Science.gov

Sample records for abnormal glucose homeostasis

  1. Canine malignant hyperthermia susceptibility: erythrocytic defects--osmotic fragility, glucose-6-phosphate dehydrogenase deficiency and abnormal Ca2+ homeostasis.

    PubMed Central

    O'Brien, P J; Forsyth, G W; Olexson, D W; Thatte, H S; Addis, P B

    1984-01-01

    Two dogs were diagnosed as malignant hyperthermia susceptible based on increased susceptibility (P less than 0.001) of biopsied muscle to caffeine-induced contracture. Erythrocytes from malignant hyperthermia and normal dogs were then examined for an antioxidant system deficiency. Values for serum muscle enzymes, reticulocytes and corpuscular hemoglobin were mildly elevated. Osmotic fragility was increased: hemolysis occurred at a NaCl concentration 10 mM higher than for normal dogs (P less than 0.001). A 35% glucose-6-phosphate dehydrogenase deficiency (P less than 0.001) with a 40% compensatory increase (P less than 0.01) in 6-phosphogluconate dehydrogenase activity was found. The membrane Ca2+-activated ATPase activity was abnormal: 100% increased with a 40% decreased Arrhenius activation energy (P less than 0.005) and increased thermostability. A 40% increased intracellular accumulation of total Ca2+ occurred in response to in vitro energy depletion in erythrocytes from one malignant hyperthermia dog (P less than 0.01). The multifactorial pattern of inheritance and the broad spectrum of malignant hyperthermia susceptibility are proposed to result from an antioxidant system deficit unmasking or aggravating an intrinsic muscle membrane anomaly. An individual from a family with a history of malignant hyperthermia or unexplained anesthetic death should be considered malignant hyperthermia susceptible if erythrocyte osmotic fragility is abnormal and there is a mild, unexplained elevation in serum creatine kinase. PMID:6150753

  2. Pancreatic regulation of glucose homeostasis.

    PubMed

    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

  3. Pancreatic regulation of glucose homeostasis.

    PubMed

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

    2016-03-11

    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.

  4. 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

  5. [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. PMID:24444521

  6. [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.

  7. Bitter taste receptors influence glucose homeostasis.

    PubMed

    Dotson, Cedrick D; Zhang, Lan; Xu, Hong; Shin, Yu-Kyong; Vigues, Stephan; Ott, Sandra H; Elson, Amanda E T; Choi, Hyun Jin; Shaw, Hillary; Egan, Josephine M; Mitchell, Braxton D; Li, Xiaodong; Steinle, Nanette I; Munger, Steven D

    2008-01-01

    TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca(2+) and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease. PMID:19092995

  8. Abnormal calcium homeostasis in peripheral neuropathies

    PubMed Central

    Fernyhough, Paul; Calcutt, Nigel A.

    2010-01-01

    Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The central impact of both alterations of Ca2+ signalling at the plasma membrane and also intracellular Ca2+ handling on sensory neuron function is discussed and related to abnormal endoplasmic reticulum performance. We also present new data highlighting sub-optimal axonal Ca 2+ signalling in diabetic neuropathy and discuss the putative role for this abnormality in the induction of axonal degeneration in peripheral neuropathies. The accumulating evidence implicating Ca2+ dysregulation with both painful and degenerative neuropathies, along with recent advances in understanding of regional variations in Ca2+ channel and pump structures, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many peripheral neuropathies. PMID:20034667

  9. 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

  10. 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.

  11. Nonnutritive sweeteners, energy balance and glucose homeostasis

    PubMed Central

    Pepino, M. Yanina; Bourne, Christina

    2012-01-01

    Purpose of review To review recent work on potential mechanisms underlying a paradoxical positive association between the consumption of nonnutritive sweeteners (NNS) and weight gain. Recent findings Several potential mechanism, not mutually exclusive, are hypothesized. First, by dissociating sweetness from calories, NNS could interfere with physiological responses that control homeostasis. Second, by changing the intestinal environment, NNS could affect the microbiota and in turn trigger inflammatory processes that are associated with metabolic disorders. Third, by interacting with novel sweet-taste receptors discovered in the gut, NNS could affect glucose absorptive capacity and glucose homeostasis. This last is the mechanism that has received the most attention recently. Some animal studies, but not all, found that NNS activate gut sweet taste-pathways that control incretin release and up-regulate glucose transporters. Human studies found that, at least for healthy fasted subjects, the sole interaction of NNS with sweet-taste gut receptors is insufficient to elicit incretin responses. The reasons for discrepancy between different studies is unknown but could be related to the species of mammal tested and the dose of NNS used. Summary Whether NNS are metabolically inactive, as previously assumed, is unclear. Further research on the potential effects of NNS on human metabolism is warranted. PMID:21505330

  12. Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and ß cell failure

    PubMed Central

    Porter, J; Barrett, T

    2005-01-01

    Type 2 diabetes mellitus is caused by a combination of insulin resistance and ß cell failure. The polygenic nature of type 2 diabetes has made it difficult to study. Although many candidate genes for this condition have been suggested, in most cases association studies have been equivocal. Monogenic forms of diabetes have now been studied extensively, and the genetic basis of many of these syndromes has been elucidated, leading to greater understanding of the functions of the genes involved. Common variations in the genes causing monogenic disorders have been associated with susceptibility to type 2 diabetes in several populations and explain some of the linkage seen in genome-wide scans. Monogenic disorders are also helpful in understanding both normal and disordered glucose and insulin metabolism. Three main areas of defect contribute to diabetes: defects in insulin signalling leading to insulin resistance; defects of insulin secretion leading to hypoinsulinaemia; and apoptosis leading to decreased ß cell mass. These three pathological pathways are reviewed, focusing on rare genetic syndromes which have diabetes as a prominent feature. Apoptosis seems to be a final common pathway in both type 1 and type 2 diabetes. Study of rare forms of diabetes may help ion determining new therapeutic targets to preserve or increase ß cell mass and function. PMID:15772126

  13. How High Glucose Levels Affect Tendon Homeostasis.

    PubMed

    Snedeker, Jess G

    2016-01-01

    Among the many factors playing a role in tendon disease, unregulated biochemical reactions between glucose and the collagen extracellular matrix are coming increasingly into focus. We have shown that formation of advanced glycation end-products that cross-link the collagen extracellular matrix can drastically affect cellular level mechanical properties of the matrix, and in turn affect cell-level biomechanical stimuli during physiological loading of the tissue. We suggest that these may adversely affect tendon cell response to matrix damage, as well as the quality of the consequent repair. If such mechanical feedback loops are altered, the ability of tendon cells to maintain tissue in a functional, healthy state may be compromised. Although key foundational elements of biochemical, biomechanical, and biological understanding are now in place, the full extent of how these aspects interact, including the precise mechanisms by which advanced glycation end-products pathologically disrupt connective tissue homeostasis and damage repair, are only beginning to be adequately appreciated. PMID:27535261

  14. Leptin, 20 years of searching for glucose homeostasis.

    PubMed

    Fernández-Formoso, Gabriela; Pérez-Sieira, Sonia; González-Touceda, David; Dieguez, Carlos; Tovar, Sulay

    2015-11-01

    Leptin was discovered in 1994 (20 years ago). In addition to having well-characterized effects on the regulation of energy homeostasis, leptin clearly also plays a major role in metabolic homeostasis. In fact, leptin plays an important role in the regulation of glucose homeostasis independent of food intake and body weight. The mechanism underlying the modulation of glucose metabolism by leptin is not completely understood, although evidence indicates that the effect occurs at both the central and peripheral levels. In this review, we will focus on the role of leptin in glucose homeostasis at the central level and its role in insulin secretion and in counteracting hormones, such as glucagon, growth hormone, cortisol and catecholamines.

  15. 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.

  16. Association of SSTR2 Polymorphisms and Glucose Homeostasis Phenotypes

    PubMed Central

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

    2009-01-01

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

  17. 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. PMID:18708284

  18. Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis.

    PubMed

    De Vadder, Filipe; Kovatcheva-Datchary, Petia; Zitoun, Carine; Duchampt, Adeline; Bäckhed, Fredrik; Mithieux, Gilles

    2016-07-12

    Beneficial effects of dietary fiber on glucose and energy homeostasis have long been described, focusing mostly on the production of short-chain fatty acids by the gut commensal bacteria. However, bacterial fermentation of dietary fiber also produces large amounts of succinate and, to date, no study has focused on the role of succinate on host metabolism. Here, we fed mice a fiber-rich diet and found that succinate was the most abundant carboxylic acid in the cecum. Dietary succinate was identified as a substrate for intestinal gluconeogenesis (IGN), a process that improves glucose homeostasis. Accordingly, dietary succinate improved glucose and insulin tolerance in wild-type mice, but those effects were absent in mice deficient in IGN. Conventional mice colonized with the succinate producer Prevotella copri exhibited metabolic benefits, which could be related to succinate-activated IGN. Thus, microbiota-produced succinate is a previously unsuspected bacterial metabolite improving glycemic control through activation of IGN. PMID:27411015

  19. 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. PMID:27217488

  20. 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.

  1. Chronic sleep disturbance impairs glucose homeostasis in rats.

    PubMed

    Barf, R Paulien; Meerlo, Peter; Scheurink, Anton J W

    2010-01-01

    Epidemiological studies have shown an association between short or disrupted sleep and an increased risk for metabolic disorders. To assess a possible causal relationship, we examined the effects of experimental sleep disturbance on glucose regulation in Wistar rats under controlled laboratory conditions. Three groups of animals were used: a sleep restriction group (RS), a group subjected to moderate sleep disturbance without restriction of sleep time (DS), and a home cage control group. To establish changes in glucose regulation, animals were subjected to intravenous glucose tolerance tests (IVGTTs) before and after 1 or 8 days of sleep restriction or disturbance. Data show that both RS and DS reduce body weight without affecting food intake and also lead to hyperglycemia and decreased insulin levels during an IVGTT. Acute sleep disturbance also caused hyperglycemia during an IVGTT, yet, without affecting the insulin response. In conclusion, both moderate and severe disturbances of sleep markedly affect glucose homeostasis and body weight control. PMID:20339560

  2. Glucose homeostasis in pregnant rats submitted to dietary protein restriction.

    PubMed

    de Mello, Maria Alice Rostom; Luciano, Eliete; Carneiro, Everardo Magalhães; Latorraca, Márcia Queiroz; Machado de Oliveira, Camnila Aparecida; Boschero, Antonio Carlos

    2003-01-01

    In the present work, we examined the effects of feeding a low protein diet during pregnancy on glucose-induced insulin secretion and glucose homeostasis in rats. Young (60 days), pregnant (P) or non-pregnant (NP) rats were fed during pregnancy or for 21 days (the NP) a normal (17%) or a low (6%) protein diet. Serum glucose and insulin levels and pancreas insulin content in the fed state; total area under serum glucose curve (AG) after a glucose load and serum glucose disappearance rate (Kitt) after insulin administration; as well as 86Rb outflow, 45Ca uptake and insulin secretion by isolated pancreatic islets in response to glucose were evaluated. Serum glucose was lower in 17%-P (12%) and 6%-P (27%) than in corresponding NP-rats. Serum insulin was higher in 17%-P (153%) and 6%-P (77%) compared to the corresponding NP-rats. Pancreatic insulin was higher in 6%-rats (55%) than in 17%-rats. No differences were found in AG among the groups whereas Kitt was lower in 6%-NP and higher in 6%-P than in the equivalent 17% rats. Increasing glucose concentration from 2.8 to 16.7 mmol/l, reduced 86Rb outflow from isolated islets from all groups. Increasing glucose concentration from 2.8 to 16.7 mmol/l elevated 45Ca uptake by 17%-NP (47%), 17%-P (40%) and 6%-P (214%) islets but not by 6%-NP ones. The increase in 45Ca uptake was followed by an increase in insulin release by the 17%-NP (2767%), 17%-P (2850%) and 6%-P (1200%) islets. In conclusion, 6%-P rats show impaired glucose induced insulin secretion related to reduced calcium uptake by pancreatic islets. However, the poor insulin secretion did not fully compensate the high peripheral sensitivity to the hormone, resulting in hypoglycemia. PMID:15686122

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

    PubMed Central

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

    2016-01-01

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

  4. Genetic Models of PGC-1 and Glucose Metabolism and Homeostasis

    PubMed Central

    Rowe, Glenn C.; Arany, Zolt

    2013-01-01

    Type II diabetes and its complications are a tremendous health burden throughout the world. Our understanding of the changes that lead to glucose imbalance and insulin resistance and ultimately diabetes remain incompletely understood. Many signaling and transcriptional pathways have been identified as being important to maintain normal glucose balance, including that of the peroxisome proliferator activated receptor gamma coactivator (PGC-1) family. This family of transcriptional coactivators strongly regulates mitochondrial and metabolic biology in numerous organs. The use of genetic models of PGC-1s, including both tissue-specific overexpression and knock-out models, has helped to reveal the specific roles that these coactivators play in each tissue. This review will thus focus on the PGC-1s and recently developed genetic rodent models that have highlighted the importance of these molecules in maintaining normal glucose homeostasis. PMID:24057597

  5. 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

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

    PubMed Central

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

    2015-01-01

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

  7. Measurement of glucose homeostasis in vivo: glucose and insulin tolerance tests.

    PubMed

    Beguinot, Francesco; Nigro, Cecilia

    2012-01-01

    The feasibility of investigating glucose tolerance and insulin action and secretion in vivo in mouse models has provided major insights into both type 2 diabetes pathogenesis and the identification of novel strategies to treat this common disorder. When initial studies provide evidence for altered levels of insulin and/or glucose in the animal blood, a number of well-characterized tests can be adopted to estimate glucose homeostasis and insulin action and secretion in vivo. These tests include model assessments, glucose and insulin sensitivity studies, and glucose clamps. None of them can be considered appropriate under all circumstances and there is significant variation in their complexity, technical ease, and invasiveness. Thus, while the euglycaemic hyperinsulinemic clamp represents the gold standard for measuring in vivo insulin action, less labor-intensive as well as invasive techinques are usually considered as the initial approach to evaluate glucose homeostasis. This section focuses on glucose and insulin tolerance tests. The clamp technique is described in Chapter 15.

  8. Impaired Glucose and Insulin Homeostasis in Moderate-Severe CKD.

    PubMed

    de Boer, Ian H; Zelnick, Leila; Afkarian, Maryam; Ayers, Ernest; Curtin, Laura; Himmelfarb, Jonathan; Ikizler, T Alp; Kahn, Steven E; Kestenbaum, Bryan; Utzschneider, Kristina

    2016-09-01

    Kidney disease leads to clinically relevant disturbances in glucose and insulin homeostasis, but the pathophysiology in moderate-severe CKD remains incompletely defined. In a cross-sectional study of 59 participants with nondiabetic CKD (mean eGFR =37.6 ml/min per 1.73 m(2)) and 39 healthy control subjects, we quantified insulin sensitivity, clearance, and secretion and glucose tolerance using hyperinsulinemic-euglycemic clamp and intravenous and oral glucose tolerance tests. Participants with CKD had lower insulin sensitivity than participants without CKD (mean[SD] 3.9[2.0] versus 5.0 [2.0] mg/min per µU/ml; P<0.01). Insulin clearance correlated with insulin sensitivity (r=0.72; P<0.001) and was also lower in participants with CKD than controls (876 [226] versus 998 [212] ml/min; P<0.01). Adjustment for physical activity, diet, fat mass, and fatfree mass in addition to demographics and smoking partially attenuated associations of CKD with insulin sensitivity (adjusted difference, -0.7; 95% confidence interval, -1.4 to 0.0 mg/min per µU/ml) and insulin clearance (adjusted difference, -85; 95% confidence interval, -160 to -10 ml/min). Among participants with CKD, eGFR did not significantly correlate with insulin sensitivity or clearance. Insulin secretion and glucose tolerance did not differ significantly between groups, but 65% of participants with CKD had impaired glucose tolerance. In conclusion, moderate-severe CKD associated with reductions in insulin sensitivity and clearance that are explained, in part, by differences in lifestyle and body composition. We did not observe a CKD-specific deficit in insulin secretion, but the combination of insulin resistance and inadequate augmentation of insulin secretion led to a high prevalence of impaired glucose tolerance.

  9. 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

  10. 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. PMID:24991093

  11. Altered Glucose Homeostasis and Hepatic Function in Obese Mice Deficient for Both Kinin Receptor Genes

    PubMed Central

    Barros, Carlos C.; Haro, Anderson; Russo, Fernanda J. V. P.; Schadock, Ines; Almeida, Sandro S.; Ribeiro, Rosane A.; Vanzela, Emerielle C.; Lanzoni, Valeria P.; Barros, Flavio C.; Moraes, Milton R.; Mori, Marcelo A.; Bacurau, Reury F. P.; Wurtele, Martin; Boschero, Antônio C.; Carneiro, Everardo M.; Bader, Michael; Pesquero, Joao B.; Araujo, Ronaldo C.

    2012-01-01

    The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM. PMID:22829877

  12. Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice.

    PubMed

    Hargett, Stefan R; Walker, Natalie N; Keller, Susanna R

    2016-02-15

    The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160(-/-)/Tbc1d1(-/-) mice). Herein, we describe abnormalities in male and female AS160(-/-)/Tbc1d1(-/-) mice on another strain background. We confirm the earlier observation that GLUT4 expression and glucose uptake defects of single-knockout mice join in AS160(-/-)/Tbc1d1(-/-) mice to affect all skeletal muscle and adipose tissues. In large mixed fiber-type skeletal muscles, changes in relative basal GLUT4 plasma membrane association in AS160(-/-) and Tbc1d1(-/-) mice also combine in AS160(-/-)/Tbc1d1(-/-) mice. However, we found different glucose uptake abnormalities in isolated skeletal muscles and adipocytes than reported previously, resulting in different interpretations of how AS160 and Tbc1d1 regulate GLUT4 translocation to the cell surface. In support of a larger role for AS160 in glucose homeostasis, in contrast with the previous study, we find similarly impaired glucose and insulin tolerance in AS160(-/-)/Tbc1d1(-/-) and AS160(-/-) mice. However, in vivo glucose uptake abnormalities in AS160(-/-)/Tbc1d1(-/-) skeletal muscles differ from those observed previously in AS160(-/-) mice, indicating additional defects due to Tbc1d1 deletion. Similar to AS160- and Tbc1d1-deficient mice, AS160(-/-)/Tbc1d1(-/-) mice show sex-specific abnormalities in glucose and energy homeostasis. In conclusion, our study supports nonredundant functions for AS160 and Tbc1d1. PMID:26625902

  13. Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice.

    PubMed

    Hargett, Stefan R; Walker, Natalie N; Keller, Susanna R

    2016-02-15

    The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160(-/-)/Tbc1d1(-/-) mice). Herein, we describe abnormalities in male and female AS160(-/-)/Tbc1d1(-/-) mice on another strain background. We confirm the earlier observation that GLUT4 expression and glucose uptake defects of single-knockout mice join in AS160(-/-)/Tbc1d1(-/-) mice to affect all skeletal muscle and adipose tissues. In large mixed fiber-type skeletal muscles, changes in relative basal GLUT4 plasma membrane association in AS160(-/-) and Tbc1d1(-/-) mice also combine in AS160(-/-)/Tbc1d1(-/-) mice. However, we found different glucose uptake abnormalities in isolated skeletal muscles and adipocytes than reported previously, resulting in different interpretations of how AS160 and Tbc1d1 regulate GLUT4 translocation to the cell surface. In support of a larger role for AS160 in glucose homeostasis, in contrast with the previous study, we find similarly impaired glucose and insulin tolerance in AS160(-/-)/Tbc1d1(-/-) and AS160(-/-) mice. However, in vivo glucose uptake abnormalities in AS160(-/-)/Tbc1d1(-/-) skeletal muscles differ from those observed previously in AS160(-/-) mice, indicating additional defects due to Tbc1d1 deletion. Similar to AS160- and Tbc1d1-deficient mice, AS160(-/-)/Tbc1d1(-/-) mice show sex-specific abnormalities in glucose and energy homeostasis. In conclusion, our study supports nonredundant functions for AS160 and Tbc1d1.

  14. [Pulmonary surfactant homeostasis associated genetic abnormalities and lung diseases].

    PubMed

    Jiang, Xiaojing; Sun, Xiuzhu; Du, Weihua; Hao, Haisheng; Zhao, Xueming; Wang, Dong; Zhu, Huabin; Liu, Yan

    2016-08-01

    Pulmonary surfactant (PS) is synthesized and secreted by alveolar epithelial type II (AEII) cells, which is a complex compound formed by proteins and lipids. Surfactant participates in a range of physiological processes such as reducing the surface tension, keeping the balance of alveolar fluid, maintaining normal alveolar morphology and conducting host defense. Genetic disorders of the surfactant homeostasis genes may result in lack of surfactant or cytotoxicity, and lead to multiple lung diseases in neonates, children and adults, including neonatal respiratory distress syndrome, interstitial pneumonia, pulmonary alveolar proteinosis, and pulmonary fibrosis. This paper has provided a review for the functions and processes of pulmonary surfactant metabolism, as well as the connection between disorders of surfactant homeostasis genes and lung diseases.

  15. 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

  16. Continuous Glucose Monitoring in Patients with Abnormal Glucose Tolerance during Pregnancy: A Case Series.

    PubMed

    Tonoike, Mie; Kishimoto, Miyako; Yamamoto, Mayumi; Yano, Tetsu; Noda, Mitsuhiko

    2016-01-01

    Abnormal glucose tolerance during pregnancy is associated with perinatal complications. We used continuous glucose monitoring (CGM) in pregnant women with glucose intolerance to achieve better glycemic control and to evaluate the maternal glucose fluctuations. We also used CGM in women without glucose intolerance (the control cases). Furthermore, the standard deviation (SD) and mean amplitude of glycemic excursions (MAGE) were calculated for each case. For the control cases, the glucose levels were tightly controlled within a very narrow range; however, the SD and MAGE values in pregnant women with glucose intolerance were relativity high, suggesting postprandial hyperglycemia. Our results demonstrate that pregnant women with glucose intolerance exhibited greater glucose fluctuations compared with the control cases. The use of CGM may help to improve our understanding of glycemic patterns and may have beneficial effects on perinatal glycemic control, such as the detection of postprandial hyperglycemia in pregnant women. PMID:26949348

  17. Importance of β-Catenin in glucose and energy homeostasis.

    PubMed

    Elghazi, Lynda; Gould, Aaron P; Weiss, Aaron J; Barker, Daniel J; Callaghan, John; Opland, Darren; Myers, Martin; Cras-Méneur, Corentin; Bernal-Mizrachi, Ernesto

    2012-01-01

    In settings of increased insulin demand, failure to expand pancreatic β-cells mass leads to diabetes. Genome-wide scans of diabetic populations have uncovered several genes associated with susceptibility to type 2 diabetes and a number of them are part of the Wnt signaling. β-Catenin, a Wnt downstream effector participates in pancreatic development, however, little is known about its action in mature β-cells. Deletion of β-Catenin in Pdx1 pancreatic progenitors leads to a decreased β-cell mass and impaired glucose tolerance. Surprisingly, loss of β-catenin made these mice resistant to high fat diet because of their increased energy expenditure and insulin sensitivity due to hyperactivity. The complexity of this phenotype was also explained in part by ectopic expression of Cre recombinase in the hypothalamus. Our data implicates β-Catenin in the regulation of metabolism and energy homeostasis and suggest that Wnt signaling modulates the susceptibility to diabetes by acting on different tissues. PMID:23012647

  18. Role of cannabinoid CB2 receptors in glucose homeostasis in rats.

    PubMed

    Bermudez-Silva, Francisco Javier; Sanchez-Vera, Irene; Suárez, Juan; Serrano, Antonia; Fuentes, Esther; Juan-Pico, Pablo; Nadal, Angel; Rodríguez de Fonseca, Fernando

    2007-06-22

    Here we show that the activation of cannabinoid CB2 receptors improved glucose tolerance after a glucose load. Blockade of cannabinoid CB2 receptors counteracted this effect, leading to glucose intolerance. Since blockade of cannabinoid CB1 receptors mimics the actions of cannabinoid CB2 receptor agonists, we propose that the endocannabinoid system modulates glucose homeostasis through the coordinated actions of cannabinoid CB1 and CB2 receptors. We also describe the presence of both cannabinoid CB1 and CB2 receptor immunoreactivity in rat pancreatic beta- and non-beta-cells, adding the endocrine pancreas to adipose tissue and the liver as potential sites for endocannabinoid regulation of glucose homeostasis.

  19. Glucose abnormalities in Asian patients with chronic hepatitis C.

    PubMed

    Bo, Qingyan; Orsenigo, Roberto; Wang, Junyi; Griffel, Louis; Brass, Clifford

    2015-01-01

    Many studies have demonstrated a potential association between type 2 diabetes (T2D) and hepatitis C virus infection in Western countries, while similar evidence is limited in Asia. We compared the prevalence of glucose abnormalities (impaired fasting glucose [IFG] and T2D) and their risk factors between Asian and non-Asian chronic hepatitis C (CHC) patients, and evaluated whether glucose abnormalities impacted the viral responses to peginterferon plus ribavirin treatment (current standard of care in most Asian countries). This study retrospectively analyzed data of 1,887 CHC patients from three Phase II/III studies with alisporivir (DEB025) as treatment for CHC. The chi-square test was used to compare the prevalence of IFG/T2D between Asian and non-Asian CHC patients, and logistic regression was used to adjust for sex, age, and cirrhosis status. Risk factors for IFG/T2D were evaluated using univariate and multivariate analysis. Our results indicated that the prevalence of IFG/T2D was high in both Asian and non-Asian CHC patients (23.0% vs 20.9%), and no significant difference was found between these two populations (adjusted odds ratio: 1.3, 95% confidence interval: 0.97, 1.7; P=0.08). Age, sex, and cirrhosis status were risk factors for IFG/T2D in both populations, while body mass index was positively associated with IFG/T2D in non-Asian but not in Asian participants. No significant differences in sustained virological response rates were seen between patients with normal fasting glucose and patients with IFG/T2D for both populations. These results demonstrate that the prevalence of glucose abnormalities in Asian CHC patients was similar to that in non-Asians, and glucose abnormalities had no impact on viral response to peginterferon plus ribavirin.

  20. 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. PMID:27478532

  1. 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

  2. Dietary Patterns and Glucose Tolerance Abnormalities in Chinese Adults

    PubMed Central

    He, Yuna; Ma, Guansheng; Zhai, Fengying; Li, Yanping; Hu, Yisong; Feskens, Edith J.M.; Yang, Xiaoguang

    2009-01-01

    OBJECTIVE To investigate the association of the dietary pattern with the presence of newly diagnosed glucose tolerance abnormalities among Chinese adults. RESEARCH DESIGN AND METHODS A total of 20,210 adults aged 45–69 years from the 2002 China National Nutrition and Health Survey were included. Information on dietary intake was collected using a validated food frequency questionnaire. Factor analysis and cluster analysis were used to identify the food factors and dietary pattern clusters. RESULTS Four dietary pattern clusters were identified (“Green Water,” “Yellow Earth,” “Western Adopter,” and “New Affluence”). The prevalence of glucose tolerance abnormalities ranged from 3.9% in the Green Water to 8.0% in the New Affluence. After adjustment for area, age, sex, current smoking, and physical activity, subjects in the Yellow Earth cluster (prevalence ratio 1.22 [95% CI 1.04–1.43]) and New Affluence cluster (2.05 [1.76–2.37]) had significantly higher prevalence rates compared with those for the Green Water cluster. After further adjustment for BMI and waist-to-height ratio, the elevated risk in the New Affluence remained statistically significant. CONCLUSIONS Dietary patterns and food factors are associated with the presence of glucose tolerance abnormalities in China, even independent of obesity. A New Affluence diet is an important modifiable risk factor, which needs attention from the prevention point of view. PMID:19675202

  3. NR4A orphan nuclear receptors in glucose homeostasis: a minireview.

    PubMed

    Close, A F; Rouillard, C; Buteau, J

    2013-12-01

    Type 2 diabetes mellitus is a disorder characterized by insulin resistance and a relative deficit in insulin secretion, both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. An ever-growing body of evidence suggests that members of the NR4A family of nuclear receptors could play a pivotal role in glucose homeostasis. This review aims to present and discuss advances so far in the evaluation of the potential role of NR4A in the regulation of glucose homeostasis and the development of type 2 diabetes. PMID:24075454

  4. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans.

    PubMed

    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; Sidossis, Labros S

    2014-12-01

    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.

  5. Transient Receptor Potential Vanilloid 1 Activation Enhances Gut Glucagon-Like Peptide-1 Secretion and Improves Glucose Homeostasis

    PubMed Central

    Wang, Peijian; Yan, Zhencheng; Zhong, Jian; Chen, Jing; Ni, Yinxing; Li, Li; Ma, Liqun; Zhao, Zhigang; Liu, Daoyan; Zhu, Zhiming

    2012-01-01

    Type 2 diabetes mellitus (T2DM) is rapidly prevailing as a serious global health problem. Current treatments for T2DM may cause side effects, thus highlighting the need for newer and safer therapies. We tested the hypothesis that dietary capsaicin regulates glucose homeostasis through the activation of transient receptor potential vanilloid 1 (TRPV1)-mediated glucagon-like peptide-1 (GLP-1) secretion in the intestinal cells and tissues. Wild-type (WT) and TRPV1 knockout (TRPV1−/−) mice were fed dietary capsaicin for 24 weeks. TRPV1 was localized in secretin tumor cell-1 (STC-1) cells and ileum. Capsaicin stimulated GLP-1 secretion from STC-1 cells in a calcium-dependent manner through TRPV1 activation. Acute capsaicin administration by gastric gavage increased GLP-1 and insulin secretion in vivo in WT but not in TRPV1−/− mice. Furthermore, chronic dietary capsaicin not only improved glucose tolerance and increased insulin levels but also lowered daily blood glucose profiles and increased plasma GLP-1 levels in WT mice. However, this effect was absent in TRPV1−/− mice. In db/db mice, TRPV1 activation by dietary capsaicin ameliorated abnormal glucose homeostasis and increased GLP-1 levels in the plasma and ileum. The present findings suggest that TRPV1 activation–stimulated GLP-1 secretion could be a promising approach for the intervention of diabetes. PMID:22664955

  6. Role of orexin in the central regulation of glucose and energy homeostasis.

    PubMed

    Tsuneki, Hiroshi; Wada, Tsutomu; Sasaoka, Toshiyasu

    2012-01-01

    Hypothalamic orexin neurons are known to regulate sleep/wake stability, feeding behavior, emotions, autonomic nerve activity, and whole-body energy metabolism. In addition, emerging evidence indicates that orexin contributes to central regulation of glucose homeostasis. Intriguingly, central administration of orexin is reported to cause blood glucose-elevating effect or blood glucose-lowering effect in rodents, depending on the experimental conditions. Here we reviewed the recent reports regarding the mode and mechanism of actions of orexin on these two opposing effects, and discuss the functional significance for the maintenance of glucose homeostasis. The fact that orexin exhibits biphasic effects on autonomic nerve activity and lipolysis suggests that orexin dually regulates the glucose appearance. In fact, orexin neurons are activated not only depending on the demand for glucose but also according to a circadian rhythm in the suprachiasmatic nucleus. The excited orexin neurons appear to alter the sympathetic or parasympathetic outflow to the periphery, and modulate the glucose production and utilization. Furthermore, deficiency of orexin action, particularly reduction of orexin 2 receptor-signaling, disrupts the mechanism for protection against insulin resistance associated with aging or induced by chronic high fat feeding in mice. Taken together, hypothalamic orexin system may manage multiple tasks to coordinate the interconnection among the arousal, feeding, circadian, and glucose homeostasis pathways. PMID:22293586

  7. IL-17 regulates adipogenesis, glucose homeostasis, and obesity.

    PubMed

    Zúñiga, Luis A; Shen, Wen-Jun; Joyce-Shaikh, Barbara; Pyatnova, Ekaterina A; Richards, Andrew G; Thom, Colin; Andrade, Sofia M; Cua, Daniel J; Kraemer, Fredric B; Butcher, Eugene C

    2010-12-01

    Inflammatory mediators have the potential to impact a surprising range of diseases, including obesity and its associated metabolic syndrome. In this paper, we show that the proinflammatory cytokine IL-17 inhibits adipogenesis, moderates adipose tissue (AT) accumulation, and regulates glucose metabolism in mice. IL-17 deficiency enhances diet-induced obesity in mice and accelerates AT accumulation even in mice fed a low-fat diet. In addition to potential systemic effects, IL-17 is expressed locally in AT by leukocytes, predominantly by γδ T cells. IL-17 suppresses adipocyte differentiation from mouse-derived 3T3-L1 preadipocytes in vitro, and inhibits expression of genes encoding proadipogenic transcription factors, adipokines, and molecules involved in lipid and glucose metabolism. IL-17 also acts on differentiated adipocytes, impairing glucose uptake, and young IL-17-deficient mice show enhanced glucose tolerance and insulin sensitivity. Our findings implicate IL-17 as a negative regulator of adipogenesis and glucose metabolism in mice, and show that it delays the development of obesity.

  8. Disturbance of Glucose Homeostasis After Pediatric Cardiac Surgery

    PubMed Central

    Hokken-Koelega, Anita C. S.; den Brinker, Marieke; Hop, Wim C. J.; van Thiel, Robert J.; Bogers, Ad J. J. C.; Helbing, Wim A.; Joosten, Koen F. M.

    2010-01-01

    This study aimed to evaluate the time course of perioperative blood glucose levels of children undergoing cardiac surgery for congenital heart disease in relation to endogenous stress hormones, inflammatory mediators, and exogenous factors such as caloric intake and glucocorticoid use. The study prospectively included 49 children undergoing cardiac surgery. Blood glucose levels, hormonal alterations, and inflammatory responses were investigated before and at the end of surgery, then 12 and 24 h afterward. In general, blood glucose levels were highest at the end of surgery. Hyperglycemia, defined as a glucose level higher than 8.3 mmol/l (>150 mg/dl) was present in 52% of the children at the end of surgery. Spontaneous normalization of blood glucose occurred in 94% of the children within 24 h. During surgery, glucocorticoids were administered to 65% of the children, and this was the main factor associated with hyperglycemia at the end of surgery (determined by univariate analysis of variance). Hyperglycemia disappeared spontaneously without insulin therapy after 12–24 h for the majority of the children. Postoperative morbidity was low in the study group, so the presumed positive effects of glucocorticoids seemed to outweigh the adverse effects of iatrogenic hyperglycemia. PMID:21082177

  9. 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

  10. Effects of morphine on glucose homeostasis in the conscious dog.

    PubMed Central

    Radosevich, P M; Williams, P E; Lacy, D B; McRae, J R; Steiner, K E; Cherrington, A D; Lacy, W W; Abumrad, N N

    1984-01-01

    This study was designed to assess the effects of morphine sulfate on glucose kinetics and on glucoregulatory hormones in conscious overnight fasted dogs. One group of experiments established a dose-response range. We studied the mechanisms of morphine-induced hyperglycemia in a second group. We also examined the effect of low dose morphine on glucose kinetics independent of changes in the endocrine pancreas by the use of somatostatin plus intraportal replacement of basal insulin and glucagon. In the dose-response group, morphine at 2 mg/h did not change plasma glucose, while morphine at 8 and 16 mg/h caused a hyperglycemic response. In the second group of experiments, morphine (16 mg/h) caused an increase in plasma glucose from a basal 99 +/- 3 to 154 +/- 13 mg/dl (P less than 0.05). Glucose production peaked at 3.9 +/- 0.7 vs. 2.5 +/- 0.2 mg/kg per min basally, while glucose clearance declined to 1.7 +/- 0.2 from 2.5 +/- 0.1 ml/kg per min (both P less than 0.05). Morphine increased epinephrine (1400 +/- 300 vs. 62 +/- 8 pg/ml), norepinephrine (335 +/- 66 vs. 113 +/- 10 pg/ml), glucagon (242 +/- 53 vs. 74 +/- 14 pg/ml), insulin (30 +/- 9 vs. 10 +/- 2 microU/ml), cortisol (11.1 +/- 3.3 vs. 0.9 +/- 0.2 micrograms/dl), and plasma beta-endorphin (88 +/- 27 vs. 23 +/- 6 pg/ml); all values P less than 0.05 compared with basal. These results show that morphine-induced hyperglycemia results from both stimulation of glucose production as well as inhibition of glucose clearance. These changes can be explained by rises in epinephrine, glucagon, and cortisol. These in turn are part of a widespread catabolic response initiated by high dose morphine that involves activation of the sympathetic nervous system, the endocrine pancreas, and the pituitary-adrenal axis. Also, we report the effect of a 2 mg/h infusion of morphine on glucose kinetics when the endocrine pancreas is clamped at basal levels. Under these conditions, morphine exerts a hypoglycemic effect (25% fall in plasma

  11. 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

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

    PubMed

    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

    2012-04-01

    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

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

    PubMed Central

    Henriksson, Pontus; Löf, Marie; Forsum, Elisabet

    2015-01-01

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

  14. 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

  15. 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.

  16. Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis.

    PubMed

    O'Neill, Brian T; Lauritzen, Hans P M M; Hirshman, Michael F; Smyth, Graham; Goodyear, Laurie J; Kahn, C Ronald

    2015-05-26

    Insulin and insulin-like growth factor 1 (IGF-1) are major regulators of muscle protein and glucose homeostasis. To determine how these pathways interact, we generated mice with muscle-specific knockout of IGF-1 receptor (IGF1R) and insulin receptor (IR). These MIGIRKO mice showed >60% decrease in muscle mass. Despite a complete lack of insulin/IGF-1 signaling in muscle, MIGIRKO mice displayed normal glucose and insulin tolerance. Indeed, MIGIRKO mice showed fasting hypoglycemia and increased basal glucose uptake. This was secondary to decreased TBC1D1 resulting in increased Glut4 and Glut1 membrane localization. Interestingly, overexpression of a dominant-negative IGF1R in muscle induced glucose intolerance in MIGIRKO animals. Thus, loss of insulin/IGF-1 signaling impairs muscle growth, but not whole-body glucose tolerance due to increased membrane localization of glucose transporters. Nonetheless, presence of a dominant-negative receptor, even in the absence of functional IR/IGF1R, induces glucose intolerance, indicating that interactions between these receptors and other proteins in muscle can impair glucose homeostasis. PMID:25981038

  17. Impact of glutamine supplementation on glucose homeostasis during and after exercise.

    PubMed

    Iwashita, Soh; Williams, Phillip; Jabbour, Kareem; Ueda, Takeo; Kobayashi, Hisamine; Baier, Shawn; Flakoll, Paul J

    2005-11-01

    The interaction of glutamine availability and glucose homeostasis during and after exercise was investigated, measuring whole body glucose kinetics with [3-3H]glucose and net organ balances of glucose and amino acids (AA) during basal, exercise, and postexercise hyperinsulinemic-euglycemic clamp periods in six multicatheterized dogs. Dogs were studied twice in random treatment order: once with glutamine (12 micromol.kg(-1).min(-1); Gln) and once with saline (Con) infused intravenously during and after exercise. Plasma glucose fell by 7 mg/dl with exercise in Con (P < 0.05), but it did not fall with Gln. Gln further stimulated whole body glucose production and utilization an additional 24% above a normal exercise response (P < 0.05). Net hepatic uptake of glutamine and alanine was greater with Gln than Con during exercise (P < 0.05). Net hepatic glucose output was increased sevenfold during exercise with Gln (P < 0.05) but not with Con. Net hindlimb glucose uptake was increased similarly during exercise in both groups (P < 0.05). During the postexercise hyperinsulinemic-euglycemic period, glucose production decreased to near zero with Con, but it did not decrease below basal levels with Gln. Gln increased glucose utilization by 16% compared with Con after exercise (P < 0.05). Furthermore, net hindlimb glucose uptake in the postexercise period was increased approximately twofold vs. basal with Gln (P < 0.05) but not with Con. Net hepatic uptake of glutamine during the postexercise period was threefold greater for Gln than Con (P < 0.05). In conclusion, glutamine availability modulates glucose homeostasis during and after exercise, which may have implications for postexercise recovery. PMID:16037406

  18. 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...

  19. GLP-2 receptor deficiency in the mouse brain impairs glucose homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In response to food intake, glucagon-like peptide-2 (GLP-2) with GLP-1 is co-secreted from enteroendocrine L cells in the gut. GLP-2 receptor (GLP-2R) is expressed in the hypothalamus, a key tissue to integrate energy signals to regulate energy balance and glucose homeostasis. However, the physiolog...

  20. TCPTP-deficiency in muscle does not alter insulin signalling and glucose homeostasis

    PubMed Central

    Loh, Kim; Merry, Troy L.; Galic, Sandra; Wu, Ben J.; Watt, Matthew J.; Zhang, Sheng; Zhang, Zhong-Yin; Neel, Benjamin G.; Tiganis, Tony

    2013-01-01

    Aims/Hypothesis Insulin activates the insulin receptor (IR) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The IR can serve as a substrate for the protein tyrosine phosphatases (PTP) 1B and TCPTP, which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the IR in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates IR signalling and gluconeogenesis in the liver. In this study we have assessed for the first time the role of TCPTP in the regulation of IR signalling in muscle. Methods We generated muscle-specific TCPTP-deficient (MCK-Cre;Ptpn2lox/lox) mice and assessed the impact on glucose homeostasis and muscle IR signalling in chow versus high fat fed mice. Results Blood glucose and insulin levels, insulin and glucose tolerances and insulininduced muscle IR activation and downstream PI3K/Akt signalling remained unaltered in chow fed MCK-Cre;Ptpn2lox/lox versus Ptpn2lox/lox mice. In addition, body weight, adiposity, energy expenditure, insulin sensitivity and glucose homeostasis were not altered in high fat fed MCK-Cre;Ptpn2lox/lox versus Ptpn2lox/lox mice. Conclusions These results indicate that TCPTP deficiency in muscle has no effect on insulin signalling and glucose homeostasis and does not prevent the development of high fat diet-induced insulin resistance. Thus, despite their high degree of sequence identity, PTP1B and TCPTP differentially contribute to IR regulation in muscle. Our results are consistent with these two highly related PTPs having distinct contributions to IR regulation in different tissues. PMID:22124607

  1. Lipid-Induced Peroxidation in the Intestine Is Involved in Glucose Homeostasis Imbalance in Mice

    PubMed Central

    Marsollier, Nicolas; Masseboeuf, Myriam; Payros, Gaëlle; Kabani, Catherine; Denom, Jessica; Lacombe, Amélie; Thiers, Jean-Claude; Negre-Salvayre, Anne; Luquet, Serge; Burcelin, Rémy; Cruciani-Guglielmacci, Céline; Magnan, Christophe

    2011-01-01

    Background Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. Methodology/Principal Findings An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. Conclusions/Significance Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity. PMID:21698161

  2. 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

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

    PubMed

    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

    2015-11-01

    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

  4. 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. PMID:8130181

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

    PubMed

    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

    2015-11-01

    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.

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

    PubMed

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

    2015-08-01

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

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

    PubMed

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

    2015-08-01

    Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1(-/-)) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1(-/-) mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1(-/-) mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1(-/-) mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1(-/-) mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1(-/-) mice and between male Tbc1d1(-/-) mice in different studies due to variations in body composition and nutrient handling. PMID:26015432

  8. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation.

    PubMed

    Jansen, Jos C; Cirak, Sebahattin; van Scherpenzeel, Monique; Timal, Sharita; Reunert, Janine; Rust, Stephan; Pérez, Belén; Vicogne, Dorothée; Krawitz, Peter; Wada, Yoshinao; Ashikov, Angel; Pérez-Cerdá, Celia; Medrano, Celia; Arnoldy, Andrea; Hoischen, Alexander; Huijben, Karin; Steenbergen, Gerry; Quelhas, Dulce; Diogo, Luisa; Rymen, Daisy; Jaeken, Jaak; Guffon, Nathalie; Cheillan, David; van den Heuvel, Lambertus P; Maeda, Yusuke; Kaiser, Olaf; Schara, Ulrike; Gerner, Patrick; van den Boogert, Marjolein A W; Holleboom, Adriaan G; Nassogne, Marie-Cécile; Sokal, Etienne; Salomon, Jody; van den Bogaart, Geert; Drenth, Joost P H; Huynen, Martijn A; Veltman, Joris A; Wevers, Ron A; Morava, Eva; Matthijs, Gert; Foulquier, François; Marquardt, Thorsten; Lefeber, Dirk J

    2016-02-01

    Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal

  9. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation.

    PubMed

    Jansen, Jos C; Cirak, Sebahattin; van Scherpenzeel, Monique; Timal, Sharita; Reunert, Janine; Rust, Stephan; Pérez, Belén; Vicogne, Dorothée; Krawitz, Peter; Wada, Yoshinao; Ashikov, Angel; Pérez-Cerdá, Celia; Medrano, Celia; Arnoldy, Andrea; Hoischen, Alexander; Huijben, Karin; Steenbergen, Gerry; Quelhas, Dulce; Diogo, Luisa; Rymen, Daisy; Jaeken, Jaak; Guffon, Nathalie; Cheillan, David; van den Heuvel, Lambertus P; Maeda, Yusuke; Kaiser, Olaf; Schara, Ulrike; Gerner, Patrick; van den Boogert, Marjolein A W; Holleboom, Adriaan G; Nassogne, Marie-Cécile; Sokal, Etienne; Salomon, Jody; van den Bogaart, Geert; Drenth, Joost P H; Huynen, Martijn A; Veltman, Joris A; Wevers, Ron A; Morava, Eva; Matthijs, Gert; Foulquier, François; Marquardt, Thorsten; Lefeber, Dirk J

    2016-02-01

    Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal

  10. 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.

  11. Apolipoprotein A-IV improves glucose homeostasis by enhancing insulin secretion

    PubMed Central

    Wang, Fei; Kohan, Alison B.; Kindel, Tammy L.; Corbin, Kathryn L.; Nunemaker, Craig S.; Obici, Silvana; Woods, Stephen C.; Davidson, W. Sean; Tso, Patrick

    2012-01-01

    Apolipoprotein A-IV (apoA-IV) is secreted by the small intestine in response to fat absorption. Here we demonstrate a potential role for apoA-IV in regulating glucose homeostasis. ApoA-IV–treated isolated pancreatic islets had enhanced insulin secretion under conditions of high glucose but not of low glucose, suggesting a direct effect of apoA-IV to enhance glucose-stimulated insulin release. This enhancement involves cAMP at a level distal to Ca2+ influx into the β cells. Knockout of apoA-IV results in compromised insulin secretion and impaired glucose tolerance compared with WT mice. Challenging apoA-IV−/− mice with a high-fat diet led to fasting hyperglycemia and more severe glucose intolerance associated with defective insulin secretion than occurred in WT mice. Administration of exogenous apoA-IV to apoA-IV−/− mice improved glucose tolerance by enhancing insulin secretion in mice fed either chow or a high-fat diet. Finally, we demonstrate that exogenous apoA-IV injection decreases blood glucose levels and stimulates a transient increase in insulin secretion in KKAy diabetic mice. These results suggest that apoA-IV may provide a therapeutic target for the regulation of glucose-stimulated insulin secretion and treatment of diabetes. PMID:22619326

  12. Methods for Assessing the In Vivo Role of PTEN in Glucose Homeostasis.

    PubMed

    Luk, Cynthia T; Schroer, Stephanie A; Woo, Minna

    2016-01-01

    PTEN plays an important role in diabetes pathogenesis not only as a key negative regulator of the PI3K/Akt pathway required for insulin action, but also via its role in other cell processes required to maintain metabolic homeostasis. We describe the generation of tissue-specific PTEN knockout mice and models of both type 1 and type 2 diabetes, which we have found useful for the study of diabetes pathogenesis. We also outline common methods suitable for the characterization of glucose homeostasis in rodent models, including techniques to measure beta cell function and insulin sensitivity. PMID:27033072

  13. TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis

    PubMed Central

    Dong, Fengqin; Ling, Qi; Ye, Dan; Zhang, Zhe; Shu, Jing; Chen, Guoping; Fei, Yang; Li, Chengjiang

    2016-01-01

    To evaluate the role of TCF7L2, a key regulator of glucose homeostasis, in estradiol (E2) and progesterone (P4)-modulated glucose metabolism, mouse insulinoma cells (MIN6) and human liver cancer cells (hepG2 and HUH7) were treated with physiological concentrations of E2 or P4 in the up- and down-regulation of TCF7L2. Insulin/proinsulin secretion was measured in MIN6 cells, while glucose uptake and production were evaluated in liver cancer cells. E2 increased insulin/proinsulin secretion under both basal and stimulated conditions, whereas P4 increased insulin/proinsulin secretion only under glucose-stimulated conditions. An antagonistic effect, possibly concentration-dependent, of E2 and P4 on the regulation of islet glucose metabolism was observed. After E2 or P4 treatment, secretion of insulin/proinsulin was positively correlated with TCF7L2 protein expression. When TCF7L2 was silenced, E2- or P4-promoted insulin/proinsulin secretion was significantly weakened. Under glucotoxicity conditions, overexpression of TCF7L2 increased insulin secretion and processing. In liver cancer cells, E2 or P4 exposure elevated TCF7L2 expression, enhanced the activity of insulin signaling (pAKT/pGSK), reduced PEPCK expression, subsequently increased insulin-stimulated glucose uptake, and decreased glucose production. Silencing TCF7L2 eliminated effects of E2 or P4. In conclusion, TCF7L2 regulates E2- or P4-modulated islet and hepatic glucose metabolism. The results have implications for glucose homeostasis in pregnancy. PMID:27108846

  14. TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis.

    PubMed

    Dong, Fengqin; Ling, Qi; Ye, Dan; Zhang, Zhe; Shu, Jing; Chen, Guoping; Fei, Yang; Li, Chengjiang

    2016-01-01

    To evaluate the role of TCF7L2, a key regulator of glucose homeostasis, in estradiol (E2) and progesterone (P4)-modulated glucose metabolism, mouse insulinoma cells (MIN6) and human liver cancer cells (hepG2 and HUH7) were treated with physiological concentrations of E2 or P4 in the up- and down-regulation of TCF7L2. Insulin/proinsulin secretion was measured in MIN6 cells, while glucose uptake and production were evaluated in liver cancer cells. E2 increased insulin/proinsulin secretion under both basal and stimulated conditions, whereas P4 increased insulin/proinsulin secretion only under glucose-stimulated conditions. An antagonistic effect, possibly concentration-dependent, of E2 and P4 on the regulation of islet glucose metabolism was observed. After E2 or P4 treatment, secretion of insulin/proinsulin was positively correlated with TCF7L2 protein expression. When TCF7L2 was silenced, E2- or P4-promoted insulin/proinsulin secretion was significantly weakened. Under glucotoxicity conditions, overexpression of TCF7L2 increased insulin secretion and processing. In liver cancer cells, E2 or P4 exposure elevated TCF7L2 expression, enhanced the activity of insulin signaling (pAKT/pGSK), reduced PEPCK expression, subsequently increased insulin-stimulated glucose uptake, and decreased glucose production. Silencing TCF7L2 eliminated effects of E2 or P4. In conclusion, TCF7L2 regulates E2- or P4-modulated islet and hepatic glucose metabolism. The results have implications for glucose homeostasis in pregnancy. PMID:27108846

  15. GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice.

    PubMed

    Bonaventura, M M; Catalano, P N; Chamson-Reig, A; Arany, E; Hill, D; Bettler, B; Saravia, F; Libertun, C; Lux-Lantos, V A

    2008-01-01

    GABA has been proposed to inhibit insulin secretion through GABAB receptors (GABABRs) in pancreatic beta-cells. We investigated whether GABABRs participated in the regulation of glucose homeostasis in vivo. The animals used in this study were adult male and female BALB/C mice, mice deficient in the GABAB1 subunit of the GABABR (GABAB(-/-)), and wild types (WT). Blood glucose was measured under fasting/fed conditions and in glucose tolerance tests (GTTs) with a Lifescan Glucose meter, and serum insulin was measured by ELISA. Pancreatic insulin content and islet insulin were released by RIA. Western blots for the GABAB1 subunit in islet membranes and immunohistochemistry for insulin and GABAB1 were performed in both genotypes. BALB/C mice preinjected with Baclofen (GABABR agonist, 7.5 mg/kg ip) presented impaired GTTs and decreased insulin secretion compared with saline-preinjected controls. GABAB(-/-) mice showed fasting and fed glucose levels similar to WT. GABAB(-/-) mice showed improved GTTs at moderate glucose overloads (2 g/kg). Baclofen pretreatment did not modify GTTs in GABAB(-/-) mice, whereas it impaired normal glycemia reinstatement in WT. Baclofen inhibited glucose-stimulated insulin secretion in WT isolated islets but was without effect in GABAB(-/-) islets. In GABAB(-/-) males, pancreatic insulin content was increased, basal and glucose-stimulated insulin secretion were augmented, and impaired insulin tolerance test and increased homeostatic model assessment of insulin resistance index were determined. Immunohistochemistry for insulin demonstrated an increase of very large islets in GABAB(-/-) males. Results demonstrate that GABABRs are involved in the regulation of glucose homeostasis in vivo and that the constitutive absence of GABABRs induces alterations in pancreatic histology, physiology, and insulin resistance. PMID:17971510

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

    PubMed

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

    2015-12-01

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

  17. Oxidative stress contributes to abnormal glucose metabolism and insulin sensitivity in two hyperlipidemia models

    PubMed Central

    Bai, Jiefei; Zheng, Shuang; Jiang, Dongdong; Han, Tingting; Li, Yangxue; Zhang, Yao; Liu, Wei; Cao, Yunshan; Hu, Yaomin

    2015-01-01

    Objective: Lipid metabolism disturbance can result in insulin resistance and glucose intolerance; however, the features of glucose metabolism are still elusive in different dyslipidemia. Our study intended to explore the characteristics and molecular mechanisms of glucose metabolism abnormal in hypercholesterolemia and hypertriglyceridemia models. Methods: Two mouse models were used in this study, one was lipoprotein lipase gene-deleted (LPL+/-) mice, and the other was high fat dietary (HFD) mice. Levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterin (HDL-c) and low-density lipoprotein-cholesterin (LDL-c) in serum were measured by full-automatic biochemical analyzer. Intraperitoneal glucose tolerance test (IPGTT) was performed to evaluate insulin sensitivity and β-cell function. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) levels in serum were measured by colorimetric determination. mRNA expression of superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase 1 (Gpx1), nuclear factor erythroid 2-related factor 2 (Nrf2a) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) in liver, skeletal muscle, visceral fat and subcutaneous fat were measured by Real-Time PCR. Results: Compared with HFD mice, the levels of serum TG were significantly higher in LPL+/- mice, whereas the levels of TC, HDL-c, LDL-c were significantly lower. The plasma glucose levels were increased at each time point of intra-peritoneal glucose tolerance test (IPGTT) in both groups. Furthermore, the level of serum fasting insulin and homeostasis model assessment index-insulin resistance (HOMA-IR) increased with a decreased ISI in both groups. In addition, the plasma MDA of HFD group was higher than that of lipoprotein lipase-deficiency (LPL+/-) group, while the activity of T-SOD in HFD group was lower than that in LPL+/- group. Real-Time PCR revealed that the expressions of SOD1, CAT and Gpx1 in liver and

  18. Long non-coding RNA-mediated regulation of glucose homeostasis and diabetes

    PubMed Central

    Sun, Xinghui; Wong, Danny

    2016-01-01

    Long non-coding RNAs (lncRNAs) represent an important class of non-coding RNAs that plays key roles in regulating the expression of genes in health and disease. Accumulating genetic, experimental, and epidemiological studies highlight a growing list of lncRNAs that control glucose homeostasis and diabetic pathologies and complications. Through interactions with chromatin, RNA, and protein, lncRNAs modulate chromatin modification, mRNA stability, microRNA activity, and the function of proteins such as transcription factors. This review highlights emerging concepts in lncRNA-mediated control of glucose homeostasis as well as some of the challenges and therapeutic opportunities in the pathogenesis of diabetes and its complications. PMID:27335687

  19. Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis

    PubMed Central

    Wang, Yan; Quagliarini, Fabiana; Gusarova, Viktoria; Gromada, Jesper; Valenzuela, David M.; Cohen, Jonathan C.; Hobbs, Helen H.

    2013-01-01

    Angiopoietin-like protein (ANGPTL)8 (alternatively called TD26, RIFL, Lipasin, and Betatrophin) is a newly recognized ANGPTL family member that has been implicated in both triglyceride (TG) and glucose metabolism. Hepatic overexpression of ANGPTL8 causes hypertriglyceridemia and increased insulin secretion. Here we examined the effects of inactivating Angptl8 on TG and glucose metabolism in mice. Angptl8 knockout (Angptl8−/−) mice gained weight more slowly than wild-type littermates due to a selective reduction in adipose tissue accretion. Plasma levels of TGs of the Angptl8−/− mice were similar to wild-type animals in the fasted state but paradoxically decreased after refeeding. The lower TG levels were associated with both a reduction in very low density lipoprotein secretion and an increase in lipoprotein lipase (LPL) activity. Despite the increase in LPL activity, the uptake of very low density lipoprotein-TG is markedly reduced in adipose tissue but preserved in hearts of fed Angptl8−/− mice. Taken together, these data indicate that ANGPTL8 plays a key role in the metabolic transition between fasting and refeeding; it is required to direct fatty acids to adipose tissue for storage in the fed state. Finally, glucose and insulin tolerance testing revealed no alterations in glucose homeostasis in mice fed either a chow or high fat diet. Thus, although absence of ANGPTL8 profoundly disrupts TG metabolism, we found no evidence that it is required for maintenance of glucose homeostasis. PMID:24043787

  20. Forkhead Box P1 (FOXP1) Transcription Factor Regulates Hepatic Glucose Homeostasis.

    PubMed

    Zou, Yongkang; Gong, Ning; Cui, Ying; Wang, Xiaojuan; Cui, Anfang; Chen, Qi; Jiao, Tao; Dong, Xueyu; Yang, Hao; Zhang, Shutian; Fang, Fude; Chang, Yongsheng

    2015-12-18

    Dysregulation of hepatic gluconeogenesis contributes to the pathogenesis of diabetes, yet the detailed molecular mechanisms remain to be fully elucidated. Here we show that FOXP1, a transcriptional repressor, plays a key role in the regulation of systemic glucose homeostasis. Hepatic expression levels of FOXP1 are decreased in diabetic mice. Modest hepatic overexpression of FOXP1 in mice inhibited the expression of gluconeogenic genes, such as peroxisome proliferators-activated receptor γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PC), leading to a decrease in hepatic glucose production and fasting blood glucose levels in normal mice and different mouse models of diabetes, including db/db diabetic and high-fat diet-induced obese mice. FOXP1 physically interacted with FOXO1 in vivo and competed with FOXO1 for binding to the insulin response element in the promoter region of gluconeogenic genes, thereby interfering expression of these genes. These results identify a previously unrecognized role for FOXP1 in the transcriptional control of hepatic glucose homeostasis.

  1. Ion channels in the central regulation of energy and glucose homeostasis

    PubMed Central

    Sohn, Jong-Woo

    2013-01-01

    Ion channels are critical regulators of neuronal excitability and synaptic function in the brain. Recent evidence suggests that ion channels expressed by neurons within the brain are responsible for regulating energy and glucose homeostasis. In addition, the central effects of neurotransmitters and hormones are at least in part achieved by modifications of ion channel activity. This review focuses on ion channels and their neuronal functions followed by a discussion of the identified roles for specific ion channels in the central pathways regulating food intake, energy expenditure, and glucose balance. PMID:23734095

  2. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:25263327

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

    PubMed Central

    Uchida, Aki; Aguirre, Vincent

    2015-01-01

    Background & Aims Leptin, the protein product of the ob gene, increases energy expenditure and reduces food intake, thereby promoting weight reduction. Leptin also regulates glucose homeostasis and hepatic insulin sensitivity via hypothalamic proopiomelanocortin neurons in mice. Roux-en-Y gastric bypass (RYGB) induces weight loss that is substantial and sustained despite reducing plasma leptin levels. In addition, patients who fail to undergo diabetes remission after RYGB are hypoletinemic compared to those who do and to lean controls. We have previously demonstrated that the beneficial effects of RYGB in mice require the melanocortin-4 receptor, a downstream effector of leptin action. Based on these observations, we hypothesized that leptin is required for sustained weight reduction and improved glucose homeostasis observed after RYGB. Methods To investigate this hypothesis, we performed RYGB or sham operations on leptin-deficient ob/ob mice maintained on regular chow. To investigate whether leptin is involved in post-RYGB weight maintenance, we challenged post-surgical mice with high fat diet. Results RYGB reduced total body weight, fat and lean mass and caused reduction in calorie intake in ob/ob mice. However, it failed to improve glucose tolerance, glucose-stimulated plasma insulin, insulin tolerance, and fasting plasma insulin. High fat diet eliminated the reduction in calorie intake observed after RYGB in ob/ob mice and promoted weight regain, although not to the same extent as in sham-operated mice. We conclude that leptin is required for the effects of RYGB on glucose homeostasis but not body weight or composition in mice. Our data also suggest that leptin may play a role in post-RYGB weight maintenance. PMID:26445459

  5. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations.

    PubMed

    la Fleur, S E; Kalsbeek, A; Wortel, J; van der Vliet, J; Buijs, R M

    2001-12-01

    The effects of melatonin on glucose metabolism are far from understood. In rats, the biological clock generates a 24-h rhythm in plasma glucose concentrations, with declining concentrations in the dark period. We hypothesized that, in the rat, melatonin enhances the dark signal of the biological clock, decreasing glucose concentrations in the dark period. We measured 24-h rhythms of plasma concentrations of glucose and insulin in pinealectomized rats fed ad libitum and subjected to a scheduled feeding regimen with six meals equally distributed over the light/dark cycle and compared them with previous data of intact rats. Pinealectomy dampened the amplitude of the 24-h rhythm in plasma glucose concentrations in rats fed ad libitum, and abolished it completely in rats subjected to the scheduled feeding regimen, while plasma insulin concentrations did not change under both conditions. Pinealectomy abolished the nocturnal decline in plasma glucose concentrations irrespective of whether rats were fed ad libitum or subjected to the scheduled feeding regimen. Melatonin replacement restored 24-h mean plasma glucose concentrations in pinealectomized rats that were subjected to the scheduled feeding regimen but, interestingly, it did not restore the 24-h rhythm. Melatonin treatment also resulted in higher meal-induced insulin responses, probably mediated via an increased sensitivity of the beta-cells. Taken together, our data demonstrate that the pineal hormone, melatonin, influences both glucose metabolism and insulin secretion from the pancreatic beta-cell. The present study also demonstrates that removal of the pineal gland cannot be compensated by mimicking plasma melatonin concentrations only.

  6. Abnormal intracellular calcium homeostasis associated with vulnerability in the nerve cells from heroin-dependent rat.

    PubMed

    Liu, Xiaoshan; Wang, Guangyong; Pu, Hongwei; Jing, Hualan

    2014-07-14

    The cellular mechanisms by which opiate addiction develops with repetitive use remain largely unresolved. Intercellular calcium homeostasis is one of the most critical elements to determine neuroadaptive changes and neuronal fate. Heroin, one of the most addictive opiates, may induce neurotoxicity potentially inducing brain impairment, especially for those chronic users who get an overdose. Here we examined changes in intracellular calcium concentration ([Ca2+]i) after repeated exposure to heroin using cultured cerebral cortical neurons. Dynamic changes in [Ca2+]i indicated by fluo-3-AM were monitored using confocal laser scan microscopy, followed by cytotoxicity assessments. It showed that the cells dissociated from heroin-dependent rats had a smaller depolarization-induced [Ca2+]i responses, and a higher elevation in [Ca2+]i when challenged with a high concentration of heroin (500 μM). The restoration ability to remove calcium after washout of these stimulants was impaired. Calcium channel blocker verapamil inhibited the heroin-induced [Ca2+]i elevations as well as the heroin-induced cell damage. The relative [Ca2+]i of the nerve cells closely correlated with the number of damaged cells induced by heroin. These results demonstrate that nerve cells from heroin-dependent rats manifest abnormal [Ca2+]i homeostasis, as well as vulnerability to heroin overdose, suggesting involvement of [Ca2+]i regulation mechanisms in heroin addiction and neurotoxicity.

  7. Heritability of phenotypes associated with glucose homeostasis and adiposity in a rural area of Brazil.

    PubMed

    Pena, Geórgia G; Dutra, Míriam Santos; Gazzinelli, Andrea; Corrêa-Oliveira, Rodrigo; Velasquez-Melendez, Gustavo

    2014-01-01

    We aimed to estimate the heritability and genetic correlation between glucose homeostasis and adiposity traits in a population in a rural community in Brazil. The Jequitinhonha Community Family Study cohort consists of subjects aged ≥18 years residing in rural areas in Brazil. The data on the following traits were assembled for 280 individuals (51.7% women): body mass index (BMI), body fat percentage, waist and mid-upper arm circumferences, triceps skinfold, conicity index, insulin, glucose, high-density lipoprotein cholesterol (HDLc), triglycerides and C-reactive protein. Extended pedigrees were constructed up to the third generation of individuals using the data management software PEDSYS. The heritability and genetic correlations were estimated using a variance component method. The age- and sex-adjusted heritability values estimated for insulin (h(2) = 52%), glucose (h(2) = 51%), HDLc (h(2) = 58%), and waist circumference (WC; h(2) = 49%) were high. Significantly adjusted genetic correlations were observed between insulin paired with each of the following phenotypes; (BMI; ρg = 0.48), WC (ρg = 0.47) and HDLc (ρg = -0.47). The homeostasis model assessment of insulin resistance (HOMA-IR) was genetically correlated with BMI (ρg = 0.53) and HDLc (ρg = -0.58). The adjusted genetic correlations between traits were consistently higher compared with the environmental correlations. In conclusion, glucose metabolism and adiposity traits are highly heritable and share common genetic effects with body adiposity traits. PMID:24359477

  8. Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)-Deficient Mice.

    PubMed

    Brial, François; Lussier, Carine R; Belleville, Karine; Sarret, Philippe; Boudreau, François

    2015-09-01

    Hepatocyte nuclear factor-1α (HNF1α) is a transcription factor expressed in tissues of endoderm origin. Mutations in HNF1A are associated with maturity-onset diabetes of the young 3 (MODY3). Mice deficient for Hnf1α are hyperglycemic, with their pancreatic β-cells being defective in glucose-sensing insulin secretion. The specific mechanisms involved in this defect are unclear. Gut hormones control glucose homeostasis. Our objective was to explore whether changes in these hormones play a role in glucose homeostasis in the absence of Hnf1α. An increase in ghrelin gene transcript and a decrease in glucose-dependent insulinotropic polypeptide (GIP) gene transcripts were observed in the gut of Hnf1α-null mice. These changes correlated with an increase of ghrelin and a decrease of GIP-labeled cells. Ghrelin serological levels were significantly induced in Hnf1α-null mice. Paradoxically, GIP levels were also induced in these mice. Treatment of Hnf1α-null mice with a ghrelin antagonist led to a recovery of the diabetic symptoms. We conclude that upregulation of ghrelin in the absence of Hnf1α impairs insulin secretion and can be reversed by pharmacological inhibition of ghrelin/GHS-R interaction. These observations open up on future strategies to counteract ghrelin action in a program that could become beneficial in controlling non-insulin-dependent diabetes. PMID:25979074

  9. 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

  10. Heritability of phenotypes associated with glucose homeostasis and adiposity in a rural area of Brazil.

    PubMed

    Pena, Geórgia G; Dutra, Míriam Santos; Gazzinelli, Andrea; Corrêa-Oliveira, Rodrigo; Velasquez-Melendez, Gustavo

    2014-01-01

    We aimed to estimate the heritability and genetic correlation between glucose homeostasis and adiposity traits in a population in a rural community in Brazil. The Jequitinhonha Community Family Study cohort consists of subjects aged ≥18 years residing in rural areas in Brazil. The data on the following traits were assembled for 280 individuals (51.7% women): body mass index (BMI), body fat percentage, waist and mid-upper arm circumferences, triceps skinfold, conicity index, insulin, glucose, high-density lipoprotein cholesterol (HDLc), triglycerides and C-reactive protein. Extended pedigrees were constructed up to the third generation of individuals using the data management software PEDSYS. The heritability and genetic correlations were estimated using a variance component method. The age- and sex-adjusted heritability values estimated for insulin (h(2) = 52%), glucose (h(2) = 51%), HDLc (h(2) = 58%), and waist circumference (WC; h(2) = 49%) were high. Significantly adjusted genetic correlations were observed between insulin paired with each of the following phenotypes; (BMI; ρg = 0.48), WC (ρg = 0.47) and HDLc (ρg = -0.47). The homeostasis model assessment of insulin resistance (HOMA-IR) was genetically correlated with BMI (ρg = 0.53) and HDLc (ρg = -0.58). The adjusted genetic correlations between traits were consistently higher compared with the environmental correlations. In conclusion, glucose metabolism and adiposity traits are highly heritable and share common genetic effects with body adiposity traits.

  11. 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.

  12. 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

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

    PubMed Central

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

    2014-01-01

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

  14. 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.

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

    PubMed

    Thorsen, Kristian; Drengstig, Tormod; Ruoff, Peter

    2014-08-15

    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.

  16. miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle.

    PubMed

    Zhang, Duo; Li, Yan; Yao, Xuan; Wang, Hui; Zhao, Lei; Jiang, Haowen; Yao, Xiaohan; Zhang, Shengjie; Ye, Cheng; Liu, Wei; Cao, Hongchao; Yu, Shuxian; Wang, Yu-Cheng; Li, Qiong; Jiang, Jingjing; Liu, Yi; Zhang, Ling; Liu, Yun; Iwai, Naoharu; Wang, Hui; Li, Jingya; Li, Jia; Li, Xihua; Jin, Zi-Bing; Ying, Hao

    2016-07-19

    Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control. PMID:27396327

  17. Effects of peripherally administered neuromedin U on energy and glucose homeostasis.

    PubMed

    Peier, Andrea M; Desai, Kunal; Hubert, James; Du, Xiaobing; Yang, Liming; Qian, Ying; Kosinski, Jennifer R; Metzger, Joseph M; Pocai, Alessandro; Nawrocki, Andrea R; Langdon, Ronald B; Marsh, Donald J

    2011-07-01

    Neuromedin U (NMU) is a highly conserved peptide reported to modulate energy homeostasis. Pharmacological studies have shown that centrally administered NMU inhibits food intake, reduces body weight, and increases energy expenditure. NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU become lean and hypophagic. Two high-affinity NMU receptors, NMUR1 and NMUR2, have been identified. NMUR1 is found primarily in the periphery and NMUR2 primarily in the brain, where it mediates the anorectic effects of centrally administered NMU. Given the broad expression pattern of NMU, we evaluated whether peripheral administration of NMU has effects on energy homeostasis. We observed that acute and chronic peripheral administration of NMU in rodents dose-dependently reduced food intake and body weight and that these effects required NMUR1. The anorectic effects of NMU appeared to be partly mediated by vagal afferents. NMU treatment also increased core body temperature and metabolic rate in mice, suggesting that peripheral NMU modulates energy expenditure. Additionally, peripheral administration of NMU significantly improved glucose excursion. Collectively, these data suggest that NMU functions as a peripheral regulator of energy and glucose homeostasis and the development of NMUR1 agonists may be an effective treatment for diabetes and obesity.

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

    PubMed

    Chiang, Yu-ting Alex; Jin, Tianru

    2014-04-01

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

  19. 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

  20. PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis.

    PubMed

    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

    2015-10-01

    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.

  1. The role of gut hormone peptide YY in energy and glucose homeostasis: twelve years on.

    PubMed

    Manning, Sean; Batterham, Rachel L

    2014-01-01

    Although the role of peptide YY (PYY) as a regulator of energy homeostasis was first highlighted only in 2002, our understanding of the physiological role of PYY has since rapidly advanced. In recent years, insights from mechanistic studies in patients undergoing bariatric surgery, from pancreatic islet research, from functional neuroimaging studies, and from exercise research have greatly added to the field, and these areas provide the focus of discussion for this narrative review. We critically discuss recent findings relating to the role of PYY in mediating the beneficial effects of bariatric surgery, the role of PYY in glucose homeostasis, the role of hepatoportal PYY in mediating its central physiological effects, the specific modulation of brain regions by PYY, and the exercise-induced PYY response.

  2. Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling.

    PubMed

    Liu, Wei; Cao, Hongchao; Ye, Cheng; Chang, Cunjie; Lu, Minghua; Jing, Yanyan; Zhang, Duo; Yao, Xuan; Duan, Zhengjun; Xia, Hongfeng; Wang, Yu-Cheng; Jiang, Jingjing; Liu, Mo-Fang; Yan, Jun; Ying, Hao

    2014-01-01

    Understanding the regulation of insulin signalling in tissues provides insights into carbohydrate and lipid metabolism in physiology and disease. Here we show that hepatic miR-378/378* expression changes in response to fasting and refeeding in mice. Mice overexpressing hepatic miR-378/378* exhibit pure hepatic insulin resistance. miR-378 inhibits hepatic insulin signalling through targeting p110α, a subunit of PI3K and hence a critical component of insulin signalling. Knockdown of hepatic p110α mimics the effect of miR-378, while restoration of p110α expression abolishes the action of miR-378 on insulin signalling as well as its systemic effects on glucose and lipid homeostasis. miR-378/378* knockout mice display hypoglycemia and increased hepatic triglyceride level with enhanced insulin sensitivity. Inhibition of hepatic p110α in miR-378/378* knockout mice corrects the abnormal glucose tolerance. Finally, we show that overexpression of hepatic miR-378/378* ameliorates hepatic steatosis in ob/ob mice without exacerbating hyperglycemia. Our findings establish fasting-responsive miR-378 as a critical regulator of hepatic insulin signalling.

  3. 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

  4. 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.

  5. 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

  6. Impaired glucose homeostasis after a transient intermittent hypoxic exposure in neonatal rats.

    PubMed

    Pae, Eung-Kwon; Ahuja, Bhoomika; Kim, Marieyerie; Kim, Gyuyoup

    2013-11-22

    This initial report presents a neonatal rat model with exposure to a transient intermittent hypoxia (IH), which results in a persisting diabetes-like condition in the young rats. Twenty-five male pups were treated at postnatal day 1 with IH exposure by alternating the level of oxygen between 10.3% and 20.8% for 5h. The treated animals were then maintained in normal ambient oxygen condition for 3 week and compared to age-matched controls. The IH treated animals exhibited a significantly higher fasting glucose level than the control animals (237.00 ± 19.66 mg/dL vs. 167.25 ± 2.95 mg/dL; P=0.003); and a significantly lower insulin level than the control (807.0 ± 72.5 pg/mL vs. 1839.8 ± 377.6 pg/mL; P=0.023). There was no difference in the mass or the number of insulin producing beta cells as well as no indicative of inflammatory changes; however, glucose tolerance tests showed a significantly disturbed glucose homeostasis. In addition, the amount of C-peptide secreted from the islets harvested from the IH animals were decreased significantly (from 914 pM in control to 809 pM in IH; P=0.0006) as well. These observations demonstrate that the neonatal exposure to the IH regimen initiates the development of deregulation in glucose homeostasis without infiltration of inflammatory cells. PMID:24183722

  7. Diagnostic value of fasting capillary glucose, fructosamine and glycosylated haemoglobin in detecting diabetes and other glucose tolerance abnormalities compared to oral glucose tolerance test.

    PubMed

    Herdzik, E; Safranow, K; Ciechanowski, K

    2002-04-01

    New diagnostic criteria for diabetes mellitus recommend lowering of the fasting plasma glucose to 7.0 mmol/l. In contrast to recommendations of the American Diabetes Association (ADA), WHO recommends using the oral glucose tolerance test (OGTT) in clinical practice. In this study. based on OGTT results and WHO 1998 criteria, we determined if measuring fasting capillary glycaemia (FCG) along with fructosamine and/or glycosylated haemoglobin allows the detection of glucose tolerance abnormalities better than FCG alone. OGTT was performed in 538 patients. Serum fructosamine was determined in 480 of the patients, and glycosylated haemoglobin in 234 of the patients. According to WHO 1998 criteria, the patients were divided into groups due to glucose tolerance abnormalities. Fructosamine correlated stronger with 2-h post-load glucose concentrations than with FCG. HbAlc correlated stronger with FCG than with 2-h post-load glucose. Combined use of fructosamine and FCG predicted 2-h post-load glucose better than combined use of FCG and HbA1c. Receiver operating characteristic curve analyses showed that FCG was the best criterion in discriminating diabetes. Combined use of FCG and fructosamine slightly improved the ability to discriminate glucose tolerance abnormalities from normal glucose tolerance. FCG is the most effective predictor of 2-h post-load glucose and the best criterion for discriminating diabetes and other glucose tolerance abnormalities from normal glucose tolerance. Fructosamine is a potentially useful post-load glycaemia index. OGTT is irreplaceable in identification of patients with high post-load glycaemia.

  8. The effects of glibenclamide on glucose homeostasis and lipoprotein metabolism in poorly controlled type 2 diabetes.

    PubMed

    Baynes, C; Elkeles, R S; Henderson, A D; Richmond, W; Johnston, D G

    1993-02-01

    Six patients with type 2 diabetes underwent detailed metabolic studies before and after a minimum of 3 months' glibenclamide therapy. Treatment was associated with a small but significant increase in body weight. Despite improvements in almost all the measured parameters of glucose homeostasis (plasma glucose, glycosylated haemoglobin (HbA1), hepatic glucose production and insulin-mediated glucose disposal) neither fasting serum triglycerides nor HDL cholesterol changed and apoprotein A1 concentrations actually decreased significantly. NEFA and glycerol in fasting plasma and during the clamp studies did not change significantly with treatment. Post-heparin lipoprotein lipase and hepatic lipase activity did not change significantly. Thus, despite substantial improvements in glycaemic control and insulin sensitivity with sulphonylurea therapy, several aspects of lipid and lipoprotein metabolism remain largely unaffected. This small study suggests either that lipoprotein concentrations in type 2 diabetes are not influenced by insulin sensitivity or that the improvement is offset by another change that occurs during this form of therapy. It also suggests that other forms of therapy will be required to improve these cardiovascular risk factors in type 2 diabetes. PMID:8458616

  9. Lack of glucagon receptor signaling and its implications beyond glucose homeostasis.

    PubMed

    Charron, Maureen J; Vuguin, Patricia M

    2015-03-01

    Glucagon action is transduced by a G protein-coupled receptor located in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, pancreatic β-cells, and placenta. Genetically modified animal models have provided important clues about the role of glucagon and its receptor (Gcgr) beyond glucose control. The PubMed database was searched for articles published between 1995 and 2014 using the key terms glucagon, glucagon receptor, signaling, and animal models. Lack of Gcgr signaling has been associated with: i) hypoglycemic pregnancies, altered placentation, poor fetal growth, and increased fetal-neonatal death; ii) pancreatic glucagon cell hyperplasia and hyperglucagonemia; iii) altered body composition, energy state, and protection from diet-induced obesity; iv) impaired hepatocyte survival; v) altered glucose, lipid, and hormonal milieu; vi) altered metabolic response to prolonged fasting and exercise; vii) reduced gastric emptying and increased intestinal length; viii) altered retinal function; and ix) prevention of the development of diabetes in insulin-deficient mice. Similar phenotypic findings were observed in the hepatocyte-specific deletion of Gcgr. Glucagon action has been involved in the modulation of sweet taste responsiveness, inotropic and chronotropic effects in the heart, satiety, glomerular filtration rate, secretion of insulin, cortisol, ghrelin, GH, glucagon, and somatostatin, and hypothalamic signaling to suppress hepatic glucose production. Glucagon (α) cells under certain conditions can transdifferentiate into insulin (β) cells. These findings suggest that glucagon signaling plays an important role in multiple organs. Thus, treatment options designed to block Gcgr activation in diabetics may have implications beyond glucose homeostasis.

  10. 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.

  11. Post-Bariatric Surgery Changes in Quinolinic and Xanthurenic Acid Concentrations Are Associated with Glucose Homeostasis

    PubMed Central

    Pigeyre, Marie; Caiazzo, Robert; Raverdy, Violeta; Verkindt, Hélène; Leloire, Audrey; Guillemin, Gilles J.; Yengo, Loïc; Allorge, Delphine; Froguel, Philippe; Pattou, François

    2016-01-01

    Background An increase of plasma kynurenine concentrations, potentially bioactive metabolites of tryptophan, was found in subjects with obesity, resulting from low-grade inflammation of the white adipose tissue. Bariatric surgery decreases low-grade inflammation associated with obesity and improves glucose control. Objective Our goal was to determine the concentrations of all kynurenine metabolites after bariatric surgery and whether they were correlated with glucose control improvement. Design Kynurenine metabolite concentrations, analysed by liquid or gas chromatography coupled with tandem mass spectrometry, circulating inflammatory markers, metabolic traits, and BMI were measured before and one year after bariatric surgery in 44 normoglycemic and 47 diabetic women with obesity. Associations between changes in kynurenine metabolites concentrations and in glucose control and metabolic traits were analysed between baseline and twelve months after surgery. Results Tryptophan and kynurenine metabolite concentrations were significantly decreased one year after bariatric surgery and were correlated with the decrease of the usCRP in both groups. Among all the kynurenine metabolites evaluated, only quinolinic acid and xanthurenic acid were significantly associated with glucose control improvement. The one year delta of quinolinic acid concentrations was negatively associated with the delta of fasting glucose (p = 0.019) and HbA1c (p = 0.014), whereas the delta of xanthurenic acid was positively associated with the delta of insulin sensitivity index (p = 0.0018). Conclusion Bariatric surgery has induced a global down-regulation of kynurenine metabolites, associated with weight loss. Our results suggest that, since kynurenine monoxygenase diverts the kynurenine pathway toward the synthesis of xanthurenic acid, its inhibition may also contribute to glucose homeostasis. PMID:27327770

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

    PubMed

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

    2015-01-01

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

  13. 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

  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. The effect of n-3 fatty acids on glucose homeostasis and insulin sensitivity.

    PubMed

    Flachs, P; Rossmeisl, M; Kopecky, J

    2014-01-01

    Type 2 diabetes (T2D) as well as cardiovascular disease (CVD) represent major complications of obesity and associated metabolic disorders (metabolic syndrome). This review focuses on the effects of long-chain n-3 polyunsaturated fatty acids (omega-3) on insulin sensitivity and glucose homeostasis, which are improved by omega-3 in many animal models of metabolic syndrome, but remain frequently unaffected in humans. Here we focus on: (i) mechanistic aspects of omega-3 action, reflecting also our experiments in dietary obese mice; and (ii) recent studies analysing omega-3's effects in various categories of human subjects. Most animal experiments document beneficial effects of omega-3 on insulin sensitivity and glucose metabolism even under conditions of established obesity and insulin resistance. Besides positive results obtained in both cross-sectional and prospective cohort studies on healthy human populations, also some intervention studies in prediabetic subjects document amelioration of impaired glucose homeostasis by omega-3. However, the use of omega-3 to reduce a risk of new-onset diabetes in prediabetic subjects still remains to be further characterized. The results of a majority of clinical trials performed in T2D patients suggest that omega-3 have none or marginal effects on metabolic control, while effectively reducing hypertriglyceridemia in these patients. Despite most of the recent randomized clinical trials do not support the role of omega-3 in secondary prevention of CVD, this issue remains still controversial. Combined interventions using omega-3 and antidiabetic or hypolipidemic drugs should be further explored and considered for treatment of patients with T2D and other diseases. PMID:24564669

  16. Preoperative glucose abnormalities in patients with pancreatic tumours

    PubMed Central

    Durlik, Marek; Kałuża, Bernadetta; Milczarczyk, Alicja; Franek, Edward

    2014-01-01

    Introduction Pancreatic cancer is a neoplasm characterised by poor prognosis. The only effective, possible treatment is radical surgery, but most patients do not qualify for surgery because of delayed diagnosis. Aim To determine if assessment of endocrine pancreatic function could serve as a means of screening for pancreatic cancer. Material and methods This prospective study was conducted on a group of 50 patients diagnosed with pancreatic tumour, who were qualified for surgery. Results From 1.07.2010 to 4.07.2011 a further 50 patients were added to the study group. They had been admitted to the hospital with pancreatic tumours. During the preoperative period, nine of these people had been treated for diabetes, 14 were newly diagnosed with diabetes and 15 had been diagnosed with impaired glucose tolerance, but only 12 had a normal glucose profile. Afterwards, patients underwent the surgical treatment. Histopathological examination revealed that out of the 50 operated patients, 36 suffered from malignant disease, and of these only four had no impaired glucose tolerance before treatment. Conclusions In most cases, patients with pancreatic tumours have impaired glucose tolerance. Screening patients over 50 years of age could speed up diagnosis and surgical treatment. PMID:25061491

  17. Influence of the traditional Brazilian drink Ilex paraguariensis tea on glucose homeostasis.

    PubMed

    Pereira, D F; Kappel, V D; Cazarolli, L H; Boligon, A A; Athayde, M L; Guesser, S M; Da Silva, E L; Silva, F R M B

    2012-07-15

    In this study we examined the acute in vivo effect and short- and long-term in vitro effects of samples from native and commercial Ilex paraguariensis on glucose homeostasis. Also, the potential effect of I. paraguariensis on serum insulin secretion was investigated. The chemical identification and quantification of methyl xanthines and polyphenols in CH₂Cl₂, EtOAc and n-BuOH fractions of native I. paraguariensis as well as infusions of green and roasted I. paraguariensis from a commercial source was verified by high-performance liquid chromatography. The results for the serum glucose-lowering indicated that both fractions and both infusions were able to improve significantly the oral glucose tolerance curve. Additionally, both the EtOAc and n-BuOH fractions induced-insulin secretion, but EtOAc induced an early (at 15 min) and late (at 60 min) biphasic peak of insulin secretion similar to glipizide stimulatory effect. Both fractions increased liver glycogen content compared with fasted normal rats. Also, EtOAc and n-BuOH fractions inhibited in vitro disaccharidases activities after an acute treatment. The maximum inhibitory effect of the EtOAc and n-BuOH fractions on maltase activity (at 5 min) was around 35%. The evident reduction of protein glycation by glucose or fructose with EtOAc and n-BuOH fractions increased from 7 to 28 days of in vitro incubation. Inhibition of bovine serum albumin glycation by glucose and fructose, by around 50% and 90%, respectively, was observed. Additionally, the green and roasted mate infusions reduced the formation of AGEs in a characteristic long-term effect. In conclusion, this study shows that I. paraguