoda, Yoshiaki; Matsuo, Kiyonari; Kitamura, Youhei; Ono, Kazunori; Ueyama, Tomomi; Matoba, Satoaki; Yamada, Hiroyuki; Wu, Tongbin; Chen, Ju; Emoto, Noriaki; Ikeda, Koji

    2015-01-01

    Skeletal muscle is the major site for glucose disposal, the impairment of which closely associates with the glucose intolerance in diabetic patients. Diabetes-related ankyrin repeat protein (DARP/Ankrd23) is a member of muscle ankyrin repeat proteins, whose expression is enhanced in the skeletal muscle under diabetic conditions; however, its role in energy metabolism remains poorly understood. Here we report a novel role of DARP in the regulation of glucose homeostasis through modulating AMP-activated protein kinase (AMPK) activity. DARP is highly preferentially expressed in skeletal muscle, and its expression was substantially upregulated during myotube differentiation of C2C12 myoblasts. Interestingly, DARP-/- mice demonstrated better glucose tolerance despite similar body weight, while their insulin sensitivity did not differ from that in wildtype mice. We found that phosphorylation of AMPK, which mediates insulin-independent glucose uptake, in skeletal muscle was significantly enhanced in DARP-/- mice compared to that in wildtype mice. Gene silencing of DARP in C2C12 myotubes enhanced AMPK phosphorylation, whereas overexpression of DARP in C2C12 myoblasts reduced it. Moreover, DARP-silencing increased glucose uptake and oxidation in myotubes, which was abrogated by the treatment with AICAR, an AMPK activator. Of note, improved glucose tolerance in DARP-/- mice was abolished when mice were treated with AICAR. Mechanistically, gene silencing of DARP enhanced protein expression of LKB1 that is a major upstream kinase for AMPK in myotubes in vitro and the skeletal muscle in vivo. Together with the altered expression under diabetic conditions, our data strongly suggest that DARP plays an important role in the regulation of glucose homeostasis under physiological and pathological conditions, and thus DARP is a new therapeutic target for the treatment of diabetes mellitus.

  2. Sprint interval training (SIT) is an effective method to maintain cardiorespiratory fitness (CRF) and glucose homeostasis in Scottish adolescents

    PubMed Central

    Martin, R; Baker, JS; Young, J; Sculthorpe, N; Grace, FM

    2015-01-01

    The present study examined the physiological impact of a school based sprint interval training (SIT) intervention in replacement of standard physical education (SPE) class on cardio-respiratory fitness (CRF) and glucose homeostasis during the semester following summer vacation. Participants (n=49) were randomly allocated to either intervention (SIT; n=26, aged 16.9 ± 0.3 yrs) or control group who underwent standard physical education (SPE; n=23, aged 16.8 ± 0.6 yrs). CRF (VO2max) and glucose homeostasis were obtained prior-to and following 7 weeks of SIT exercise. Significant group x time interaction was observed for CRF (P < 0.01) with non-significant trends for fasting insulin (P= 0.08), and HOMA-IR (P=0.06). CRF decreased (P < 0.01) in SPE such that POST intervention CRF was significantly lower (P< 0.05) in SPE. Fasting plasma glucose (P < 0.01), insulin (P< 0.01) and HOMA-IR (P< 0.01) increased significantly amongst SPE. The main finding of the present study is that 7-weeks of SIT exercise is an effective method of maintaining (but not improving) CRF and fasting insulin homeostasis amongst school-going adolescents. SIT exercise demonstrates potential as a time efficient physiological adjunct to standard PE class in order to maintain CRF during the school term. PMID:26681833

  3. 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

  4. Interoception beyond homeostasis: affect, cognition and mental health

    PubMed Central

    Tsakiris, Manos; Critchley, Hugo

    2016-01-01

    Interoception refers to the sensing of the internal state of one's body. Interoception is distinct from the processing of sensory information concerning external (non-self) stimuli (e.g. vision, hearing, touch and smell) and is the afferent axis to internal (autonomic and hormonal) physiological control. However, the impact of interoception extends beyond homeostatic/allostatic reflexes: it is proposed to be fundamental to motivation, emotion (affective feelings and behaviours), social cognition and self-awareness. This view is supported by a growing body of experimental evidence that links peripheral physiological states to mental processes. Within this framework, the representation of self is constructed from early development through continuous integrative representation of biological data from the body, to form the basis for those aspects of conscious awareness grounded on the subjective sense of being a unique individual. This theme issue of the Philosophical Transactions of the Royal Society B draws together state-of-the-art knowledge concerning theoretical, experimental and clinical facets of interoception with the emphasis on cognitive and affective neuroscience. The multidisciplinary and cross-disciplinary perspectives represented in this theme issue disseminate and entrench knowledge about interoception across the scientific community and provide a reference for the conceptualization and further study of interoception across behavioural sciences. PMID:28080961

  5. Gallic acid regulates body weight and glucose homeostasis through AMPK activation.

    PubMed

    Doan, Khanh V; Ko, Chang Mann; Kinyua, Ann W; Yang, Dong Joo; Choi, Yun-Hee; Oh, In Young; Nguyen, Nguyen Minh; Ko, Ara; Choi, Jae Won; Jeong, Yangsik; Jung, Min Ho; Cho, Won Gil; Xu, Shanhua; Park, Kyu Sang; Park, Woo Jin; Choi, Soo Yong; Kim, Hyoung Shik; Moh, Sang Hyun; Kim, Ki Woo

    2015-01-01

    Gallic acid [3,4,5-trihydroxybenzoic acid (GA)], a natural phytochemical, is known to have a variety of cellular functions including beneficial effects on metabolic syndromes. However, the molecular mechanism by which GA exerts its beneficial effects is not known. Here we report that GA plays its role through the activation of AMP-activated protein kinase (AMPK) and by regulating mitochondrial function via the activation of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Sirtuin 1 (Sirt1) knockdown significantly blunted GA's effect on PGC1α activation and downstream genes, suggesting a critical role of the AMPK/Sirt1/PGC1α pathway in GA's action. Moreover, diet-induced obese mice treated with GA showed significantly improved glucose and insulin homeostasis. In addition, the administration of GA protected diet-induced body weight gain without a change in food intake. Biochemical analyses revealed a marked activation of AMPK in the liver, muscle, and interscapular brown adipose tissue of the GA-treated mice. Moreover, uncoupling protein 1 together with other genes related to energy expenditure was significantly elevated in the interscapular brown adipose tissue. Taken together, these results indicate that GA plays its beneficial metabolic roles by activating the AMPK/Sirt1/PGC1α pathway and by changing the interscapular brown adipose tissue genes related to thermogenesis. Our study points out that targeting the activation of the AMPK/Sirt1/PGC1α pathway by GA or its derivatives might be a potential therapeutic intervention for insulin resistance in metabolic diseases.

  6. Fisetin improves glucose homeostasis through the inhibition of gluconeogenic enzymes in hepatic tissues of streptozotocin induced diabetic rats.

    PubMed

    Prasath, Gopalan Sriram; Pillai, Subramanian Iyyam; Subramanian, Sorimuthu Pillai

    2014-10-05

    Liver plays a vital role in blood glucose homeostasis. Recent studies have provided considerable evidence that hepatic glucose production (HGP) plays an important role in the development of fasting hyperglycemia in diabetes. From this perspective, diminution of HGP has certainly been considered for the treatment of diabetes. In the present study, we have analyzed the modulatory effects of fisetin, a flavonoid of strawberries, on the expression of key enzymes of carbohydrate metabolism in STZ induced experimental diabetic rats. The physiological criterions such as food and fluid intake were regularly monitored. The levels of blood glucose, plasma insulin, hemoglobin and glycosylated hemoglobin were analyzed. The mRNA and protein expression levels of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were determined by immunoblot as well as PCR analysis. Diabetic group of rats showed significant increase in food and water intake when compared with control group of rats. Upon oral administration of fisetin as well as gliclazide to diabetic group of rats, the levels were found to be decreased. Oral administration of fisetin (10 mg/kg body weight) to diabetic rats for 30 days established a significant decline in blood glucose and glycosylated hemoglobin levels and a significant increase in plasma insulin level. The mRNA and protein expression levels of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), were decreased in liver tissues upon treatment with fisetin. The results of the present study suggest that fisetin improves glucose homeostasis by direct inhibition of gluconeogenesis in liver.

  7. Epigallocatechin gallate affects glucose metabolism and increases fitness and lifespan in Drosophila melanogaster.

    PubMed

    Wagner, Anika E; Piegholdt, Stefanie; Rabe, Doerte; Baenas, Nieves; Schloesser, Anke; Eggersdorfer, Manfred; Stocker, Achim; Rimbach, Gerald

    2015-10-13

    In this study, we tested whether a standardized epigallocatechin-3-gallate (EGCG) rich green tea extract (comprising > 90% EGCG) affects fitness and lifespan as well as parameters of glucose metabolism and energy homeostasis in the fruit fly, Drosophila melanogaster. Following the application of the green tea extract a significant increase in the mean lifespan (+ 3.3 days) and the 50% survival (+ 4.3 days) as well as improved fitness was detected. These effects went along an increased expression of Spargel, the homolog of mammalian PGC1α, which has been reported to affect lifespan in flies. Intriguingly, in flies, treatment with the green tea extract decreased glucose concentrations, which were accompanied by an inhibition of α-amylase and α-glucosidase activity. Computational docking analysis proved the potential of EGCG to dock into the substrate binding pocket of α-amylase and to a greater extent into α-glucosidase. Furthermore, we demonstrate that EGCG downregulates insulin-like peptide 5 and phosphoenolpyruvate carboxykinase, major regulators of glucose metabolism, as well as the Drosophila homolog of leptin, unpaired 2. We propose that a decrease in glucose metabolism in connection with an upregulated expression of Spargel contribute to the better fitness and the extended lifespan in EGCG-treated flies.

  8. Epigallocatechin gallate affects glucose metabolism and increases fitness and lifespan in Drosophila melanogaster

    PubMed Central

    Wagner, Anika E.; Piegholdt, Stefanie; Rabe, Doerte; Baenas, Nieves; Schloesser, Anke; Eggersdorfer, Manfred; Stocker, Achim; Rimbach, Gerald

    2015-01-01

    In this study, we tested whether a standardized epigallocatechin-3-gallate (EGCG) rich green tea extract (comprising > 90% EGCG) affects fitness and lifespan as well as parameters of glucose metabolism and energy homeostasis in the fruit fly, Drosophila melanogaster. Following the application of the green tea extract a significant increase in the mean lifespan (+ 3.3 days) and the 50% survival (+ 4.3 days) as well as improved fitness was detected. These effects went along an increased expression of Spargel, the homolog of mammalian PGC1α, which has been reported to affect lifespan in flies. Intriguingly, in flies, treatment with the green tea extract decreased glucose concentrations, which were accompanied by an inhibition of α-amylase and α-glucosidase activity. Computational docking analysis proved the potential of EGCG to dock into the substrate binding pocket of α-amylase and to a greater extent into α-glucosidase. Furthermore, we demonstrate that EGCG downregulates insulin-like peptide 5 and phosphoenolpyruvate carboxykinase, major regulators of glucose metabolism, as well as the Drosophila homolog of leptin, unpaired 2. We propose that a decrease in glucose metabolism in connection with an upregulated expression of Spargel contribute to the better fitness and the extended lifespan in EGCG-treated flies. PMID:26375250

  9. Hepatic fat and abdominal adiposity in early pregnancy together predict impaired glucose homeostasis in mid-pregnancy

    PubMed Central

    De Souza, L R; Berger, H; Retnakaran, R; Vlachou, P A; Maguire, J L; Nathens, A B; Connelly, P W; Ray, J G

    2016-01-01

    Hepatic fat and abdominal adiposity individually reflect insulin resistance, but their combined effect on glucose homeostasis in mid-pregnancy is unknown. A cohort of 476 pregnant women prospectively underwent sonographic assessment of hepatic fat and visceral (VAT) and total (TAT) adipose tissue at 11–14 weeks' gestation. Logistic regression was used to assess the relation between the presence of maternal hepatic fat and/or the upper quartile (Q) of either VAT or TAT and the odds of developing the composite outcome of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or gestational diabetes mellitus at 24–28 weeks' gestation, based on a 75 g OGTT. Upon adjusting for maternal age, ethnicity, family history of DM and body mass index (BMI), the co-presence of hepatic fat and quartile 4 (Q4) of VAT (adjusted odds ratio (aOR) 6.5, 95% CI: 2.3–18.5) or hepatic fat and Q4 of TAT (aOR 7.8 95% CI 2.8–21.7) were each associated with the composite outcome, relative to women with neither sonographic feature. First-trimester sonographic evidence of maternal hepatic fat and abdominal adiposity may independently predict the development of impaired glucose homeostasis and GDM in mid-pregnancy. PMID:27643724

  10. Effects of 9-cis- and all-trans-retinoic acids on blood glucose homeostasis in the fiddler crab, Uca pugilator.

    PubMed

    Zou, Enmin; Bonvillain, Ryan

    2003-11-01

    9-cis-Retinoic acid (9CRA) and all-trans-retinoic acid (ATRA) are known to be involved in the regulation of glucose homeostasis in vertebrates by inducing insulin release and expression of glucose transporter proteins. In view of the fact that both 9CRA and ATRA are endogenous to the fiddler crab, Uca pugilator, that a retinoid X receptor exists in this fiddler crab and that activities of insulin-like and insulin-like growth factor-like peptides have been reported for crustaceans, we investigated whether 9CRA and ATRA also play a role in glucose homeostasis in U. pugilator. Neither 9CRA nor ATRA was found to produce hypoglycemic effects at a dose of 10 microg/g live mass. However, 9CRA, but not ATRA, induced hyperglycemia. Such 9CRA-induced hyperglycemia was apparently mediated by the eyestalk hormone CHH since injection of 9CRA into eyestalk-ablated crabs did not result in hyperglycemia. ATRA was found to have an inhibitory effect on the recovery of blood glucose concentration following ATRA administration. Discussion on the possible mechanisms for the actions of 9CRA and ATRA was presented.

  11. Glucose Homeostasis and Weight Loss in Morbidly Obese Patients Undergoing Banded Sleeve Gastrectomy: A Prospective Clinical Study

    PubMed Central

    Miguel, Gustavo Peixoto Soares; Azevedo, Joao Luiz Moreira Coutinho; Neto, Carlos Gicovate; Moreira, Cora Lavigne Castelo Branco; Viana, Elaine Cristina; Carvalho, Perseu Seixas

    2009-01-01

    OBJECTIVE To assess glucose homeostasis and weight loss in morbidly obese patients undergoing Silastic® ring sleeve gas-trectomy. METHODS This was a prospective clinical study. Thirty-three female patients with a mean body mass index (BMI) of 42.33 ± 1.50 kg/m2 (range: 40–45 kg/m2), a mean age of 36.7 ± 9.4 years and a mean waist circumference of 118.7 ± 5.98 cm were included in this study. Type 2 diabetes mellitus was observed in 11 patients (33.3%), and glucose intolerance was observed in 4 patients (12.1%). Mean plasma fasting glucose levels were 109.77 ± 44.19 mg/dl (75–320) in the preoperative period. All Silastic® ring sleeve gastrectomy procedures were performed by the same surgical team using the same anesthetic technique. The patients were monitored for at least 12 months after surgery. RESULTS The mean weight of the patients decreased from 107.69 ± 6.57 kg to 70.52 ± 9.36 kg (p < 0.001), the mean BMI decreased to 27.4 ± 2.42 kg/m2 (p < 0.001), and the mean waist circumference decreased to 89.87 cm ± 6.66 (p < 0.001) in the postoperative period. Excess BMI loss was 86.5 ± 14.2%. Fasting glucose levels were reduced to 80.94 ± 6.3 mg/dl (p < 0.001). Remission of diabetes and glucose intolerance was observed in all patients. CONCLUSION Silastic® ring sleeve gastrectomy was effective in promoting weight loss, waist circumference reduction and control of glucose homeostasis in morbidly obese patients. PMID:19936183

  12. A retrospective review of the roles of multifunctional glucose-6-phosphatase in blood glucose homeostasis: Genesis of the tuning/retuning hypothesis

    PubMed Central

    Nordlie, Robert C.; Foster, James D.

    2010-01-01

    In a scientific career spanning from 1955–2000, my research focused on phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Grounded in basic enzymology, and initially pursuing the steady-state rate behavior of isolated preparations of these critically important gluconeogenic enzymes, our key findings were confirmed and extended by in situ enzyme rate experiments exploiting isolated liver perfusions. These efforts culminated in the discovery of the liver cytosolic isozyme of carboxykinase, known today as (GTP)PEPCK-C (EC4.1.1.32) and also revealed a biosynthetic function and multicomponent nature of glucose-6-phosphatase (EC3.1.3.9). Discovery that glucose-6-phosphatase possessed an intrinsically biosynthetic activity, now known as carbamyl-P:glucose phosphotransferase– along with a deeper consideration of the enzyme’s hydrolytic activity as well as the action of liver glucokinase resulted in the evolution of Tuning/Retuning Hypothesis for blood glucose homeostasis in health and disease. This THEN & NOW review shares with the reader the joy and exhilaration of major scientific discovery and also contrasts the methodologies and approaches on which I relied with those currently in use. PMID:20603134

  13. Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis

    PubMed Central

    Sebastián, David; Hernández-Alvarez, María Isabel; Segalés, Jessica; Sorianello, Eleonora; Muñoz, Juan Pablo; Sala, David; Waget, Aurélie; Liesa, Marc; Paz, José C.; Gopalacharyulu, Peddinti; Orešič, Matej; Pich, Sara; Burcelin, Rémy; Palacín, Manuel; Zorzano, Antonio

    2012-01-01

    Mitochondria are dynamic organelles that play a key role in energy conversion. Optimal mitochondrial function is ensured by a quality-control system tightly coupled to fusion and fission. In this connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and undergoes repression in muscle from obese or type 2 diabetic patients. Here, we provide in vivo evidence that Mfn2 plays an essential role in metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to numerous metabolic abnormalities, characterized by glucose intolerance and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin signaling in liver and muscle. Furthermore, Mfn2 deficiency was associated with endoplasmic reticulum stress, enhanced hydrogen peroxide concentration, altered reactive oxygen species handling, and active JNK. Chemical chaperones or the antioxidant N-acetylcysteine ameliorated glucose tolerance and insulin signaling in liver-specific Mfn2 KO mice. This study provides an important description of a unique unexpected role of Mfn2 coordinating mitochondria and endoplasmic reticulum function, leading to modulation of insulin signaling and glucose homeostasis in vivo. PMID:22427360

  14. Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience.

    PubMed

    Hunsberger, Joshua G; Machado-Vieira, Rodrigo; Austin, Daniel R; Zarate, Carlos; Chuang, De-Maw; Chen, Guang; Reed, John C; Manji, Husseini K

    2011-07-27

    The endoplasmic reticulum (ER) is a critical site for intracellular calcium storage as well as protein synthesis, folding, and trafficking. Disruption of these processes is gaining support for contributing to heritable vulnerability of certain diseases. Here, we investigated Bax inhibitor 1 (BI-1), an anti-apoptotic protein that primarily resides in the ER and associates with B-cell lymphoma 2 (Bcl-2) and Bcl-XL, as an affective resiliency factor through its modulation of calcium homeostasis. We found that transgenic (TG) mice with BI-1 reinforced expression, via the neuronal specific enolase promoter, showed protection against the learned helplessness (LH) paradigm, an animal model to test stress coping. TG mice were also protected against anhedonia following both serotonin and catecholamine depletion as measured in two different models, the female urine sniffing test and the saccharine preference test. In addition, we used primary mouse cortical cultures to explore the ability of BI-1 to influence calcium homeostasis under basal conditions and also following challenge with thapsigargin (THPS), an inhibitor of sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) that disrupts calcium homeostasis. TG neurons showed decreased basal cytosolic calcium levels and decreased Ca(2+) cytosolic accumulation following challenge with THPS as compared to WT neuronal cultures. Together, these data suggest that BI-1, through its actions on calcium homeostasis, may confer affective resiliency in multiple animal models of depression and anhedonia.

  15. Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience

    PubMed Central

    Hunsberger, Joshua G.; Machado-Vieira, Rodrigo; Austin, Daniel R.; Zarate, Carlos; Chuang, De-Maw; Chen, Guang; Reed, John C.; Manji, Husseini K.

    2011-01-01

    The endoplamic reticulum (ER) is a critical site for intracellular calcium storage as well as protein synthesis, folding, and trafficking. Disruption of these processes is gaining support for contributing to heritable vulnerability of certain diseases. Here, we investigated Bax inhibitor 1 (BI-1), an anti-apoptotic protein that primarily resides in the ER and associates with B-cell lymphoma 2 (Bcl-2) and Bcl-XL, as an affective resiliency factor through its modulation of calcium homeostasis. We found that transgenic (TG) mice with BI-1 reinforced expression, via the neuronal specific enolase promoter, showed protection against the learned helplessness (LH) paradigm, an animal model to test stress coping. TG mice were also protected against anhedonia following both serotonin and catecholamine depletion as measured in two different models, the female urine sniffing test and the saccharine preference test. In addition, we used primary mouse cortical cultures to explore the ability of BI-1 to influence calcium homeostasis under basal conditions and also following challenge with thapsigargin (THPS), an inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) that disrupts calcium homeostasis. TG neurons showed decreased basal cytosolic calcium levels and decreased Ca2+ cytosolic accumulation following challenge with THPS as compared to WT neuronal cultures. Together, these data suggest that BI-1, through its actions on calcium homeostasis, may confer affective resiliency in multiple animal models of depression and anhedonia. PMID:21718971

  16. 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

  17. 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

  18. Overexpression of apolipoprotein A5 in mice is not protective against body weight gain and aberrant glucose homeostasis.

    PubMed

    Pamir, Nathalie; McMillen, Timothy S; Li, Yu-I; Lai, Ching-Mei; Wong, Howard; LeBoeuf, Renée C

    2009-04-01

    Apolipoprotein A5 (APOA5) is expressed primarily in the liver and modulates plasma triglyceride levels in mice and humans. Mice overexpressing APOA5 exhibit reduced plasma triglyceride levels. Because there is a tight association between plasma triglyceride concentration and traits of the metabolic syndrome, we used transgenic mice overexpressing human APOA5 to test the concept that these mice would be protected from diet-induced obesity and insulin resistance. Male and female transgenic and wild-type mice on the FVB/N genetic background were fed standard rodent chow or a diet rich in fat and sucrose for 18 weeks, during which time clinical phenotypes associated with obesity and glucose homeostasis were measured. We found that APOA5 transgenic (A5tg) mice were resistant to diet-induced changes in plasma triglyceride but not total cholesterol levels. Body weights were similar between the genotypes for females and males, although male A5tg mice showed a modest but significant increase in the relative size of inguinal fat pads. Although male A5tg mice showed a significantly increased ratio of plasma glucose to insulin, profiles of glucose clearance as evaluated after injections of glucose or insulin failed to reveal any differences between genotypes. Overall, our data showed that there was no advantage to responses to diet-induced obesity with chronic reduction of plasma triglyceride levels as mediated by overexpression of APOA5.

  19. Longitudinal Effects of MRI-Measured Hepatic Steatosis on Biomarkers of Glucose Homeostasis and Hepatic Apoptosis in Obese Youth

    PubMed Central

    Kim, Grace; Giannini, Cosimo; Pierpont, Bridget; Feldstein, Ariel E.; Santoro, Nicola; Kursawe, Romy; Shaw, Melissa; Duran, Elvira; Goldberg, Rachel; Dziura, James; Caprio, Sonia

    2013-01-01

    OBJECTIVE We used fast-gradient magnetic resonance imaging (MRI) to determine the longitudinal associations between the hepatic fat content (HFF), glucose homeostasis, and a biomarker of hepatocellular apoptosis in obese youth. RESEARCH DESIGN AND METHODS Baseline and longitudinal liver and abdominal MRI were performed with an oral glucose tolerance test in 76 obese youth followed for an average of 1.9 years. Cytokeratin-18 (CK-18) was measured at baseline and follow-up as a biomarker of hepatic apoptosis. The relationship between baseline HFF and metabolic parameters and circulating levels of CK-18 at follow-up were assessed using a bivariate correlation. RESULTS At baseline, 38% had hepatic steatosis based on %HFF ≥5.5% with alterations in indices of insulin sensitivity and secretion. At follow-up, BMI increased in both groups and baseline %HFF correlated strongly with the follow-up %HFF (r = 0.81, P < 0.001). Over time, markers of insulin sensitivity and 2-h glucose improved significantly in the group without fatty liver, in contrast with the persistence of the insulin resistance and associated correlates in the fatty liver group. Baseline HFF correlated with 2-h glucose (r = 0.38, P = 0.001), whole-body insulin sensitivity (r = −0.405, P = 0.001), adiponectin (r = −0.44, P < 0.001), CK-18 levels, (r = 0.63, P < 0.001), and disposition index (r = −0.272, P = 0.021) at follow-up. In a multivariate analysis, we showed that baseline HFF is an independent predictor of 2-h glucose and whole-body insulin sensitivity. CONCLUSIONS In obese youth, the phenotype of MRI-measured hepatic steatosis is persistent. Baseline HFF strongly modulates longitudinally 2-h blood glucose, biomarkers of insulin resistance, and hepatocellular apoptosis. PMID:22933439

  20. 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

  1. Osteoid osteoma is an osteocalcinoma affecting glucose metabolism.

    PubMed

    Confavreux, C B; Borel, O; Lee, F; Vaz, G; Guyard, M; Fadat, C; Carlier, M-C; Chapurlat, R; Karsenty, G

    2012-05-01

    Osteocalcin is a hormone secreted by osteoblasts, which regulates energy metabolism by increasing β-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. This has been demonstrated in mice, but to date, the evidence implicating osteocalcin in the regulation of energy metabolism in humans are indirect. To address this question more directly, we asked whether a benign osteoblastic tumor, such as osteoma osteoid in young adults, may secrete osteocalcin. The study was designed to assess the effect of surgical resection of osteoid osteoma on osteocalcin and blood glucose levels in comparison with patients undergoing knee surgery and healthy volunteers. Blood collections were performed the day of surgery and the following morning after overnight fasting. Patients and controls were recruited in the orthopedic surgery department of New York Presbiterian Hospital, NY-USA and Hospices Civils de Lyon, France. Seven young males were included in the study: two had osteoid osteoma, two underwent knee surgery, and three were healthy volunteers. After resection of the osteoid osteomas, we observed a decrease of osteocalcin by 62% and 30% from the initial levels. Simultaneously, blood glucose increased respectively by 32% and 15%. Bone turnover markers were not affected. This case study shows for the first time that osteocalcin in humans affects blood glucose level. This study also suggests that ostoid osteoma may be considered, at least in part, as an osteocalcinoma.

  2. Protective action of Citrullus colocynthis seed extracts against the deleterious effect of streptozotocin on both in vitro glucose-stimulated insulin release from rat pancreatic islets and in vivo glucose homeostasis

    PubMed Central

    BENARIBA, NABILA; BELLAKDHAR, WAFAA; DJAZIRI, RABEH; HUPKENS, EMELINE; LOUCHAMI, KARIM; MALAISSE, WILLY J.

    2013-01-01

    Citrullus colocynthis extracts improve glucose homeostasis in alloxan- or streptozotocin (STZ)-induced diabetic rats. Little is known, however, regarding the protective effect of these extracts against the β-cytotoxic action of STZ. In the present study, an H2O-methanol extract was found to suppress the inhibition of glucose-stimulated insulin secretion by STZ in rat-isolated pancreatic islets. Similarly, when an aqueous extract from Citrullus colocynthis seeds was injected daily for 21 days prior to STZ administration, the perturbation of glucose homeostasis otherwise generated by the β-cytotoxic agent was minimized in rats. PMID:24648906

  3. 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.

  4. Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis

    PubMed Central

    Hodakoski, Cindy; Hopkins, Benjamin D.; Barrows, Douglas; Mense, Sarah M.; Keniry, Megan; Anderson, Karen E.; Kern, Philip A.; Hawkins, Phillip T.; Stephens, Len R.; Parsons, Ramon

    2014-01-01

    Insulin activation of phosphoinositide 3-kinase (PI3K) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (PTEN) blocks PI3K signaling by dephosphorylating PIP3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-REX2). The mechanism of inhibition and its physiological significance are not known. Here, we report that P-REX2 interacts with PTEN via two interfaces. The pleckstrin homology (PH) domain of P-REX2 inhibits PTEN by interacting with the catalytic region of PTEN, and the inositol polyphosphate 4-phosphatase domain of P-REX2 provides high-affinity binding to the postsynaptic density-95/Discs large/zona occludens-1-binding domain of PTEN. P-REX2 inhibition of PTEN requires C-terminal phosphorylation of PTEN to release the P-REX2 PH domain from its neighboring diffuse B-cell lymphoma homology domain. Consistent with its function as a PTEN inhibitor, deletion of Prex2 in fibroblasts and mice results in increased Pten activity and decreased insulin signaling in liver and adipose tissue. Prex2 deletion also leads to reduced glucose uptake and insulin resistance. In human adipose tissue, P-REX2 protein expression is decreased and PTEN activity is increased in insulin-resistant human subjects. Taken together, these results indicate a functional role for P-REX2 PH-domain–mediated inhibition of PTEN in regulating insulin sensitivity and glucose homeostasis and suggest that loss of P-REX2 expression may cause insulin resistance. PMID:24367090

  5. Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis.

    PubMed

    Hodakoski, Cindy; Hopkins, Benjamin D; Barrows, Douglas; Mense, Sarah M; Keniry, Megan; Anderson, Karen E; Kern, Philip A; Hawkins, Phillip T; Stephens, Len R; Parsons, Ramon

    2014-01-07

    Insulin activation of phosphoinositide 3-kinase (PI3K) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (PTEN) blocks PI3K signaling by dephosphorylating PIP3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-REX2). The mechanism of inhibition and its physiological significance are not known. Here, we report that P-REX2 interacts with PTEN via two interfaces. The pleckstrin homology (PH) domain of P-REX2 inhibits PTEN by interacting with the catalytic region of PTEN, and the inositol polyphosphate 4-phosphatase domain of P-REX2 provides high-affinity binding to the postsynaptic density-95/Discs large/zona occludens-1-binding domain of PTEN. P-REX2 inhibition of PTEN requires C-terminal phosphorylation of PTEN to release the P-REX2 PH domain from its neighboring diffuse B-cell lymphoma homology domain. Consistent with its function as a PTEN inhibitor, deletion of Prex2 in fibroblasts and mice results in increased Pten activity and decreased insulin signaling in liver and adipose tissue. Prex2 deletion also leads to reduced glucose uptake and insulin resistance. In human adipose tissue, P-REX2 protein expression is decreased and PTEN activity is increased in insulin-resistant human subjects. Taken together, these results indicate a functional role for P-REX2 PH-domain-mediated inhibition of PTEN in regulating insulin sensitivity and glucose homeostasis and suggest that loss of P-REX2 expression may cause insulin resistance.

  6. Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice

    PubMed Central

    Wilson, C H; Nikolic, A; Kentish, S J; Shalini, S; Hatzinikolas, G; Page, A J; Dorstyn, L; Kumar, S

    2016-01-01

    Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2−/−) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2−/− mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18–22 months) male Casp2−/− mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2−/− mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2−/− mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2−/− mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner. PMID:27551503

  7. 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.

  8. Effect of a deacyl gymnemic acid on glucose homeostasis & metabolic parameters in a rat model of metabolic syndrome

    PubMed Central

    Bhansali, Shobhit; Shafiq, Nusrat; Pandhi, Promila; Singh, Amrit Pal; Singh, Inderjeet; Singh, Pawan Kumar; Sharma, Sadhna; Malhotra, Samir

    2013-01-01

    Background & objectives: Metabolic syndrome (MS) comprises several cardio-metabolic risk factors, which include obesity, hypertension, hyperglycaemia, hypertriglyceridaemia and decreased HDL cholesterol. Leaf extract of Gymnema sylvestre has been shown to possess glucose lowering activity in animal models. This study was carried out to evaluate the efficacy of deacyl gymnemic acid (DAGA), active constituent of G. sylvestre, in a rat model of MS. Methods: Six groups consisting of six wistar rats in each, were studied. Group I received the normal diet, while the remaining five groups received high fructose diet (HFD) for 20 days to induce MS. HFD was continued in these five groups for the next 20 days along with group II received vehicle solution, group III received pioglitazone and groups IV- VI received DAGA in variable doses. Systolic blood pressure (SBP) was measured using tail-cuff method. Oral glucose tolerance test (OGTT) was done at baseline and at days 20 and 40. Blood samples were collected for glucose, insulin and lipid profile. Results: Administration of HFD for 20 days resulted in weight gain (>10%), increase in SBP, fasting plasma glucose (FPG) and triglycerides fulfilling the criteria for MS. Administration of DAGA (200 mg/kg) reduced SBP and significantly improved the FPG and HOMA-IR (homeostatis model assessment-insulin resistance) with modest improvement in lipid profile without decrease in body weight similar to pioglitazone. Interpretation & conclusions: Our findings show that DAGA decreases SBP and improves parameters of glucose-insulin homeostasis in a rat model of MS induced by HFD. Further studies are required to elucidate the mechanism of action. PMID:23852298

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

    PubMed Central

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

    2015-01-01

    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. PMID:26015432

  10. Mice Deficient in GEM GTPase Show Abnormal Glucose Homeostasis Due to Defects in Beta-Cell Calcium Handling

    PubMed Central

    Gunton, Jenny E.; Sisavanh, Mary; Stokes, Rebecca A.; Satin, Jon; Satin, Leslie S.; Zhang, Min; Liu, Sue M.; Cai, Weikang; Cheng, Kim; Cooney, Gregory J.; Laybutt, D. Ross; So, Trina; Molero, Juan-Carlos; Grey, Shane T.; Andres, Douglas A.

    2012-01-01

    Aims and Hypothesis Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo. Methods Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets. Results Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency. Conclusions These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling. PMID:22761801

  11. Global identification of genes affecting iron-sulfur cluster biogenesis and iron homeostasis.

    PubMed

    Hidese, Ryota; Mihara, Hisaaki; Kurihara, Tatsuo; Esaki, Nobuyoshi

    2014-03-01

    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-(14)C]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-(14)C]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.

  12. Metabolomics reveals the protective of Dihydromyricetin on glucose homeostasis by enhancing insulin sensitivity

    PubMed Central

    Le, Liang; Jiang, Baoping; Wan, Wenting; Zhai, Wei; Xu, Lijia; Hu, Keping; Xiao, Peigen

    2016-01-01

    Dihydromyricetin (DMY), an important flavanone found in Ampelopsis grossedentata, possesses antioxidative properties that ameliorate skeletal muscle insulin sensitivity and exert a hepatoprotective effect. However, little is known about the effects of DMY in the context of high-fat diet (HFD)-induced hepatic insulin resistance. Male Sprague-Dawley(SD) rats were fed a HFD(60% fat) supplemented with DMY for 8 weeks. The administration of DMY to the rats with HFD-induced insulin resistance reduces hyperglycemia, plasma levels of insulin, and steatosis in the liver. Furthermore, DMY treatment modulated 24 metabolic pathways, including glucose metabolism, the TCA cycle. DMY significantly enhanced glucose uptake and improved the translocation of glucose transporter 1. The specificity of DMY promoted the phosphorylation of AMP-activated protein kinase (AMPK). In addition, the exposure of HepG2 cells to high glucose concentrations impaired the insulin-stimulated phosphorylation of Akt2 Ser474 and insulin receptor substrate-1 (IRS-1) Ser612, increased GSK-3β phosphorylation, and upregulated G6Pase and PEPCK expression. Collectively, DMY improved glucose-related metabolism while reducing lipid levels in the HFD-fed rats. These data suggest that DMY might be a useful drug for use in type 2 diabetes insulin resistance therapy and for the treatment of hepatic steatosis. PMID:27796348

  13. Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance.

    PubMed

    Luria, Ayala; Bettaieb, Ahmed; Xi, Yannan; Shieh, Guang-Jong; Liu, Hsin-Chen; Inoue, Hiromi; Tsai, Hsing-Ju; Imig, John D; Haj, Fawaz G; Hammock, Bruce D

    2011-05-31

    Visceral obesity has been defined as an important element of the metabolic syndrome and contributes to the development of insulin resistance and cardiovascular disease. Increasing endogenous levels of epoxyeicosatrienoic acids (EETs) are known for their analgesic, antihypertensive, and antiinflammatory effects. The availability of EETs is limited primarily by the soluble epoxide hydrolase (sEH, EPHX2), which metabolizes EETs to their less active diols. In this study, we tested the hypothesis that EETs are involved in glucose regulation and in retarding the development of insulin resistance. To address the role of EETs in regulating glucose homeostasis and insulin signaling, we used mice with targeted gene deletion of sEH (Ephx2-null mice) and a subsequent study with a selective sEH inhibitor. When wild-type mice are fed a high fat diet, insulin resistance develops. However, knockout or inhibition of sEH activity resulted in a significant decrease in plasma glucose. These findings are characterized by enhancement of tyrosyl phosphorylation of the insulin receptor, insulin receptor substrate 1, and their downstream cascade. In addition, pancreatic islets were larger when sEH was disrupted. This effect was associated with an increase in vasculature. These observations were supported by pharmacological inhibition of sEH. These data suggest that an increase in EETs due to sEH-gene knockout leads to an increase in the size of islets and improved insulin signaling and sensitivity.

  14. Polyunsaturated Fatty Acids Stimulate De novo Lipogenesis and Improve Glucose Homeostasis during Refeeding with High Fat Diet

    PubMed Central

    Crescenzo, Raffaella; Mazzoli, Arianna; Cancelliere, Rosa; Bianco, Francesca; Giacco, Antonia; Liverini, Giovanna; Dulloo, Abdul G.; Iossa, Susanna

    2017-01-01

    Aims: The recovery of body weight after a period of caloric restriction is accompanied by an enhanced efficiency of fat deposition and hyperinsulinemia—which are exacerbated by isocaloric refeeding on a high fat diet rich in saturated and monounsaturated fatty acids (SFA-MUFA), and poor in polyunsaturated fatty acids (PUFA), and associated with a blunting of de novo lipogenesis in adipose tissue and liver. As high fat diets rich in PUFA have been shown to limit the excess fat deposition and improve glucose homeostasis, we investigated here the extent to which de novo lipogenesis in liver and adipose tissues (white and brown), as well as hepatic oxidative stress, are influenced by refeeding on diets rich in PUFA. Design: In rats calorically restricted for 14 days and refed for 14 days on isocaloric amounts of a high fat diet rich in lard (i.e., high SFA-MUFA) or in safflower and linseed oils (rich in PUFA), we investigated energy balance, body composition, glycemic profile, and the regulation of fatty acid synthase (rate-limiting enzyme of de novo lipogenesis) in liver, white and brown adipose tissue. We also evaluated oxidative stress in liver and skeletal muscle and markers of hepatic inflammation. Results: Rats refed the PUFA diet gained less lipids and more proteins compared to rats refed SFA-MUFA diet and showed lower amount of visceral and epididymal white adipose tissue, but increased depots of interscapular brown adipose tissue, with higher expression of the uncoupling protein 1. A significant increase in non-protein respiratory quotient and carbohydrate utilization was found in rats refed PUFA diet. Rats refed PUFA diet showed improved glucose homeostasis, as well as lower triglycerides and cholesterol levels. Fatty acid synthase activity was significantly higher in liver, white and brown adipose tissue, while lipid peroxidation and the degree of inflammation in the liver were significantly lower, in rats refed PUFA diet. Conclusions: When considering the

  15. Heparanase Overexpression Reduces Hepcidin Expression, Affects Iron Homeostasis and Alters the Response to Inflammation

    PubMed Central

    Asperti, Michela; Stuemler, Tanja; Poli, Maura; Gryzik, Magdalena; Lifshitz, Lena; Meyron-Holtz, Esther G.; Vlodavsky, Israel

    2016-01-01

    Hepcidin is the key regulator of systemic iron availability that acts by controlling the degradation of the iron exporter ferroportin. It is expressed mainly in the liver and regulated by iron, inflammation, erythropoiesis and hypoxia. The various agents that control its expression act mainly via the BMP6/SMAD signaling pathway. Among them are exogenous heparins, which are strong hepcidin repressors with a mechanism of action not fully understood but that may involve the competition with the structurally similar endogenous Heparan Sulfates (HS). To verify this hypothesis, we analyzed how the overexpression of heparanase, the HS degrading enzyme, modified hepcidin expression and iron homeostasis in hepatic cell lines and in transgenic mice. The results showed that transient and stable overexpression of heparanase in HepG2 cells caused a reduction of hepcidin expression and of SMAD5 phosphorylation. Interestingly, the clones showed also altered level of TfR1 and ferritin, indices of a modified iron homeostasis. The heparanase transgenic mice showed a low level of liver hepcidin, an increase of serum and liver iron with a decrease in spleen iron content. The hepcidin expression remained surprisingly low even after treatment with the inflammatory LPS. The finding that modification of HS structure mediated by heparanase overexpression affects hepcidin expression and iron homeostasis supports the hypothesis that HS participate in the mechanisms controlling hepcidin expression. PMID:27711215

  16. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  18. A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism

    PubMed Central

    Amoasii, Leonela; Holland, William; Sanchez-Ortiz, Efrain; Baskin, Kedryn K.; Pearson, Mackenzie; Burgess, Shawn C.; Nelson, Benjamin R.; Bassel-Duby, Rhonda; Olson, Eric N.

    2016-01-01

    The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit MED13 in mice, we discovered a gene regulatory mechanism by which skeletal muscle modulates the response of the liver to a high-fat diet. Skeletal muscle-specific deletion of MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. The consequent insulin-sensitizing effect within skeletal muscle lowered systemic glucose and insulin levels independently of weight gain and adiposity and prevented hepatic lipid accumulation. MED13 suppressed the expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. These findings reveal a fundamental molecular mechanism for the governance of glucose metabolism and the control of hepatic lipid accumulation by skeletal muscle. Intriguingly, MED13 exerts opposing metabolic actions in skeletal muscle and the heart, highlighting the customized, tissue-specific functions of the Mediator complex. PMID:26883362

  19. Regulatory role of mucosal maltase-glucoamylase in starch digestion and glucose homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  20. A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism.

    PubMed

    Amoasii, Leonela; Holland, William; Sanchez-Ortiz, Efrain; Baskin, Kedryn K; Pearson, Mackenzie; Burgess, Shawn C; Nelson, Benjamin R; Bassel-Duby, Rhonda; Olson, Eric N

    2016-02-15

    The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit MED13 in mice, we discovered a gene regulatory mechanism by which skeletal muscle modulates the response of the liver to a high-fat diet. Skeletal muscle-specific deletion of MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. The consequent insulin-sensitizing effect within skeletal muscle lowered systemic glucose and insulin levels independently of weight gain and adiposity and prevented hepatic lipid accumulation. MED13 suppressed the expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. These findings reveal a fundamental molecular mechanism for the governance of glucose metabolism and the control of hepatic lipid accumulation by skeletal muscle. Intriguingly, MED13 exerts opposing metabolic actions in skeletal muscle and the heart, highlighting the customized, tissue-specific functions of the Mediator complex.

  1. Exercise training is an effective alternative to estrogen supplementation for improving glucose homeostasis in ovariectomized rats

    PubMed Central

    MacDonald, Tara L; Ritchie, Kerry L; Davies, Sarah; Hamilton, Melissa J; Cervone, Daniel T; Dyck, David J

    2015-01-01

    The irreversible loss of estrogen (specifically 17-β-estradiol; E2) compromises whole-body glucose tolerance in women. Hormone replacement therapy (HRT) is frequently prescribed to treat estrogen deficiency, but has several deleterious side effects. Exercise has been proposed as an HRT substitute, however, their relative abilities to treat glucose intolerance are unknown. Thirty ovariectomized (OVX) and 20 SHAM (control) rats underwent glucose tolerance tests (GTT) 10 weeks post surgery. Area under the curve (AUC) for OVX rats was 60% greater than SHAM controls (P = 0.0005). Rats were then randomly assigned to the following treatment groups: SHAM sedentary (sed) or exercise (ex; 60 min, 5×/weeks), OVX sed, ex, or E2 (28 μg/kg bw/day) for 4 weeks. OVX ex rats experienced a ∼45% improvement in AUC relative to OVX sed rats, whereas OVX E2 underwent a partial reduction (17%; P = 0.08). Maximal insulin-stimulated glucose uptake in soleus and EDL was not impaired in OVX rats, or augmented with exercise or E2. Akt phosphorylation did not differ in soleus, EDL, or liver of any group. However, OVX ex and OVX E2 experienced greater increases in p-Akt Ser473 in VAT and SQ tissues compared with SHAM and OVX sed groups. Mitochondrial markers CS, COXIV, and core1 were increased in soleus posttraining in OVX ex rats. The content of COXIV was reduced by 52% and 61% in SQ of OVX sed and E2 rats, compared to SHAM controls, but fully restored in OVX ex rats. In summary, exercise restores glucose tolerance in OVX rats more effectively than E2. This is not reflected by alterations in muscle maximal insulin response, but increased insulin signaling in adipose depots may underlie whole-body improvements. PMID:26603453

  2. Effect of somatostatin on nonesterified fatty acid levels modifies glucose homeostasis during fasting

    SciTech Connect

    Hendrick, G.K.; Frizzell, R.T.; Cherrington, A.D. )

    1987-10-01

    In the 7-days fasted conscious dog, unlike the postabsorptive conscious dog, somatostatin infusion results in decreased levels of nonesterified fatty acids (NEFA) and increased glucose utilization (R{sub d}) even when insulin and glucagon levels are held constant. The aim of this study was to determine whether NEFA replacement in such animals would prevent the increase in R{sub d}. In each of three protocols there was an 80-min tracer equilibration period, a 40-min basal period, and a 3-h test period. During the test period in the first protocol saline was infused, in the second protocol somatostatin was infused along with intraportal replacement amounts of insulin and glucagon (hormone replacement), while in the third protocol somatostatin plus the pancreatic hormones were infused with concurrent heparin plus Intralipid infusion. Glucose turnover was assessed using (3-{sup 3}H)glucose. The peripheral levels of insulin, glucagon, and glucose were similar and constant in all three protocols; however, during somatostatin infusion, exogenous glucose infusion was necessary to maintain euglycemia. The NEFA level was constant during saline infusion and decreased in the hormone replacement protocol. In the hormone replacement plus NEFA protocol, the NEFA level did not change during the first 90-min period and then increased during the second 90-min period. After a prolonged fast in the dog, (1) somatostatin directly or indirectly inhibits adipose tissue NEFA release and causes a decrease in the plasma NEFA level, and (2) this decrease in the NEFA level causes an increase in R{sub d}.

  3. Ethnic Differences in Glucose Homeostasis Markers between the Kyushu-Okinawa Population Study and the Framingham Offspring Study

    PubMed Central

    Ikezaki, Hiroaki; Ai, Masumi; Schaefer, Ernst J.; Otokozawa, Seiko; Asztalos, Bela F.; Nakajima, Katsuyuki; Zhou, Yanhua; Liu, Ching-Ti; Jacques, Paul F.; Cupples, L. Adrienne; Furusyo, Norihiro

    2016-01-01

    We compared markers of glucose homeostasis and their association with diabetes and impaired fasting glucose (IFG) in Fukuoka, Japanese subjects (n = 1108) and age-, gender- and menopausal status-matched participants in the Framingham Offspring Study (n = 1096). The markers examined included fasting glucose, insulin, adiponectin, and glycated albumin, as well as body mass index (BMI), use of medications, and history of diabetes. The results showed that IFG prevalence in Japanese men (15.9%) and women (7.4%) were 50% less than those observed in Framingham men (34.5%) and women (21.4%) (P < 0.001). However, the diabetes prevalence in Japanese men at 13.3% was twice as high (P < 0.01) as the rate in Framingham men at 6.5%, while these rates were similar in women. Median insulin levels in Japanese men (4.6 μIU/mL) and women (4.3 μIU/mL) were about 50% lower (P < 0.001) than those in Framingham men (10.8 μIU/mL) and women (9.9 μIU/mL), as were insulin resistance values (P < 0.001). These population differences were also observed after subjects were stratified by glucose levels. In conclusion, our data indicate that there is significantly less IFG, lower insulin levels, and insulin resistance, but higher diabetes prevalence in Fukuoka men than in Framingham men, indicating that insulin deficiency may be an important cause of diabetes in Japan. PMID:27830830

  4. 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.

  5. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system.

    PubMed

    Arriola Apelo, Sebastian I; Neuman, Joshua C; Baar, Emma L; Syed, Faizan A; Cummings, Nicole E; Brar, Harpreet K; Pumper, Cassidy P; Kimple, Michelle E; Lamming, Dudley W

    2016-02-01

    Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA-approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.

  6. Impact of sleep and sleep loss on glucose homeostasis and appetite regulation

    PubMed Central

    Knutson, Kristen L

    2007-01-01

    Synopsis Over the past 30 years there has been an increase in the prevalence of obesity and diabetes, both of which can have serious consequences for longevity and quality of life. Sleep durations may have also decreased over this time period. This chapter reviews laboratory and epidemiologic evidence for an association between sleep loss and impairments in glucose metabolism and appetite regulation, which could increase the risk of diabetes or weight gain. PMID:18516218

  7. Maintenance of Glucose Homeostasis through Acetylation of the Metabolic Transcriptional Coactivator PGC1-alpha

    DTIC Science & Technology

    2009-02-01

    highlight that PGC-1α chemical acetylation is directly controlled by two enzymes: GCN5 and SIRT1 ; this strengths the possibility to use small...acetylated through GCN5 acetyltransferase activity, however under low nutrient conditions Sirt1 deacetylase will keep PGC-1α de-acetylated in an active form...acetylated by GCN5, we decided to use R13 because it did not respond to low glucose levels or Sirt1 activators. We think that the additional acetylation

  8. Glucose homeostasis with infinite gain: further lessons from the Daisyworld parable?

    PubMed

    Koeslag, J H; Saunders, P T; Wessels, J A

    1997-08-01

    A major unresolved physiological problem is how the rate of hepatic glucose production is increased to match the increased rate of glucose utilization during exercise without a change in arterial blood glucose level. A homeostat with such capabilities is said to have infinite gain. Daisyworld is an imaginary planet orbiting a variable star. The only life is black and white daisies. Black daisies retain heat, slightly warming the planet; white daisies cool it. When the two types of daisies grow best at slightly different temperatures, variations in solar luminosity (over a wide range) cause the ratio of white:black daisies to vary in a manner that keeps the planetary temperature constant. This model therefore achieves infinite gain by having two opposing but interdependent controllers. Here we suggest that the pancreatic islet alpha- and beta-cells might act as black and white daisies. For the analogy to apply, glucagon and insulin must not only have opposing effects on the blood sugar concentration, but the secretion of the one has, at some quantum level, to be at the expense of the other. Electrical coupling between heterocellular groups of alpha- and beta-cells within the pancreatic islets suggests that this might indeed be the case. alpha-Cell activity must, furthermore, promote secretory activity in other alpha-cells; similarly with beta-cells. This is probably mediated via pancreastatin and gamma-amino butyric acid (GABA) which are paracrinically co-secreted with glucagon and insulin, respectively. alpha-Cell activity spreads (at the expense of beta-cell activity) when the blood glucose level is below set point, while beta-cell activity progressively replaces alpha-cell activity above set point. At set point changes in the ratio of alpha:beta-cell activity are inhibited.

  9. Hepatitis B virus X protein regulates hepatic glucose homeostasis via activation of inducible nitric oxide synthase.

    PubMed

    Shin, Hye-Jun; Park, Young-Ho; Kim, Sun-Uk; Moon, Hyung-Bae; Park, Do Sim; Han, Ying-Hao; Lee, Chul-Ho; Lee, Dong-Seok; Song, In-Sung; Lee, Dae Ho; Kim, Minhye; Kim, Nam-Soon; Kim, Dae-Ghon; Kim, Jin-Man; Kim, Sang-Keun; Kim, Yo Na; Kim, Su Sung; Choi, Cheol Soo; Kim, Young-Bum; Yu, Dae-Yeul

    2011-08-26

    Dysregulation of liver functions leads to insulin resistance causing type 2 diabetes mellitus and is often found in chronic liver diseases. However, the mechanisms of hepatic dysfunction leading to hepatic metabolic disorder are still poorly understood in chronic liver diseases. The current work investigated the role of hepatitis B virus X protein (HBx) in regulating glucose metabolism. We studied HBx-overexpressing (HBxTg) mice and HBxTg mice lacking inducible nitric oxide synthase (iNOS). Here we show that gene expressions of the key gluconeogenic enzymes were significantly increased in HepG2 cells expressing HBx (HepG2-HBx) and in non-tumor liver tissues of hepatitis B virus patients with high levels of HBx expression. In the liver of HBxTg mice, the expressions of gluconeogenic genes were also elevated, leading to hyperglycemia by increasing hepatic glucose production. However, this effect was insufficient to cause systemic insulin resistance. Importantly, the actions of HBx on hepatic glucose metabolism are thought to be mediated via iNOS signaling, as evidenced by the fact that deficiency of iNOS restored HBx-induced hyperglycemia by suppressing the gene expression of gluconeogenic enzymes. Treatment of HepG2-HBx cells with nitric oxide (NO) caused a significant increase in the expression of gluconeogenic genes, but JNK1 inhibition was completely normalized. Furthermore, hyperactivation of JNK1 in the liver of HBxTg mice was also suppressed in the absence of iNOS, indicating the critical role for JNK in the mutual regulation of HBx- and iNOS-mediated glucose metabolism. These findings establish a novel mechanism of HBx-driven hepatic metabolic disorder that is modulated by iNOS-mediated activation of JNK.

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

    PubMed Central

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

    2010-01-01

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

  11. Expression of an insulin-responsive glucose transporter (GLUT4) minigene in transgenic mice: effect of exercise and role in glucose homeostasis.

    PubMed

    Ikemoto, S; Thompson, K S; Itakura, H; Lane, M D; Ezaki, O

    1995-01-31

    The effects of a GLUT4 mini-transgene (containing 7 kb of 5' flanking and 1 kb of 3' flanking sequence and all exons and introns of the GLUT4 gene as well as a small foreign DNA tag) and of exercise training on expression of GLUT4 and glycemic control in mice were investigated. Transgenic mice harboring the minigene expressed < or = 2-fold the normal level of GLUT4 mRNA and protein in skeletal (gastrocnemius) muscle and adipose tissue. This modest tissue-specific increase in GLUT4 expression led to an unexpectedly rapid blood glucose clearance rate following oral glucose administration. In nontransgenic animals exercise caused a 1.5-fold increase in expression of GLUT4 mRNA and protein as well as a significant improvement of glycemic control. In transgenic animals harboring the minigene exercise increased expression of GLUT4 mRNA and protein derived from the minigene and endogenous gene and led to a further improvement of glycemic control. These findings indicate that the cis-regulatory element(s) controlling exercise-induced expression of the GLUT4 gene is located within the nucleotide sequence encompassed by the GLUT4 minigene. The fact that glycemic control is markedly improved by a relatively low level of expression of GLUT4 caused by the transfected minigene and is further enhanced by exercise in transgenic animals demonstrates that GLUT4 plays a pivotal role in glucose homeostasis in vivo. Of the effectors--i.e., cAMP, insulin, and arachidonic acid--known to down-regulate expression of GLUT4 by 3T3-L1 adipocytes in culture, only the decline in circulating arachidonate level in vivo correlated with up-regulation of GLUT4 caused by exercise.

  12. 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.

  13. Disruption of glucose homeostasis and induction of insulin resistance by elevated free fatty acids in human L02 hepatocytes.

    PubMed

    Wan, X-D; Yang, W-B; Xia, Y-Z; Wang, J-F; Lu, T; Wang, X-M

    2009-05-01

    Free fatty acids (FFA) have been implicated as an important causative link between obesity, insulin resistance, and Type 2 diabetes. However, the underlying mechanisms especially for FFA-mediated hepatic insulin resistance are not fully elucidated. Here, we investigated the impaired sites in insulin signaling pathways and mechanisms of insulin resistance induced by elevated FFA in L02 hepatocytes. L02 cells were cultured in Dulbecco's modified eagle medium containing various concentrations of palmitic acid (PA) for 24 h followed by 10(-7) mol/l insulin stimulation. In some experiments, cells were pre-treated with enzymatic inhibitor Wortmannin (10(-6) mol/l). Glucose levels in medium, cytosolic glycogen contents, and phosphoenolpyruvate carboxykinase (PEPCK) activity were measured. Protein level of insulin receptor substrate (IRS)-2 and phosphorylated Akt were detected by Western blot analysis. L02 cells treated with high levels of PA exhibited increased glucose levels, whereas hepatic glycogen contents were decreased in a dose-dependent manner as compared to the control cells. There was a significant attenuation of IRS- 2 protein expression in the cells cultured with PA, and Wortmannin intervention exhibited different IRS-2 protein level with or without PA treatment. In accordance with the reduced IRS-2 level, the insulin-stimulated phosphorylation of Akt was diminished in the PA-treated cells. Basal PEPCK activity and insulin- regulated PEPCK activity were overstimulated in the cells incubated with PA. These data indicate high levels of FFA can disrupt glucose homeostasis, inflict some defects in insulin signaling, and induce insulin resistance in L02 cells.

  14. Prenatal androgen treatment alters body composition and glucose homeostasis in male rats.

    PubMed

    Lazic, Milos; Aird, Fraser; Levine, Jon E; Dunaif, Andrea

    2011-03-01

    Prenatal androgen produces many reproductive and metabolic features of polycystic ovary syndrome in female rodents, sheep, and monkeys. We investigated the impact of such prenatal treatment in adult male rats. Pregnant dams received free testosterone (T; aromatizable androgen), dihydrotestosterone (D; nonaromatizable androgen), or vehicle control (C) on embryonic days 16-19. Neither of the prenatal androgen treatments resulted in increased body weight from weaning to age 65 days in males. However, at 65 days, there were significant increases in retroperitoneal (P < 0.001 T versus C; P < 0.05 D versus C), epididymal (P < 0.05 T versus C), and subcutaneous (P < 0.01 T versus C) fat pads in prenatally androgenized males. While both androgens altered body composition, subcutaneous fat depots increased only in T males. T males had elevated glucose levels (P < 0.01) compared to C males. There were no differences among the three groups in insulin sensitivity, circulating lipid and leptin levels, or hepatic triglyceride content. Real-time PCR analysis of insulin signaling pathway genes in retroperitoneal fat revealed a transcriptional downregulation of adipsin and insulin receptor substrate-1 in T and α-1D adrenergic receptor in D compared to C males. We conclude that transient exposure to androgen excess in utero increases body fat in adult male rats. Only T males exhibit increased circulating glucose levels and subcutaneous fat suggesting that these changes may be mediated by aromatization of androgen to estrogen rather than by direct androgenic actions.

  15. Ras-GRF1 signaling is required for normal β-cell development and glucose homeostasis

    PubMed Central

    Font de Mora, Jaime; Esteban, Luis Miguel; Burks, Deborah J.; Núñez, Alejandro; Garcés, Carmen; García-Barrado, María José; Iglesias-Osma, María Carmen; Moratinos, Julio; Ward, Jerrold M.; Santos, Eugenio

    2003-01-01

    Development of diabetes generally reflects an inadequate mass of insulin-producing β-cells. β-cell proliferation and differentiation are regulated by a variety of growth factors and hormones, including insulin-like growth factor I (IGF-I). GRF1 is a Ras-guanine nucleotide exchange factor known previously for its restricted expression in brain and its role in learning and memory. Here we demonstrate that GRF1 is also expressed in pancreatic islets. Interest ingly, our GRF1-deficient mice exhibit reduced body weight, hypoinsulinemia and glucose intolerance owing to a reduction of β-cells. Whereas insulin resistance is not detected in peripheral tissues, GRF1 knockout mice are leaner due to increased lipid catabolism. The reduction in circulating insulin does not reflect defective glucose sensing or insulin production but results from impaired β-cell proliferation and reduced neogenesis. IGF-I treatment of isolated islets from GRF1 knockouts fails to activate critical downstream signals such as Akt and Erk. The observed phenotype is similar to manifestations of preclinical type 2 diabetes. Thus, our observations demonstrate a novel and specific role for Ras-GRF1 pathways in the development and maintenance of normal β-cell number and function. PMID:12805218

  16. Role of Myotonic Dystrophy Protein Kinase (DMPK) in Glucose Homeostasis and Muscle Insulin Action

    PubMed Central

    Marti, Luc; Liesa, Marc; Camps, Marta; Ciaraldi, Theodore P.; Kondo, Richard; Reddy, Sita; Dillmann, Wolfgang H.; Palacin, Manuel; Zorzano, Antonio; Ruiz-Lozano, Pilar; Gomis, Ramon; Kaliman, Perla

    2007-01-01

    Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes. PMID:17987120

  17. 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

  18. 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.

  19. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis.

    PubMed

    Gao, Yan; Sartori, Daniel J; Li, Changhong; Yu, Qian-Chun; Kushner, Jake A; Simon, M Celeste; Diehl, J Alan

    2012-12-01

    Germ line PERK mutations are associated with diabetes mellitus and growth retardation in both rodents and humans. In contrast, late embryonic excision of PERK permits islet development and was found to prevent onset of diabetes, suggesting that PERK may be dispensable in the adult pancreas. To definitively establish the functional role of PERK in adult pancreata, we generated mice harboring a conditional PERK allele in which excision is regulated by tamoxifen administration. Deletion of PERK in either young adult or mature adult mice resulted in hyperglycemia associated with loss of islet and β cell architecture. PERK excision triggered intracellular accumulation of proinsulin and Glut2, massive endoplasmic reticulum (ER) expansion, and compensatory activation of the remaining unfolded-protein response (UPR) signaling pathways specifically in pancreatic tissue. Although PERK excision increased β cell death, this was not a result of decreased proliferation as previously reported. In contrast, a significant and specific increase in β cell proliferation was observed, a result reflecting increased cyclin D1 accumulation. This work demonstrates that contrary to expectations, PERK is required for secretory homeostasis and β cell survival in adult mice.

  20. Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-hour standardized meals: time course of glucose homeostasis in leptin replacement treatment.

    PubMed

    Andreev, V P; Paz-Filho, G; Wong, M-L; Licinio, J

    2009-02-01

    Minimally invasive methodology, mathematical model, and software for analysis of glucose homeostasis by deconvolution of insulin secretion, hepatic extraction, post-hepatic delivery, and sensitivity from 24-hour standardized meals test have been developed and illustrated by the study of glucose homeostasis of a genetically based leptin-deficient patient before and after leptin replacement treatment. The only genetically leptin-deficient adult man identified in the world was treated for 24 months with recombinant methionyl human leptin. Blood was collected every 7 minutes for 24 hours, with standardized meals consumed during the 4 visits: at baseline, one-week, 18-months, and 24-months after initiation of the treatment. Concentrations of insulin, C-peptide, and plasma glucose were measured. Insulin secretion was obtained by deconvolution of C-peptide data. Hepatic insulin extraction was determined based on our modifications of the insulin kinetics model . Insulin sensitivity for each of the four meals was calculated by using the minimal glucose model approach. Hepatic extraction of insulin was the first element of glucose homeostasis to respond to leptin replacement treatment and increased 2-fold after one week of treatment. Insulin secretion and delivery rates decreased more than 2-fold and insulin sensitivity increased 10-fold after 24 months of treatment. Computer programs for analysis of 24-hour insulin secretion, extraction, delivery, and action are available upon request.

  1. Short-term consumption of sucralose, a nonnutritive sweetener, is similar to water with regard to select markers of hunger signaling and short-term glucose homeostasis in women.

    PubMed

    Brown, Andrew W; Bohan Brown, Michelle M; Onken, Kristine L; Beitz, Donald C

    2011-12-01

    Nonnutritive sweeteners have been used to lower the energy density of foods with the intention of affecting weight loss or weight maintenance. However, some epidemiological and animal evidence indicates an association between weight gain or insulin resistance and artificial sweetener consumption. In the present study, we hypothesized that the nonnutritive sweetener sucralose, a trichlorinated sucrose molecule, would elicit responses similar to water but different from sucrose and sucrose combined with sucralose on subjective and hormonal indications of hunger and short-term glucose homeostasis. Eight female volunteers (body mass index, 22.16 ± 1.71 kg/m(2); age, 21.75 ± 2.25 years) consumed sucrose and/or sucralose in water in a factorial design. Blood samples were taken at fasting and 30 and 60 minutes after treatment followed by a standardized breakfast across treatments, and blood samples were taken 30, 60, 90, and 120 minutes after breakfast. Plasma was analyzed for glucose, insulin, glucagon, triacylglycerols (TAG), and acylated ghrelin. Perceptions of hunger and other subjective measurements were assessed before each blood sample. No differences were detected in subjective responses, circulating triacylglycerol, or glucagon concentrations among treatments over time. Significant differences were observed in insulin, glucose, and acylated ghrelin concentrations over time only between sucrose-containing treatments and non-sucrose-containing treatments regardless of sucralose consumption. Therefore, sucralose may be a relatively inert nonnutritive sweetener with regard to hunger signaling and short-term glucose homeostasis.

  2. Role of FGF19 induced FGFR4 activation in the regulation of glucose homeostasis.

    PubMed

    Wu, Xinle; Li, Yang

    2009-12-09

    FGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors. Because they contain intra-molecular disulfide bonds and show reduced affinity toward heparan sulfate located in the extracellular space, it is thought that, in contrast to other FGFs, they function as endocrine hormones. FGF23 and its co-receptor alphaKlotho are involved in the control of aging, but it is not known if the same holds true for FGF19, which can also signal through alphaKlotho. However, considerable evidence supports a role for FGF19 in controlling various aspects of metabolism. We have recently fully characterized FGF19/FGFR/co-factor interactions and signaling, and in the current manuscript discuss the contribution of the FGF19/FGFR4 axis to bile acid and glucose regulation.

  3. Identification of Yeast Genes Involved in K+ Homeostasis: Loss of Membrane Traffic Genes Affects K+ Uptake

    PubMed Central

    Fell, Gillian L.; Munson, Amanda M.; Croston, Merriah A.; Rosenwald, Anne G.

    2011-01-01

    Using the homozygous diploid Saccharomyces deletion collection, we searched for strains with defects in K+ homeostasis. We identified 156 (of 4653 total) strains unable to grow in the presence of hygromycin B, a phenotype previously shown to be indicative of ion defects. The most abundant group was that with deletions of genes known to encode membrane traffic regulators. Nearly 80% of these membrane traffic defective strains showed defects in uptake of the K+ homolog, 86Rb+. Since Trk1, a plasma membrane protein localized to lipid microdomains, is the major K+ influx transporter, we examined the subcellular localization and Triton-X 100 insolubility of Trk1 in 29 of the traffic mutants. However, few of these showed defects in the steady state levels of Trk1, the localization of Trk1 to the plasma membrane, or the localization of Trk1 to lipid microdomains, and most defects were mild compared to wild-type. Three inositol kinase mutants were also identified, and in contrast, loss of these genes negatively affected Trk1 protein levels. In summary, this work reveals a nexus between K+ homeostasis and membrane traffic, which does not involve traffic of the major influx transporter, Trk1. PMID:22384317

  4. Identification of yeast genes involved in k homeostasis: loss of membrane traffic genes affects k uptake.

    PubMed

    Fell, Gillian L; Munson, Amanda M; Croston, Merriah A; Rosenwald, Anne G

    2011-06-01

    Using the homozygous diploid Saccharomyces deletion collection, we searched for strains with defects in K(+) homeostasis. We identified 156 (of 4653 total) strains unable to grow in the presence of hygromycin B, a phenotype previously shown to be indicative of ion defects. The most abundant group was that with deletions of genes known to encode membrane traffic regulators. Nearly 80% of these membrane traffic defective strains showed defects in uptake of the K(+) homolog, (86)Rb(+). Since Trk1, a plasma membrane protein localized to lipid microdomains, is the major K(+) influx transporter, we examined the subcellular localization and Triton-X 100 insolubility of Trk1 in 29 of the traffic mutants. However, few of these showed defects in the steady state levels of Trk1, the localization of Trk1 to the plasma membrane, or the localization of Trk1 to lipid microdomains, and most defects were mild compared to wild-type. Three inositol kinase mutants were also identified, and in contrast, loss of these genes negatively affected Trk1 protein levels. In summary, this work reveals a nexus between K(+) homeostasis and membrane traffic, which does not involve traffic of the major influx transporter, Trk1.

  5. 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

  6. Calbindin-D9k Ablation Disrupt Glucose/Pancreatic Insulin Homeostasis

    PubMed Central

    Ahn, Changhwan; Lee, Dongoh; Lee, Jae-Hwan; Yang, Hyun; An, Beum-Soo

    2016-01-01

    It has been proposed that cellular Ca2+ signals activate hormone secretion. In pancreatic β cells, which produce insulin, Ca2+ signals have been known to contribute to insulin secretion. Prior to this study, we confirmed that insulin-secreting β cells express CaBP-9k, and assumed that CaBP-9k play a role in β cell insulin synthesis or secretion. Using CaBP-9k knock out (KO) mice, we demonstrated that ablation of CaBP-9k causes reducing insulin secretion and increasing serum glucose. To compare the role of CaBP-9k with pathophysiological conditions, we exposed wild-type and CaBP-9k KO mice to hypoxic conditions for 10 days. Hypoxia induced endoplasmic reticulum (ER) stress, increasing both insulin signaling and insulin resistance. By exposing hypoxia, CaBP-9k KO mice showed an increased level of ER stress marker protein relative to wild type mice. Without hypoxic conditions, CaBP-9K ablation regulates calcium channels and causes ER stress in a CaBP-9K specific manner. Ablation of CaBP-9k also showed decreased levels of sulfonylurea receptor1 (SUR1) and inward-rectifier potassium ion channel 6.2 (Kir6.2), which are insulin secretion marker genes. Overall, the results of the present study demonstrated that CaBP-9k regulates synthesis of insulin and is part of the insulin-secreting calcium signaling. PMID:27736926

  7. Plasma 25-Hydroxyvitamin D Is Related to Protein Signaling Involved in Glucose Homeostasis in a Tissue-Specific Manner

    PubMed Central

    Parker, Lewan; Levinger, Itamar; Mousa, Aya; Howlett, Kirsten; de Courten, Barbora

    2016-01-01

    Vitamin D has been suggested to play a role in glucose metabolism. However, previous findings are contradictory and mechanistic pathways remain unclear. We examined the relationship between plasma 25-hydroxyvitamin D (25(OH)D), insulin sensitivity, and insulin signaling in skeletal muscle and adipose tissue. Seventeen healthy adults (Body mass index: 26 ± 4; Age: 30 ± 12 years) underwent a hyperinsulinemic-euglycemic clamp, and resting skeletal muscle and adipose tissue biopsies. In this cohort, the plasma 25(OH)D concentration was not associated with insulin sensitivity (r = 0.19, p = 0.56). However, higher plasma 25(OH)D concentrations correlated with lower phosphorylation of glycogen synthase kinase-3 (GSK-3) αSer21 and βSer9 in skeletal muscle (r = −0.66, p = 0.015 and r = −0.53, p = 0.06, respectively) and higher GSK-3 αSer21 and βSer9 phosphorylation in adipose tissue (r = 0.82, p < 0.01 and r = 0.62, p = 0.042, respectively). Furthermore, higher plasma 25(OH)D concentrations were associated with greater phosphorylation of both protein kinase-B (AktSer473) (r = 0.78, p < 0.001) and insulin receptor substrate-1 (IRS-1Ser312) (r = 0.71, p = 0.01) in adipose tissue. No associations were found between plasma 25(OH)D concentration and IRS-1Tyr612 phosphorylation in skeletal muscle and adipose tissue. The divergent findings between muscle and adipose tissue with regard to the association between 25(OH)D and insulin signaling proteins may suggest a tissue-specific interaction with varying effects on glucose homeostasis. Further research is required to elucidate the physiological relevance of 25(OH)D in each tissue. PMID:27754361

  8. 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.

  9. Effect of Maternal Factors and Fetomaternal Glucose Homeostasis on Birth Weight and Postnatal Growth

    PubMed Central

    Özbörü Aşkan, Öykü; Bozaykut, Abdülkadir; Sezer, Rabia Gönül; Güran, Tülay; Bereket, Abdullah

    2015-01-01

    Objective: It is important to identify the possible risk factors for the occurrence of large for gestational age (LGA) in newborns and to determine the effect of birth weight and metabolic parameters on subsequent growth. We aimed to determine the effects of maternal weight, weight gain during pregnancy, maternal hemoglobin A1c (HbA1c), C-peptide and insulin as well as cord C-peptide and insulin levels on birth weight and postnatal growth during the first two years of life. Methods: Healthy, non-diabetic mothers and term singleton newborns were included in this prospective case-control cohort study. Fasting maternal glucose, HbA1c, C-peptide and insulin levels were studied. Cord blood was analyzed for C-peptide and insulin. At birth, newborns were divided into two groups according to birth size: LGA and appropriate for GA (AGA). Infants were followed at six-month intervals for two years and their length and weight were recorded. Results: Forty LGA and 43 AGA infants were included in the study. Birth weight standard deviation score (SDS) was positively correlated with maternal body mass index (BMI) before delivery (r=0.2, p=0.04) and with weight gain during pregnancy (r=0.2, p=0.04). In multivariate analyses, the strongest association with macrosomia was a maternal C-peptide level >3.85 ng/mL (OR=20). Although the LGA group showed decreased growth by the 6-month of follow-up, the differences between the LGA and AGA groups in weight and length SDS persisted over the 2 years of follow-up. Conclusion: The control of maternal BMI and prevention of overt weight gain during pregnancy may prevent excessive birth weight. The effect of the in utero metabolic environment on the weight and length SDS of infants born LGA persists until at least two years of age. PMID:26831549

  10. Gallic Acid Ameliorated Impaired Glucose and Lipid Homeostasis in High Fat Diet-Induced NAFLD Mice

    PubMed Central

    Chao, Jung; Huo, Teh-Ia; Cheng, Hao-Yuan; Tsai, Jen-Chieh; Liao, Jiunn-Wang; Lee, Meng-Shiou; Qin, Xue-Mei; Hsieh, Ming-Tsuen; Pao, Li-Heng; Peng, Wen-Huang

    2014-01-01

    Gallic acid (GA), a naturally abundant plant phenolic compound in vegetables and fruits, has been shown to have potent anti-oxidative and anti-obesity activity. However, the effects of GA on nonalcoholic fatty liver disease (NAFLD) are poorly understood. In this study, we investigated the beneficial effects of GA administration on nutritional hepatosteatosis model by a more “holistic view” approach, namely 1H NMR-based metabolomics, in order to prove efficacy and to obtain information that might lead to a better understanding of the mode of action of GA. Male C57BL/6 mice were placed for 16 weeks on either a normal chow diet, a high fat diet (HFD, 60%), or a high fat diet supplemented with GA (50 and 100 mg/kg/day, orally). Liver histopathology and serum biochemical examinations indicated that the daily administration of GA protects against hepatic steatosis, obesity, hypercholesterolemia, and insulin resistance among the HFD-induced NAFLD mice. In addition, partial least squares discriminant analysis scores plots demonstrated that the cluster of HFD fed mice is clearly separated from the normal group mice plots, indicating that the metabolic characteristics of these two groups are distinctively different. Specifically, the GA-treated mice are located closer to the normal group of mice, indicating that the HFD-induced disturbances to the metabolic profile were partially reversed by GA treatment. Our results show that the hepatoprotective effect of GA occurs in part through a reversing of the HFD caused disturbances to a range of metabolic pathways, including lipid metabolism, glucose metabolism (glycolysis and gluconeogenesis), amino acids metabolism, choline metabolism and gut-microbiota-associated metabolism. Taken together, this study suggested that a 1H NMR-based metabolomics approach is a useful platform for natural product functional evaluation. The selected metabolites are potentially useful as preventive action biomarkers and could also be used to help

  11. The Effects of Transdermally Delivered Oleanolic Acid on Malaria Parasites and Blood Glucose Homeostasis in P. berghei-Infected Male Sprague-Dawley Rats

    PubMed Central

    Mabandla, Musa V.

    2016-01-01

    The present study investigated the effects of transdermally delivered oleanolic acid (OA) monotherapy and in combination with chloroquine (CHQ) on malaria parasites and glucose homeostasis of P. berghei-infected male Sprague-Dawley rats. Oral glucose test (OGT) responses to OA-pectin patch and CHQ-OA combination matrix patch were monitored in non-infected and infected rats. To evaluate the short-term effects of treatment, percentage parasitaemia, blood glucose, glycogen and plasma insulin were monitored in separate groups of animals treated with either OA-patch monotherapy or CHQ-OA combination pectin patch over a 21-days period. Animals treated with drug-free pectin and CHQ acted as untreated and treated positive controls, respectively. Infected control rats exhibited significantly increased parasitaemia which was accompanied by hypoglycaemia. Both OA monotherapy and CHQ-OA combination therapy reduced and cleared the malaria parasites within a period of 4 and 3 days, respectively. Compared to respective controls groups, OGT responses of animals treated with OA monotherapy or CHQ-OA combination therapy exhibited lower blood glucose levels at all time points. A once-off transdermal application of OA-patch or CHQ-OA combination patch significantly improved blood glucose concentrations inducing any changes in insulin concentration. Transdermal OA used as a monotherapy or in combination with CHQ is able to clear and reduce the malaria parasites within a shorter period of time without eliciting any adverse effects on glucose homeostasis of P. berghei-infected rats. PMID:27907019

  12. Altered glucose and lipid homeostasis in liver and adipose tissue pre-dispose inducible NOS knockout mice to insulin resistance

    PubMed Central

    Kanuri, Babu Nageswararao; Kanshana, Jitendra S.; Rebello, Sanjay C.; Pathak, Priya; Gupta, Anand P.; Gayen, Jiaur R.; Jagavelu, Kumaravelu; Dikshit, Madhu

    2017-01-01

    On the basis of diet induced obesity and KO mice models, nitric oxide is implied to play an important role in the initiation of dyslipidemia induced insulin resistance. However, outcomes using iNOS KO mice have so far remained inconclusive. The present study aimed to assess IR in iNOS KO mice after 5 weeks of LFD feeding by monitoring body composition, energy homeostasis, insulin sensitivity/signaling, nitrite content and gene expressions changes in the tissues. We found that body weight and fat content in KO mice were significantly higher while the respiratory exchange ratio (RER), volume of carbon dioxide (VCO2), and heat production were lower as compared to WT mice. Furthermore, altered systemic glucose tolerance, tissue insulin signaling, hepatic gluconeogenesis, augmented hepatic lipids, adiposity, as well as gene expression regulating lipid synthesis, catabolism and efflux were evident in iNOS KO mice. Significant reduction in eNOS and nNOS gene expression, hepatic and adipose tissue nitrite content, circulatory nitrite was also observed. Oxygen consumption rate of mitochondrial respiration has remained unaltered in KO mice as measured using extracellular flux analyzer. Our findings establish a link between the NO status with systemic and tissue specific IR in iNOS KO mice at 5 weeks. PMID:28106120

  13. Maintenance of Glucose Homeostasis Through Acetylation of the Metabolic Transcriptional Coactivator PGC1-alpha

    DTIC Science & Technology

    2011-02-01

    transcriptional components have been identified that control gene expression of these enzymes including transcription factors CREB, FOXO1, HNF4a, GR and C /EBPs...estingly, the repression of PGC-1a by GCN5 also affected the mitochondrial genes cytochrome c and b-ATP-synthase (Figure 5A). These results indicate that...zymatic activity may provide a target for therapeutic drugs to435 A R T I C L EFigure 6. Inhibition of gluconeogenic gene expres- sion by GCN5

  14. 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.

  15. 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

  16. 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

  17. Life stage dependent responses to the lampricide, 3-trifluoromethyl-4-nitrophenol (TFM), provide insight into glucose homeostasis and metabolism in the sea lamprey (Petromyzon marinus).

    PubMed

    Henry, Matthew; Birceanu, Oana; Clifford, Alexander M; McClelland, Grant B; Wang, Yuxiang S; Wilkie, Michael P

    2015-03-01

    The primary method of sea lamprey (Petromyzon marinus) control in the Great Lakes is the treatment of streams and rivers with the pesticide 3-trifluoromethyl-4-nitrophenol (TFM), which targets larval sea lamprey. However, less is known about the effects of TFM on other stages of the sea lamprey's complex life cycle. The goal of this study was to determine how TFM affected internal energy stores, metabolites, and ion balance in larval, juvenile (parasitic) and adult sea lamprey. The larvae were more tolerant to TFM than the adults, with a 2-fold higher 12h TFM LC50 and a 1.5-fold higher LC99.9. Acute (3h) exposure of the larvae, parasites and adults to their respective 12h TFM LC99.9 led to marked reductions in glycogen and phosphocreatine in the adult brain, with lesser or no effect in the larvae and parasites. Increased lactate in the brain, at less than the expected stoichiometry, suggested that it was exported to the blood. Kidney glycogen declined after TFM exposure, suggesting that this organ plays an important role in glucose homeostasis. TFM-induced disturbances to ion balance were minimal. In conclusion, TFM perturbs energy metabolism in all major stages of the sea lamprey life cycle in a similar fashion, but the adults appear to be the most sensitive. Thus, the adult stage could be a viable and effective target for TFM treatment, particularly when used in combination with other existing and emerging strategies of sea lamprey control.

  18. Bright morning light advances the human circadian system without affecting NREM sleep homeostasis.

    PubMed

    Dijk, D J; Beersma, D G; Daan, S; Lewy, A J

    1989-01-01

    Eight male subjects were exposed to either bright light or dim light between 0600 and 0900 h for 3 consecutive days each. Relative to the dim light condition, the bright light treatment advanced the evening rise in plasma melatonin and the time of sleep termination (sleep onset was held constant) for an average approximately 1 h. The magnitude of the advance of the plasma melatonin rise was dependent on its phase in dim light. The reduction in sleep duration was at the expense of rapid-eye-movement (REM) sleep. Spectral analysis of the sleep electroencephalogram (EEG) revealed that the advance of the circadian pacemaker did not affect EEG power densities between 0.25 and 15.0 Hz during either non-REM or REM sleep. The data show that shifting the human circadian pacemaker by 1 h does not affect non-REM sleep homeostasis. These findings are in accordance with the predictions of the two-process model of sleep regulation.

  19. Glucose positions affect the phloem mobility of glucose-fipronil conjugates.

    PubMed

    Lei, Zhiwei; Wang, Jie; Mao, Genlin; Wen, Yingjie; Tian, Yuxin; Wu, Huawei; Li, Yufeng; Xu, Hanhong

    2014-07-02

    In our previous work, a glucose-fipronil (GTF) conjugate at the C-1 position was synthesized via click chemistry and a glucose moiety converted a non-phloem-mobile insecticide fipronil into a moderately phloem-mobile insecticide. In the present paper, fipronil was introduced into the C-2, C-3, C-4, and C-6 positions of glucose via click chemistry to obtain four new conjugates and to evaluate the effects of the different glucose isomers on phloem mobility. The phloem mobility of the four new synthetic conjugates and GTF was tested using the Ricinus seedling system. The results confirmed that conjugation of glucose at different positions has a significant influence on the phloem mobility of GTF conjugates.

  20. Sustained sleep fragmentation affects brain temperature, food intake and glucose tolerance in mice.

    PubMed

    Baud, Maxime O; Magistretti, Pierre J; Petit, Jean-Marie

    2013-02-01

    Sleep fragmentation is present in numerous sleep pathologies and constitutes a major feature of patients with obstructive sleep apnea. A prevalence of metabolic syndrome, diabetes and obesity has been shown to be associated to obstructive sleep apnea. While sleep fragmentation has been shown to impact sleep homeostasis, its specific effects on metabolic variables are only beginning to emerge. In this context, it is important to develop realistic animal models that would account for chronic metabolic effects of sleep fragmentation. We developed a 14-day model of instrumental sleep fragmentation in mice, and show an impact on both brain-specific and general metabolism. We first report that sleep fragmentation increases food intake without affecting body weight. This imbalance was accompanied by the inability to adequately decrease brain temperature during fragmented sleep. In addition, we report that sleep-fragmented mice develop glucose intolerance. We also observe that sleep fragmentation slightly increases the circadian peak level of glucocorticoids, a factor that may be involved in the observed metabolic effects. Our results confirm that poor-quality sleep with sustained sleep fragmentation has similar effects on general metabolism as actual sleep loss. Altogether, these results strongly suggest that sleep fragmentation is an aggravating factor for the development of metabolic dysfunctions that may be relevant for sleep disorders such as obstructive sleep apnea.

  1. Animal models of bariatric/metabolic surgery shed light on the mechanisms of weight control and glucose homeostasis: view from the chair.

    PubMed

    Sharkey, K A

    2011-09-01

    Bariatric/metabolic surgeries are remarkably effective in reducing weight over a sustained period of time, and they also have significant beneficial effects on glucose homeostasis. Interestingly, the metabolic benefits of these surgeries frequently occur before significant weight loss. Given these findings, it is perhaps not surprising that obesity researchers are asking, how does bariatric/metabolic surgery work? Establishing these mechanisms can offer new insights into the physiology of energy balance and the control of metabolism. In the second half of the 13(th) International Symposium of the Merck Frosst/CIHR Research Chair in Obesity, four papers that address the mechanisms of bariatric/metabolic surgery were presented. The papers that follow this viewpoint all make use of animal models to reveal the neurohumoral mechanisms underlying weight loss and improved glucose homeostasis after experimental bariatric surgery. The rodent models of the commonly used clinical procedures have shown that energy intake is increased, food reward is altered and that the proximal gut is important in the control of energy balance and glucose homeostasis. Taken together, these models shed light on the mechanisms of bariatric/metabolic surgery and offer new insights that, in the future, may lead to less invasive therapies.

  2. Disturbed intestinal nitrogen homeostasis in a mouse model of high-fat diet-induced obesity and glucose intolerance.

    PubMed

    Do, Thi Thu Huong; Hindlet, Patrick; Waligora-Dupriet, Anne-Judith; Kapel, Nathalie; Neveux, Nathalie; Mignon, Virginie; Deloménie, Claudine; Farinotti, Robert; Fève, Bruno; Buyse, Marion

    2014-03-01

    The oligopeptide transporter peptide cotransporter-1 Slc15a1 (PEPT1) plays a major role in the regulation of nitrogen supply, since it is responsible for 70% of the dietary nitrogen absorption. Previous studies demonstrated that PEPT1 expression and function in jejunum are reduced in diabetes and obesity, suggesting a nitrogen malabsorption from the diet. Surprisingly, we reported here a decrease in gut nitrogen excretion in high-fat diet (HFD)-fed mice and further investigated the mechanisms that could explain this apparent contradiction. Upon HFD, mice exhibited an increased concentration of free amino acids (AAs) in the portal vein (60%) along with a selective increase in the expression of two AA transporters (Slc6a20a, Slc36a1), pointing to a specific and adaptive absorption of some AAs. A delayed transit time (+40%) and an increased intestinal permeability (+80%) also contribute to the increase in nitrogen absorption. Besides, HFD mice exhibited a 2.2-fold decrease in fecal DNA resulting from a reduction in nitrogen catabolism from cell desquamation and/or in the intestinal microbiota. Indeed, major quantitative (2.5-fold reduction) and qualitative alterations of intestinal microbiota were observed in feces of HFD mice. Collectively, our results strongly suggest that both increased AA transporters, intestinal permeability and transit time, and changes in gut microbiota are involved in the increased circulating AA levels. Modifications in nitrogen homeostasis provide a new insight in HFD-induced obesity and glucose intolerance; however, whether these modifications are beneficial or detrimental for the HFD-associated metabolic complications remains an open issue.

  3. Temporal evaluation of body composition, glucose homeostasis and lipid profile of male rats programmed by maternal protein restriction during lactation.

    PubMed

    Fagundes, A T S; Moura, E G; Passos, M C F; Santos-Silva, A P; de Oliveira, E; Trevenzoli, I H; Casimiro-Lopes, G; Nogueira-Neto, J F; Lisboa, P C

    2009-12-01

    Neonatal protein restriction causes lower body weight and hormonal dysfunctions in 6 months-old rats. In this model, we studied the body composition, glycogen content, serum lipid, serum protein, and hormones related to glucose homeostasis in the offspring during development. At birth, lactating rats were divided into: control dams - fed a normal diet (23% protein) and protein restricted dams - fed a diet with 8% protein. After weaning, pups received normal diet. Offspring were killed at 21, 90, and 180 days-old. Protein restricted offspring showed lower visceral fat (90th day: 14%; 180th day: 19%) and lower total fat (90th day: 16%; 180th day: 14%) that explain their lower body weight. They presented lower glycemia (180th day: 17%), lower insulinemia (21st day: 63%; 180th day: 24%), higher adiponectinemia (21st day: 169%), higher liver glycogen (21st day: 104%), and higher muscle glycogen (180th day: 106%), suggesting a higher insulin sensitivity. The higher serum corticosterone (50%), higher adrenal total catecholamines content (98%) as well as in vitro catecholamine secretion (26%) of adult protein restricted offspring, suggest a programming stimulatory effect upon adrenal gland. They also presented several biochemical changes, such as lower serum total protein, albumin and globulin (21st day: 17, 21, 12%, respectively), higher LDL-c (21st day: 69%), lower triglycerides (21st day: 42%; 90th day: 39%), and lower total cholesterol (180th day: 16%). Thus, maternal protein restriction during lactation induces an energy-protein malnutrition, characterized by an impairment of the pup's protein anabolism and, after weaning, the lower adiposity suggests lower lipogenesis and higher lipolytic activity, probably caused by catecholamine and glucocorticoid action.

  4. Unexpected severe consequences of Pikfyve deletion by aP2- or Aq-promoter-driven Cre expression for glucose homeostasis and mammary gland development.

    PubMed

    Ikonomov, Ognian C; Sbrissa, Diego; Delvecchio, Khortnal; Rillema, James A; Shisheva, Assia

    2016-06-01

    Systemic deficiency of PIKfyve, the evolutionarily conserved phosphoinositide kinase synthesizing cellular PtdIns5P and PtdIns(3,5)P2 and implicated in insulin signaling, causes early embryonic death in mice. In contrast, mice with muscle-specific Pikfyve disruption have normal lifespan but exhibit early-age whole-body glucose intolerance and muscle insulin resistance, thus establishing the key role of muscle PIKfyve in glucose homeostasis. Fat and muscle tissues control postprandial glucose clearance through different mechanisms, raising questions as to whether adipose Pikfyve disruption will also trigger whole-body metabolic abnormalities, and if so, what the mechanism might be. To clarify these issues, here we have characterized two new mouse models with adipose tissue disruption of Pikfyve through Cre recombinase expression driven by adipose-specific aP2- or adiponectin (Aq) promoters. Whereas both mouse lines were ostensibly normal until adulthood, their glucose homeostasis and systemic insulin sensitivity were severely dysregulated. These abnormalities stemmed in part from accelerated fat-cell lipolysis and elevated serum FFA Intriguingly, aP2-Cre-PIKfyve(fl/fl) but not Aq-Cre-PIKfyve(fl/fl) females had severely impaired pregnancy-induced mammary gland differentiation and lactogenesis, consistent with aP2-Cre-mediated Pikfyve excision in nonadipogenic tissues underlying this defect. Intriguingly, whereas mammary glands from postpartum control and Aq-Cre-PIKfyve(fl/fl) mice or ex vivo mammary gland explants showed profound upregulation of PIKfyve protein levels subsequent to prolactin receptor activation, such increases were not apparent in aP2-Cre-PIKfyve(fl/fl) females. Collectively, our data identify for the first time that adipose tissue Pikfyve plays a key role in the mechanisms regulating glucose homeostasis and that the PIKfyve pathway is critical in mammary epithelial differentiation during pregnancy and lactogenesis downstream of prolactin receptor

  5. Pancreatic alpha-cell dysfunction contributes to the disruption of glucose homeostasis and compensatory insulin hypersecretion in glucocorticoid-treated rats.

    PubMed

    Rafacho, Alex; Gonçalves-Neto, Luiz M; Santos-Silva, Junia C; Alonso-Magdalena, Paloma; Merino, Beatriz; Taboga, Sebastião R; Carneiro, Everardo M; Boschero, Antonio C; Nadal, Angel; Quesada, Ivan

    2014-01-01

    Glucocorticoid (GC)-based therapies can cause insulin resistance (IR), glucose intolerance, hyperglycemia and, occasionally, overt diabetes. Understanding the mechanisms behind these metabolic disorders could improve the management of glucose homeostasis in patients undergoing GC treatment. For this purpose, adult rats were treated with a daily injection of dexamethasone (1 mg/kg b.w., i.p.) (DEX) or saline as a control for 5 consecutive days. The DEX rats developed IR, augmented glycemia, hyperinsulinemia and hyperglucagonemia. Treatment of the DEX rats with a glucagon receptor antagonist normalized their blood glucose level. The characteristic inhibitory effect of glucose on glucagon secretion was impaired in the islets of the DEX rats, while no direct effects were found on α-cells in islets that were incubated with DEX in vitro. A higher proportion of docked secretory granules was found in the DEX α-cells as well as a trend towards increased α-cell mass. Additionally, insulin secretion in the presence of glucagon was augmented in the islets of the DEX rats, which was most likely due to their higher glucagon receptor content. We also found that the enzyme 11βHSD-1, which participates in GC metabolism, contributed to the insulin hypersecretion in the DEX rats under basal glucose conditions. Altogether, we showed that GC treatment induces hyperglucagonemia, which contributes to an imbalance in glucose homeostasis and compensatory β-cell hypersecretion. This hyperglucagonemia may result from altered α-cell function and, likely, α-cell mass. Additionally, blockage of the glucagon receptor seems to be effective in preventing the elevation in blood glucose levels induced by GC administration.

  6. Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism.

    PubMed

    Welty, Nathan E; Staley, Christopher; Ghilardi, Nico; Sadowsky, Michael J; Igyártó, Botond Z; Kaplan, Daniel H

    2013-09-23

    Dendritic cells (DCs) in the intestinal lamina propria (LP) are composed of two CD103(+) subsets that differ in CD11b expression. We report here that Langerin is expressed by human LP DCs and that transgenic human langerin drives expression in CD103(+)CD11b(+) LP DCs in mice. This subset was ablated in huLangerin-DTA mice, resulting in reduced LP Th17 cells without affecting Th1 or T reg cells. Notably, cognate DC-T cell interactions were not required for Th17 development, as this response was intact in huLangerin-Cre I-Aβ(fl/fl) mice. In contrast, responses to intestinal infection or flagellin administration were unaffected by the absence of CD103(+)CD11b(+) DCs. huLangerin-DTA x BatF3(-/-) mice lacked both CD103(+) LP DC subsets, resulting in defective gut homing and fewer LP T reg cells. Despite these defects in LP DCs and resident T cells, we did not observe alterations of intestinal microbial communities. Thus, CD103(+) LP DC subsets control T cell homeostasis through both nonredundant and overlapping mechanisms.

  7. The Dehydratase ADT3 Affects ROS Homeostasis and Cotyledon Development1[OPEN

    PubMed Central

    Para, Alessia; Muhammad, DurreShahwar; Naldrett, Michael J.; Warpeha, Katherine M.

    2016-01-01

    During the transition from seed to seedling, emerging embryos strategically balance available resources between building up defenses against environmental threats and initiating the developmental program that promotes the switch to autotrophy. We present evidence of a critical role for the phenylalanine (Phe) biosynthetic activity of AROGENATE DEHYDRATASE3 (ADT3) in coordinating reactive oxygen species (ROS) homeostasis and cotyledon development in etiolated Arabidopsis (Arabidopsis thaliana) seedlings. We show that ADT3 is expressed in the cotyledon and shoot apical meristem, mainly in the cytosol, and that the epidermis of adt3 cotyledons contains higher levels of ROS. Genome-wide proteomics of the adt3 mutant revealed a general down-regulation of plastidic proteins and ROS-scavenging enzymes, corroborating the hypothesis that the ADT3 supply of Phe is required to control ROS concentration and distribution to protect cellular components. In addition, loss of ADT3 disrupts cotyledon epidermal patterning by affecting the number and expansion of pavement cells and stomata cell fate specification; we also observed severe alterations in mesophyll cells, which lack oil bodies and normal plastids. Interestingly, up-regulation of the pathway leading to cuticle production is accompanied by an abnormal cuticle structure and/or deposition in the adt3 mutant. Such impairment results in an increase in cell permeability and provides a link to understand the cell defects in the adt3 cotyledon epidermis. We suggest an additional role of Phe in supplying nutrients to the young seedling. PMID:27540109

  8. Metabolic regulation of fatty acid esterification and effects of conjugated linoleic acid on glucose homeostasis in pig hepatocytes.

    PubMed

    Conde-Aguilera, J A; Lachica, M; Nieto, R; Fernández-Fígares, I

    2012-02-01

    Conjugated linoleic acids (CLAs) are geometric and positional isomers of linoleic acid (LA) that promote growth, alter glucose metabolism and decrease body fat in growing animals, although the mechanisms are poorly understood. A study was conducted to elucidate the effects of CLA on glucose metabolism, triglyceride (TG) synthesis and IGF-1 synthesis in primary culture of porcine hepatocytes. In addition, hormonal regulation of TG and IGF-1 synthesis was addressed. Hepatocytes were isolated from piglets (n = 5, 16.0 ± 1.98 kg average body weight) by collagenase perfusion and seeded into collagen-coated T-25 flasks. Hepatocytes were cultured in William's E containing dexamethasone (10-8 and 10-7 M), insulin (10 and 100 ng/ml), glucagon (0 and 100 ng/ml) and CLA (1 : 1 mixture of cis-9, trans-11 and trans-10, cis-12 CLA, 0.05 and 0.10 mM) or LA (0.05 and 0.10 mM). Addition of CLA decreased gluconeogenesis (P < 0.05), whereas glycogen synthesis and degradation, TG synthesis and IGF-1 synthesis were not affected compared with LA. Increased concentration of fatty acids in the media decreased IGF-1 production (P < 0.001) and glycogen synthesis (P < 0.01), and increased gluconeogenesis (P < 0.001) and TG synthesis (P < 0.001). IGF-1 synthesis increased (P < 0.001) and TG synthesis decreased (P < 0.001) as dexamethasone concentration in the media rose. High insulin/glucagon increased TG synthesis. These results indicate that TG synthesis in porcine hepatocytes is hormonally regulated so that dexamethasone decreases and insulin/glucagon increases it. In addition, CLA decreases hepatic glucose production through decreased gluconeogenesis.

  9. SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome.

    PubMed

    Perez, Yonatan; Shorer, Zamir; Liani-Leibson, Keren; Chabosseau, Pauline; Kadir, Rotem; Volodarsky, Michael; Halperin, Daniel; Barber-Zucker, Shiran; Shalev, Hanna; Schreiber, Ruth; Gradstein, Libe; Gurevich, Evgenia; Zarivach, Raz; Rutter, Guy A; Landau, Daniel; Birk, Ohad S

    2017-02-09

    A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9's highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through

  10. Multiple mechanisms of GW-9508, a selective G protein-coupled receptor 40 agonist, in the regulation of glucose homeostasis and insulin sensitivity.

    PubMed

    Ou, Horng-Yih; Wu, Hung-Tsung; Hung, Hao-Chang; Yang, Yi-Ching; Wu, Jin-Shang; Chang, Chih-Jen

    2013-03-15

    Activation of G protein-coupled receptor 40 (GPR40) by agonists increases insulin release in isolated islets, whereas it is inconclusive whether GPR40 antagonists decrease blood glucose and increase insulin sensitivity. Although some clinical trials indicated that administration of a GPR40 agonist shows benefits in the regulation of blood glucose homeostasis, the pharmacological mechanisms of this receptor in the improvement of glycemic control remain unclear. Therefore, we used a selective GPR40 agonist, GW-9508, to clarify the role of GPR40 in the regulation of blood glucose. Bolus intraperitoneal injection of GW-9508 in mice showed a slight decrease in blood glucose, with an increase in plasma insulin levels under glucose stimuli. However, long-term treatment with low doses of GW-9508 in high-fat diet-induced (HFD) diabetic mice decreased blood glucose with decreased plasma insulin significantly and improved glucose intolerance and insulin resistance. Using small interfering ribonucleic acid to delete GPR40 in HepG2 cells, we demonstrated that GW-9508 reversed palmitate-induced insulin signaling impairment through a GPR40-dependent pathway. We also found that GW-9508 activates the Akt/GSK-3β pathway to increase glycogen levels in HepG2 cells. Furthermore, administration of GW-9508 decreased the hepatic expression of fetuin-A in HFD mice significantly and regulated high-glucose- or palmitate-induced fetuin-A expression to increase insulin sensitivity through a GPR40/PLC/PKC pathway in HepG2 cells. Taken together, GW-9508 exerts a partial agonist effect to regulate blood glucose through multiple mechanisms. Investigation of chemicals that act on GPR40 might be a new strategy for the treatment of diabetes.

  11. 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.

  12. Accumulation of distinct prelamin A variants in human diploid fibroblasts differentially affects cell homeostasis

    SciTech Connect

    Candelario, Jose; Borrego, Stacey; Reddy, Sita; Comai, Lucio

    2011-02-01

    levels of the basal transcription factor TATA-binding protein (TBP) and global transcription, and severely limited cell growth. Expression of a prelamin A variant that cannot be farnesylated, although did not appreciably influence cell growth, resulted in the formation of lamin A nucleoplasmic foci and caused, in a minor subpopulation of cells, changes in nuclear morphology that were accompanied by reduced levels of TBP and transcription. In contrast, expression of mature lamin A did not affect any of these parameters. These data demonstrate that accumulation of any partially processed prelamin A protein alters cellular homeostasis to some degree, even though the most dramatic effects are caused by variants with a permanently farnesylated carboxyl-terminal tail.

  13. Pancreas-Specific Deletion of Prox1 Affects Development and Disrupts Homeostasis of the Exocrine Pancreas

    PubMed Central

    WESTMORELAND, JOBY J.; KILIC, GAMZE; SARTAIN, CAROLINE; SIRMA, SEMA; BLAIN, JENNIFER; REHG, JEROLD; HARVEY, NATASHA; SOSA–PINEDA, BEATRIZ

    2012-01-01

    BACKGROUND & AIMS The exocrine portion of the pancreas functions in digestion and preserves pancreatic homeostasis. Learning how this tissue forms during embryogenesis could improve our understanding of human pancreatic diseases. Expression of the homeo-box gene Prox1 in the exocrine pancreas changes throughout development in mice. We investigated the role of Prox1 in development of the exocrine pancreas in mice. METHODS Mice with pancreas-specific deletion of Prox1 (Prox1ΔPanc) were generated and their pancreatic tissues were analyzed using immunohistochemistry, transmission electron microscopy, histologic techniques, quantitative real-time polymerase chain reaction, immunoblotting, and morphometric analysis. RESULTS Loss of Prox1 from the pancreas led to multiple exocrine alterations, most notably premature acinar cell differentiation, increased ductal cell proliferation, altered duct morphogenesis, and imbalanced expression of claudin proteins. Prox1ΔPanc mice also had some minor alterations in islet cells, but beta-cell development was not affected. The exocrine congenital defects of Prox1ΔPanc pancreata appeared to initiate a gradual process of deterioration that resulted in extensive loss of acinar cells, lipomatosis, and damage to ductal tissue in adult mice. CONCLUSIONS Pancreas-specific deletion of Prox1 causes premature differentiation of acinar cells and poor elongation of epithelial branches; these defects indicate that Prox1 controls the expansion of tip progenitors in the early developing pancreas. During later stages of embryogenesis, Prox1 appears to regulate duct cell proliferation and morphogenesis. These findings identify Prox1 as an important regulator of pancreatic exocrine development. PMID:22178591

  14. Seasonal Temperature Changes Do Not Affect Cardiac Glucose Metabolism

    PubMed Central

    Schildt, Jukka; Loimaala, Antti; Hippeläinen, Eero; Nikkinen, Päivi; Ahonen, Aapo

    2015-01-01

    FDG-PET/CT is widely used to diagnose cardiac inflammation such as cardiac sarcoidosis. Physiological myocardial FDG uptake often creates a problem when assessing the possible pathological glucose metabolism of the heart. Several factors, such as fasting, blood glucose, and hormone levels, influence normal myocardial glucose metabolism. The effect of outdoor temperature on myocardial FDG uptake has not been reported before. We retrospectively reviewed 29 cancer patients who underwent PET scans in warm summer months and again in cold winter months. We obtained myocardial, liver, and mediastinal standardized uptake values (SUVs) as well as quantitative cardiac heterogeneity and the myocardial FDG uptake pattern. We also compared age and body mass index to other variables. The mean myocardial FDG uptake showed no significant difference between summer and winter months. Average outdoor temperature did not correlate significantly with myocardial SUVmax in either summer or winter. The heterogeneity of myocardial FDG uptake did not differ significantly between seasons. Outdoor temperature seems to have no significant effect on myocardial FDG uptake or heterogeneity. Therefore, warming the patients prior to attending cardiac PET studies in order to reduce physiological myocardial FDG uptake seems to be unnecessary. PMID:26858844

  15. Sweet future: fluctuating blood glucose levels affect future discounting.

    PubMed

    Wang, X T; Dvorak, Robert D

    2010-02-01

    This study explored metabolic mechanisms of future (delay) discounting, a choice phenomenon where people value present goods over future goods. Using fluctuating blood glucose as an index of body-energy budget, optimal discounting should regulate choice among rewards as a function of temporal caloric requirement. We identified this novel link between blood glucose levels measured in the lab and future-discounting rates of participants, who made choices between a "smaller and sooner" reward and a "larger but later" option, with possible actual monetary rewards. A group of participants who drank a soft drink that contained sugar showed a reduced rate of future discounting afterward, when we controlled for sex, age, body mass index, and the taste of the drink. In contrast, a group of participants who drank a soft drink that contained artificial sweetener showed an increased rate of future discounting. Blood glucose levels not only varied as a result of caloric intake but also regulated the rate of future discounting, according to participants' dynamic body-energy budget.

  16. Acute effect of 3β-hidroxihop-22(29)ene on insulin secretion is mediated by GLP-1, potassium and calcium channels for the glucose homeostasis.

    PubMed

    Castro, Allisson Jhonatan Gomes; Cazarolli, Luisa Helena; de Carvalho, Francieli Kanumfre; da Luz, Gabrielle; Altenhofen, Delsi; dos Santos, Adair Roberto Soares; Pizzolatti, Moacir Geraldo; Silva, Fátima Regina Mena Barreto

    2015-06-01

    The effect of 3β-hidroxihop-22(29)ene (3-BHO) on insulin and glucagon-like peptide 1 (GLP-1) secretion as well as the mechanism of action of the compound in pancreatic islet on glucose homeostasis was investigated. The data from in vivo treatment show that 3-BHO significantly reduces the hyperglycemia by increasing the insulin and GLP-1 secretion, as well as by accumulating hepatic glycogen in hyperglycemic rats. In rat pancreatic β-cell, 3-BHO stimulates the glucose uptake, insulin vesicles translocation to the plasma membrane and thus the insulin secretion through the involvement of potassium channels (ATP- and Ca(2+)-dependent K(+) channels) and calcium channels (L-type voltage-dependent calcium channels (L-VDCC)). Furthermore, this study also provides evidence for a crosstalk between intracellular high calcium concentration, PKA and PKC in the signal transduction of 3-BHO to stimulate insulin secretion. In conclusion, 3-BHO diminishes glycaemia, stimulates GLP-1 secretion and potentiates insulin secretion and increase hepatic glycogen content. Moreover, this triterpene modulates calcium influx characterizing ATP-K(+), Ca(2+)-K(+) and L-VDCC channels-dependent pathways as well as PKA and PKC activity in pancreatic islets underlying the signaling of 3-BHO for the secretory activity and contribution on glucose homeostasis.

  17. Regulation of lipid and glucose homeostasis by mango tree leaf extract is mediated by AMPK and PI3K/AKT signaling pathways.

    PubMed

    Zhang, Yi; Liu, Xuefeng; Han, Lifeng; Gao, Xiumei; Liu, Erwei; Wang, Tao

    2013-12-01

    Ethanolic extract of Mangifera indica (mango) dose-dependently decreased serum glucose and triglyceride in KK-A(y) mice. Our in vitro and in vivo investigations revealed that the effect of mango leave extract (ME) on glucose and lipid homeostasis is mediated, at least in part, through the PI3K/AKT and AMPK signaling pathway. ME up-regulated the expression of PI3K, AKT and GYS genes by 2.0-fold, 3.2-fold, and 2.7-fold, respectively, leading to a decrease in glucose level. On the other hand, ME up-regulated AMPK and altered lipid metabolism. ME also down-regulated ACC (2.8-fold), HSL (1.6-fold), FAS (1.8-fold) and PPAR-γ (4.0-fold). Finally, we determined that active metabolites of benzophenone C-glucosides, Iriflophenone 3-C-β-glucoside and Foliamangiferoside A from ME, may play a dominant role in this integrated regulation of sugar and lipid homeostasis.

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

    PubMed Central

    Berger, Alta; Kablan, Ahmed; Yao, Catherine; Ho, Thuy; Podyma, Brandon

    2016-01-01

    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. PMID:26671183

  19. 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.

  20. 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.

  1. Energized by love: thinking about romantic relationships increases positive affect and blood glucose levels.

    PubMed

    Stanton, Sarah C E; Campbell, Lorne; Loving, Timothy J

    2014-10-01

    We assessed the impact of thinking of a current romantic partner on acute blood glucose responses and positive affect over a short period of time. Participants in romantic relationships were randomly assigned to reflect on their partner, an opposite-sex friend, or their morning routine. Blood glucose levels were assessed prior to reflection, as well as at 10 and 25 min postreflection. Results revealed that individuals in the routine and friend conditions exhibited a decline in glucose over time, whereas individuals in the partner condition did not exhibit this decline (rather, a slight increase) in glucose over time. Reported positive affect following reflection was positively associated with increases in glucose, but only for individuals who reflected on their partner, suggesting this physiological response reflects eustress. These findings add to the literature on eustress in relationships and have implications for relationship processes.

  2. Quinoa extract enriched in 20-hydroxyecdysone affects energy homeostasis and intestinal fat absorption in mice fed a high-fat diet.

    PubMed

    Foucault, Anne-Sophie; Even, Patrick; Lafont, René; Dioh, Waly; Veillet, Stanislas; Tomé, Daniel; Huneau, Jean-François; Hermier, Dominique; Quignard-Boulangé, Annie

    2014-04-10

    In a previous study, we have demonstrated that a supplementation of a high-fat diet with a quinoa extract enriched in 20-hydroxyecdysone (QE) or pure 20-hydroxyecdysone (20E) could prevent the development of obesity. In line with the anti-obesity effect of QE, we used indirect calorimetry to examine the effect of dietary QE and 20E in high-fat fed mice on different components of energy metabolism. Mice were fed a high-fat (HF) diet with or without supplementation by QE or pure 20E for 3 weeks. As compared to mice maintained on a low-fat diet, HF feeding resulted in a marked physiological shift in energy homeostasis, associating a decrease in global energy expenditure (EE) and an increase in lipid utilization as assessed by the lower respiratory quotient (RQ). Supplementation with 20E increased energy expenditure while food intake and activity were not affected. Furthermore QE and 20E promoted a higher rate of glucose oxidation leading to an increased RQ value. In QE and 20E-treated HFD fed mice, there was an increase in fecal lipid excretion without any change in stool amount. Our study indicates that anti-obesity effect of QE can be explained by a global increase in energy expenditure, a shift in glucose metabolism towards oxidation to the detriment of lipogenesis and a decrease in dietary lipid absorption leading to reduced dietary lipid storage in adipose tissue.

  3. Chickens from lines artificially selected for juvenile low and high body weight differ in glucose homeostasis and pancreas physiology.

    PubMed

    Sumners, L H; Zhang, W; Zhao, X; Honaker, C F; Zhang, S; Cline, M A; Siegel, P B; Gilbert, E R

    2014-06-01

    Artificial selection of White Plymouth Rock chickens for juvenile (day 56) body weight resulted in two divergent genetic lines: hypophagic low weight (LWS) chickens and hyperphagic obese high weight (HWS) chickens, with the latter more than 10-fold heavier than the former at selection age. A study was designed to investigate glucose regulation and pancreas physiology at selection age in LWS chickens and HWS chickens. Oral glucose tolerance and insulin sensitivity tests revealed differences in threshold sensitivity to insulin and glucose clearance rate between the lines. Results from real-time PCR showed greater pancreatic mRNA expression of four glucose regulatory genes (preproinsulin, PPI; preproglucagon, PPG; glucose transporter 2, GLUT2; and pancreatic duodenal homeobox 1, Pdx1) in LWS chickens, than HWS chickens. Histological analysis of the pancreas revealed that HWS chickens have larger pancreatic islets, less pancreatic islet mass, and more pancreatic inflammation than LWS chickens, all of which presumably contribute to impaired glucose metabolism.

  4. Hydrodynamic delivery of interleukin 15 gene promotes resistance to high fat diet-induced obesity, fatty liver and improves glucose homeostasis.

    PubMed

    Sun, H; Liu, D

    2015-04-01

    The objective of this study is to examine the effect of hydrodynamic delivery of plasmid containing Il-15 gene on high fat diet-induced obesity and obesity-associated metabolic disorders. We demonstrate that Il-15 gene transfer results in multiple beneficial effects, including blockade of weight gain, alleviation of fatty liver and improvement in glucose homeostasis in mice. These effects are accompanied by suppressed expression of genes involved in lipogenesis and gluconeogenesis including Scd-1, Fas, Pdk4, Pepck and G6p, and enhanced expression of genes responsible for lipolysis and glucose metabolism such as Cpt1-α, Cpt1-β, Acadm, Acadl and Glut-4. Collectively, our results suggest that Il-15 gene transfer is an effective approach in preventing diet-induced obesity and obesity-associated complications.

  5. Dietary Fatty Acids Differentially Associate with Fasting Versus 2-Hour Glucose Homeostasis: Implications for The Management of Subtypes of Prediabetes

    PubMed Central

    Guess, Nicola; Perreault, Leigh; Kerege, Anna; Strauss, Allison; Bergman, Bryan C.

    2016-01-01

    Over-nutrition has fuelled the global epidemic of type 2 diabetes, but the role of individual macronutrients to the diabetogenic process is not well delineated. We aimed to examine the impact of dietary fatty acid intake on fasting and 2-hour plasma glucose concentrations, as well as tissue-specific insulin action governing each. Normoglycemic controls (n = 15), athletes (n = 14), and obese (n = 23), as well as people with prediabetes (n = 10) and type 2 diabetes (n = 11), were queried about their habitual diet using a Food Frequency Questionnaire. All subjects were screened by an oral glucose tolerance test (OGTT) and studied using the hyperinsulinemic/euglycemic clamp with infusion of 6,62H2-glucose. Multiple regression was performed to examine relationships between dietary fat intake and 1) fasting plasma glucose, 2) % suppression of endogenous glucose production, 3) 2-hour post-OGTT plasma glucose, and 4) skeletal muscle insulin sensitivity (glucose rate of disappearance (Rd) and non-oxidative glucose disposal (NOGD)). The %kcal from saturated fat (SFA) was positively associated with fasting (β = 0.303, P = 0.018) and 2-hour plasma glucose (β = 0.415, P<0.001), and negatively related to % suppression of hepatic glucose production (β = -0.245, P = 0.049), clamp Rd (β = -0.256, P = 0.001) and NOGD (β = -0.257, P = 0.001). The %kcal from trans fat was also negatively related to clamp Rd (β = -0.209, P = 0.008) and NOGD (β = -0.210, P = 0.008). In contrast, the %kcal from polyunsaturated fat (PUFA) was negatively associated with 2-hour glucose levels (β = -0.383, P = 0.001), and positively related to Rd (β = 0.253, P = 0.007) and NOGD (β = 0.246, P = 0.008). Dietary advice to prevent diabetes should consider the underlying pathophysiology of the prediabetic state. PMID:26999667

  6. 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

  7. 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.

  8. (+)-Rutamarin as a Dual Inducer of Both GLUT4 Translocation and Expression Efficiently Ameliorates Glucose Homeostasis in Insulin-Resistant Mice

    PubMed Central

    Shen, Hong; Chen, Jing; Li, Chenjing; Chen, Lili; Zheng, Mingyue; Ye, Jiming; Hu, Lihong; Shen, Xu; Jiang, Hualiang

    2012-01-01

    Glucose transporter 4 (GLUT4) is a principal glucose transporter in response to insulin, and impaired translocation or decreased expression of GLUT4 is believed to be one of the major pathological features of type 2 diabetes mellitus (T2DM). Therefore, induction of GLUT4 translocation or/and expression is a promising strategy for anti-T2DM drug discovery. Here we report that the natural product (+)-Rutamarin (Rut) functions as an efficient dual inducer on both insulin-induced GLUT4 translocation and expression. Rut-treated 3T3-L1 adipocytes exhibit efficiently enhanced insulin-induced glucose uptake, while diet-induced obese (DIO) mice based assays further confirm the Rut-induced improvement of glucose homeostasis and insulin sensitivity in vivo. Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B (PTP1B) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin-induced GLUT4 translocation through PI3 kinase-AKT/PKB pathway, while as an agonist of retinoid X receptor α (RXRα), Rut potently increases GLUT4 expression. Furthermore, by using molecular modeling and crystallographic approaches, the possible binding modes of Rut to these two targets have been also determined at atomic levels. All our results have thus highlighted the potential of Rut as both a valuable lead compound for anti-T2DM drug discovery and a promising chemical probe for GLUT4 associated pathways exploration. PMID:22384078

  9. (+)-Rutamarin as a dual inducer of both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice.

    PubMed

    Zhang, Yu; Zhang, Haitao; Yao, Xin-Gang; Shen, Hong; Chen, Jing; Li, Chenjing; Chen, Lili; Zheng, Mingyue; Ye, Jiming; Hu, Lihong; Shen, Xu; Jiang, Hualiang

    2012-01-01

    Glucose transporter 4 (GLUT4) is a principal glucose transporter in response to insulin, and impaired translocation or decreased expression of GLUT4 is believed to be one of the major pathological features of type 2 diabetes mellitus (T2DM). Therefore, induction of GLUT4 translocation or/and expression is a promising strategy for anti-T2DM drug discovery. Here we report that the natural product (+)-Rutamarin (Rut) functions as an efficient dual inducer on both insulin-induced GLUT4 translocation and expression. Rut-treated 3T3-L1 adipocytes exhibit efficiently enhanced insulin-induced glucose uptake, while diet-induced obese (DIO) mice based assays further confirm the Rut-induced improvement of glucose homeostasis and insulin sensitivity in vivo. Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B (PTP1B) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin-induced GLUT4 translocation through PI3 kinase-AKT/PKB pathway, while as an agonist of retinoid X receptor α (RXRα), Rut potently increases GLUT4 expression. Furthermore, by using molecular modeling and crystallographic approaches, the possible binding modes of Rut to these two targets have been also determined at atomic levels. All our results have thus highlighted the potential of Rut as both a valuable lead compound for anti-T2DM drug discovery and a promising chemical probe for GLUT4 associated pathways exploration.

  10. Changes in Plasma Levels of N-Arachidonoyl Ethanolamine and N-Palmitoylethanolamine following Bariatric Surgery in Morbidly Obese Females with Impaired Glucose Homeostasis

    PubMed Central

    Mallipedhi, Akhila; Prior, Sarah L.; Dunseath, Gareth; Bracken, Richard M.; Barry, Jonathan; Caplin, Scott; Eyre, Nia; Morgan, James; Baxter, John N.; O'Sullivan, Saoirse E.; Sarmad, Sarir; Barrett, David A.; Bain, Stephen C.; Luzio, Steve D.

    2015-01-01

    Aim. We examined endocannabinoids (ECs) in relation to bariatric surgery and the association between plasma ECs and markers of insulin resistance. Methods. A study of 20 participants undergoing bariatric surgery. Fasting and 2-hour plasma glucose, lipids, insulin, and C-peptide were recorded preoperatively and 6 months postoperatively with plasma ECs (AEA, 2-AG) and endocannabinoid-related lipids (PEA, OEA). Results. Gender-specific analysis showed differences in AEA, OEA, and PEA preoperatively with reductions in AEA and PEA in females postoperatively. Preoperatively, AEA was correlated with 2-hour glucose (r = 0.55, P = 0.01), HOMA-IR (r = 0.61, P = 0.009), and HOMA %S (r = −0.71, P = 0.002). OEA was correlated with weight (r = 0.49, P = 0.03), waist circumference (r = 0.52, P = 0.02), fasting insulin (r = 0.49, P = 0.04), and HOMA-IR (r = 0.48, P = 0.05). PEA was correlated with fasting insulin (r = 0.49, P = 0.04). 2-AG had a negative correlation with fasting glucose (r = −0.59, P = 0.04). Conclusion. Gender differences exist in circulating ECs in obese subjects. Females show changes in AEA and PEA after bariatric surgery. Specific correlations exist between different ECs and markers of obesity and insulin and glucose homeostasis. PMID:25874237

  11. Effect of garlic (Allium sativum) on nickel II or chromium VI induced alterations of glucose homeostasis and hepatic antioxidant status under sub-chronic exposure conditions.

    PubMed

    Das Gupta, Amrita; Dhara, Prakash C; Dhundasi, Salim A; Das, Kusal K

    2009-01-01

    Garlic (Allium sativum) has a profound effect in reducing plasma glucose and increasing serum insulin in diabetic rats. We studied the effect of a garlic extract on nickel- or chromium-induced alteration of plasma glucose and hepatic glycogen levels and anti-oxidant status in rats. Adult male albino rats (n=36) divided into six groups of six animals each were treated as follows: Group I, untreated controls; Group II, fresh aqueous homogenate of garlic; Group III, nickel sulfate; Group IV, nickel sulfate + garlic; Group V, potassium dichromate; Group VI, potassium dichromate + garlic. In Groups IV and VI, the simultaneous administration of garlic abrogated a significant nickel- or chromium-induced increase in plasma glucose and decrease in liver glycogen. Nickel and chromium alone also increased lipid peroxide (LPO) and decreased glutathione levels, as well as the activity of superoxide dismutase (SOD), catalase, and glutathione peroxidase. Simultaneous garlic administration significantly reduced the LPO level and remarkably improved SOD activity. Hence, we postulate that the administration of garlic can prevent nickel II- or chromium VI-induced alterations in blood glucose homeostasis while exerting a hepatoprotective effect on glycogen levels and antioxidant status in male albino rats.

  12. Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and Type 2 diabetic obese African-American women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and...

  13. (Val(8))GLP-1-Glu-PAL: a GLP-1 agonist that improves hippocampal neurogenesis, glucose homeostasis, and β-cell function in high-fat-fed mice.

    PubMed

    Lennox, Rachael; Porter, David W; Flatt, Peter R; Gault, Victor A

    2013-04-01

    This study examined the biological properties of a novel GLP-1 peptide, (Val(8))GLP-1-Glu-PAL, engineered with an Ala(8)→Val(8) substitution and additional incorporation of a C(16) fatty acid moiety at Lys(26) via a glutamic acid linker. GLP-1 underwent 75 % degradation by DPP-IV over 8 h, whereas (Val(8))GLP-1 and (Val(8))GLP-1-Glu-PAL remained intact. All GLP-1 peptides significantly stimulated insulin secretion at 5.6 mM (1.3- to 4.9-fold, p<0.01 to p<0.001) and 16.7 mM glucose (1.5- to 2.3-fold, p<0.001). At higher concentrations (Val(8))GLP-1-Glu-PAL was significantly more potent at stimulating insulin secretion (1.2- to 1.3-fold, p<0.05). In high-fat-fed mice, all GLP-1 peptides significantly lowered plasma glucose concentrations (41-66 % decrease, p<0.05 to p<0.001), with (Val(8))GLP-1-Glu-PAL eliciting protracted glucose-lowering actions (32-59 % decrease, p<0.05 to p<0.01) when administered 8 h prior to a glucose load. Twice-daily administration of (Val(8))GLP-1-Glu-PAL in high-fat-fed mice for 21 days had no effect on bodyweight or food intake, but significantly lowered non-fasting plasma glucose (43-46 % decrease, p<0.05). (Val(8))GLP-1-Glu-PAL markedly decreased glycemic excursion following intraperitoneal glucose (32-48 % decrease, p<0.05), enhanced insulin response to glucose (2- to 2.3-fold, p<0.05 to p<0.01), and improved insulin sensitivity (25-38 % decrease in plasma glucose, p<0.05). O(2) consumption, CO(2) production, RER, and energy expenditure were not altered by (Val(8))GLP-1-Glu-PAL therapy. Treatment with (Val(8))GLP-1-Glu-PAL resulted in a significant increase in BrdU-positive cells (1.3-fold, p<0.05) in the granule cell layer of the dentate gyrus. These data demonstrate that (Val(8))GLP-1-Glu-PAL is a long-acting GLP-1 peptide that significantly improves hippocampal neurogenesis, glucose homeostasis, and insulin secretion in high-fat-fed mice.

  14. Growth hormone receptor antagonist (GHA) transgenic mice have increased subcutaneous adipose tissue mass, altered glucose homeostasis, and no change in white adipose tissue cellular senescence

    PubMed Central

    Comisford, Ross; Lubbers, Ellen R.; Householder, Lara; Suer, Ozan; Tchkonia, Tamara; Kirkland, James L.; List, Edward O.; Kopchick, John J.; Berryman, Darlene E.

    2015-01-01

    Background Growth hormone (GH) resistant/deficient mice experience improved glucose homeostasis and substantially increased lifespan. Recent evidence suggests long-lived GH resistant/deficient mice are protected from white adipose tissue (WAT) dysfunction, including WAT cellular senescence, impaired adipogenesis and loss of subcutaneous WAT in old age. This preservation of WAT function has been suggested to be a potential mechanism for the extended lifespan of these mice. OBJECTIVE The objective of this study was to examine white adipose tissue (WAT) senescence, WAT distribution, and glucose homeostasis in dwarf growth hormone receptor antagonist (GHA) transgenic mice, a unique mouse strain having decreased GH action but normal longevity. METHODS 18mo old female GHA mice and wild type (WT) littermate controls were used. Prior to dissection, body composition, fasting blood glucose, and glucose and insulin tolerance tests were performed. WAT distribution was determined by weighing four distinct WAT depots at the time of dissection. Cellular senescence in four WAT depots was assessed using senescence-associated β-galactosidase (SA-β-gal) staining to quantify the senescent cell burden and real time qPCR to quantify gene expression of senescence markers p16 and IL-6. RESULTS GHA mice had a 22% reduction in total body weight, 33% reduction in lean mass, and a 10% increase in body fat percentage compared to WT controls. GHA mice had normal fasting blood glucose and improved insulin sensitivity; however, they exhibited impaired glucose tolerance. Moreover, GHA mice displayed enhanced lipid storage in the inguinal subcutaneous WAT depot (p<.05) and a 1.7 fold increase in extra-/intraperitoneal WAT ratio compared to controls (p<.05). Measurements of WAT cellular senescence showed no difference between GHA mice and WT controls. CONCLUSIONS Similar to other mice with decreased GH action, female GHA mice display reduced age-related lipid redistribution and improved insulin

  15. A comparative study on effect of metformin and metformin-conjugated nanotubes on blood glucose homeostasis in diabetic rats.

    PubMed

    Mirazi, Naser; Shoaei, Jamileh; Khazaei, Ardeshir; Hosseini, Abdolkarim

    2015-09-01

    Diabetes mellitus is one of the most prevalent metabolic disorders. Carbon nanotubes have the advantage to cross the plasma membrane without damaging the cells, improving the biological effect of a drug and reducing its side effects. In the present study, the effect of metformin and metformin-conjugated nanotubes was investigated on blood glucose level in the streptozotocin-induced male diabetic rats. Diabetes in the animals was induced with a single dose of streptozotocin (60 mg/kg; i.p.) and after 3 days the blood glucose was analyzed. Animals showing fasting blood glucose higher than 250 mg/dL were considered as diabetic rats. The animals were treated with metformin and metformin-conjugated nanotubes (150 mg/kg; p.o.) daily and every 48-h for 1 week. Changes in animals' serum blood glucose level were evaluated daily during the treatment period. The results of this study showed that metformin reduced blood glucose levels in diabetic animals. Metformin-conjugated nanotubes significantly reduced the blood glucose levels in diabetic rats (p < 0.01). There was no significant difference in blood glucose level between metformin and metformin-conjugated nanotubes groups (p > 0.05). However, when both formulations of metformin were administered every 48-h, metformin-conjugated nanotubes reduced glycaemia for a longer time than metformin alone (p < 0.001). This study showed that the metformin-conjugated nanotubes would be able to reduce the blood glucose, prolong drug delivery and efficacy duration in animals which were treated with metformin-conjugated nanotubes compared with metformin alone.

  16. Osteopontin Affects Insulin Vesicle Localization and Ca2+ Homeostasis in Pancreatic Beta Cells from Female Mice

    PubMed Central

    Mollet, Inês G.; Knutsson, Anki; Bolmgren, Victor S.; Hultgårdh-Nilsson, Anna; Gomez, Maria F.; Eliasson, Lena

    2017-01-01

    Type 2 diabetic patients suffer from insulin resistance and reduced insulin secretion. Osteopontin (OPN), a versatile protein expressed in several tissues throughout the body including the islets of Langerhans, has previously been implicated in the development of insulin resistance. Here we have investigated the role of OPN in insulin secretion using an OPN knock out mouse model (OPN-/-). Ultra-structural analyzes of islets from OPN-/- and WT mice indicated weaker cell-cell connections between the islet cells in the OPN-/- mouse compared to WT. Analysis of the insulin granule distribution in the beta cells showed that although OPN-/- and WT beta cells have the same number of insulin granules OPN-/- beta cells have significantly fewer docked granules. Both OPN-/- and WT islets displayed synchronized Ca2+ oscillations indicative of an intact beta cell communication. OPN-/- islets displayed higher intracellular Ca2+ concentrations when stimulated with 16.7 mM glucose than WT islets and the initial dip upon elevated glucose concentrations (which is associated with Ca2+ uptake into ER) was significantly lower in these islets. Glucose-induced insulin secretion was similar in OPN-/- and WT islets. Likewise, non-fasted blood glucose levels were the same in both groups. In summary, deletion of OPN results in several minor beta-cell defects that can be compensated for in a healthy system. PMID:28107503

  17. Resistant starch does not affect zinc homeostasis in rural Malawian children☆,☆☆

    PubMed Central

    Thakwalakwa, Chrissie; Ordiz, M. Isabel; Maleta, Ken; Westcott, Jamie; Ryan, Kelsey; Hambidge, K. Michael; Miller, Leland V.; Young, Graeme; Mortimer, Elissa; Manary, Mark J.; Krebs, Nancy F.

    2015-01-01

    Objective This study tested the hypothesis that Malawian children at risk for zinc deficiency will have reduced endogenous fecal zinc (EFZ) and increased net absorbed zinc (NAZ) following the addition of high amylose maize resistant starch (RS) to their diet. Methods This was a small controlled clinical trial to determine the effects of added dietary RS on zinc homeostasis among 17 stunted children, aged 3–5 years consuming a plant-based diet and at risk for perturbed zinc homeostasis. Dual zinc stable isotope studies were performed before and after 28 d of intervention with RS, so that each child served as their own control. The RS was incorporated into fried wheat flour dough and given under direct observation twice daily for 28 d. Changes in zinc homeostatic measures were compared using paired Student's t-tests and linear regression analysis. Results Children had a mean height-for-age Z-score of −3.3, and consumed animal source foods ≤twice per month. Their habitual diet contained a phytate:zinc molar ratio of 34:1. Children avidly consumed the RS without complaints. EFZ was 0.8±0.4 mg/d (mean±SD) both before and after the intervention. Fractional absorption of zinc was 0.38±0.08 and 0.35±0.06 before and after the RS intervention respectively. NAZ was 1.1±0.5 and 0.6±0.7 before and after the RS intervention. This reduction of NAZ corresponded with diminished dietary zinc intake on the study day following intervention with RS. Regression analysis indicated no change in zinc absorption relative to dietary intake as a result of the RS intervention. Conclusion Consumption of RS did not improve zinc homeostasis in rural African children without zinc deficiency. RS was well tolerated in this setting. PMID:25744509

  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 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

  19. 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.

  20. The molecular mechanisms affecting N-acetylaspartate homeostasis following experimental graded traumatic brain injury.

    PubMed

    Di Pietro, Valentina; Amorini, Angela Maria; Tavazzi, Barbara; Vagnozzi, Roberto; Logan, Ann; Lazzarino, Giacomo; Signoretti, Stefano; Lazzarino, Giuseppe; Belli, Antonio

    2014-03-24

    To characterize the molecular mechanisms of N-acetylaspartate (NAA) metabolism following traumatic brain injury (TBI), we measured the NAA, adenosine triphosphate (ATP) and adenosine diphosphate (ADP) concentrations and calculated the ATP/ADP ratio at different times from impact, concomitantly evaluating the gene and protein expressions controlling NAA homeostasis (the NAA synthesizing and degrading enzymes N-acetyltransferase 8-like and aspartoacylase, respectively) in rats receiving either mild or severe TBI. The reversible changes in NAA induced by mild TBI were due to a combination of transient mitochondrial malfunctioning with energy crisis (decrease in ATP and in the ATP/ADP ratio) and modulation in the gene and protein levels of N-acetyltransferase 8-like and increase of aspartoacylase levels. The irreversible decrease in NAA following severe TBI, was instead characterized by profound mitochondrial malfunctioning (constant 65% decrease of the ATP/ADP indicating permanent impairment of the mitochondrial phosphorylating capacity), dramatic repression of the N-acetyltransferase 8-like gene and concomitant remarkable increase in the aspartoacylase gene and protein levels. The mechanisms underlying changes in NAA homeostasis following graded TBI might be of note for possible new therapeutic approaches and will help in understanding the effects of repeat concussions occurring during particular periods of the complex NAA recovery process, coincident with the so called window of brain vulnerability.

  1. Meta-analysis investigating associations between healthy diet and fasting glucose and insulin levels and modification by loci associated with glucose homeostasis in data from 15 cohorts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether...

  2. The effect of long-term taurine supplementation and fructose feeding on glucose and lipid homeostasis in Wistar rats.

    PubMed

    Larsen, Lea Hüche; Orstrup, Laura Kofoed Hvidsten; Hansen, Svend Høime; Grunnet, Niels; Quistorff, Bjørn; Mortensen, Ole Hartvig

    2013-01-01

    The nonprotein amino acid taurine has been shown to counteract the negative effects of a high-fructose diet in rats with regard to insulin resistance and dyslipidemia. Here we examined the long-term (26 weeks) effects of oral taurine supplementation (2% in the drinking water) in fructose-fed Wistar rats.The combination of fructose and taurine caused a significant increase in fasting glucose compared to the control diet without changing hepatic phosphoenol pyruvate carboxykinase mRNA levels. The combination of fructose and taurine also improved glucose tolerance compared to control. Neither a high-fructose diet nor taurine supplementation induced significant changes in body weight, body fat or total calorie intake, fasting insulin levels, HOMA-IR, or insulin-induced Akt phosphorylation in skeletal muscle.Fructose alone caused a decrease in liver triglyceride content, with taurine supplementation preventing this. There was no effect of long-term fructose diet and/or taurine supplementation on plasma triglycerides, plasma nonesterified fatty acids, as well as plasma HDL, LDL, and total cholesterol.In conclusion, the study suggests that long-term taurine supplementation improves glucose tolerance and normalize hepatic triglyceride content following long-term fructose feeding. However, as the combination of taurine and fructose also increased fasting glucose levels, the beneficial effect of taurine supplementation towards amelioration of glucose intolerance and insulin resistance may be questionable.

  3. Maternal high-fat diet modulates hepatic glucose, lipid homeostasis and gene expression in the PPAR pathway in the early life of offspring.

    PubMed

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

    2014-08-25

    Maternal dietary modifications determine the susceptibility to metabolic diseases in adult life. However, whether maternal high-fat feeding can modulate glucose and lipid metabolism in the early life of offspring is less understood. Furthermore, we explored the underlying mechanisms that influence the phenotype. Using C57BL/6J mice, we examined the effects on the offspring at weaning from dams fed with a high-fat diet or normal chow diet throughout pregnancy and lactation. Gene array experiments and quantitative real-time PCR were performed in the liver tissues of the offspring mice. The offspring of the dams fed the high-fat diet had a heavier body weight, impaired glucose tolerance, decreased insulin sensitivity, increased serum cholesterol and hepatic steatosis at weaning. Bioinformatic analyses indicated that all differentially expressed genes of the offspring between the two groups were mapped to nine pathways. Genes in the peroxisome proliferator-activated receptor (PPAR) signaling pathway were verified by quantitative real-time PCR and these genes were significantly up-regulated in the high-fat diet offspring. A maternal high-fat diet during pregnancy and lactation can modulate hepatic glucose, lipid homeostasis, and gene expression in the PPAR signaling in the early life of offspring, and our results suggested that potential mechanisms that influences this phenotype may be related partially to up-regulate some gene expression in the PPAR signalling pathway.

  4. 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.

  5. Acute ethanol exposure affects spermatogonial stem cell homeostasis in pre-pubertal mice.

    PubMed

    Caires, Kyle C; Shima, Christina M; de Avila, Jeanene; McLean, Derek J

    2012-01-01

    Ethanol is a known modulator of neural stem cell development, but the consequences of ethanol toxicity on the cell fate decisions of spermatogonial stem cells (SSCs) is poorly understood. Using an in vivo treatment and stem cell transplantation approach, we investigated the effects of acute ethanol exposure on formation of the growing adult SSC population in neonatal and pre-pubertal mice. Treatment with a single dose of ethanol disrupted SSC homeostasis in vivo evidenced by a significant reduction (7-fold) of stem cell colonization efficiency in the testes of recipient mice following transplantation. Ethanol treatment also increased the rate of apoptosis in adult differentiating germ cells in situ. Gene expression analysis indicates that ethanol exposure has transient and long-term effects on the expression of GDNF and VEGF family molecules and supports the hypothesis that the niche microenvironment for SSCs is sensitive to ethanol toxicity during pre-pubertaland adult life.

  6. Does hyperketonemia affect protein or glucose kinetics in postabsorptive or traumatized man

    SciTech Connect

    Crowe, P.J.; Royle, G.T.; Wagner, D.; Burke, J.F. )

    1989-10-01

    Leucine and glucose turnover were measured using simultaneous infusions of (13C)leucine and (2H)glucose before and during an infusion of Na DL-hydroxybutyrate (Na DL-HB) in overnight-fasted patients the day before and 3 days after total hip replacement. The ketone body infusion before surgery resulted in a significant increase in plasma leucine concentration and leucine turnover, while glucose concentration and turnover decreased. Surgery increased leucine turnover. Ketone body infusion after surgery caused a further increased leucine turnover while turnover fell as before surgery. We suggest that exogenous ketone bodies decrease hepatic glucose production and probably stimulate a rise in protein synthesis above breakdown leading to a decreased nitrogen excretion as observed by other investigators. Despite the metabolic adaptation to trauma, this response was not affected by surgery.

  7. Mucosal maltase-glucoamylase plays a crucial role in starch digestion and prandial glucose homeostasis of mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Starch is the major source of food glucose, and its digestion requires small intestinal alpha-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 anot...

  8. Exposure to atrazine affects the expression of key genes in metabolic pathways integral to energy homeostasis in Xenopus laevis tadpoles.

    PubMed

    Zaya, Renee M; Amini, Zakariya; Whitaker, Ashley S; Ide, Charles F

    2011-08-01

    In our laboratory, Xenopus laevis tadpoles exposed throughout development to 200 or 400 μg/L atrazine, concentrations reported to periodically occur in puddles, vernal ponds and runoff soon after application, were smaller and had smaller fat bodies (the tadpole's lipid storage organ) than controls. It was hypothesized that these changes were due to atrazine-related perturbations of energy homeostasis. To investigate this hypothesis, selected metabolic responses to exposure at the transcriptional and biochemical levels in atrazine-exposed tadpoles were measured. DNA microarray technology was used to determine which metabolic pathways were affected after developmental exposure to 400 μg/L atrazine. From these data, genes representative of the affected pathways were selected for assay using quantitative real time polymerase chain reaction (qRT-PCR) to measure changes in expression during a 2-week exposure to 400 μg/L. Finally, ATP levels were measured from tadpoles both early in and at termination of exposure to 200 and 400 μg/L. Microarray analysis revealed significant differential gene expression in metabolic pathways involved with energy homeostasis. Pathways with increased transcription were associated with the conversion of lipids and proteins into energy. Pathways with decreased transcription were associated with carbohydrate metabolism, fat storage, and protein synthesis. Using qRT-PCR, changes in gene expression indicative of an early stress response to atrazine were noted. Exposed tadpoles had significant decreases in acyl-CoA dehydrogenase (AD) and glucocorticoid receptor protein (GR) mRNA after 24 h of exposure, and near-significant (p=0.07) increases in peroxisome proliferator-activated receptor β (PPAR-β) mRNA by 72 h. Decreases in AD suggested decreases in fatty acid β-oxidation while decreases in GR may have been a receptor desensitization response to a glucocorticoid surge. Involvement of PPAR-β, an energy homeostasis regulatory molecule, also

  9. Oocyte aging-induced Neuronatin (NNAT) hypermethylation affects oocyte quality by impairing glucose transport in porcine

    PubMed Central

    Gao, Ying-Ying; Chen, Li; Wang, Tao; Nie, Zheng-Wen; Zhang, Xia; Miao, Yi-Liang

    2016-01-01

    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. PMID:27782163

  10. mRNA GPR162 changes are associated with decreased food intake in rat, and its human genetic variants with impairments in glucose homeostasis in two Swedish cohorts.

    PubMed

    Caruso, Vanni; Sreedharan, Smitha; Carlini, Valeria P; Jacobsson, Josefin A; Haitina, Tatjana; Hammer, Joanna; Stephansson, Olga; Crona, Filip; Sommer, Wolfgang H; Risérus, Ulf; Lannfelt, Lars; Marcus, Claude; Heilig, Markus; de Barioglio, Susana R; Fredriksson, Robert; Schiöth, Helgi B

    2016-05-01

    G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating intercellular interactions of fundamental physiological importance for survival including regulation of food intake, blood pressure, and hormonal sensing signaling, among other roles. Homeostatic alterations in the physiological status of GPCRs are often associated with underlying causes of disease, and to date, several orphan GPCRs are still uncharacterized. Findings from our previous study demonstrate that the Rhodopsin family protein GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in hypothalamus, amygdala, and ventral tegmental area, regions strictly interconnected and involved in the regulation of energy homeostasis and hedonic feeding. In this study, we provide a further anatomical characterization of GPR162 in mouse brain via in situ hybridization as well as detailed mRNA expression in a panel of rat tissues complementing a specie-specific mapping of the receptor. We also provide an attempt to demonstrate a functional implication of GPR162 in food intake-related behavior via antisense knockdown studies. Furthermore, we performed human genetic studies in which for the first time, variants of the GPR162 gene were associated with impairments in glucose homeostasis.

  11. Plasma inflammatory and vascular homeostasis biomarkers increase during human pregnancy but are not affected by oily fish intake.

    PubMed

    García-Rodríguez, Cruz E; Olza, Josune; Aguilera, Concepción M; Mesa, María D; Miles, Elizabeth A; Noakes, Paul S; Vlachava, Maria; Kremmyda, Lefkothea-Stella; Diaper, Norma D; Godfrey, Keith M; Calder, Philip C; Gil, Angel

    2012-07-01

    The Salmon in Pregnancy Study investigated whether the increased consumption of (n-3) long-chain PUFA (LC-PUFA) from farmed Atlantic salmon affects immune function during pregnancy and atopic disease in neonates compared with a habitual diet low in oily fish. In this context, because the ingestion of (n-3) LC-PUFA may lower the concentrations of inflammatory biomarkers, we investigated whether the consumption of oily fish affects the levels of inflammatory cytokines and vascular adhesion factors during pregnancy. Pregnant women (n = 123) were randomly assigned to continue their habitual diet (control group, n = 61), which was low in oily fish, or to consume two 150-g salmon portions/wk (salmon group, n = 62; providing 3.45 g EPA plus DHA) from 20 wk of gestation until delivery. Plasma inflammatory cytokines and vascular adhesion factors were measured in maternal plasma samples. Inflammatory biomarkers, including IL-8, hepatocyte growth factor, and monocyte chemotactic protein, increased over the course of pregnancy (P < 0.001), whereas plasma matrix metalloproteinase 9, IL-6, TNFα, and nerve growth factor concentrations were not affected. Vascular homeostasis biomarkers soluble E-selectin, soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule (sICAM)-1, and total plasminogen activator inhibitor-1 increased as pregnancy progressed (P < 0.001). The plasma sICAM-1 concentration was greater in the control group than in the salmon group at wk 20 (baseline) and 38 (P = 0.007) but there was no group x time interaction, and when baseline concentration was used as a covariate, the groups did not differ (P = 0.69). The remaining biomarkers analyzed were similar in both groups. Therefore, although some inflammatory and vascular homeostasis biomarkers change during pregnancy, they are not affected by the increased intake of farmed salmon.

  12. Fluoride affects calcium homeostasis and osteogenic transcription factor expressions through L-type calcium channels in osteoblast cell line.

    PubMed

    Duan, Xiao-Qin; Zhao, Zhi-Tao; Zhang, Xiu-Yun; Wang, Ying; Wang, Huan; Liu, Da-Wei; Li, Guang-Sheng; Jing, Ling

    2014-12-01

    Osteoblast L-type voltage-dependent calcium channels (VDCC) play important roles in maintaining intracellular homeostasis and influencing multiple cellular processes. In particular, they contribute to the activities and functions of osteoblasts (OBs). In order to study how L-type VDCC modulate calcium ion (Ca(2+)) homeostasis and the expression of osteogenic transcription factors in OBs exposed to fluoride, MC3T3-E1 cells were exposed to a gradient of concentrations of fluoride (0, 2.0, 5.0, 10.0 mg/L) in combination with 10 μM nifedipine, a specific inhibitor of VDCC, for 48 h. We examined messenger RNA (mRNA) and protein levels of Cav1.2, the main subunit of VDCC, and c-fos, c-jun, runt-related transcription factor 2 (Runx2), osterix (OSX), and intracellular free Ca(2+) ([Ca(2+)]i) concentrations in MC3T3-E1 cells. Our results showed that [Ca(2+)]i levels increased in a dose-dependent manner with increase in concentration of fluoride. Meantime, results indicated that lower concentrations of fluoride (less than 5 mg/L, especially 2 mg/L) can lead to high expression of Cav1.2 and enhance osteogenic function, while high concentration of fluoride (10 mg/L) can induce decreased Cav1.2 and osteogenic transcriptional factors in MC3T3E1 cells exposed to fluoride. However, the levels of [Ca(2+)]i, Cav1.2, c-fos, c-jun, Runx2, and OSX induced by fluoride were significantly altered and even reversed in the presence of nifedipine. These results demonstrate that L-type calcium channels play a crucial role in Ca(2+) homeostasis and they affect the expression of osteogenic transcription factors in fluoride-treated osteoblasts.

  13. The trehalose pathway and intracellular glucose phosphates as modulators of potassium transport and general cation homeostasis in yeast.

    PubMed

    Mulet, Jose M; Alejandro, Santiago; Romero, Carlos; Serrano, Ramón

    2004-05-01

    Trk, encoded by the partially redundant genes TRK1 and TRK2, is the major potassium transporter of Saccharomyces cerevisiae. This system is specific for potassium and rubidium but, by reducing the electrical membrane potential of the plasma membrane, Trk decreases the uptake of toxic cations such as lithium, calcium, aminoglycosides and polyamines, which are transported by other systems. Gain- and loss-of-function studies indicate that TPS1, a gene encoding trehalose-6-phosphate synthase and known to modulate glucose metabolism, activates Trk and reduces the sensitivity of yeast cells to many toxic cations. This effect is independent of known regulators of Trk, such as the Hal4 and Hal5 protein kinases and the protein phosphatase calcineurin. Mutants defective in isoform 2 of phosphoglucomutase (pgm2) and mutants defective in isoform 2 of hexokinase (hxk2) exhibit similar phenotypes of reduced Trk activity and increased sensitivity to toxic cations compared with tps1 mutants. In all cases Trk activity was positively correlated with levels of glucose phosphates (glc-1-P and glc-6-P). These results indicate that Tps1, like Pgm2 and Hxk2, increases the levels of glucose phosphates and suggest that these metabolites, directly or indirectly, activate Trk.

  14. The effect of type and amount of dietary carbohydrate on biomarkers of glucose homeostasis and C-reactive protein in overweight or obese adults: Results from the OmniCarb trial

    PubMed Central

    Juraschek, Stephen P; Miller, Edgar R; Selvin, Elizabeth; Carey, Vincent J; Appel, Lawrence J; Christenson, Robert H; Sacks, Frank M.

    2016-01-01

    OBJECTIVE The glycemic index (GI) of dietary carbohydrate is thought to affect glucose homeostasis. Recently, the OmniCarb Trial reported that a low GI diet did not improve insulin sensitivity. We conducted this ancillary study of the OmniCarb Trial to determine the effects of GI and carbohydrate content on glucose homeostasis and inflammation. RESEARCH DESIGN AND METHODS OmniCarb was a randomized crossover feeding study conducted in overweight or obese adults without diabetes (N=163). Participants were fed each of 4 diets for 5 weeks with 2-week washout periods. Weight was held constant. Diets were: high GI (GI≥65) with high carbohydrate (58% kcal), low GI (GI≤45) with low carbohydrate (40% kcal), low GI with high carbohydrate; and high GI with low carbohydrate. We measured glycated albumin (GA), fructosamine, and high sensitivity C-reactive protein (CRP) at baseline and following each dietary period. These biomarkers were compared within-person between diets. RESULTS The study population was 52% female and 50% black. Mean age was 53 (SD, 11) years; mean BMI was 32 (SD, 6) kg/m2. Reducing GI had no effect on GA or fructosamine, but increased fasting glucose in the setting of a high carbohydrate diet (+2.2 mg/dl; P=0.02). Reducing carbohydrate content decreased GA in the setting of a high GI diet (−0.2%; P=0.03) and decreased fructosamine in the setting of a low GI diet (−4 μmol/L; P=0.003). Reducing carbohydrate while simultaneously increasing GI significantly reduced both GA (−0.2%; P=0.04) and fructosamine (−4 μmol/L; P=0.009). Neither reducing GI nor amount of carbohydrate affected insulin or CRP. CONCLUSIONS Reducing carbohydrate, regardless of high or low GI, decreased GA and fructosamine. This suggests that reducing carbohydrate content, rather than GI, is a better strategy for lowering glycemia in adults at risk for diabetes. PMID:26636424

  15. Effect of type and amount of dietary carbohydrate on biomarkers of glucose homeostasis and C reactive protein in overweight or obese adults: results from the OmniCarb trial

    PubMed Central

    Juraschek, Stephen P; Miller, Edgar R; Selvin, Elizabeth; Carey, Vincent J; Appel, Lawrence J; Christenson, Robert H; Sacks, Frank M

    2016-01-01

    Objective The glycemic index (GI) of dietary carbohydrate is thought to affect glucose homeostasis. Recently, the Effect of Amount and Type of Dietary Carbohydrates on Risk for Cardiovascular Heart Disease and Diabetes Study (OmniCarb) trial reported that a low-GI diet did not improve insulin sensitivity. We conducted this ancillary study of the OmniCarb trial to determine the effects of GI and carbohydrate content on glucose homeostasis and inflammation. Research design and methods OmniCarb was a randomized cross-over feeding study conducted in overweight or obese adults without diabetes (N=163). Participants were fed each of 4 diets for 5 weeks with 2-week washout periods. Weight was held constant. Diets were: high GI (GI≥65) with high carbohydrate (58% kcal), low GI (GI≤45) with low carbohydrate (40% kcal), low GI with high carbohydrate, and high GI with low carbohydrate. We measured glycated albumin (GA), fructosamine, and high sensitivity C reactive protein (CRP) at baseline and following each dietary period. These biomarkers were compared within-person between diets. Results The study population was 52% female and 50% black. Mean age was 53 (SD, 11) years; mean body mass index was 32 (SD 6) kg/m2. Reducing GI had no effect on GA or fructosamine, but increased fasting glucose in the setting of a high-carbohydrate diet (+2.2 mg/dL; p=0.02). Reducing carbohydrate content decreased GA in the setting of a high-GI diet (−0.2%; p=0.03) and decreased fructosamine in the setting of a low-GI diet (−4 µmol/L; p=0.003). Reducing carbohydrate while simultaneously increasing GI significantly reduced both GA (−0.2%; p=0.04) and fructosamine (−4 µmol/L; p=0.009). Neither reducing GI nor amount of carbohydrate affected insulin or CRP. Conclusions Reducing carbohydrate, regardless of high or low GI, decreased GA and fructosamine. This suggests that reducing carbohydrate content, rather than GI, is a better strategy for lowering glycemia in adults at risk

  16. 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.

  17. Vitamin D status and resistance exercise training independently affect glucose tolerance in older adults.

    PubMed

    Kobza, Vanessa M; Fleet, James C; Zhou, Jing; Conley, Travis B; Peacock, Munro; IglayReger, Heidi B; DePalma, Glen; Campbell, Wayne W

    2013-05-01

    We assessed the influence of serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone (PTH) concentrations on oral glucose tolerance, body composition, and muscle strength in older, nondiabetic adults who performed resistance exercise training (RT) while consuming diets with either 0.9 or 1.2 g protein kg(-1) d(-1). We hypothesized that individuals with insufficient 25(OH)D and/or high PTH would have less improvement in glucose tolerance after 12 weeks of RT compared with individuals with sufficient 25(OH)D and lower PTH. Sixteen men and 19 women (aged 61 ± 8 years; range, 50-80 years; body mass index, 26.3 ± 3.6 kg/m(2)) performed RT 3 times/wk for 12 weeks, with oral glucose tolerance tests done at baseline and postintervention. Protein intake did not influence the responses described below. Plasma glucose area under the curve (P = .02) and 2-hour plasma glucose concentration (P = .03) were higher for vitamin D-insufficient subjects (25[OH]D <50 nmol/L, n = 7) vs vitamin D-sufficient subjects (25[OH]D ≥50 nmol/L, n = 28). These differences remained significant after adjustment for age and body mass index. Resistance exercise training reduced fat mass (mean ± SD, -6% ± 7%; P < .001) and increased lean body mass (2% ± 3%, P < .001) and whole-body muscle strength (32% ± 17%, P < .001) in these weight-stable subjects but did not affect 25(OH)D or PTH concentrations. Oral glucose tolerance improved after RT (-10% ± 16% in glucose area under the curve and -21% ± 40% in 2-hour glucose, P = .001), but baseline 25(OH)D and PTH did not influence these RT-induced changes. These findings indicate that vitamin D status and RT independently affect glucose tolerance, and a training-induced improvement in glucose tolerance does not offset the negative effect of insufficient vitamin D status in older, nondiabetic adults.

  18. Protective role of sodium butyrate, a HDAC inhibitor on beta-cell proliferation, function and glucose homeostasis through modulation of p38/ERK MAPK and apoptotic pathways: study in juvenile diabetic rat.

    PubMed

    Khan, S; Jena, G B

    2014-04-25

    Type 1 diabetes (T1D) also known as juvenile diabetes is a chronic autoimmune disorder that precipitates in genetically susceptible individuals by environmental factors particularly during early age. Both genetic and epigenetic factors are implicated in the beta-cell development, proliferation, differentiation and function. Recent evidences suggested that there is a link between diabetes and histone deacetylases (HDACs), because HDAC inhibitors promote beta-cell development, proliferation and function as well as improve glucose homeostasis. Sodium butyrate (NaB) is a short chain fatty acid having HDAC inhibition activity. The present study was aimed to investigate the protective role of NaB treatment on the beta-cell proliferation, function and glucose homeostasis as well as apoptosis in juvenile diabetic rat. Diabetes was induced by single injection of STZ (60 mg/kg, i.p.) in chilled citrate buffer, while NaB (500 mg/kg/day) was administrated by i.p. route for 21 days as pre- and post-treatment schedule. Plasma glucose and insulin levels, HbA1c, glucose tolerance, apoptosis, and expression of proliferating cell nuclear antigen (PCNA), p38, p53, caspase-3, extracellular signal-regulated kinase-1/2 (ERK-1/2), forkhead box protein O1 (FOXO1) and insulin receptor substrate-1 (IRS-1) as well as histone acetylation were evaluated. NaB treatment decreased plasma glucose, HbA1c, beta-cell apoptosis and improved plasma insulin level and glucose homeostasis through HDAC inhibition and histone acetylation in diabetic animal as compared to control. NaB treatment improved the beta-cell proliferation, function and glucose homeostasis as well as reduced beta-cell apoptosis in juvenile diabetic rat by the modulation of p38/ERK MAPK and apoptotic pathway.

  19. 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.

  20. Low-Intensity swimming training after weaning improves glucose and lipid homeostasis in MSG hypothalamic obese mice.

    PubMed

    Scomparin, Dionízia Xavier; Grassiolli, Sabrina; Gomes, Rodrigo Mello; Torrezan, Rosana; de Oliveira, Júlio Cezar; Gravena, Clarice; Pêra, Carolina Costa; Mathias, Paulo Cezar de Freitas

    2011-01-01

    Low-intensity swimming training, started at an early age, was undertaken to observe glycemic control in hypothalamic obese mice produced by neonatal monosodium l-glutamate (MSG) treatment. Although swimming exercises by weaning pups inhibited hypothalamic obesity onset and recovered sympathoadrenal axis activity, this event was not observed when exercise training is applied to young adult mice. However, the mechanisms producing this improved metabolism are still not fully understood. Current work verifies whether, besides reducing fat tissue accumulation, low-intensity swimming in MSG-weaned mice also improves glycemic control. Although MSG and control mice swam for 15 min/day, 3 days a week, from the weaning stage up to 90 days old, sedentary MSG and normal mice did not exercise at all. After 14 h of fasting, animals were killed at 90 days of age. Retroperitonial fat accumulation was measured to estimate obesity. Fasting blood glucose and insulin concentrations were also measured. Mice were also submitted to ipGTT. MSG obese mice showed fasting hyperglycemia, hyperinsulinemia, and glucose intolerance and insulin resistance. However, the exercise was able to block MSG treatment effects. Higher total cholesterol and triglycerides observed in MSG mice were normalized by exercise after weaning. Exercised MSG animals had higher HDLc than the sedentary group. Data suggest that early exercise training maintains normoglycemia, insulin tissue sensitivity, and normal lipid profile in mice programmed to develop metabolic syndrome.

  1. Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPK.

    PubMed

    Park, Sung-Jun; Ahmad, Faiyaz; Um, Jee-Hyun; Brown, Alexandra L; Xu, Xihui; Kang, Hyeog; Ke, Hengming; Feng, Xuesong; Ryall, James; Philp, Andrew; Schenk, Simon; Kim, Myung K; Sartorelli, Vittorio; Chung, Jay H

    2017-03-14

    The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner. Inhibiting the cAMP effector protein Epac prevents SRT1720 from activating AMPK or Sirt1 in myotubes. Moreover, SRT1720 does not increase mitochondrial function or improve glucose tolerance in AMPKα2 knockout mice. Interestingly, weight loss induced by SRT1720 is not sufficient to improve glucose tolerance. Therefore, contrary to current belief, the metabolic effects produced by SRT1720 require AMPK, which can be activated independently of Sirt1.

  2. Quantity and quality of nocturnal sleep affect morning glucose measurement in acutely burned children.

    PubMed

    Mayes, Theresa; Gottschlich, Michele M; Khoury, Jane; Simakajornboon, Narong; Kagan, Richard J

    2013-01-01

    Hyperglycemia after severe burn injury has long been recognized, whereas sleep deprivation after burns is a more recent finding. The postburn metabolic effects of poor sleep are not clear despite reports in other populations demonstrating the association between sleep insufficiency and deleterious endocrine consequences. The aim of this study was to determine whether a relationship between sleep and glucose dynamics exists in acutely burned children. Two overnight polysomnography runs (2200 to 0600) per subject were conducted in 40 patients with a mean (± SEM) age of 9.4 ± 0.7 years, 50.1 ± 2.9% TBSA burn, and 43.2 ± 3.6% full-thickness injury. Serum glucose was drawn in the morning (0600) immediately after the sleep test. Insulin requirements during the 24-hour period preceding the 0600 glucose measurement were recorded. Generalized linear models were used by the authors to evaluate percent time in each stage of sleep, percent wake time, total sleep time, sleep efficiency, and morning serum glucose, accounting for insulin use. Increased time awake (P = .04, linear; P = .02, quadratic) and reduced time spent in stage 1 sleep (P = .03, linear) were associated with higher glucose levels. Sleep efficiency (P = .01, linear; P = .02, quadratic) and total sleep time (P = .01 linear; P = .02, quadratic) were inversely associated with glucose level. Morning glucose levels appear to be affected by the quality and quantity of overnight sleep in children who have sustained extensive burn injuries. Future research is needed to elucidate the metabolic and neuroendocrine consequences of sleep deprivation on metabolism after burns.

  3. 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 egg ormore » 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

  4. 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.

  5. Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling

    PubMed Central

    Nemazanyy, Ivan; Montagnac, Guillaume; Russell, Ryan C.; Morzyglod, Lucille; Burnol, Anne-Françoise; Guan, Kun-Liang; Pende, Mario; Panasyuk, Ganna

    2015-01-01

    Defective hepatic insulin receptor (IR) signalling is a pathogenic manifestation of metabolic disorders including obesity and diabetes. The endo/lysosomal trafficking system may coordinate insulin action and nutrient homeostasis by endocytosis of IR and the autophagic control of intracellular nutrient levels. Here we show that class III PI3K—a master regulator of endocytosis, endosomal sorting and autophagy—provides negative feedback on hepatic insulin signalling. The ultraviolet radiation resistance-associated gene protein (UVRAG)-associated class III PI3K complex interacts with IR and is stimulated by insulin treatment. Acute and chronic depletion of hepatic Vps15, the regulatory subunit of class III PI3K, increases insulin sensitivity and Akt signalling, an effect that requires functional IR. This is reflected by FoxO1-dependent transcriptional defects and blunted gluconeogenesis in Vps15 mutant cells. On depletion of Vps15, the metabolic syndrome in genetic and diet-induced models of insulin resistance and diabetes is alleviated. Thus, feedback regulation of IR trafficking and function by class III PI3K may be a therapeutic target in metabolic conditions of insulin resistance. PMID:26387534

  6. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

    PubMed Central

    Benyamin, Beben; Esko, Tonu; Ried, Janina S; Radhakrishnan, Aparna; Vermeulen, Sita H; Traglia, Michela; Gögele, Martin; Anderson, Denise; Broer, Linda; Podmore, Clara; Luan, Jian’an; Kutalik, Zoltan; Sanna, Serena; van der Meer, Peter; Tanaka, Toshiko; Wang, Fudi; Westra, Harm-Jan; Franke, Lude; Mihailov, Evelin; Milani, Lili; Häldin, Jonas; Winkelmann, Juliane; Meitinger, Thomas; Thiery, Joachim; Peters, Annette; Waldenberger, Melanie; Rendon, Augusto; Jolley, Jennifer; Sambrook, Jennifer; Kiemeney, Lambertus A; Sweep, Fred C; Sala, Cinzia F; Schwienbacher, Christine; Pichler, Irene; Hui, Jennie; Demirkan, Ayse; Isaacs, Aaron; Amin, Najaf; Steri, Maristella; Waeber, Gérard; Verweij, Niek; Powell, Joseph E; Nyholt, Dale R; Heath, Andrew C; Madden, Pamela AF; Visscher, Peter M; Wright, Margaret J; Montgomery, Grant W; Martin, Nicholas G; Hernandez, Dena; Bandinelli, Stefania; van der Harst, Pim; Uda, Manuela; Vollenweider, Peter; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; van Duijn, Cornelia; Beilby, John; Pramstaller, Peter P; Hicks, Andrew A; Ouwehand, Willem H; Oexle, Konrad; Gieger, Christian; Metspalu, Andres; Camaschella, Clara; Toniolo, Daniela; Swinkels, Dorine W; Whitfield, John B

    2014-01-01

    Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here we analyse genetic association data on biochemical markers of iron status from eleven European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find eleven genome-wide-significant (p < 5 × 10−8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease. PMID:25352340

  7. Sodium Orthovanadate and Trigonella Foenum Graecum Prevents Neuronal Parameters Decline and Impaired Glucose Homeostasis in Alloxan Diabetic Rats.

    PubMed

    Kumar, Pardeep; Taha, Asia; Kumar, Nitin; Kumar, Vinod; Baquer, Najma Zaheer

    2015-01-01

    Hyperglycemia is the most important contributor in the onset and progress of diabetic complications mainly by producing oxidative stress. The present study was carried out to observe, the antihyperglycemic effect of sodium orthovanadate (SOV) and Trigonella foenum graecum seed powder (TSP) administration on blood glucose and insulin levels, membrane linked enzymes (monoamine oxidase, acetylcholinesterase, Ca2+ATPase), intracellular calcium (Ca2+) levels, lipid peroxidation, membrane fluidity and neurolipofuscin accumulation in brain of the alloxan induced diabetic rats and to see whether the treatment with SOV and TSP was capable of reversing the diabetic effects. Diabetes was induced by administration of alloxan monohydrate (15 mg/100 g body weight) and rats were treated with 2 IU insulin, 0.6 mg/ml SOV, 5% TSP in the diet and a combination of 0.2 mg/ml SOV and 5% TSP separately for three weeks. Diabetic rats showed hyperglycemia with almost four fold high blood glucose levels. Activities of acetylcholinesterase and Ca2+ATPase decreased in diabetic rat brain. Diabetic rats exhibited an increased level of intracellular Ca2+ levels, lipid peroxidation, neurolipofuscin accumulations and monoamine oxidase activity. Treatment of diabetic rats with insulin, TSP, SOV and a combined therapy of lower dose of SOV with TSP revived normoglycemia and restored the altered level of membrane bound enzymes, lipid peroxidation and neurolipofuscin accumulation. Our results showed that lower doses of SOV (0.2 mg/ml) could be used in combination with TSP in normalization of altered metabolic parameters and membrane linked enzymes without any harmful side effect.

  8. Nicotinamide improves glucose metabolism and affects the hepatic NAD-sirtuin pathway in a rodent model of obesity and type 2 diabetes.

    PubMed

    Yang, Soo Jin; Choi, Jung Mook; Kim, Lisa; Park, Se Eun; Rhee, Eun Jung; Lee, Won Young; Oh, Ki Won; Park, Sung Woo; Park, Cheol-Young

    2014-01-01

    Nicotinic acid (NA) and nicotinamide (NAM) are major forms of niacin and exert their physiological functions as precursors of nicotinamide adenine dinucleotide (NAD). Sirtuins, which are NAD-dependent deacetylases, regulate glucose and lipid metabolism and are implicated in the pathophysiology of aging, diabetes, and hepatic steatosis. The aim of this study was to investigate the effects of two NAD donors, NA and NAM, on glucose metabolism and the hepatic NAD-sirtuin pathway. The effects were investigated in OLETF rats, a rodent model of obesity and type 2 diabetes. OLETF rats were divided into five groups: (1) high fat (HF) diet, (2) HF diet and 10 mg NA/kg body weight (BW)/day (NA 10), (3) HF diet and 100 mg NA/kg BW/day (NA 100), (4) HF diet and 10 mg NAM/kg BW/day (NAM 10), and (5) HF diet and 100 mg NAM/kg BW/day (NAM 100). NA and NAM were delivered via drinking water for four weeks. NAM 100 treatment affected glucose control significantly, as shown by lower levels of accumulative area under the curve during oral glucose tolerance test, serum fasting glucose, serum fasting insulin, and homeostasis model assessment of insulin resistance, and higher levels of serum adiponectin. With regard to NAD-sirtuin pathway, intracellular nicotinamide phosphoribosyltransferase, NAD, the NAD/NADH ratio, Sirt1, 2, 3, and 6 mRNA expressions, and Sirt1 activity all increased in livers of NAM 100-treated rats. These alterations were accompanied by the increased levels of proliferator-activated receptor gamma, coactivator 1 alpha and mitochondrial DNA. The effect of NA treatment was less evident than that of NAM 100. These results demonstrate that NAM is more effective than NA on the regulation of glucose metabolism and the NAD-sirtuin pathway, which may relate to the altered mitochondrial biogenesis.

  9. Meta-analysis investigating associations between healthy diet and fasting glucose and insulin levels and modification by loci associated with glucose homeostasis in data from 15 cohorts.

    PubMed

    Nettleton, Jennifer A; Hivert, Marie-France; Lemaitre, Rozenn N; McKeown, Nicola M; Mozaffarian, Dariush; Tanaka, Toshiko; Wojczynski, Mary K; Hruby, Adela; Djoussé, Luc; Ngwa, Julius S; Follis, Jack L; Dimitriou, Maria; Ganna, Andrea; Houston, Denise K; Kanoni, Stavroula; Mikkilä, Vera; Manichaikul, Ani; Ntalla, Ioanna; Renström, Frida; Sonestedt, Emily; van Rooij, Frank J A; Bandinelli, Stefania; de Koning, Lawrence; Ericson, Ulrika; Hassanali, Neelam; Kiefte-de Jong, Jessica C; Lohman, Kurt K; Raitakari, Olli; Papoutsakis, Constantina; Sjogren, Per; Stirrups, Kathleen; Ax, Erika; Deloukas, Panos; Groves, Christopher J; Jacques, Paul F; Johansson, Ingegerd; Liu, Yongmei; McCarthy, Mark I; North, Kari; Viikari, Jorma; Zillikens, M Carola; Dupuis, Josée; Hofman, Albert; Kolovou, Genovefa; Mukamal, Kenneth; Prokopenko, Inga; Rolandsson, Olov; Seppälä, Ilkka; Cupples, L Adrienne; Hu, Frank B; Kähönen, Mika; Uitterlinden, André G; Borecki, Ingrid B; Ferrucci, Luigi; Jacobs, David R; Kritchevsky, Stephen B; Orho-Melander, Marju; Pankow, James S; Lehtimäki, Terho; Witteman, Jacqueline C M; Ingelsson, Erik; Siscovick, David S; Dedoussis, George; Meigs, James B; Franks, Paul W

    2013-01-15

    Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 U.S. and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = -0.004 mmol/L, 95% confidence interval: -0.005, -0.003) and FI (β = -0.008 ln-pmol/L, 95% confidence interval: -0.009, -0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.

  10. 7-Rhamnosylated Flavonols Modulate Homeostasis of the Plant Hormone Auxin and Affect Plant Development*

    PubMed Central

    Kuhn, Benjamin M.; Errafi, Sanae; Bucher, Rahel; Dobrev, Petre; Geisler, Markus; Bigler, Laurent; Zažímalová, Eva; Ringli, Christoph

    2016-01-01

    Flavonols are a group of secondary metabolites that affect diverse cellular processes. They are considered putative negative regulators of the transport of the phytohormone auxin, by which they influence auxin distribution and concomitantly take part in the control of plant organ development. Flavonols are accumulating in a large number of glycosidic forms. Whether these have distinct functions and diverse cellular targets is not well understood. The rol1-2 mutant of Arabidopsis thaliana is characterized by a modified flavonol glycosylation profile that is inducing changes in auxin transport and growth defects in shoot tissues. To determine whether specific flavonol glycosides are responsible for these phenotypes, a suppressor screen was performed on the rol1-2 mutant, resulting in the identification of an allelic series of UGT89C1, a gene encoding a flavonol 7-O-rhamnosyltransferase. A detailed analysis revealed that interfering with flavonol rhamnosylation increases the concentration of auxin precursors and auxin metabolites, whereas auxin transport is not affected. This finding provides an additional level of complexity to the possible ways by which flavonols influence auxin distribution and suggests that flavonol glycosides play an important role in regulating plant development. PMID:26742840

  11. 7-Rhamnosylated Flavonols Modulate Homeostasis of the Plant Hormone Auxin and Affect Plant Development.

    PubMed

    Kuhn, Benjamin M; Errafi, Sanae; Bucher, Rahel; Dobrev, Petre; Geisler, Markus; Bigler, Laurent; Zažímalová, Eva; Ringli, Christoph

    2016-03-04

    Flavonols are a group of secondary metabolites that affect diverse cellular processes. They are considered putative negative regulators of the transport of the phytohormone auxin, by which they influence auxin distribution and concomitantly take part in the control of plant organ development. Flavonols are accumulating in a large number of glycosidic forms. Whether these have distinct functions and diverse cellular targets is not well understood. The rol1-2 mutant of Arabidopsis thaliana is characterized by a modified flavonol glycosylation profile that is inducing changes in auxin transport and growth defects in shoot tissues. To determine whether specific flavonol glycosides are responsible for these phenotypes, a suppressor screen was performed on the rol1-2 mutant, resulting in the identification of an allelic series of UGT89C1, a gene encoding a flavonol 7-O-rhamnosyltransferase. A detailed analysis revealed that interfering with flavonol rhamnosylation increases the concentration of auxin precursors and auxin metabolites, whereas auxin transport is not affected. This finding provides an additional level of complexity to the possible ways by which flavonols influence auxin distribution and suggests that flavonol glycosides play an important role in regulating plant development.

  12. Deletion of a fur-Like Gene Affects Iron Homeostasis and Magnetosome Formation in Magnetospirillum gryphiswaldense▿ †

    PubMed Central

    Uebe, René; Voigt, Birgit; Schweder, Thomas; Albrecht, Dirk; Katzmann, Emanuel; Lang, Claus; Böttger, Lars; Matzanke, Berthold; Schüler, Dirk

    2010-01-01

    Magnetotactic bacteria synthesize specific organelles, the magnetosomes, which are membrane-enveloped crystals of the magnetic mineral magnetite (Fe3O4). The biomineralization of magnetite involves the uptake and intracellular accumulation of large amounts of iron. However, it is not clear how iron uptake and biomineralization are regulated and balanced with the biochemical iron requirement and intracellular homeostasis. In this study, we identified and analyzed a homologue of the ferric uptake regulator Fur in Magnetospirillum gryphiswaldense, which was able to complement a fur mutant of Escherichia coli. A fur deletion mutant of M. gryphiswaldense biomineralized fewer and slightly smaller magnetite crystals than did the wild type. Although the total cellular iron accumulation of the mutant was decreased due to reduced magnetite biomineralization, it exhibited an increased level of free intracellular iron, which was bound mostly to a ferritin-like metabolite that was found significantly increased in Mössbauer spectra of the mutant. Compared to that of the wild type, growth of the fur mutant was impaired in the presence of paraquat and under aerobic conditions. Using a Fur titration assay and proteomic analysis, we identified constituents of the Fur regulon. Whereas the expression of most known magnetosome genes was unaffected in the fur mutant, we identified 14 proteins whose expression was altered between the mutant and the wild type, including five proteins whose genes constitute putative iron uptake systems. Our data demonstrate that Fur is a regulator involved in global iron homeostasis, which also affects magnetite biomineralization, probably by balancing the competing demands for biochemical iron supply and magnetite biomineralization. PMID:20562310

  13. Dietary starch sources affect net portal appearance of amino acids and glucose in growing pigs.

    PubMed

    Li, T-J; Dai, Q-Z; Yin, Y-L; Zhang, J; Huang, R-L; Ruan, Z; Deng, Z; Xie, M

    2008-05-01

    Four male pigs (Duroc × Landrace × Yorkshire; average initial (mean ± SEM) BW = 22.5 ± 1.1 kg), fitted with permanent catheters in the portal vein, ileal vein and carotid artery, were used in a 4 × 4 Latin square experimental design to measure the effect of dietary starch sources on the net portal appearance of glucose and amino acids. Dietary starch sources were resistant starch (RS), maize, sticky rice and brown rice. Diets were provided at 0730, 1530 and 2330 h during a 6-day adjustment period and 1-day collection period. On day 7 of each period, blood samples were collected from the portal vein and carotid artery at 0730 h (prior to feeding) and hourly up to 8 h after meal. Blood samples were used to determine glucose, amino acid, packed cell volume and partial pressure of oxygen (pO2). When calculated per 100 g feed intake, cumulative portal glucose appearance was lower (P < 0.05) for resistant starch than for maize, sticky rice or brown rice up to 8 h after the meal. Cumulative portal glucose appearance was higher (P < 0.05) for sticky rice and brown rice than for other diets until 4 h after the meal, but maize had higher cumulative glucose appearance after 4 h. Net cumulative portal concentrations of most amino acids for resistant starch were also reduced (P < 0.05) than for the other starch sources. Cumulative portal appearance of amino acid represented 48.39%, 63.76%, 61.80% and 59.18% of dietary intake for resistant starch, maize, sticky rice and brown rice, respectively. Collectively, our results indicate that dietary starch sources substantially affect the appearance of amino acids and glucose in the portal circulation.

  14. Antidiabetic and Antilipidemic Effect of Musa balbisiana Root Extract: A Potent Agent for Glucose Homeostasis in Streptozotocin-Induced Diabetic Rat

    PubMed Central

    Kalita, Himadri; Boruah, Dulal C.; Deori, Meetali; Hazarika, Ankita; Sarma, Rahul; Kumari, Sima; Kandimalla, Raghuram; Kotoky, Jibon; Devi, Rajlakshmi

    2016-01-01

    Folklore studies have revealed that Musa balbisiana Colla (MB; Family: Musaceae) has high medicinal properties. The purpose of the present study is to evaluate antihyperglycemic, and antioxidant activity of MB extracts in streptozotocin (STZ) induced diabetic rats. In vitro antioxidant and antidiabetic activity of MB extracts, i.e., root extract (RE), shoot extract and inflorescence extract were determined by using various methods viz 1,-1-diphenyl-2-picrylhydrazyl (DPPH) and a method to assess their possible effect on glucose diffusion across gastrointestinal tract and identify bioactive compound of potent extract. In vivo antilipidemic and antidiabetic activity was evaluated by administrating oral dose of RE for 15 days on STZ- induced diabetic rat. RE showed highest antioxidant activity by scavenging DPPH radical (IC50 32.96 μg/ml) and inhibit 30% glucose movement in vitro. The methanol extract of root showed the presence of calyx [4] arene category of the compound. Furthermore, RE treated rat revealed a reduction in fasting blood glucose (62.5%), serum total cholesterol (36.2%), triglyceride (54.5%), and low-density lipoprotein (50.94%) after 15 days as compared to STZ treated animal. There was an initiation of regenerative structures of the affected organs after 15 days of RE treatment. Histopathological observations clearly differentiate the structural changes in pancreas, liver, and kidney of STZ and RE treated group. The presence of calyx [4] arene class of compound may be responsible for its antioxidant and antidiabetic properties by absorbing glucose in vivo. PMID:27199747

  15. Lifetime Exposure to a Constant Environment Amplifies the Impact of a Fructose-Rich Diet on Glucose Homeostasis during Pregnancy.

    PubMed

    Song, Aleida; Astbury, Stuart; Hoedl, Abha; Nielsen, Brent; Symonds, Michael E; Bell, Rhonda C

    2017-03-25

    The need to refine rodent models of human-related disease is now being recognized, in particular the rearing environment that can profoundly modulate metabolic regulation. Most studies on pregnancy and fetal development purchase and transport young females into the research facility, which after a short period of acclimation are investigated (Gen0). We demonstrate that female offspring (Gen1) show an exaggerated hyperinsulinemic response to pregnancy when fed a standard diet and with high fructose intake, which continues throughout pregnancy. Markers of maternal hepatic metabolism were differentially influenced, as the gene expression of acetyl-CoA-carboxylase was raised in Gen1 given fructose and controls, whereas glucose transporter 5 and fatty acid synthase expression were only raised with fructose. Gen1 rats weighed more than Gen0 throughout the study, although fructose feeding raised the percent body fat but not body weight. We show that long-term habituation to the living environment has a profound impact on the animal's metabolic responses to nutritional intervention and pregnancy. This has important implications for interpreting many studies investigating the influence of maternal consumption of fructose on pregnancy outcomes and offspring to date.

  16. Effect of Vanadyl Rosiglitazone, a New Insulin-Mimetic Vanadium Complexes, on Glucose Homeostasis of Diabetic Mice.

    PubMed

    Jiang, Pingzhe; Dong, Zhen; Ma, Baicheng; Ni, Zaizhong; Duan, Huikun; Li, Xiaodan; Wang, Bin; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Li, Minggang

    2016-11-01

    Diabetes has been cited as the most challenging health problem in the twenty-first century. Accordingly, it is urgent to develop a new type of efficient and low-toxic antidiabetic medication. Since vanadium compounds have insulin-mimetic and potential hypoglycemic activities for type 1 and type 2 diabetes, a new trend has been developed using vanadium and organic ligands to form a new compound in order to increase the intestinal absorption and reduce the toxicity of vanadium compound. In the current investigation, a new organic vanadium compounds, vanadyl rosiglitazone, was synthesized and determined by infrared spectra. Vanadyl rosiglitazone and three other organic vanadium compounds were administered to the diabetic mice through oral administration for 5 weeks. The results of mouse model test indicated that vanadyl rosiglitazone could regulate the blood glucose level and relieve the symptoms of polydipsia, polyphagia, polyuria, and weight loss without side effects and was more effective than the other three organic vanadium compounds including vanadyl trehalose, vanadyl metformin, and vanadyl quercetin. The study indicated that vanadyl rosiglitazone presents insulin-mimetic activities, and it will be a good potential candidate for the development of a new type of oral drug for type 2 diabetes.

  17. Targeting of the circadian clock via CK1δ/ε to improve glucose homeostasis in obesity

    PubMed Central

    Cunningham, Peter S.; Ahern, Siobhán A.; Smith, Laura C.; da Silva Santos, Carla S.; Wager, Travis T.; Bechtold, David A.

    2016-01-01

    Growing evidence indicates that disruption of our internal timing system contributes to the incidence and severity of metabolic diseases, including obesity and type 2 diabetes. This is perhaps not surprising since components of the circadian clockwork are tightly coupled to metabolic processes across the body. In the current study, we assessed the impact of obesity on the circadian system in mice at a behavioural and molecular level, and determined whether pharmacological targeting of casein kinase 1δ and ε (CK1δ/ε), key regulators of the circadian clock, can confer metabolic benefit. We demonstrate that although behavioural rhythmicity was maintained in diet-induced obesity (DIO), gene expression profiling revealed tissue-specific alteration to the phase and amplitude of the molecular clockwork. Clock function was most significantly attenuated in visceral white adipose tissue (WAT) of DIO mice, and was coincident with elevated tissue inflammation, and dysregulation of clock-coupled metabolic regulators PPARα/γ. Further, we show that daily administration of a CK1δ/ε inhibitor (PF-5006739) improved glucose tolerance in both DIO and genetic (ob/ob) models of obesity. These data further implicate circadian clock disruption in obesity and associated metabolic disturbance, and suggest that targeting of the clock represents a therapeutic avenue for the treatment of metabolic disorders. PMID:27439882

  18. Fatty acid metabolism during maturation affects glucose uptake and is essential to oocyte competence.

    PubMed

    Paczkowski, M; Schoolcraft, W B; Krisher, R L

    2014-10-01

    Fatty acid β-oxidation (FAO) is essential for oocyte maturation in mice. The objective of this study was to determine the effect of etomoxir (a FAO inhibitor; 100 μM), carnitine (1 mM), and palmitic acid (1 or 100 μM) during maturation on metabolism and gene expression of the oocyte and cumulus cells, and subsequent embryo development in the mouse. Carnitine significantly increased embryo development, while there was a decrease in development following maturation with 100 μM palmitic acid or etomoxir (P<0.05) treatment. Glucose consumption per cumulus-oocyte complex (COC) was decreased after treatment with carnitine and increased following etomoxir treatment (P<0.05). Intracellular oocyte lipid content was decreased after carnitine or etomoxir exposure (P<0.05). Abundance of Slc2a1 (Glut1) was increased after etomoxir treatment in the oocyte and cumulus cells (P<0.05), suggesting stimulation of glucose transport and potentially the glycolytic pathway for energy production when FAO is inhibited. Abundance of carnitine palmitoyltransferase 2 (Cpt2) tended to increase in oocytes (P=0.1) after treatment with 100 μM palmitic acid and in cumulus cells after exposure to 1 μM palmitic acid (P=0.07). Combined with carnitine, 1 μM palmitic acid increased the abundance of Acsl3 (P<0.05) and Cpt2 tended to increase (P=0.07) in cumulus cells, suggesting FAO was increased during maturation in response to stimulators and fatty acids. In conclusion, fatty acid and glucose metabolism are related to the mouse COC, as inhibition of FAO increases glucose consumption. Stimulation of FAO decreases glucose consumption and lipid stores, positively affecting subsequent embryo development, while an overabundance of fatty acid or reduced FAO negatively affects oocyte quality.

  19. Knockdown of the coenzyme Q synthesis gene Smed-dlp1 affects planarian regeneration and tissue homeostasis.

    PubMed

    Shiobara, Yumiko; Harada, Chiaki; Shiota, Takeshi; Sakamoto, Kimitoshi; Kita, Kiyoshi; Tanaka, Saeko; Tabata, Kenta; Sekie, Kiyoteru; Yamamoto, Yorihiro; Sugiyama, Tomoyasu

    2015-12-01

    The freshwater planarian is a model organism used to study tissue regeneration that occupies an important position among multicellular organisms. Planarian genomic databases have led to the identification of genes that are required for regeneration, with implications for their roles in its underlying mechanism. Coenzyme Q (CoQ) is a fundamental lipophilic molecule that is synthesized and expressed in every cell of every organism. Furthermore, CoQ levels affect development, life span, disease and aging in nematodes and mice. Because CoQ can be ingested in food, it has been used in preventive nutrition. In this study, we investigated the role of CoQ in planarian regeneration. Planarians synthesize both CoQ9 and rhodoquinone 9 (RQ9). Knockdown of Smed-dlp1, a trans-prenyltransferase gene that encodes an enzyme that synthesizes the CoQ side chain, led to a decrease in CoQ9 and RQ9 levels. However, ATP levels did not consistently decrease in these animals. Knockdown animals exhibited tissue regression and curling. The number of mitotic cells decreased in Smed-dlp1 (RNAi) animals. These results suggested a failure in physiological cell turnover and stem cell function. Accordingly, regenerating planarians died from lysis or exhibited delayed regeneration. Interestingly, the observed phenotypes were partially rescued by ingesting food supplemented with α-tocopherol. Taken together, our results suggest that oxidative stress induced by reduced CoQ9 levels affects planarian regeneration and tissue homeostasis.

  20. Knockdown of the coenzyme Q synthesis gene Smed-dlp1 affects planarian regeneration and tissue homeostasis

    PubMed Central

    Shiobara, Yumiko; Harada, Chiaki; Shiota, Takeshi; Sakamoto, Kimitoshi; Kita, Kiyoshi; Tanaka, Saeko; Tabata, Kenta; Sekie, Kiyoteru; Yamamoto, Yorihiro; Sugiyama, Tomoyasu

    2015-01-01

    The freshwater planarian is a model organism used to study tissue regeneration that occupies an important position among multicellular organisms. Planarian genomic databases have led to the identification of genes that are required for regeneration, with implications for their roles in its underlying mechanism. Coenzyme Q (CoQ) is a fundamental lipophilic molecule that is synthesized and expressed in every cell of every organism. Furthermore, CoQ levels affect development, life span, disease and aging in nematodes and mice. Because CoQ can be ingested in food, it has been used in preventive nutrition. In this study, we investigated the role of CoQ in planarian regeneration. Planarians synthesize both CoQ9 and rhodoquinone 9 (RQ9). Knockdown of Smed-dlp1, a trans-prenyltransferase gene that encodes an enzyme that synthesizes the CoQ side chain, led to a decrease in CoQ9 and RQ9 levels. However, ATP levels did not consistently decrease in these animals. Knockdown animals exhibited tissue regression and curling. The number of mitotic cells decreased in Smed-dlp1 (RNAi) animals. These results suggested a failure in physiological cell turnover and stem cell function. Accordingly, regenerating planarians died from lysis or exhibited delayed regeneration. Interestingly, the observed phenotypes were partially rescued by ingesting food supplemented with α-tocopherol. Taken together, our results suggest that oxidative stress induced by reduced CoQ9 levels affects planarian regeneration and tissue homeostasis. PMID:26516985

  1. Leucine supplementation improves adiponectin and total cholesterol concentrations despite the lack of changes in adiposity or glucose homeostasis in rats previously exposed to a high-fat diet

    PubMed Central

    2011-01-01

    Background Studies suggest that leucine supplementation (LS) has a therapeutic potential to prevent obesity and to promote glucose homeostasis. Furthermore, regular physical exercise is a widely accepted strategy for body weight maintenance and also for the prevention of obesity. The aim of this study was to determine the effect of chronic LS alone or combined with endurance training (ET) as potential approaches for reversing the insulin resistance and obesity induced by a high-fat diet (HFD) in rats. Methods Forty-seven rats were randomly divided into two groups. Animals were fed a control diet-low fat (n = 10) or HFD (n = 37). After 15 weeks on HFD, all rats received the control diet-low fat and were randomly divided according to treatment: reference (REF), LS, ET, and LS+ET (n = 7-8 rats per group). After 6 weeks of treatment, the animals were sacrificed and body composition, fat cell volume, and serum concentrations of total cholesterol, HDL-cholesterol, triacylglycerol, glucose, adiponectin, leptin and tumor necrosis factor-alpha (TNF-α) were analyzed. Results At the end of the sixth week of treatment, there was no significant difference in body weight between the REF, LS, ET and LS+ET groups. However, ET increased lean body mass in rats (P = 0.019). In addition, ET was more effective than LS in reducing adiposity (P = 0.019), serum insulin (P = 0.022) and TNF-α (P = 0.044). Conversely, LS increased serum adiponectin (P = 0.021) levels and reduced serum total cholesterol concentration (P = 0.042). Conclusions The results showed that LS had no beneficial effects on insulin sensitivity or adiposity in previously obese rats. On the other hand, LS was effective in increasing adiponectin levels and in reducing total cholesterol concentration. PMID:21899736

  2. Mice lacking C1q are protected from high fat diet-induced hepatic insulin resistance and impaired glucose homeostasis.

    PubMed

    Hillian, Antoinette D; McMullen, Megan R; Sebastian, Becky M; Roychowdhury, Sanjoy; Rowchowdhury, Sanjoy; Kashyap, Sangeeta R; Schauer, Philip R; Kirwan, John P; Feldstein, Ariel E; Nagy, Laura E

    2013-08-02

    Complement activation is implicated in the development of obesity and insulin resistance, and loss of signaling by the anaphylatoxin C3a prevents obesity-induced insulin resistance in mice. Here we have identified C1q in the classical pathway as required for activation of complement in response to high fat diets. After 8 weeks of high fat diet, wild-type mice became obese and developed glucose intolerance. This was associated with increased apoptotic cell death and accumulation of complement activation products (C3b/iC3b/C3c) in liver and adipose tissue. Previous studies have shown that high fat diet-induced apoptosis is dependent on Bid; here we report that Bid-mediated apoptosis was required for complement activation in adipose and liver. Although C1qa deficiency had no effect on high fat diet-induced apoptosis, accumulation of complement activation products and the metabolic complications of high fat diet-induced obesity were dependent on C1q. When wild-type mice were fed a high fat diet for only 3 days, hepatic insulin resistance was associated with the accumulation of C3b/iC3b/C3c in the liver. Mice deficient in C3a receptor were protected against this early high fat diet-induced hepatic insulin resistance, whereas mice deficient in the negative complement regulator CD55/DAF were more sensitive to the high fat diet. C1qa(-/-) mice were also protected from high fat diet-induced hepatic insulin resistance and complement activation. Evidence of complement activation was also detected in adipose tissue of obese women compared with lean women. Together, these studies reveal an important role for C1q in the classical pathway of complement activation in the development of high fat diet-induced insulin resistance.

  3. Ectopic Expression of WRINKLED1 Affects Fatty Acid Homeostasis in Brachypodium distachyon Vegetative Tissues1[OPEN

    PubMed Central

    Yang, Yang; Munz, Jacob; Cass, Cynthia; Zienkiewicz, Agnieszka; Kong, Que; Ma, Wei; Sedbrook, John; Benning, Christoph

    2015-01-01

    Triacylglycerol (TAG) is a storage lipid used for food purposes and as a renewable feedstock for biodiesel production. WRINKLED1 (WRI1) is a transcription factor that governs fatty acid (FA) synthesis and, indirectly, TAG accumulation in oil-storing plant tissues, and its ectopic expression has led to TAG accumulation in vegetative tissues of different dicotyledonous plants. The ectopic expression of BdWRI1 in the grass Brachypodium distachyon induced the transcription of predicted genes involved in glycolysis and FA biosynthesis, and TAG content was increased up to 32.5-fold in 8-week-old leaf blades. However, the ectopic expression of BdWRI1 also caused cell death in leaves, which has not been observed previously in dicotyledonous plants such as Arabidopsis (Arabidopsis thaliana). Lipid analysis indicated that the free FA content was 2-fold elevated in BdWRI1-expressing leaf blades of B. distachyon. The transcription of predicted genes involved in β-oxidation was induced. In addition, linoleic FA treatment caused cell death in B. distachyon leaf blades, an effect that was reversed by the addition of the FA biosynthesis inhibitor cerulenin. Taken together, ectopic expression of BdWRI1 in B. distachyon enhances FA biosynthesis and TAG accumulation in leaves, as expected, but also leads to increased free FA content, which has cytotoxic effects leading to cell death. Thus, while WRI appears to ubiquitously affect FA biosynthesis and TAG accumulation in diverse plants, its ectopic expression can lead to undesired side effects depending on the context of the specific lipid metabolism of the respective plant species. PMID:26419778

  4. Ectopic Expression of WRINKLED1 Affects Fatty Acid Homeostasis in Brachypodium distachyon Vegetative Tissues.

    PubMed

    Yang, Yang; Munz, Jacob; Cass, Cynthia; Zienkiewicz, Agnieszka; Kong, Que; Ma, Wei; Sedbrook, John; Benning, Christoph

    2015-11-01

    Triacylglycerol (TAG) is a storage lipid used for food purposes and as a renewable feedstock for biodiesel production. WRINKLED1 (WRI1) is a transcription factor that governs fatty acid (FA) synthesis and, indirectly, TAG accumulation in oil-storing plant tissues, and its ectopic expression has led to TAG accumulation in vegetative tissues of different dicotyledonous plants. The ectopic expression of BdWRI1 in the grass Brachypodium distachyon induced the transcription of predicted genes involved in glycolysis and FA biosynthesis, and TAG content was increased up to 32.5-fold in 8-week-old leaf blades. However, the ectopic expression of BdWRI1 also caused cell death in leaves, which has not been observed previously in dicotyledonous plants such as Arabidopsis (Arabidopsis thaliana). Lipid analysis indicated that the free FA content was 2-fold elevated in BdWRI1-expressing leaf blades of B. distachyon. The transcription of predicted genes involved in β-oxidation was induced. In addition, linoleic FA treatment caused cell death in B. distachyon leaf blades, an effect that was reversed by the addition of the FA biosynthesis inhibitor cerulenin. Taken together, ectopic expression of BdWRI1 in B. distachyon enhances FA biosynthesis and TAG accumulation in leaves, as expected, but also leads to increased free FA content, which has cytotoxic effects leading to cell death. Thus, while WRI appears to ubiquitously affect FA biosynthesis and TAG accumulation in diverse plants, its ectopic expression can lead to undesired side effects depending on the context of the specific lipid metabolism of the respective plant species.

  5. Minireview: Toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes.

    PubMed

    Karamitri, Angeliki; Renault, Nicolas; Clement, Nathalie; Guillaume, Jean-Luc; Jockers, Ralf

    2013-08-01

    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.

  6. Dose and Latency Effects of Leucine Supplementation in Modulating Glucose Homeostasis: Opposite Effects in Healthy and Glucocorticoid-Induced Insulin-Resistance States

    PubMed Central

    Zanchi, Nelo Eidy; Guimarães-Ferreira, Lucas; de Siqueira-Filho, Mário Alves; Felitti, Vitor; Nicastro, Humberto; Bueno, Carlos; Lira, Fábio Santos; Naimo, Marshall Alan; Campos-Ferraz, Patrícia; Nunes, Maria Tereza; Seelaender, Marília; de Oliveira Carvalho, Carla Roberta; Blachier, François; Lancha, Antonio Herbert

    2012-01-01

    Dexamethasone (DEXA) is a potent immunosupressant and anti-inflammatory agent whose main side effects are muscle atrophy and insulin resistance in skeletal muscles. In this context, leucine supplementation may represent a way to limit the DEXA side effects. In this study, we have investigated the effects of a low and a high dose of leucine supplementation (via a bolus) on glucose homeostasis, muscle mass and muscle strength in energy-restricted and DEXA-treated rats. Since the leucine response may also be linked to the administration of this amino acid, we performed a second set of experiments with leucine given in bolus (via gavage) versus leucine given via drinking water. Leucine supplementation was found to produce positive effects (e.g., reduced insulin levels) only when administrated in low dosage, both via the bolus or via drinking water. However, under DEXA treatment, leucine administration was found to significantly influence this response, since leucine supplementation via drinking water clearly induced a diabetic state, whereas the same effect was not observed when supplied via the gavage. PMID:23363994

  7. GLUT-4, tumour necrosis factor, essential fatty acids and daf-genes and their role in glucose homeostasis, insulin resistance, non-insulin dependent diabetes mellitus, and longevity.

    PubMed

    Das, U N

    1999-04-01

    GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes seem to play an important and essential role in the maintenance of glucose homeostasis, and in the pathobiology of obesity and non-insulin dependent diabetes mellitus (NIDDM). Daf-genes encode for proteins which are 35% identical to the human insulin receptor, a transforming growth factor-beta (TGF-beta) type signal and can also enhance the expression of superoxide dismutase (SOD). On the other hand, EFAs and their metabolites can increase the cell membrane fluidity and thus, enhance the expression of GLUT-4 and insulin receptors. In addition, EFAs can suppress TNF-alpha production and secretion and thus, are capable of reversing insulin resistance. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Hence, it is likely that there is a close interaction between GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin that may have relevance to the development of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing.

  8. Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice.

    PubMed

    Kodo, Kazuki; Sugimoto, Satoru; Nakajima, Hisakazu; Mori, Jun; Itoh, Ikuyo; Fukuhara, Shota; Shigehara, Keiichi; Nishikawa, Taichiro; Kosaka, Kitaro; Hosoi, Hajime

    2017-01-01

    's improvement of obesity and glucose homeostasis can be attributed to increased iBAT thermogenic capacity and activation of BAT's endocrine functions.

  9. Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice

    PubMed Central

    Kodo, Kazuki; Sugimoto, Satoru; Mori, Jun; Itoh, Ikuyo; Fukuhara, Shota; Shigehara, Keiichi; Nishikawa, Taichiro; Kosaka, Kitaro; Hosoi, Hajime

    2017-01-01

    s improvement of obesity and glucose homeostasis can be attributed to increased iBAT thermogenic capacity and activation of BAT’s endocrine functions. PMID:28288167

  10. 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

  11. Folic acid supplementation affects apoptosis and differentiation of embryonic neural stem cells exposed to high glucose.

    PubMed

    Jia, De-yong; Liu, Hui-juan; Wang, Fu-wu; Liu, Shang-ming; Ling, Eng-Ang; Liu, Kai; Hao, Ai-jun

    2008-07-25

    Folic acid (FA) supplementation has been shown to be extremely effective in reducing the occurrence of neural tube defects (NTDs), one of the most common birth defects associated with diabetic pregnancy. However, the antiteratogenic mechanism of FA in diabetes-induced NTDs is unclear. This study investigated the neuroprotective mechanism of FA in neural stem cells (NSCs) exposed to high glucose in vitro. The undifferentiated or differentiated NSCs were cultured in normal D-glucose concentration (NG) or high D-glucose concentration (HG) with or without FA. FA supplementation significantly decreased apoptosis induced by HG and lowered the expression of p53 in the nucleus of undifferentiated NSCs exposed to HG. Administration of FA in differentiated NSCs did not alter their precocious differentiation induced by HG. The increased mRNA expression levels of the basic helix-loop-helix factors including Neurog1, Neurog2, NeuroD2, Mash1, Id1, Id2, and Hes5 in the presence of HG were not significantly affected by FA. The present results provided a cellular mechanism by which FA supplementation may have a potential role in prevention of NTDs in diabetic pregnancies. On the other hand, FA increased the mRNA expression levels of the above transcription factors and accelerated the differentiation of NSCs in the NG medium, suggesting that it may adversely affect the normal differentiation of NSCs. Therefore, the timing and dose of FA would be critical factors in considering FA supplementation in normal maternal pregnancy.

  12. Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species

    PubMed Central

    Lee, Mi Jin; Lee, Seung Jun; Yun, Su Jin; Jang, Ji-Young; Kang, Hangoo; Kim, Kyongmin; Choi, In-Hong; Park, Sun

    2016-01-01

    The silver nanoparticle (AgNP) is a candidate for anticancer therapy because of its effects on cell survival and signaling. Although numerous reports are available regarding their effect on cell death, the effect of AgNPs on metabolism is not well understood. In this study, we investigated the effect of AgNPs on glucose metabolism in hepatoma cell lines. Lactate release from both HepG2 and Huh7 cells was reduced with 5 nm AgNPs as early as 1 hour after treatment, when cell death did not occur. Treatment with 5 nm AgNPs decreased glucose consumption in HepG2 cells but not in Huh7 cells. Treatment with 5 nm AgNPs reduced nuclear factor erythroid 2-like 2 expression in both cell types without affecting its activation at the early time points after AgNPs’ treatment. Increased reactive oxygen species (ROS) production was detected 1 hour after 5 nm AgNPs’ treatment, and lactate release was restored in the presence of an ROS scavenger. Our results suggest that 5 nm AgNPs affect glucose metabolism by producing ROS. PMID:26730190

  13. Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species.

    PubMed

    Lee, Mi Jin; Lee, Seung Jun; Yun, Su Jin; Jang, Ji-Young; Kang, Hangoo; Kim, Kyongmin; Choi, In-Hong; Park, Sun

    2016-01-01

    The silver nanoparticle (AgNP) is a candidate for anticancer therapy because of its effects on cell survival and signaling. Although numerous reports are available regarding their effect on cell death, the effect of AgNPs on metabolism is not well understood. In this study, we investigated the effect of AgNPs on glucose metabolism in hepatoma cell lines. Lactate release from both HepG2 and Huh7 cells was reduced with 5 nm AgNPs as early as 1 hour after treatment, when cell death did not occur. Treatment with 5 nm AgNPs decreased glucose consumption in HepG2 cells but not in Huh7 cells. Treatment with 5 nm AgNPs reduced nuclear factor erythroid 2-like 2 expression in both cell types without affecting its activation at the early time points after AgNPs' treatment. Increased reactive oxygen species (ROS) production was detected 1 hour after 5 nm AgNPs' treatment, and lactate release was restored in the presence of an ROS scavenger. Our results suggest that 5 nm AgNPs affect glucose metabolism by producing ROS.

  14. Multifunctional Thioredoxin-Like Protein from the Gastrointestinal Parasitic Nematodes Strongyloides ratti and Trichuris suis Affects Mucosal Homeostasis

    PubMed Central

    Hansmann, Jan; Winter, Dominic; Schramm, Guido; Erttmann, Klaus D.; Liebau, Eva

    2016-01-01

    The cellular redox state is important for the regulation of multiple functions and is essential for the maintenance of cellular homeostasis and antioxidant defense. In the excretory/secretory (E/S) products of Strongyloides ratti and Trichuris suis sequences for thioredoxin (Trx) and Trx-like protein (Trx-lp) were identified. To characterize the antioxidant Trx-lp and its interaction with the parasite's mucosal habitat, S. ratti and T. suis Trx-lps were cloned and recombinantly expressed. The primary antioxidative activity was assured by reduction of insulin and IgM. Further analysis applying an in vitro mucosal 3D-cell culture model revealed that the secreted Trx-lps were able to bind to monocytic and intestinal epithelial cells and induce the time-dependent release of cytokines such as TNF-α, IL-22, and TSLP. In addition, the redox proteins also possessed chemotactic activity for monocytic THP-1 cells and fostered epithelial wound healing activity. These results confirm that the parasite-secreted Trx-lps are multifunctional proteins that can affect the host intestinal mucosa. PMID:27872753

  15. AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle.

    PubMed

    de Laat, M A; Robinson, M A; Gruntmeir, K J; Liu, Y; Soma, L R; Lacombe, V A

    2015-09-01

    Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P <0.05) in blood glucose and an increase (P <0.05) in insulin concentration without a change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P <0.05) in skeletal muscle. While GLUT4 and GLUT1 protein expression remained unchanged, GLUT8 was increased (P <0.05) following AICAR treatment. Up-regulation of GLUT8 protein expression by AICAR suggests that this novel GLUT isoform plays an important role in equine muscle glucose transport. In addition, the data suggest that AMPK activation enhances pancreatic insulin secretion. Collectively, the findings suggest that AICAR acutely promotes muscle glucose uptake in healthy horses and thus its therapeutic potential for managing IR requires investigation.

  16. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis.

    PubMed

    Qian, Shu-Wen; Tang, Yan; Li, Xi; Liu, Yuan; Zhang, You-You; Huang, Hai-Yan; Xue, Rui-Dan; Yu, Hao-Yong; Guo, Liang; Gao, Hui-Di; Liu, Yan; Sun, Xia; Li, Yi-Ming; Jia, Wei-Ping; Tang, Qi-Qun

    2013-02-26

    Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces "white adipocytes" with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4's role in altering insulin sensitivity by affecting WAT development.

  17. Overexpression of the Novel Arabidopsis Gene At5g02890 Alters Inflorescence Stem Wax Composition and Affects Phytohormone Homeostasis

    PubMed Central

    Xu, Liping; Zeisler, Viktoria; Schreiber, Lukas; Gao, Jie; Hu, Kaining; Wen, Jing; Yi, Bin; Shen, Jinxiong; Ma, Chaozhi; Tu, Jinxing; Fu, Tingdong

    2017-01-01

    The cuticle is composed of cutin and cuticular wax. It covers the surfaces of land plants and protects them against environmental damage. At5g02890 encodes a novel protein in Arabidopsis thaliana. In the current study, protein sequence analysis showed that At5g02890 is highly conserved in the Brassicaceae. Arabidopsis lines overexpressing At5g02890 (OE-At5g02890 lines) and an At5g02890 orthologous gene from Brassica napus (OE-Bn1 lines) exhibited glossy stems. Chemical analysis revealed that overexpression of At5g02890 caused significant reductions in the levels of wax components longer than 28 carbons (C28) in inflorescence stems, whereas the levels of wax molecules of chain length C28 or shorter were significantly increased. Transcriptome analysis indicated that nine of 11 cuticular wax synthesis-related genes with different expression levels in OE-At5g02890 plants are involved in very-long-chain fatty acid (VLCFA) elongation. At5g02890 is localized to the endoplasmic reticulum (ER), which is consistent with its function in cuticular wax biosynthesis. These results demonstrate that the overexpression of At5g02890 alters cuticular wax composition by partially blocking VLCFA elongation of C28 and higher. In addition, detailed analysis of differentially expressed genes associated with plant hormones and endogenous phytohormone levels in wild-type and OE-At5g02890 plants indicated that abscisic acid (ABA), jasmonic acid (JA), and jasmonoyl-isoleucine (JA-Ile) biosynthesis, as well as polar auxin transport, were also affected by overexpression of At5g02890. Taken together, these findings indicate that overexpression of At5g02890 affects both cuticular wax biosynthesis and phytohormone homeostasis in Arabidopsis. PMID:28184233

  18. Subchronic effects of inhaled ambient particulate matter on glucose homeostasis and target organ damage in a type 1 diabetic rat model

    SciTech Connect

    Yan, Yuan-Horng; Charles, Chou C.-K.; Wang, Jyh-Seng; Tung, Chun-Liang; Li, Ya-Ru; Lo, Kai; Cheng, Tsun-Jen

    2014-12-01

    Epidemiological studies have reported associations between particulate matter (PM) and cardiovascular effects, and diabetes mellitus (DM) patients might be susceptible to these effects. The chief chronic injuries resulting from DM are small vascular injuries (micro-vascular complications) or large blood vessel injuries (macro-vascular complications). However, toxicological data regarding the effects of PM on DM-related cardiovascular complications is limited. Our objective was to investigate whether subchronic PM exposure alters glucose homeostasis and causes cardiovascular complications in a type 1 DM rat model. We constructed a real world PM{sub 2.5} exposure system, the Taipei Air Pollution Exposure System for Health Effects (TAPES), to continuously deliver non-concentrated PM for subchronic exposure. A type 1 DM rat model was induced using streptozotocin. Between December 22, 2009 and April 9, 2010, DM rats were exposed to PM or to filtered air (FA) using TAPES in Taipei, Taiwan, 24 h/day, 7 days/week, for a total of 16 weeks. The average concentrations (mean [SD]) of PM{sub 2.5} in the exposure and control chambers of the TAPES were 13.30 [8.65] and 0.13 [0.05] μg/m{sup 3}, respectively. Glycated hemoglobin A1c (HbA1c) was significantly elevated after exposure to PM compared with exposure to FA (mean [SD], 7.7% [3.1%] vs. 4.7% [1.0%], P < 0.05). Interleukin 6 and fibrinogen levels were significantly increased after PM exposure. PM caused focal myocarditis, aortic medial thickness, advanced glomerulosclerosis, and accentuation of tubular damage of the kidney (tubular damage index: 1.76 [0.77] vs. 1.15 [0.36], P < 0.001). PM exposure might induce the macro- and micro-vascular complications in DM through chronic hyperglycemia and systemic inflammation. - Highlights: • The study demonstrated cardiovascular and renal effects of PM in a rat model of DM. • TAPES is a continuous, real world, long-term PM exposure system. • HbA1c, a marker of glycemic

  19. Sex-specific associations of low birth weight with adult-onset diabetes and measures of glucose homeostasis: Brazilian Longitudinal Study of Adult Health

    PubMed Central

    Yarmolinsky, James; Mueller, Noel T; Duncan, Bruce B; Chor, Dóra; Bensenor, Isabela M; Griep, Rosane H; Appel, Lawrence J; Barreto, Sandhi M; Schmidt, Maria Inês

    2016-01-01

    Emerging evidence suggests sex differences in the early origins of adult metabolic disease, but this has been little investigated in developing countries. We investigated sex-specific associations between low birth weight (LBW; <2.5 kg) and adult-onset diabetes in 12,525 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Diabetes was defined by self-reported information and laboratory measurements. In confounder-adjusted analyses, LBW (vs. 2.5–4 kg) was associated with higher prevalence of diabetes in women (Prevalence Ratio (PR) 1.54, 95% CI: 1.32–1.79), not in men (PR 1.06, 95% CI: 0.91–1.25; Pheterogeneity = 0.003). The association was stronger among participants with maternal diabetes (PR 1.60, 95% CI: 1.35–1.91), than those without (PR 1.15, 95% CI: 0.99–1.32; Pheterogeneity = 0.03). When jointly stratified by sex and maternal diabetes, the association was observed for women with (PR 1.77, 95% CI: 1.37–2.29) and without (PR 1.45, 95% CI: 1.20–1.75) maternal diabetes. In contrast, in men, LBW was associated with diabetes in participants with maternal diabetes (PR 1.45, 95% CI: 1.15–1.83), but not in those without (PR 0.92, 95% CI: 0.74–1.14). These sex-specific findings extended to continuous measures of glucose homeostasis. LBW was associated with higher diabetes prevalence in Brazilian women, and in men with maternal diabetes, suggesting sex-specific intrauterine effects on adult metabolic health. PMID:27845438

  20. Long-Term Fgf23 Deficiency Does Not Influence Aging, Glucose Homeostasis, or Fat Metabolism in Mice with a Nonfunctioning Vitamin D Receptor

    PubMed Central

    Streicher, Carmen; Zeitz, Ute; Andrukhova, Olena; Rupprecht, Anne; Pohl, Elena; Larsson, Tobias E.; Windisch, Wilhelm; Lanske, Beate

    2012-01-01

    It is still controversial whether the bone-derived hormone fibroblast growth factor-23 (FGF23) has additional physiological functions apart from its well-known suppressive actions on renal phosphate reabsorption and vitamin D hormone synthesis. Here we analyzed premature aging, mineral homeostasis, carbohydrate metabolism, and fat metabolism in 9-month-old male wild-type (WT) mice, vitamin D receptor mutant mice (VDRΔ/Δ) with a nonfunctioning vitamin D receptor, and Fgf23−/−/VDRΔ/Δ compound mutant mice on both a standard rodent chow and a rescue diet enriched with calcium, phosphorus, and lactose. Organ atrophy, lung emphysema, and ectopic tissue or vascular calcifications were absent in compound mutants. In addition, body weight, glucose tolerance, insulin tolerance, insulin secretory capacity, pancreatic beta cell volume, and retroperitoneal and epididymal fat mass as well as serum cholesterol and triglycerides were indistinguishable between vitamin D receptor and compound mutants. In contrast to VDRΔ/Δ and Fgf23−/−/VDRΔ/Δ mice, which stayed lean, WT mice showed obesity-induced insulin resistance. To rule out alopecia and concomitantly elevated energy expenditure present in 9-month-old VDRΔ/Δ and Fgf23−/−/VDRΔ/Δ mice as a confounding factor for the lacking effect of Fgf23 deficiency on fat mass, we analyzed whole-body composition in WT, Fgf23−/−, VDRΔ/Δ, and Fgf23−/−/VDRΔ/Δ mice at the age of 4 wk, when the coat in VDRΔ/Δ mice is still normal. Whole-body fat mass was reduced in Fgf23−/− mice but almost identical in WT, VDRΔ/Δ, and Fgf23−/−/VDRΔ/Δ mice. In conclusion, our data indicate that Fgf23 has no molecular vitamin D-independent role in aging, insulin signaling, or fat metabolism in mice. PMID:22294750

  1. Functional delineation of rice MADS29 reveals its role in embryo and endosperm development by affecting hormone homeostasis

    PubMed Central

    Kapoor, Sanjay

    2013-01-01

    Rice MADS29 has recently been reported to cause programmed cell death of maternal tissues, the nucellus, and the nucellar projection during early stages of seed development. However, analyses involving OsMADS29 protein expression domains and characterization of OsMADS29 gain-of-function and knockdown phenotypes revealed novel aspects of its function in maintaining hormone homeostasis, which may have a role in the development of embryo and plastid differentiation and starch filling in endosperm cells. The MADS29 transcripts accumulated to high levels soon after fertilization; however, protein accumulation was found to be delayed by at least 4 days. Immunolocalization studies revealed that the protein accumulated initially in the dorsal-vascular trace and the outer layers of endosperm, and subsequently in the embryo and aleurone and subaleurone layers of the endosperm. Ectopic expression of MADS29 resulted in a severely dwarfed phenotype, exhibiting elevated levels of cytokinin, thereby suggesting that cytokinin biosynthesis pathway could be one of the major targets of OsMADS29. Overexpression of OsMADS29 in heterologous BY2 cells was found to mimic the effects of exogenous application of cytokinins that causes differentiation of proplastids to starch-containing amyloplasts and activation of genes involved in the starch biosynthesis pathway. Suppression of MADS29 expression by RNAi severely affected seed set. The surviving seeds were smaller in size, with developmental abnormalities in the embryo and reduced size of endosperm cells, which also contained loosely packed starch granules. Microarray analysis of overexpression and knockdown lines exhibited altered expression of genes involved in plastid biogenesis, starch biosynthesis, cytokinin signalling and biosynthesis. PMID:23929654

  2. Regulation of sulphur assimilation is essential for virulence and affects iron homeostasis of the human-pathogenic mould Aspergillus fumigatus.

    PubMed

    Amich, Jorge; Schafferer, Lukas; Haas, Hubertus; Krappmann, Sven

    2013-01-01

    Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

  3. Genetic determinants of glucose homeostasis.

    PubMed

    Barker, Adam; Langenberg, Claudia; Wareham, Nicholas J

    2012-04-01

    Type 2 diabetes is a complex metabolic disorder characterised by varying degrees of impairment in insulin secretion and resistance to the action of insulin. Considerable progress has been made recently in understanding the genetic determinants of diabetes. A logical next step is to describe how these variants relate to the underlying pathophysiological processes that lead to diabetes as this may provide insights into pathways to disease. These quantitative traits are, of course, of direct interest in themselves and a growing literature is now emerging on the genetic determinants of insulin secretion and insulin resistance. This review article focuses on describing the complex associations between type 2 diabetes risk variants and quantitative glycaemic traits and the relationship between variants initially discovered in association studies of these traits and risk of type 2 diabetes.

  4. Ocean Acidification Affects Redox-Balance and Ion-Homeostasis in the Life-Cycle Stages of Emiliania huxleyi

    PubMed Central

    Rokitta, Sebastian D.; John, Uwe; Rost, Björn

    2012-01-01

    Ocean Acidification (OA) has been shown to affect photosynthesis and calcification in the coccolithophore Emiliania huxleyi, a cosmopolitan calcifier that significantly contributes to the regulation of the biological carbon pumps. Its non-calcifying, haploid life-cycle stage was found to be relatively unaffected by OA with respect to biomass production. Deeper insights into physiological key processes and their dependence on environmental factors are lacking, but are required to understand and possibly estimate the dynamics of carbon cycling in present and future oceans. Therefore, calcifying diploid and non-calcifying haploid cells were acclimated to present and future CO2 partial pressures (pCO2; 38.5 Pa vs. 101.3 Pa CO2) under low and high light (50 vs. 300 µmol photons m−2 s−1). Comparative microarray-based transcriptome profiling was used to screen for the underlying cellular processes and allowed to follow up interpretations derived from physiological data. In the diplont, the observed increases in biomass production under OA are likely caused by stimulated production of glycoconjugates and lipids. The observed lowered calcification under OA can be attributed to impaired signal-transduction and ion-transport. The haplont utilizes distinct genes and metabolic pathways, reflecting the stage-specific usage of certain portions of the genome. With respect to functionality and energy-dependence, however, the transcriptomic OA-responses resemble those of the diplont. In both life-cycle stages, OA affects the cellular redox-state as a master regulator and thereby causes a metabolic shift from oxidative towards reductive pathways, which involves a reconstellation of carbon flux networks within and across compartments. Whereas signal transduction and ion-homeostasis appear equally OA-sensitive under both light intensities, the effects on carbon metabolism and light physiology are clearly modulated by light availability. These interactive effects can be attributed

  5. Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium

    PubMed Central

    Palmer, Nicholette D.; Goodarzi, Mark O.; Langefeld, Carl D.; Wang, Nan; Guo, Xiuqing; Taylor, Kent D.; Fingerlin, Tasha E.; Norris, Jill M.; Buchanan, Thomas A.; Xiang, Anny H.; Haritunians, Talin; Ziegler, Julie T.; Williams, Adrienne H.; Stefanovski, Darko; Cui, Jinrui; Mackay, Adrienne W.; Henkin, Leora F.; Bergman, Richard N.; Gao, Xiaoyi; Gauderman, James; Varma, Rohit; Hanis, Craig L.; Cox, Nancy J.; Highland, Heather M.; Below, Jennifer E.; Williams, Amy L.; Burtt, Noel P.; Aguilar-Salinas, Carlos A.; Huerta-Chagoya, Alicia; Gonzalez-Villalpando, Clicerio; Orozco, Lorena; Haiman, Christopher A.; Tsai, Michael Y.; Johnson, W. Craig; Yao, Jie; Rasmussen-Torvik, Laura; Pankow, James; Snively, Beverly; Jackson, Rebecca D.; Liu, Simin; Nadler, Jerry L.; Kandeel, Fouad; Chen, Yii-Der I.; Bowden, Donald W.; Rich, Stephen S.; Raffel, Leslie J.

    2015-01-01

    Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10−8) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D. PMID:25524916

  6. Timothy hays differing in dietary cation-anion difference affect the capability of dairy cows to maintain their calcium homeostasis.

    PubMed

    Heron, V S; Tremblay, G F; Oba, M

    2009-01-01

    Forages low in dietary cation-anion difference (DCAD) can be used to decrease the DCAD in prepartum diet but the extent to which DCAD needs to be reduced is of recent interest. The objective of this study was to evaluate the effectiveness of timothy hays differing in DCAD at maintaining Ca homeostasis. Six nonlactating and nonpregnant multiparous Holstein cows were fed diets containing timothy (Phleum pratense L.) hay with DCAD values of 4.1 +/- 3.6 (LOW), 14.1 +/- 3.0 (MED), or 25.1 +/- 2.5 (HIGH) mEq per 100 g of DM in a duplicated 3 x 3 Latin square design with 14-d experimental periods. The LOW and MED hays were produced by fertilizing established timothy fields at a rate of 224 kg CaCl(2) per ha, and HIGH hay was obtained from the same field where LOW hay was produced, but from a section not fertilized with CaCl(2). Experimental diets, containing LOW, MED, or HIGH timothy hay at 71% of dietary DM, had DCAD values of 0.7, 7.3, and 14.4 mEq per 100 g of DM, respectively. Animals were fed at 6% of metabolic body weight, which provided 108% of their daily energy requirement. For each period, after a 12 d diet adaptation, cows were subjected to an EDTA challenge (3 cows each on d 13 and 14). Infusion of EDTA solution into the jugular vein decreases the concentration of blood ionized Ca, and the EDTA challenge protocol determined the resistance time and recovery time: the time required for the blood ionized Ca concentration to decrease to 60%, and the time required to recover to 90% of the prechallenge concentrations, respectively. Urine pH was lower when cows were fed LOW compared with HIGH diet (6.88 vs. 7.83), but urine pH when cows were fed MED diet (7.15) did not differ from that when cows received the LOW or HIGH diet. However, immediately before the EDTA challenge, blood pH was lower when cows were fed LOW or MED compared with HIGH diet (7.44 vs. 7.47). Although the resistance time was not affected by treatments, the recovery time was shorter when cows were

  7. Lack of Intestinal Epithelial Atg7 Affects Paneth Cell Granule Formation but Does Not Compromise Immune Homeostasis in the Gut

    PubMed Central

    Wittkopf, Nadine; Günther, Claudia; Martini, Eva; Waldner, Maximilian; Amann, Kerstin U.; Neurath, Markus F.; Becker, Christoph

    2012-01-01

    Genetic polymorphisms of autophagy-related genes have been associated with an increased risk to develop inflammatory bowel disease (IBD). Autophagy is an elementary process participating in several cellular events such as cellular clearance and nonapoptotic programmed cell death. Furthermore, autophagy may be involved in intestinal immune homeostasis due to its participation in the digestion of intracellular pathogens and in antigen presentation. In the present study, the role of autophagy in the intestinal epithelial layer was investigated. The intestinal epithelium is essential to maintain gut homeostasis, and defects within this barrier have been associated with the pathogenesis of IBD. Therefore, mice with intestinal epithelial deletion of Atg7 were generated and investigated in different mouse models. Knockout mice showed reduced size of granules and decreased levels of lysozyme in Paneth cells. However, this was dispensable for gut immune homeostasis and had no effect on susceptibility in mouse models of experimentally induced colitis. PMID:22291845

  8. Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

    PubMed

    Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

    2016-06-01

    Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model.

  9. Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer-affected patients.

    PubMed

    Mannello, Ferdinando; Tonti, Gaetana A; Medda, Virginia; Simone, Patrizia; Darbre, Philippa D

    2011-04-01

    Aluminium is not a physiological component of the breast but has been measured recently in human breast tissues and breast cyst fluids at levels above those found in blood serum or milk. Since the presence of aluminium can lead to iron dyshomeostasis, levels of aluminium and iron-binding proteins (ferritin, transferrin) were measured in nipple aspirate fluid (NAF), a fluid present in the breast duct tree and mirroring the breast microenvironment. NAFs were collected noninvasively from healthy women (NoCancer; n = 16) and breast cancer-affected women (Cancer; n = 19), and compared with levels in serum (n = 15) and milk (n = 45) from healthy subjects. The mean level of aluminium, measured by ICP-mass spectrometry, was significantly higher in Cancer NAF (268.4 ± 28.1 μg l(-1) ; n = 19) than in NoCancer NAF (131.3 ± 9.6 μg l(-1) ; n = 16; P < 0.0001). The mean level of ferritin, measured through immunoassay, was also found to be higher in Cancer NAF (280.0 ± 32.3 μg l(-1) ) than in NoCancer NAF (55.5 ± 7.2 μg l(-1) ), and furthermore, a positive correlation was found between levels of aluminium and ferritin in the Cancer NAF (correlation coefficient R = 0.94, P < 0.001). These results may suggest a role for raised levels of aluminium and modulation of proteins that regulate iron homeostasis as biomarkers for identification of women at higher risk of developing breast cancer. The reasons for the high levels of aluminium in NAF remain unknown but possibilities include either exposure to aluminium-based antiperspirant salts in the adjacent underarm area and/or preferential accumulation of aluminium by breast tissues.

  10. 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.

  11. Polymorphisms near SOCS3 are associated with obesity and glucose homeostasis traits in Hispanic Americans from the Insulin Resistance Atherosclerosis Family Study.

    PubMed

    Talbert, Matthew E; Langefeld, Carl D; Ziegler, Julie; Mychaleckyj, Josyf C; Haffner, Steven M; Norris, Jill M; Bowden, Donald W

    2009-03-01

    The SOCS3 gene product participates in the feedback inhibition of a range of cytokine signals. Most notably, SOCS3 inhibits the functioning of leptin and downstream steps in insulin signaling after being expressed by terminal transcription factors, such as STAT3 and c-fos. The SOCS3 gene is located in the chromosome region 17q24-17q25, previously linked to body mass index (BMI), visceral adipose tissue (VAT), and waist circumference (WAIST) in Hispanic families in the Insulin Resistance Atherosclerosis Family Study (IRASFS). A high density map of 1,536 single nucleotide polymorphisms (SNPs) was constructed to cover a portion of the 17q linkage interval in 1,425 Hispanic subjects from 90 extended families in IRASFS. Analysis of this dense SNP map data revealed evidence of association of rs9914220 (located 10 kb 5' of the SOCS3 gene) with BMI, VAT, and WAIST (P-value ranging from 0.003 to 0.017). Using a tagging SNP approach, rs9914220 and 22 additional SOCS3 SNPs were genotyped for genetic association analysis with measures of adiposity and glucose homeostasis. The adiposity phenotypes utilized in association analyses included BMI, WAIST, waist to hip ratio (WHR), subcutaneous adipose tissue, VAT, and visceral to subcutaneous ratio (VSR). Linkage disequilibrium calculations revealed three haplotype blocks near SOCS3. Haplotype Block 3 (5' of SOCS3) contained SNPs consistently associated with BMI, WAIST, WHR, and VAT (P-values ranging from 2.00 x 10(-4) to 0.036). Haplotype Block 1 contained single-SNPs that were associated with most adiposity traits except for VSR (P-values ranging from 0.002 to 0.047). When trait associated SNPs were included in linkage analyses as covariates, a reduction of VAT LOD score from 1.26 to 0.76 above the SOCS3 locus (110 cM) was observed. Multi-SNP haplotype testing using the quantitative pedigree disequilibrium test was broadly consistent with the single-SNP associations. In conclusion, these results support a role for SOCS3 genetic

  12. Dosing obese cats based on body weight spuriously affects some measures of glucose tolerance.

    PubMed

    Reeve-Johnson, M K; Rand, J S; Anderson, S T; Appleton, D J; Morton, J M; Vankan, D

    2016-10-01

    The primary objective was to investigate whether dosing glucose by body weight results in spurious effects on measures of glucose tolerance in obese cats because volume of distribution does not increase linearly with body weight. Healthy research cats (n = 16; 6 castrated males, 10 spayed females) were used. A retrospective study was performed using glucose concentration data from glucose tolerance and insulin sensitivity tests before and after cats were fed ad libitum for 9 to 12 mo to promote weight gain. The higher dose of glucose (0.5 vs 0.3 g/kg body weight) in the glucose tolerance tests increased 2-min glucose concentrations (P < 0.001), and there was a positive correlation between 2-min and 2-h glucose (r = 0.65, P = 0.006). Two-min (P = 0.016 and 0.019, respectively), and 2-h (P = 0.057 and 0.003, respectively) glucose concentrations, and glucose half-life (T1/2; P = 0.034 and <0.001 respectively) were positively associated with body weight and body condition score. Glucose dose should be decreased by 0.05 g for every kg above ideal body weight. Alternatively, for every unit of body condition score above 5 on a 9-point scale, observed 2-h glucose concentration should be adjusted down by 0.1 mmol/L. Dosing glucose based on body weight spuriously increases glucose concentrations at 2 h in obese cats and could lead to cats being incorrectly classified as having impaired glucose tolerance. This has important implications for clinical studies assessing the effect of interventions on glucose tolerance when lean and obese cats are compared.

  13. 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

  14. Peroxisomal polyamine oxidase and NADPH-oxidase cross-talk for ROS homeostasis which affects respiration rate in Arabidopsis thaliana

    PubMed Central

    Andronis, Efthimios A.; Moschou, Panagiotis N.; Toumi, Imene; Roubelakis-Angelakis, Kalliopi A.

    2014-01-01

    Homeostasis of reactive oxygen species (ROS) in the intracellular compartments is of critical importance as ROS have been linked with nearly all cellular processes and more importantly with diseases and aging. PAs are nitrogenous molecules with an evolutionary conserved role in the regulation of metabolic and energetic status of cells. Recent evidence also suggests that polyamines (PA) are major regulators of ROS homeostasis. In Arabidopsis the backconversion of the PAs spermidine (Spd) and spermine to putrescine and Spd, respectively, is catalyzed by two peroxisomal PA oxidases (AtPAO). However, the physiological role of this pathway remains largely elusive. Here we explore the role of peroxisomal PA backconversion and in particular that catalyzed by the highly expressed AtPAO3 in the regulation of ROS homeostasis and mitochondrial respiratory burst. Exogenous PAs exert an NADPH-oxidase dependent stimulation of oxygen consumption, with Spd exerting the strongest effect. This increase is attenuated by treatment with the NADPH-oxidase blocker diphenyleneiodonium iodide (DPI). Loss-of-function of AtPAO3 gene results to increased NADPH-oxidase-dependent production of superoxide anions (O2•− ), but not H2O2, which activate the mitochondrial alternative oxidase pathway (AOX). On the contrary, overexpression of AtPAO3 results to an increased but balanced production of both H2O2 and O2•− . These results suggest that the ratio of O2•− /H2O2 regulates respiratory chain in mitochondria, with PA-dependent production of O2•− by NADPH-oxidase tilting the balance of electron transfer chain in favor of the AOX pathway. In addition, AtPAO3 seems to be an important component in the regulating module of ROS homeostasis, while a conserved role for PA backconversion and ROS across kingdoms is discussed. PMID:24765099

  15. Factors affecting initial training success of blood glucose testing in captive chimpanzees (Pan troglodytes).

    PubMed

    Reamer, Lisa A; Haller, Rachel L; Thiele, Erica J; Freeman, Hani D; Lambeth, Susan P; Schapiro, Steven J

    2014-01-01

    Type 2 diabetes can be a problem for captive chimpanzees. Accurate blood glucose (BG) readings are necessary to monitor and treat this disease. Thus, obtaining voluntary samples from primates through positive reinforcement training (PRT) is critical. The current study assessed the voluntary participation of 123 chimpanzees in BG sampling and investigated factors that may contribute to individual success. All subjects participate in regular PRT sessions as part of a comprehensive behavioral management program. Basic steps involved in obtaining BG values include: voluntarily presenting a finger/toe; allowing digit disinfection; holding for the lancet device; and allowing blood collection onto a glucometer test strip for analysis. We recorded the level of participation (none, partial, or complete) when each chimpanzee was first asked to perform the testing procedure. Nearly 30% of subjects allowed the entire procedure in one session, without any prior specific training for the target behavior. Factors that affected this initial successful BG testing included sex, personality (chimpanzees rated higher on the factor "openness" were more likely to participate with BG testing), and past training performance for "present-for-injection" (chimpanzees that presented for their most recent anesthetic injection were more likely to participate). Neither age, rearing history, time since most recent anesthetic event nor social group size significantly affected initial training success. These results have important implications for captive management and training program success, underlining individual differences in training aptitude and the need for developing individual management plans in order to provide optimal care and treatment for diabetic chimpanzees in captivity.

  16. Hydrogen peroxide produced by glucose oxidase affects the performance of laccase cathodes in glucose/oxygen fuel cells: FAD-dependent glucose dehydrogenase as a replacement.

    PubMed

    Milton, Ross D; Giroud, Fabien; Thumser, Alfred E; Minteer, Shelley D; Slade, Robert C T

    2013-11-28

    Hydrogen peroxide production by glucose oxidase (GOx) and its negative effect on laccase performance have been studied. Simultaneously, FAD-dependent glucose dehydrogenase (FAD-GDH), an O2-insensitive enzyme, has been evaluated as a substitute. Experiments focused on determining the effect of the side reaction of GOx between its natural electron acceptor O2 (consumed) and hydrogen peroxide (produced) in the electrolyte. Firstly, oxygen consumption was investigated by both GOx and FAD-GDH in the presence of substrate. Relatively high electrocatalytic currents were obtained with both enzymes. O2 consumption was observed with immobilized GOx only, whilst O2 concentration remained stable for the FAD-GDH. Dissolved oxygen depletion effects on laccase electrode performances were investigated with both an oxidizing and a reducing electrode immersed in a single compartment. In the presence of glucose, dramatic decreases in cathodic currents were recorded when laccase electrodes were combined with a GOx-based electrode only. Furthermore, it appeared that the major loss of performance of the cathode was due to the increase of H2O2 concentration in the bulk solution induced laccase inhibition. 24 h stability experiments suggest that the use of O2-insensitive FAD-GDH as to obviate in situ peroxide production by GOx is effective. Open-circuit potentials of 0.66 ± 0.03 V and power densities of 122.2 ± 5.8 μW cm(-2) were observed for FAD-GDH/laccase biofuel cells.

  17. A probing dose of phenylacetate does not affect glucose production and gluconeogenesis in humans.

    PubMed

    Wajngot, A; Chandramouli, V; Schumann, W C; Brunengraber, H; Efendic, S; Landau, B R

    2000-09-01

    Phenylacetate ingestion has been used to probe Krebs cycle metabolism and to augment waste nitrogen excretion in urea cycle disorders. Phenylalkanoic acids, including phenylacetate, have been proposed as potential therapeutic agents in the treatment of diabetes. They inhibit gluconeogenesis in the liver in vitro and reduce the blood glucose concentration in diabetic rats. The effect of sodium phenylacetate ingestion on blood glucose and the contribution of gluconeogenesis to glucose production have now been studied in 7 type 2 diabetic patients. The study was not designed to test whether the changes in glucose metabolism observed in the rat could be reproduced in humans. After an overnight fast, over a period of 1 hour, 4.8 g phenylacetate was ingested, which is the highest dose used to probe Krebs cycle metabolism. Glucose production was measured by tracer kinetics using [6,6-(2)H2]glucose and gluconeogenesis by the labeling of the hydrogens of blood glucose on (2)H20 ingestion. The concentration of phenylacetate in plasma peaked by 2 hours after its ingestion, and about 40% of the dose was excreted in 5 hours. The plasma glucose concentration and production, and the contribution of gluconeogenesis to glucose production, were unaffected by phenylacetate ingestion at the highest dose used to probe Krebs cycle metabolism.

  18. Eukaryotic release factor 1-2 affects Arabidopsis responses to glucose and phytohormones during germination and early seedling development

    PubMed Central

    Zhou, Xiangjun; Cooke, Peter; Li, Li

    2010-01-01

    Germination and early seedling development are coordinately regulated by glucose and phytohormones such as ABA, GA, and ethylene. However, the molecules that affect plant responses to glucose and phytohormones remain to be fully elucidated. Eukaryotic release factor 1 (eRF1) is responsible for the recognition of the stop codons in mRNAs during protein synthesis. Accumulating evidence indicates that eRF1 functions in other processes in addition to translation termination. The physiological role of eRF1-2, a member of the eRF1 family, in Arabidopsis was examined here. The eRF1-2 gene was found to be specifically induced by glucose. Arabidopsis plants overexpressing eRF1-2 were hypersensitive to glucose during germination and early seedling development. Such hypersensitivity to glucose was accompanied by a dramatic reduction of the expression of glucose-regulated genes, chlorophyll a/b binding protein and plastocyanin. The hypersensitive response was not due to the enhanced accumulation of ABA. In addition, the eRF1-2 overexpressing plants showed increased sensitivity to paclobutrazol, an inhibitor of GA biosynthesis, and exogenous GA restored their normal growth. By contrast, the loss-of-function erf1-2 mutant exhibited resistance to paclobutrazol, suggesting that eRF1-2 may exert a negative effect on the GA signalling pathway. Collectively, these data provide evidence in support of a novel role of eRF1-2 in affecting glucose and phytohormone responses in modulating plant growth and development. PMID:19939886

  19. 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.

  20. NOS2 Is Critical to the Development of Emphysema in Sftpd Deficient Mice but Does Not Affect Surfactant Homeostasis

    PubMed Central

    Guo, Chang-Jiang; Scott, Pamela A.; Haenni, Beat; Beers, Michael F.; Ochs, Matthias; Gow, Andrew J.

    2014-01-01

    Rationale Surfactant protein D (SP-D) has important immuno-modulatory properties. The absence of SP-D results in an inducible NO synthase (iNOS, coded by NOS2 gene) related chronic inflammation, development of emphysema-like pathophysiology and alterations of surfactant homeostasis. Objective In order to test the hypothesis that SP-D deficiency related abnormalities in pulmonary structure and function are a consequence of iNOS induced inflammation, we generated SP-D and iNOS double knockout mice (DiNOS). Methods Structural data obtained by design-based stereology to quantify the emphysema-like phenotype and disturbances of the intracellular surfactant were correlated to invasive pulmonary function tests and inflammatory markers including activation markers of alveolar macrophages and compared to SP-D (Sftpd−/−) and iNOS single knockout mice (NOS2−/−) as well as wild type (WT) littermates. Measurements and Results DiNOS mice had reduced inflammatory cells in BAL and BAL-derived alveolar macrophages showed an increased expression of markers of an alternative activation as well as reduced inflammation. As evidenced by increased alveolar numbers and surface area, emphysematous changes were attenuated in DiNOS while disturbances of the surfactant system remained virtually unchanged. Sftpd−/− demonstrated alterations of intrinsic mechanical properties of lung parenchyma as shown by reduced stiffness and resistance at its static limits, which could be corrected by additional ablation of NOS2 gene in DiNOS. Conclusion iNOS related inflammation in the absence of SP-D is involved in the emphysematous remodeling leading to a loss of alveoli and associated alterations of elastic properties of lung parenchyma while disturbances of surfactant homeostasis are mediated by different mechanisms. PMID:24465666

  1. Deletion of CDKAL1 Affects High-Fat Diet–Induced Fat Accumulation and Glucose-Stimulated Insulin Secretion in Mice, Indicating Relevance to Diabetes

    PubMed Central

    Takeuchi, Fumihiko; Isono, Masato; Akiyama, Koichi; Shimizu, Yukiko; Goto, Motohito; Liang, Yi-Qiang; Yamamoto, Ken; Katsuya, Tomohiro; Fujioka, Akihiro; Ohnaka, Keizo; Takayanagi, Ryoichi; Ogihara, Toshio; Yamori, Yukio; Kato, Norihiro

    2012-01-01

    Background/Objective The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects. Methods In Cdkal1-deficient (Cdkal1−/−) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese. Principal Findings On a standard diet, Cdkal1−/− mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1−/− mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1−/− mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1−/− mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1−/− mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI. Conclusions Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect

  2. Preservation of blood glucose homeostasis in slow-senescing somatotrophism-deficient mice subjected to intermittent fasting begun at middle or old age.

    PubMed

    Arum, Oge; Saleh, Jamal K; Boparai, Ravneet K; Kopchick, John J; Khardori, Romesh K; Bartke, Andrzej

    2014-06-01

    Poor blood glucose homeostatic regulation is common, consequential, and costly for older and elderly populations, resulting in pleiotrophically adverse clinical outcomes. Somatotrophic signaling deficiency and dietary restriction have each been shown to delay the rate of senescence, resulting in salubrious phenotypes such as increased survivorship. Using two growth hormone (GH) signaling-related, slow-aging mouse mutants we tested, via longitudinal analyses, whether genetic perturbations that increase survivorship also improve blood glucose homeostatic regulation in senescing mammals. Furthermore, we institute a dietary restriction paradigm that also decelerates aging, an intermittent fasting (IF) feeding schedule, as either a short-term or a sustained intervention beginning at either middle or old age, and assess its effects on blood glucose control. We find that either of the two genetic alterations in GH signaling ameliorates fasting hyperglycemia; additionally, both longevity-inducing somatotrophic mutations improve insulin sensitivity into old age. Strikingly, we observe major and broad improvements in blood glucose homeostatic control by IF: IF improves ad libitum-fed hyperglycemia, glucose tolerance, and insulin sensitivity, and reduces hepatic gluconeogenesis, in aging mutant and normal mice. These results on correction of aging-resultant blood glucose dysregulation have potentially important clinical and public health implications for our ever-graying global population, and are consistent with the Longevity Dividend concept.

  3. 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

    SciTech Connect

    Nelson, S.; Dhar, M.

    2003-01-01

    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 hyperinsulinemia 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.

  4. Short-Term Thermal-Humidity Shock Affects Point-of-Care Glucose Testing: Implications for Health Professionals and Patients.

    PubMed

    Lam, Mandy; Louie, Richard F; Curtis, Corbin M; Ferguson, William J; Vy, John H; Truong, Anh-Thu; Sumner, Stephanie L; Kost, Gerald J

    2014-01-01

    The objective was to assess the effects of short-term (≤1 hour) static high temperature and humidity stresses on the performance of point-of-care (POC) glucose test strips and meters. Glucose meters are used by medical responders and patients in a variety of settings including hospitals, clinics, homes, and the field. Reagent test strips and instruments are potentially exposed to austere environmental conditions. Glucose test strips and meters were exposed to a mean relative humidity of 83.0% (SD = 8.0%) and temperature of 42°C (107.6°F, SD = 3.2) in a Tenney BTRC environmental chamber. Stressed and unstressed glucose reagent strips and meters were tested with spiked blood samples (n = 40 measurements per time point for each of 4 trials) after 15, 30, 45, and 60 minutes of exposure. Wilcoxon's signed rank test was applied to compare measurements test strip and meter measurements to isolate and characterize the magnitude of meter versus test strip effects individually. Stressed POC meters and test strips produced elevated glucose results, with stressed meter bias as high as 20 mg/dL (17.7% error), and stressed test strip bias as high as 13 mg/dL (12.2% error). The aggregate stress effect on meter and test strips yielded a positive bias as high as 33 mg/dL (30.1% error) after 15 minutes of exposure. Short-term exposure (15 minutes) to high temperature and humidity can significantly affect the performance of POC glucose test strips and meters, with measurement biases that potentially affect clinical decision making and patient safety.

  5. Cytosolic NADPH Homeostasis in Glucose-starved Procyclic Trypanosoma brucei Relies on Malic Enzyme and the Pentose Phosphate Pathway Fed by Gluconeogenic Flux*

    PubMed Central

    Allmann, Stefan; Morand, Pauline; Ebikeme, Charles; Gales, Lara; Biran, Marc; Hubert, Jane; Brennand, Ana; Mazet, Muriel; Franconi, Jean-Michel; Michels, Paul A. M.; Portais, Jean-Charles; Boshart, Michael; Bringaud, Frédéric

    2013-01-01

    All living organisms depend on NADPH production to feed essential biosyntheses and for oxidative stress defense. Protozoan parasites such as the sleeping sickness pathogen Trypanosoma brucei adapt to different host environments, carbon sources, and oxidative stresses during their infectious life cycle. The procyclic stage develops in the midgut of the tsetse insect vector, where they rely on proline as carbon source, although they prefer glucose when grown in rich media. Here, we investigate the flexible and carbon source-dependent use of NADPH synthesis pathways in the cytosol of the procyclic stage. The T. brucei genome encodes two cytosolic NADPH-producing pathways, the pentose phosphate pathway (PPP) and the NADP-dependent malic enzyme (MEc). Reverse genetic blocking of those pathways and a specific inhibitor (dehydroepiandrosterone) of glucose-6-phosphate dehydrogenase together established redundancy with respect to H2O2 stress management and parasite growth. Blocking both pathways resulted in ∼10-fold increase of susceptibility to H2O2 stress and cell death. Unexpectedly, the same pathway redundancy was observed in glucose-rich and glucose-depleted conditions, suggesting that gluconeogenesis can feed the PPP to provide NADPH. This was confirmed by (i) a lethal phenotype of RNAi-mediated depletion of glucose-6-phosphate isomerase (PGI) in the glucose-depleted Δmec/Δmec null background, (ii) an ∼10-fold increase of susceptibility to H2O2 stress observed for the Δmec/Δmec/RNAiPGI double mutant when compared with the single mutants, and (iii) the 13C enrichment of glycolytic and PPP intermediates from cells incubated with [U-13C]proline, in the absence of glucose. Gluconeogenesis-supported NADPH supply may also be important for nucleotide and glycoconjugate syntheses in the insect host. PMID:23665470

  6. Oral administration of SR-110, a peroxynitrite decomposing catalyst, enhances glucose homeostasis, insulin signaling, and islet architecture in B6D2F1 mice fed a high fat diet.

    PubMed

    Johns, Michael; Esmaeili Mohsen Abadi, Sakineh; Malik, Nehal; Lee, Joshua; Neumann, William L; Rausaria, Smita; Imani-Nejad, Maryam; McPherson, Timothy; Schober, Joseph; Kwon, Guim

    2016-04-15

    Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577-578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 ± 1.5 g vs 34 ± 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and β-cell insulin content under nutrient overload.

  7. Changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis induced by an acetyl-L-carnitine and nicotinamide treatment in dyslipidaemic insulin-resistant rats.

    PubMed

    Ferreira, Maria R; Camberos, Maria del C; Selenscig, Dante; Martucci, Lucía C; Chicco, Adriana; Lombardo, Yolanda B; Cresto, Juan C

    2013-03-01

    Normal rats fed a sucrose-rich diet (SRD) develop dyslipidaemia and insulin resistance. The present study examined whether administration of the mitochondrial nutrients nicotinamide and acetyl-L-carnitine reversed or improved these metabolic abnormalities. Male Wistar rats were fed an SRD for 90 days. Half the rats then received daily injections of nicotinamide (25 mg/kg, i.p.) and acetyl-L-carnitine (50 mg/kg, i.p.) for a further 90 days. The remaining rats in the SRD-fed group and those in a normal chow-fed control group were injected with an equal volume of saline solution for the same period. The following parameters were determined in all groups: (i) liver activity of fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and carnitine-palmitoyl transferase-1 (CPT-1); (ii) hepatic and skeletal muscle triacylglycerol content, plasma glucose, insulin, free fatty acid (FFA) and triacylglycerol levels and pancreatic insulin content; and (iii) glucose tolerance. Administration of nicotinamide and acetyl-L-carnitine to the SRD-fed rats reduced dyslipidaemia, liver steatosis, muscle triacylglycerol content and hepatic FAS and ACC activities and increased CPT-1 activity. In addition nicotinamide and acetyl-L-carnitine improved the glucose disappearance rate (K(g)), normalized plasma glucose levels and moderately increased insulinaemia without altering pancreatic insulin content. Finally, nicotinamide and acetyl-l-carnitine administration reduced bodyweight gain and visceral adiposity. The results of the present study suggest that altering key hepatic lipogenic and fatty acid oxidative enzymatic activity could improve dyslipidaemia, liver steatosis and visceral adiposity. Indeed, administration of nicotinamide and acetyl-l-carnitine improved glucose intolerance and normalized plasma glucose levels.

  8. Cocoa and Whey Protein Differentially Affect Markers of Lipid and Glucose Metabolism and Satiety.

    PubMed

    Campbell, Caroline L; Foegeding, E Allen; Harris, G Keith

    2016-03-01

    Food formulation with bioactive ingredients is a potential strategy to promote satiety and weight management. Whey proteins are high in leucine and are shown to decrease hunger ratings and increase satiety hormone levels; cocoa polyphenolics moderate glucose levels and slow digestion. This study examined the effects of cocoa and whey proteins on lipid and glucose metabolism and satiety in vitro and in a clinical trial. In vitro, 3T3-L1 preadipocytes were treated with 0.5-100 μg/mL cocoa polyphenolic extract (CPE) and/or 1-15 mM leucine (Leu) and assayed for lipid accumulation and leptin production. In vivo, a 6-week clinical trial consisted of nine panelists (age: 22.6 ± 1.7; BMI: 22.3 ± 2.1) consuming chocolate-protein beverages once per week, including placebo, whey protein isolate (WPI), low polyphenolic cocoa (LP), high polyphenolic cocoa (HP), LP-WPI, and HP-WPI. Measurements included blood glucose and adiponectin levels, and hunger ratings at baseline and 0.5-4.0 h following beverage consumption. At levels of 50 and 100 μg/mL, CPE significantly inhibited preadipocyte lipid accumulation by 35% and 50%, respectively, and by 22% and 36% when combined with 15 mM Leu. Leu treatment increased adipocyte leptin production by 26-37%. In the clinical trial, all beverages significantly moderated blood glucose levels 30 min postconsumption. WPI beverages elicited lowest peak glucose levels and HP levels were significantly lower than LP. The WPI and HP beverage treatments significantly increased adiponectin levels, but elicited no significant changes in hunger ratings. These trends suggest that combinations of WPI and cocoa polyphenols may improve markers of metabolic syndrome and satiety.

  9. Stable oxyntomodulin analogues exert positive effects on hippocampal neurogenesis and gene expression as well as improving glucose homeostasis in high fat fed mice.

    PubMed

    Pathak, N M; Pathak, V; Lynch, A M; Irwin, N; Gault, V A; Flatt, P R

    2015-09-05

    The weight-lowering and gluco-regulatory actions of oxyntomodulin (Oxm) have been well-documented however potential actions of this peptide in brain regions associated with learning and memory have not yet been evaluated. The present study examined the long-term actions of a stable acylated analogue of Oxm, (dS(2))Oxm(K-γ-glu-Pal), together with parent (dS(2))Oxm peptide, on hippocampal neurogenesis, gene expression and metabolic control in high fat (HF) mice. Groups of HF mice (n = 12) received twice-daily injections of Oxm analogues (both at 25 nmol/kg body weight) or saline vehicle (0.9% wt/vol) over 28 days. Hippocampal gene expression and histology were assessed together with evaluation of energy intake, body weight, non-fasting glucose and insulin, glucose tolerance, insulin sensitivity and lipids. Oxm analogues significantly reduced body weight, improved glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity, islet architecture and lipid profile. Analysis of brain histology revealed significant reduction in hippocampal oxidative damage (8-oxoguanine), enhanced hippocampal neurogenesis (doublecortin) and improved hippocampal and cortical synaptogenesis (synaptophysin) following treatment. Furthermore, Oxm analogues up-regulated hippocampal mRNA expression of MASH1, Synaptophysin, SIRT1, GLUT4 and IRS1, and down-regulated expression of LDL-R and GSK3β. These data demonstrate potential of stable Oxm analogues, and particularly (dS(2))Oxm(K-γ-glu-Pal) to improve metabolic function and enhance neurogenesis, synaptic plasticity, insulin signalling and exert protective effects against oxidative damage in hippocampus and cortex brain regions in HF mice.

  10. Metabolically distinct weight loss by 10,12 CLA and caloric restriction highlight the importance of subcutaneous white adipose tissue for glucose homeostasis in mice

    PubMed Central

    Wang, Shari; Goodspeed, Leela; Wietecha, Tomasz; Houston, Barbara; Omer, Mohamed; Ogimoto, Kayoko; Subramanian, Savitha; Gowda, G. A. Nagana; O’Brien, Kevin D.; Kaiyala, Karl J.; Morton, Gregory J.; Chait, Alan

    2017-01-01

    Background Widely used as a weight loss supplement, trans-10,cis-12 conjugated linoleic acid (10,12 CLA) promotes fat loss in obese mice and humans, but has also been associated with insulin resistance. Objective We therefore sought to directly compare weight loss by 10,12 CLA versus caloric restriction (CR, 15–25%), an acceptable healthy method of weight loss, to determine how 10,12 CLA-mediated weight loss fails to improve glucose metabolism. Methods Obese mice with characteristics of human metabolic syndrome were either supplemented with 10,12 CLA or subjected to CR to promote weight loss. Metabolic endpoints such as energy expenditure, glucose and insulin tolerance testing, and trunk fat distribution were measured. Results By design, 10,12 CLA and CR caused equivalent weight loss, with greater fat loss by 10,12 CLA accompanied by increased energy expenditure, reduced respiratory quotient, increased fat oxidation, accumulation of alternatively activated macrophages, and browning of subcutaneous white adipose tissue (WAT). Moreover, 10,12 CLA-supplemented mice better defended their body temperature against a cold challenge. However, 10,12 CLA concurrently induced the detrimental loss of subcutaneous WAT without reducing visceral WAT, promoted reduced plasma and WAT adipokine levels, worsened hepatic steatosis, and failed to improve glucose metabolism. Obese mice undergoing CR were protected from subcutaneous-specific fat loss, had improved hepatic steatosis, and subsequently showed the expected improvements in WAT adipokines, glucose metabolism and WAT inflammation. Conclusions These results suggest that 10,12 CLA mediates the preferential loss of subcutaneous fat that likely contributes to hepatic steatosis and maintained insulin resistance, despite significant weight loss and WAT browning in mice. Collectively, we have shown that weight loss due to 10,12 CLA supplementation or CR results in dramatically different metabolic phenotypes, with the latter

  11. Transgenic expression of n-3 fatty acid desaturase (fat-1) in C57/BL6 mice: Effects on glucose homeostasis and body weight.

    PubMed

    Ji, Shaonin; Hardy, Robert W; Wood, Philip A

    2009-07-01

    The fat-1 gene, derived from Caenorhabditis elegans, encodes for a fatty acid n-3 desaturase. In order to study the potential metabolic benefits of n-3 fatty acids, independent of dietary fatty acids, we developed seven lines of fat-1 transgenic mice (C57/BL6) controlled by the regulatory sequences of the adipocyte protein-2 (aP2) gene for adipocyte-specific expression (AP-lines). We were unable to obtain homozygous fat-1 transgenic offspring from the two highest expressing lines, suggesting that excessive expression of this enzyme may be lethal during gestation. Serum fatty acid analysis of fat-1 transgenic mice (AP-3) fed a high n-6 unsaturated fat (HUSF) diet had an n-6/n-3 fatty acid ratio reduced by 23% (P < 0.025) and the n-3 fatty acid eicosapentaenoic acid (EPA) concentration increased by 61% (P < 0.020). Docosahexaenoic acid (DHA) was increased by 19% (P < 0.015) in white adipose tissue. Male AP-3-fat-1 line of mice had improved glucose tolerance and reduced body weight with no change in insulin sensitivity when challenged with a high-carbohydrate (HC) diet. In contrast, the female AP-3 mice had reduced glucose tolerance and no change in insulin sensitivity or body weight. These findings indicate that male transgenic fat-1 mice have improved glucose tolerance likely due to increased insulin secretion while female fat-1 mice have reduced glucose tolerance compared to wild-type mice. Finally the inability of fat-1 transgenic mice to generate homozygous offspring suggests that prolonged exposure to increased concentrations of n-3 fatty acids may be detrimental to reproduction.

  12. Coconut-derived D-xylose affects postprandial glucose and insulin responses in healthy individuals

    PubMed Central

    Bae, Yun Jung; Bak, Youn-Kyung; Kim, Bumsik; Kim, Min-Sun; Lee, Jin-Hee

    2011-01-01

    Metabolic alterations including postprandial hyperglycemia have been implicated in the development of obesity-related diseases. Xylose is a sucrase inhibitor suggested to suppress the postprandial glucose surge. The objectives of this study were to assess the inhibitory effects of two different concentrations of xylose on postprandial glucose and insulin responses and to evaluate its efficacy in the presence of other macronutrients. Randomized double-blind cross-over studies were conducted to examine the effect of D-xylose on postprandial glucose and insulin response following the oral glucose tolerance test (OGTT). In study 1, the overnight-fasted study subjects (n = 49) consumed a test sucrose solution (50 g sucrose in 130 ml water) containing 0, 5, or 7.5 g D-xylose powder. In study 2, the overnight-fasted study subjects (n = 50) consumed a test meal (50 g sucrose in a 60 g muffin and 200 ml sucrose-containing solution). The control meal provided 64.5 g of carbohydrates, 4.5 g of fat, and 10 g of protein. The xylose meal was identical to the control meal except 5 g of xylose was added to the muffin mix. In study 1, the 5 g xylose-containing solutions exhibited significantly lower area under the glucose curve (AUCg) and area under the insulin curve (AUCi) values for 0-15 min (P < 0.0001, P < 0.0001), 0-30 min (P < 0.0001, P < 0.0001), 0-45 min (P < 0.0001, P < 0.0001), 0-60 min (P < 0.0001, P < 0.0001), 0-90 min (P < 0.0001, P < 0.0001) and 0-120 min (P = 0.0071, P = 0.0016). In study 2, the test meal exhibited significantly lower AUCg and AUCi values for 0-15 min (P < 0.0001, P < 0.0001), 0-30 min (P < 0.0001, P < 0.0001), 0-45 min (P < 0.0001, P = 0.0005), 0-60 min (P = 0.0002, P = 0.0025), and 0-90 min (P = 0.0396, P = 0.0246). In conclusion, xylose showed an acute suppressive effect on the postprandial glucose and insulin surges. PMID:22259678

  13. Structure-function relationships affecting the sensing mechanism of monolayer-protected cluster doped xerogel amperometric glucose biosensors.

    PubMed

    DiPasquale, Luke T; Poulos, Nicholas G; Hall, Jackson R; Minocha, Aastha; Bui, Tram Anh; Leopold, Michael C

    2015-07-15

    A systematic study of the structure-function relationships critical to understanding the sensing mechanism of 1st generation amperometric glucose biosensors with an embedded nanoparticle (NP) network is presented. Xerogel-based films featuring embedded glucose oxidase enzyme and doped with alkanethiolate-protected gold NPs, known as monolayer protected clusters (MPCs), exhibit significantly enhanced performance compared to analogous systems without NPs including higher sensitivity, faster response time, and extended linear/dynamic ranges. The proposed mechanism involves diffusion of the glucose to glucose oxidase within the xerogel, enzymatic reaction production of H2O2 with subsequent diffusion to the embedded network of MPCs where it is oxidized, an event immediately reported via fast electron transfer (ET) through the MPC system to the working electrode. Various aspects of the film construct and strategy are systematically probed using amperometry, voltammetry, and solid-state electronic conductivity measurements, including the effects of MPC peripheral chain length, MPC functionalization via place-exchange reaction, MPC core size, and the MPC density or concentration within the xerogel composite films. The collective results of these experiments support the proposed mechanism and identify interparticle spacing and the electronic communication through the MPC network is the most significant factor in the sensing scheme with the diffusional aspects of the mechanism that may be affected by film/MPC hydrophobicity and functionality (i.e., glucose and H2O2 diffusion) shown to be less substantial contributors to the overall enhanced performance. Understanding the structure-function relationships of effective sensing schemes allows for the employment of the strategy for future biosensor design toward clinically relevant targets.

  14. Intestinal glucose absorption in calves as affected by different carbohydrate sources.

    PubMed

    Klinger, S; Noci, B; Müller, K; Breves, G

    2013-04-01

    From numerous recent studies, it has been demonstrated that the development of the forestomach system in ruminants and thus microbial carbohydrate fermentation do not exclude the potential of the small intestines for enzymatic carbohydrate digestion and subsequent monosaccharide absorption. However, the role of regulatory nutritional factors is still under discussion. Therefore, we investigated the kinetic parameters of intestinal Na(+) -dependent glucose absorption and SGLT1 expression using isolated brush border membrane vesicles (BBMV) from the jejunum of 10-week-old calves kept on either hay, concentrate or corn silage-based diets in addition to milk replacer. While the maximal transport capacity was significantly higher for concentrate and corn silage-fed animals, SGLT1 protein expression was highest in BBMV isolated from hay-fed animals. This observation differs from the prevalent conception that induction of Na(+) -dependent glucose uptake via SGLT1 is based on an increased number of transporters at the brush border membrane.

  15. Resistant starch and arabinoxylan augment SCFA absorption, but affect postprandial glucose and insulin responses differently.

    PubMed

    Ingerslev, Anne Krog; Theil, Peter Kappel; Hedemann, Mette Skou; Lærke, Helle Nygaard; Bach Knudsen, Knud Erik

    2014-05-01

    The effects of increased colonic fermentation of dietary fibres (DF) on the net portal flux (NPF) of carbohydrate-derived metabolites (glucose, SCFA and, especially, butyrate), hormones (insulin, C-peptide, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide) and NEFA were studied in a healthy catheterised pig model. A total of six pigs weighing 59 (SEM 1·6) kg were fitted with catheters in the mesenteric artery and in the portal and hepatic veins, and a flow probe around the portal vein, and included in a double 3 × 3 cross-over design with three daily feedings (at 09.00, 14.00 and 19.00 hours). Fasting and 5 h postprandial blood samples were collected after 7 d adaptation to each diet. The pigs were fed a low-DF Western-style control diet (WSD) and two high-DF diets (an arabinoxylan-enriched diet (AXD) and a resistant starch-enriched diet (RSD)). The NPF of insulin was lower (P= 0·04) in AXD-fed pigs (4·6 nmol/h) than in RSD-fed pigs (10·5 nmol/h), despite the lowest NPF of glucose being observed in RSD-fed pigs (203 mmol/h, P= 0·02). The NPF of total SCFA, acetate, propionate and butyrate were high, intermediate and low (P< 0·01) in AXD-, RSD- and WSD-fed pigs, respectively, with the largest relative increase being observed for butyrate in response to arabinoxylan supplementation. In conclusion, the RSD and AXD had different effects on the NPF of insulin and glucose, suggesting different impacts of arabinoxylan and resistant starch on human health.

  16. Lower maternal body condition during pregnancy affects skeletal muscle structure and glut-4 protein levels but not glucose tolerance in mature adult sheep.

    PubMed

    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; Green, Lucy R

    2013-10-01

    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/mm(2), P < .05) and fast myofiber density (HBCS, 226 ± 10; LBCS 194 ± 10 fibers/mm(2), 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.

  17. Isolation and characterization of ack and pta mutations in Azotobacter vinelandii affecting acetate-glucose diauxie.

    PubMed Central

    McKenney, D; Melton, T

    1986-01-01

    Azotobacter vinelandii mutants defective for acetate utilization that were resistant to fluoroacetate (FA) were isolated. FA-resistant mutant AM6 failed to transport [14C]acetate and lacked enzymatic activity for both acetate kinase and phosphotransacetylase. Growth of wild-type A. vinelandii was sensitive to 10 mM glycine; however, all FA-resistant strains were resistant to glycine toxicity. Isolated mutants that were spontaneously resistant to glycine were also resistant to FA and lacked both acetate kinase and phosphotransacetylase activity. The glycine-resistant mutant AM3, unlike mutant AM6, was capable of growth on acetate. The mutant strain AM6 was unable to growth under acetate-glucose diauxie conditions. Glucose utilization in this mutant, unlike that in wild-type A. vinelandii, was permanently arrested in the presence of acetate. Revertants of strain AM6 were selected on plates with acetate or acetate-glucose. Two classes of revertants were isolated. Class I revertant mutants AM31 and AM35 were positive for both acetate kinase and phosphotransacetylase activities. These revertants were also sensitive to both FA and glycine. Class II revertant strains AM32 and AM34 still lacked acetate kinase and phophotransacetylase activity. Both of these revertants remained resistant to FA and glycine. PMID:3001033

  18. Regulation of liver cell glucose homeostasis by dehydroabietic acid, abietic acid and squalene isolated from balsam fir (Abies balsamea (L.) Mill.) a plant of the Eastern James Bay Cree traditional pharmacopeia.

    PubMed

    Nachar, Abir; Saleem, Ammar; Arnason, John T; Haddad, Pierre S

    2015-09-01

    In our previous study, Abies balsamea (L.) Mill., a plant used in Cree traditional medicine, had a strong effect on the regulation of glucose homeostasis in liver cells. This study aimed to isolate and identify its active constituents using a bioassay-guided fractionation approach as well as to elucidate their mechanism(s) of action. The effect of the crude extract and its constituents was evaluated on the activity of Glucose-6-Phosphatase (G6Pase) and Glycogen Synthase (GS) and phosphorylation of three kinases, AMP-activated protein kinase (AMPK), Akt and Glycogen Synthase Kinase-3 (GSK-3). Three compounds, abietic acid, dehydroabietic acid and squalene, were isolated from the most active fraction in the bioassays (hexane). The compounds were able to decrease the activity of G6Pase and to stimulate GS. Their effect on G6Pase activity involved both Akt and AMPK phosphorylation with significant correlations between insulin-dependent and -independent pathways and the bioassay. In addition, the compounds were able to stimulate GS through GSK-3 phosphorylation with a significant correlation between the signaling pathway and the bioassay. Dehydroabietic acid stood out for its strongest effect in all the experiments close to that of the crude extract. These compounds may have potential applications in the treatment of type 2 diabetes and insulin resistance.

  19. Blood spot-based measures of glucose homeostasis and diabetes prevalence in a nationally representative population of young U.S. adults

    PubMed Central

    Nguyen, Quynh C.; Whitsel, Eric A.; Tabor, Joyce W.; Cuthbertson, Carmen C.; Wener, Mark H.; Potter, Alan J.; Halpern, Carolyn T.; Killeya-Jones, Ley A; Hussey, Jon M.; Suchindran, Chirayath; Harris, Kathleen Mullan

    2014-01-01

    Purpose We investigated under-studied, biomarker-based diabetes among young U.S. adults, traditionally characterized by low cardiovascular disease risk. Methods We examined 15,701 participants aged 24–32 years at Wave IV of the National Longitudinal Study of Adolescent Health (Add Health, 2008). The study used innovative and relatively non-invasive methods to collect capillary whole blood via finger prick at in-home examinations in all fifty states. Results Assays of dried blood spots produced reliable and accurate values of HbA1c. Reliability was lower for fasting glucose and lowest for random glucose. Mean (standard deviation) HbA1c was 5.6% (0.8%). More than a quarter (27.4%) had HbA1c-defined pre-diabetes. HbA1c was highest in the black, non-Hispanic race/ethnic group; inversely associated with education; and more common among the overweight/obese, and physically inactive. The prevalence of diabetes defined by previous diagnosis or use of anti-diabetic medication was 2.9%. Further incorporating HbA1c and glucose values, the prevalence increased to 6.8%, and among these participants, 38.9% had a previous diagnosis of diabetes (i.e., aware). Among those aware, 37.6% were treated and 64.0% were controlled (i.e., HbA1c < 7%). Conclusions A contemporary cohort of young adults faces a historically high risk of diabetes but there is ample opportunity for early detection and intervention. PMID:25444890

  20. Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: Development of a mouse model for arsenic-induced diabetes

    SciTech Connect

    Paul, David S.; Hernandez-Zavala, Araceli; Walton, Felecia S.; Adair, Blakely M.; Dedina, Jiri; Matousek, Tomas; Styblo, Miroslav

    2007-08-01

    Previous epidemiologic studies found increased prevalences of type 2 diabetes mellitus in populations exposed to high levels of inorganic arsenic (iAs) in drinking water. Although results of epidemiologic studies in low-exposure areas or occupational settings have been inconclusive, laboratory research has shown that exposures to iAs can produce effects that are consistent with type 2 diabetes. The current paper reviews the results of laboratory studies that examined the effects of iAs on glucose metabolism and describes new experiments in which the diabetogenic effects of iAs exposure were reproduced in a mouse model. Here, weanling male C57BL/6 mice drank deionized water with or without the addition of arsenite (25 or 50 ppm As) for 8 weeks. Intraperitoneal glucose tolerance tests revealed impaired glucose tolerance in mice exposed to 50 ppm As, but not to 25 ppm As. Exposure to 25 and 50 ppm As in drinking-water resulted in proportional increases in the concentration of iAs and its metabolites in the liver and in organs targeted by type 2 diabetes, including pancreas, skeletal muscle and adipose tissue. Dimethylarsenic was the predominant form of As in the tissues of mice in both 25 and 50 ppm groups. Notably, the average concentration of total speciated arsenic in livers from mice in the 50 ppm group was comparable to the highest concentration of total arsenic reported in the livers of Bangladeshi residents who had consumed water with an order of magnitude lower level of iAs. These data suggest that mice are less susceptible than humans to the diabetogenic effects of chronic exposure to iAs due to a more efficient clearance of iAs or its metabolites from target tissues.

  1. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet.

    PubMed

    Vickers, Steven P; Cheetham, Sharon C; Headland, Katie R; Dickinson, Keith; Grempler, Rolf; Mayoux, Eric; Mark, Michael; Klein, Thomas

    2014-01-01

    The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes.

  2. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet

    PubMed Central

    Vickers, Steven P; Cheetham, Sharon C; Headland, Katie R; Dickinson, Keith; Grempler, Rolf; Mayoux, Eric; Mark, Michael; Klein, Thomas

    2014-01-01

    The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes. PMID:25061325

  3. Inhibition of Protease-Activated Receptor 1 Does not Affect Dendritic Homeostasis of Cultured Mouse Dentate Granule Cells

    PubMed Central

    Schuldt, Gerlind; Galanis, Christos; Strehl, Andreas; Hick, Meike; Schiener, Sabine; Lenz, Maximilian; Deller, Thomas; Maggio, Nicola; Vlachos, Andreas

    2016-01-01

    Protease-activated receptors (PARs) are widely expressed in the central nervous system (CNS). While a firm link between PAR1-activation and functional synaptic and intrinsic neuronal properties exists, studies on the role of PAR1 in neural structural plasticity are scarce. The physiological function of PAR1 in the brain remains not well understood. We here sought to determine whether prolonged pharmacologic PAR1-inhibition affects dendritic morphologies of hippocampal neurons. To address this question we employed live-cell microscopy of mouse dentate granule cell dendrites in 3-week old entorhino-hippocampal slice cultures prepared from Thy1-GFP mice. A subset of cultures were treated with the PAR1-inhibitor SCH79797 (1 μM; up to 3 weeks). No major effects of PAR1-inhibition on static and dynamic parameters of dentate granule cell dendrites were detected under control conditions. Granule cells of PAR1-deficient slice cultures showed unaltered dendritic morphologies, dendritic spine densities and excitatory synaptic strength. Furthermore, we report that PAR1-inhibition does not prevent dendritic retraction following partial deafferentation in vitro. Consistent with this finding, no major changes in PAR1-mRNA levels were detected in the denervated dentate gyrus (DG). We conclude that neural PAR1 is not involved in regulating the steady-state dynamics or deafferentation-induced adaptive changes of cultured dentate granule cell dendrites. These results indicate that drugs targeting neural PAR1-signals may not affect the stability and structural integrity of neuronal networks in healthy brain regions. PMID:27378862

  4. Tetrahydro iso-alpha acids from hops improve glucose homeostasis and reduce body weight gain and metabolic endotoxemia in high-fat diet-fed mice.

    PubMed

    Everard, Amandine; Geurts, Lucie; Van Roye, Marie; Delzenne, Nathalie M; Cani, Patrice D

    2012-01-01

    Obesity and related metabolic disorders such as insulin resistance and type 2 diabetes are associated with a low-grade inflammatory state possibly through changes in gut microbiota composition and the development of higher plasma lipopolysaccharide (LPS) levels, i.e. metabolic endotoxemia. Various phytochemical compounds have been investigated as potential tools to regulate these metabolic features. Humulus lupulus L. (hops) contains several classes of compounds with anti-inflammatory potential. Recent evidence suggests that hops-derived compounds positively impact adipocyte metabolism and glucose tolerance in obese and diabetic rodents via undefined mechanisms. In this study, we found that administration of tetrahydro iso-alpha acids (termed META060) to high-fat diet (HFD)-fed obese and diabetic mice for 8 weeks reduced body weight gain, the development of fat mass, glucose intolerance, and fasted hyperinsulinemia, and normalized insulin sensitivity markers. This was associated with reduced portal plasma LPS levels, gut permeability, and higher intestinal tight junction proteins Zonula occludens-1 and occludin. Moreover, META060 treatment increased the plasma level of the anti-inflammatory cytokine interleukin-10 and decreased the plasma level of the pro-inflammatory cytokine granulocyte colony-stimulating factor. In conclusion, this research allows us to decipher a novel mechanism contributing to the positive effects of META060 treatment, and supports the need to investigate such compounds in obese and type 2 diabetic patients.

  5. Exposure to GSM RF fields does not affect calcium homeostasis in human endothelial cells, rat pheocromocytoma cells or rat hippocampal neurons.

    PubMed

    O'Connor, Rodney P; Madison, Steve D; Leveque, Philippe; Roderick, H Llewelyn; Bootman, Martin D

    2010-07-27

    In the course of modern daily life, individuals are exposed to numerous sources of electromagnetic radiation that are not present in the natural environment. The strength of the electromagnetic fields from sources such as hairdryers, computer display units and other electrical devices is modest. However, in many home and office environments, individuals can experience perpetual exposure to an "electromagnetic smog", with occasional peaks of relatively high electromagnetic field intensity. This has led to concerns that such radiation can affect health. In particular, emissions from mobile phones or mobile phone masts have been invoked as a potential source of pathological electromagnetic radiation. Previous reports have suggested that cellular calcium (Ca2+) homeostasis is affected by the types of radiofrequency fields emitted by mobile phones. In the present study, we used a high-throughput imaging platform to monitor putative changes in cellular Ca2+ during exposure of cells to 900 MHz GSM fields of differing power (specific absorption rate 0.012-2 W/Kg), thus mimicking the type of radiation emitted by current mobile phone handsets. Data from cells experiencing the 900 Mhz GSM fields were compared with data obtained from paired experiments using continuous wave fields or no field. We employed three cell types (human endothelial cells, PC-12 neuroblastoma and primary hippocampal neurons) that have previously been suggested to be sensitive to radiofrequency fields. Experiments were designed to examine putative effects of radiofrequency fields on resting Ca2+, in addition to Ca2+ signals evoked by an InsP(3)-generating agonist. Furthermore, we examined putative effects of radiofrequency field exposure on Ca2+ store emptying and store-operated Ca2+ entry following application of the Ca2+ATPase inhibitor thapsigargin. Multiple parameters (e.g., peak amplitude, integrated Ca2+ signal, recovery rates) were analysed to explore potential impact of radiofrequency field

  6. Exposure to GSM RF Fields Does Not Affect Calcium Homeostasis in Human Endothelial Cells, Rat Pheocromocytoma Cells or Rat Hippocampal Neurons

    PubMed Central

    O'Connor, Rodney P.; Madison, Steve D.; Leveque, Philippe; Roderick, H. Llewelyn; Bootman, Martin D.

    2010-01-01

    In the course of modern daily life, individuals are exposed to numerous sources of electromagnetic radiation that are not present in the natural environment. The strength of the electromagnetic fields from sources such as hairdryers, computer display units and other electrical devices is modest. However, in many home and office environments, individuals can experience perpetual exposure to an “electromagnetic smog”, with occasional peaks of relatively high electromagnetic field intensity. This has led to concerns that such radiation can affect health. In particular, emissions from mobile phones or mobile phone masts have been invoked as a potential source of pathological electromagnetic radiation. Previous reports have suggested that cellular calcium (Ca2+) homeostasis is affected by the types of radiofrequency fields emitted by mobile phones. In the present study, we used a high-throughput imaging platform to monitor putative changes in cellular Ca2+ during exposure of cells to 900 MHz GSM fields of differing power (specific absorption rate 0.012–2 W/Kg), thus mimicking the type of radiation emitted by current mobile phone handsets. Data from cells experiencing the 900 Mhz GSM fields were compared with data obtained from paired experiments using continuous wave fields or no field. We employed three cell types (human endothelial cells, PC-12 neuroblastoma and primary hippocampal neurons) that have previously been suggested to be sensitive to radiofrequency fields. Experiments were designed to examine putative effects of radiofrequency fields on resting Ca2+, in addition to Ca2+ signals evoked by an InsP3-generating agonist. Furthermore, we examined putative effects of radiofrequency field exposure on Ca2+ store emptying and store-operated Ca2+ entry following application of the Ca2+ATPase inhibitor thapsigargin. Multiple parameters (e.g., peak amplitude, integrated Ca2+ signal, recovery rates) were analysed to explore potential impact of radiofrequency field

  7. Critical role of the Src homology 2 (SH2) domain of neuronal SH2B1 in the regulation of body weight and glucose homeostasis in mice.

    PubMed

    Morris, David L; Cho, Kae Won; Rui, Liangyou

    2010-08-01

    SH2B1 is an SH2 domain-containing adaptor protein that plays a key role in the regulation of energy and glucose metabolism in both rodents and humans. Genetic deletion of SH2B1 in mice results in obesity and type 2 diabetes. Single-nucleotide polymorphisms in the SH2B1 loci and chromosomal deletions of the SH2B1 loci associate with obesity and insulin resistance in humans. In cultured cells, SH2B1 promotes leptin and insulin signaling by binding via its SH2 domain to phosphorylated tyrosines in Janus kinase 2 and the insulin receptor, respectively. Here we generated three lines of mice to analyze the role of the SH2 domain of SH2B1 in the central nervous system. Transgenic mice expressing wild-type, SH2 domain-defective (R555E), or SH2 domain-alone (DeltaN503) forms of SH2B1 specifically in neurons were crossed with SH2B1 knockout mice to generate KO/SH2B1, KO/R555E, or KO/DeltaN503 compound mutant mice. R555E had a replacement of Arg(555) with Glu within the SH2 domain. DeltaN503 contained an intact SH2 domain but lacked amino acids 1-503. Neuron-specific expression of recombinant SH2B1, but not R555E or DeltaN503, corrected hyperphagia, obesity, glucose intolerance, and insulin resistance in SH2B1 null mice. Neuron-specific expression of R555E in wild-type mice promoted obesity and insulin resistance. These results indicate that in addition to the SH2 domain, N-terminal regions of neuronal SH2B1 are also required for the maintenance of normal body weight and glucose metabolism. Additionally, mutations in the SH2 domain of SH2B1 may increase the susceptibility to obesity and type 2 diabetes in a dominant-negative manner.

  8. Aminocarnitine and acylaminocarnitines: Carnitine acyltransferase inhibitors affecting long-chain fatty acid and glucose metabolism

    SciTech Connect

    Clark, D.J.

    1989-01-01

    DL-Aminocarnitine (DL-3-amino-4-trimethylaminobutyrate) and the acylaminocarnitines acetyl-, decanoyl- and palmitoyl-DL-aminocarnitine have been synthesized and tested as inhibitors of carnitine palmitoyl-transferase and carnitine acetyltransferase in vitro and in vivo. Acetyl-DL-aaminocarnitine is the most potent reversible inhibitor of carnitine acetyltransferase reported to date, and is competitive with respect to acetyl-L-carnitine. Mice given acetyl-DL-aminocarnitine metabolize (U-{sup 14}C)acetyl-L-carnitine at about 60% of the rate of control mice. Palmitoyl-DL-aminocarnitine is the most potent reversible inhibitor of carnitine palmitoyltransferase reported to date. Decanoyl-DL-aminocarnitine and DL-aminocarnitine are also very potent inhibitors; all compounds inhibit the catabolism of ({sup 14}C)palmitate to {sup 14}CO{sub 2} in intact mice by at least 50%. Carnitine palmitoyltransferase controls the entry of long-chain fatty acids into the mitochondrial matrix for {beta}-oxidation. The inhibition of carnitine palmitoyltransferase by aminocarnitine or acylaminocarnitines in vivo prevents or reverses ketogenesis in fasted mice, and causes the reversible accumulation of triglycerides in liver, kidney and plasma. Administration of DL-aminocarnitine to streptozotocindiabetic mice lowers plasma glucose levels and improves the glucose tolerance test.

  9. The sex of the foetus affects maternal blood glucose concentrations in overweight and obese pregnant women.

    PubMed

    Seneviratne, Sumudu N; Derraik, José G B; Jiang, Yannan; McCowan, Lesley M E; Gusso, Silmara; Cutfield, Wayne S; Hofman, Paul L

    2016-12-26

    There is increasing evidence that the sex of the foetus may alter the maternal metabolic milieu during pregnancy. Following a randomized controlled trial of exercise in overweight and obese pregnant women, we assessed whether the sex of the foetus was associated with changes in maternal metabolism. Data were analysed on 74 randomized participants who completed the trial, including 38 mothers carrying males and 36 mothers carrying females. At 19 weeks of gestation, mothers carrying boys had higher blood glucose concentrations than those carrying girls (5.4 vs 4.9 mmol/l; p = .046). At 36 weeks of gestation, differences were more marked, with blood glucose concentrations 15% higher in mothers carrying females (5.7 vs 5.0 mmol/l; p = .004). In addition, mothers carrying girls had higher concentrations of hs-CRP across pregnancy (5.0 vs 3.6 mg/l; p = .029). Our findings provide further evidence that the sex of the foetus appears to influence maternal metabolism.

  10. Osmotic Homeostasis

    PubMed Central

    Zeidel, Mark L.

    2015-01-01

    Alterations in water homeostasis can disturb cell size and function. Although most cells can internally regulate cell volume in response to osmolar stress, neurons are particularly at risk given a combination of complex cell function and space restriction within the calvarium. Thus, regulating water balance is fundamental to survival. Through specialized neuronal “osmoreceptors” that sense changes in plasma osmolality, vasopressin release and thirst are titrated in order to achieve water balance. Fine-tuning of water absorption occurs along the collecting duct, and depends on unique structural modifications of renal tubular epithelium that confer a wide range of water permeability. In this article, we review the mechanisms that ensure water homeostasis as well as the fundamentals of disorders of water balance. PMID:25078421

  11. Standardized chungkookjang, short-term fermented soybeans with Bacillus lichemiformis, improves glucose homeostasis as much as traditionally made chungkookjang in diabetic rats.

    PubMed

    Yang, Hye Jeong; Kim, Hyun Jin; Kim, Min Jung; Kang, Suna; Kim, Da Sol; Daily, James W; Jeong, Do Youn; Kwon, Dae Young; Park, Sunmin

    2013-01-01

    As the traditional homemade chungkookjang is replaced by standardized chungkookjang fermented by inoculating Bacillus spp., it is desirable to maintain the anti-diabetic efficacy of the most potent traditional varieties. Preliminary in vitro research suggested that anti-diabetic efficacy can be achieved by using B. lichemiformis as a starter and fermenting for 48 h. Experimental type 2 diabetic male rats induced by partial pancreatectomy and high fat diets were administered either control diet, 10% cooked soybeans, 10% traditional chungkookjang with potent anti-diabetic efficacy, or standardized chungkookjang fermented with B. lichemiformis for 48 h. Rats were fed their respective diets for 8 weeks after surgery. Cooked soybeans as well as both chungkookjangs partially restored fasting serum glucose concentrations, but only the chungkoojangs increased fasting insulin levels. That trend was also seen in the glucose-stimulated insulin secretion during hyperglycemic clamp and was explained by the greater β-cell mass and BrdU incorporation indicating increased proliferation of β-cells. The euglycemic hyperinsulinemic clamp indicated that all soy products improved insulin sensitivity. Phosphorylation of Akt and AMPK in the liver increased in an ascending order of the control, cooked soybeans, traditional chungkookjang and standardized chungkookjang while PEPCK expression was lowered in a descending order of the control, cooked soybeans, traditional chungkookjang and standardized chungkookjang. These results indicate that standardized chungkookjang is most effective for improving hepatic insulin signaling. In conclusion, chungkookjang fermented with B. lichemiformis retains the anti-diabetic properties of the most efficacious traditional chungkookjang and it may be even more effective for improving insulin function than traditionally prepared chungkookjang.

  12. Physiological fluctuations in brain temperature as a factor affecting electrochemical evaluations of extracellular glutamate and glucose in behavioral experiments.

    PubMed

    Kiyatkin, Eugene A; Wakabayashi, Ken T; Lenoir, Magalie

    2013-05-15

    The rate of any chemical reaction or process occurring in the brain depends on temperature. While it is commonly believed that brain temperature is a stable, tightly regulated homeostatic parameter, it fluctuates within 1-4 °C following exposure to salient arousing stimuli and neuroactive drugs, and during different behaviors. These temperature fluctuations should affect neural activity and neural functions, but the extent of this influence on neurochemical measurements in brain tissue of freely moving animals remains unclear. In this Review, we present the results of amperometric evaluations of extracellular glutamate and glucose in awake, behaving rats and discuss how naturally occurring fluctuations in brain temperature affect these measurements. While this temperature contribution appears to be insignificant for glucose because its extracellular concentrations are large, it is a serious factor for electrochemical evaluations of glutamate, which is present in brain tissue at much lower levels, showing smaller phasic fluctuations. We further discuss experimental strategies for controlling the nonspecific chemical and physical contributions to electrochemical currents detected by enzyme-based biosensors to provide greater selectivity and reliability of neurochemical measurements in behaving animals.

  13. Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates β-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis.

    PubMed

    Vierra, Nicholas C; Dadi, Prasanna K; Jeong, Imju; Dickerson, Matthew; Powell, David R; Jacobson, David A

    2015-11-01

    Two-pore domain K+ (K2P) channels play an important role in tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TWIK-related alkaline pH-activated K2P (TALK)-1 is linked to type 2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 channels are expressed in mouse and human β-cells, where they serve as key regulators of electrical excitability and GSIS. We find that the rs1535500 polymorphism, which results in an alanine-to-glutamate substitution in the C-terminus of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in β-cell membrane potential depolarization, increased islet Ca2+ influx, and enhanced second-phase GSIS. Moreover, mice lacking TALK-1 channels are resistant to high-fat diet-induced elevations in fasting glycemia. These findings reveal TALK-1 channels as important modulators of second-phase insulin secretion and suggest a clinically relevant mechanism for rs1535500, which may increase type 2 diabetes risk by limiting GSIS.

  14. Macrophage-Derived upd3 Cytokine Causes Impaired Glucose Homeostasis and Reduced Lifespan in Drosophila Fed a Lipid-Rich Diet

    PubMed Central

    Woodcock, Katie J.; Kierdorf, Katrin; Pouchelon, Clara A.; Vivancos, Valérie; Dionne, Marc S.; Geissmann, Frédéric

    2015-01-01

    Summary Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic activation of JAK-STAT signaling, reduced insulin sensitivity, hyperglycemia, and a shorter lifespan. Drosophila macrophages produced the JAK-STAT-activating cytokine upd3, in a scavenger-receptor (crq) and JNK-dependent manner. Genetic depletion of macrophages or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-κB signaling made no contribution to the phenotype observed. These results identify an evolutionarily conserved “scavenger receptor-JNK-type 1 cytokine” cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway. PMID:25601202

  15. Type 2 Diabetes–Associated K+ Channel TALK-1 Modulates β-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis

    PubMed Central

    Vierra, Nicholas C.; Dadi, Prasanna K.; Jeong, Imju; Dickerson, Matthew; Powell, David R.

    2015-01-01

    Two-pore domain K+ (K2P) channels play an important role in tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TWIK-related alkaline pH-activated K2P (TALK)-1 is linked to type 2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 channels are expressed in mouse and human β-cells, where they serve as key regulators of electrical excitability and GSIS. We find that the rs1535500 polymorphism, which results in an alanine-to-glutamate substitution in the C-terminus of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in β-cell membrane potential depolarization, increased islet Ca2+ influx, and enhanced second-phase GSIS. Moreover, mice lacking TALK-1 channels are resistant to high-fat diet–induced elevations in fasting glycemia. These findings reveal TALK-1 channels as important modulators of second-phase insulin secretion and suggest a clinically relevant mechanism for rs1535500, which may increase type 2 diabetes risk by limiting GSIS. PMID:26239056

  16. CAPER is vital for energy and redox homeostasis by integrating glucose-induced mitochondrial functions via ERR-α-Gabpa and stress-induced adaptive responses via NF-κB-cMYC.

    PubMed

    Kang, Yun Kyoung; Putluri, Nagireddy; Maity, Suman; Tsimelzon, Anna; Ilkayeva, Olga; Mo, Qianxing; Lonard, David; Michailidis, George; Sreekumar, Arun; Newgard, Christopher B; Wang, Meng; Tsai, Sophia Y; Tsai, Ming-Jer; O'Malley, Bert W

    2015-04-01

    Ever since we developed mitochondria to generate ATP, eukaryotes required intimate mito-nuclear communication. In addition, since reactive oxygen species are a cost of mitochondrial oxidative phosphorylation, this demands safeguards as protection from these harmful byproducts. Here we identified a critical transcriptional integrator which eukaryotes share to orchestrate both nutrient-induced mitochondrial energy metabolism and stress-induced nuclear responses, thereby maintaining carbon-nitrogen balance, and preserving life span and reproductive capacity. Inhibition of nutrient-induced expression of CAPER arrests nutrient-dependent cell proliferation and ATP generation and induces autophagy-mediated vacuolization. Nutrient signaling to CAPER induces mitochondrial transcription and glucose-dependent mitochondrial respiration via coactivation of nuclear receptor ERR-α-mediated Gabpa transcription. CAPER is also a coactivator for NF-κB that directly regulates c-Myc to coordinate nuclear transcriptome responses to mitochondrial stress. Finally, CAPER is responsible for anaplerotic carbon flux into TCA cycles from glycolysis, amino acids and fatty acids in order to maintain cellular energy metabolism to counter mitochondrial stress. Collectively, our studies reveal CAPER as an evolutionarily conserved 'master' regulatory mechanism by which eukaryotic cells control vital homeostasis for both ATP and antioxidants via CAPER-dependent coordinated control of nuclear and mitochondrial transcriptomic programs and their metabolisms. These CAPER dependent bioenergetic programs are highly conserved, as we demonstrated that they are essential to preserving life span and reproductive capacity in human cells-and even in C. elegans.

  17. Active immunization against leptin fails to affect reproduction and exerts only marginal effects on glucose metabolism in young female goats.

    PubMed

    Sauerwein, H; Heintges, U; Bruhns, S C; Hennies, M; Gertler, A

    2006-08-01

    Approximately 150 days before expected breeding time, 12 female goats (3 months of age) were actively immunized against ovine leptin. Booster injections were given throughout the following year. Control animals (n = 6) were sham-immunized. After the first observed oestrus, a buck was introduced and goats were mated. Blood samples were collected twice weekly and frequent blood sampling series were performed on days -15, 76, 153 and 286 relative to the first immunization. Nine of the immunized goats developed titres within 3 months and had elevated serum concentrations of leptin compared with controls (p < 0.0001). Hematological parameters and blood chemistry were not affected by the immunization. No differences were detectable in all reproductive parameters recorded. Serum insulin was higher in immunized goats during the frequent blood sampling series of day 287 after the first immunization. Glucose metabolism was investigated during pregnancy using hyperglycaemic and euglycaemic/hyperinsulinaemic clamps. None of the parameters derived from the clamp studies was different (p > 0.05) between the two groups. During the hyperglycaemic clamp there was a trend (p < 0.15) towards increased insulin concentrations in immunized animals whereas glucose infusion rates were not different between the groups. This indicates decreased insulin sensitivity in immunized goats. Our study describes the ontogenesis of serum concentrations of leptin during growth, puberty and first pregnancy and parturition for the caprine species. The effects of the immunization were not detectable or only marginal and the approach aimed at therefore not effective to investigate leptin action in detail.

  18. Inactivation of 5HT transport in mice: modeling altered 5HT homeostasis implicated in emotional dysfunction, affective disorders, and somatic syndromes.

    PubMed

    Lesch, K P; Mössner, R

    2006-01-01

    Animal models have not only become an essential tool for investigating the neurobiological function of genes that are involved in the etiopathogenesis of human behavioral and psychiatric disorders but are also fundamental in the development novel therapeutic strategies. As an example, inactivation of the serotonin (5HT) transporter (5Htt, Slc6a4) gene in mice expanded our view of adaptive 5HT uptake regulation and maintenance of 5HT homeostasis in the developing human brain and molecular processes underlying anxiety-related traits, as well as affective spectrum disorders including depression. 5Htt-deficient mice have been employed as a model complementary to direct studies of genetically complex traits and disorders, with important findings in biochemical, morphological, behavioral, and pharmacological areas. Based on growing evidence for a critical role of the 5HTT in the integration of synaptic connections in the rodent, nonhuman primate, and human brain during critical periods of development and adult life, more in-depth knowledge of the molecular mechanisms implicated in these fine-tuning processes is currently evolving. Moreover, demonstration of a joint influence of the 5HTT variation and environmental sources during early brain development advanced our understanding of the mechanism of genexgene and genexenvironment interactions in the developmental neurobiology of anxiety and depression. Lastly, imaging techniques, which become increasingly elaborate in displaying the genomic influence on brain system activation in response to environmental cues, have provided the means to bridge the gap between small effects of 5HTT variation and complex behavior, as well as psychopathological dimensions. The combination of elaborate genetic, epigenetic, imaging, and behavioral analyses will continue to generate new insight into 5HTT's role as a master control gene of emotion regulation.

  19. Exposure to elevated ozone levels differentially affects the antioxidant capacity and the redox homeostasis of two subtropical Phaseolus vulgaris L. varieties.

    PubMed

    Caregnato, Fernanda Freitas; Bortolin, Rafael Calixto; Divan Junior, Armando Molina; Moreira, José Cláudio Fonseca

    2013-09-01

    Ozone (O3) has become one of the most toxic air pollutants to plants worldwide. However, investigations on O3 impacts on crops health and productivity in South America countries are still scarce. The present study analyzed the differences on the enzymatic and non-enzymatic antioxidant system in foliar tissue of two subtropical Phaseolus vulgaris varieties exposed to high O3 concentration. Both varieties were negatively impacted by the pollutant, but the responses between each variety were quite distinct. Results revealed that Irai has higher constitutive levels of reactive oxygen species (ROS) and ascorbate (AsA) concentration, but lower total thiol levels and catalase immunocontent. In this variety catalase protein concentration was increased after O3 exposure, indicating a better cellular capacity to reduce hydrogen peroxide. On the opposite, Fepagro 26-exposed plants increased ROS generation and AsA concentration, but had the levels of total thiol content and catalase protein unchanged. Furthermore, O3 treatment reduced the levels of chlorophylls a and b, and the relationship analysis between the chlorophyll ratio (a/b) and protein concentration were positively correlated indicating that photosynthetic apparatus is compromised, and thus probably is the biomass acquisition on Fepagro 26. Differently, O3 treatment of Irai did not affect chlorophylls a and b content, and loss on the protein content was lower. Altogether, these data suggest that early accumulation of ROS on Fepagro 26 are associated with an insufficient leaf antioxidant capacity, which leads to cell structure disruption and impairs the photosynthesis. Irai seems to be more tolerant to O3 toxic effects than Fepagro 26, and the observed differences on O3 sensitivity between the two varieties are apparently based on constitutive differences involved in the maintenance of intracellular redox homeostasis.

  20. Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.

    PubMed

    Pronicka, Ewa; Węglewska-Jurkiewicz, Anna; Taybert, Joanna; Pronicki, Maciej; Szymańska-Dębińska, Tamara; Karkucińska-Więckowska, Agnieszka; Jakóbkiewicz-Banecka, Joanna; Kowalski, Paweł; Piekutowska-Abramczuk, Dorota; Pajdowska, Magdalena; Socha, Piotr; Sykut-Cegielska, Jolanta; Węgrzyn, Grzegorz

    2011-02-01

    Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogenicity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled,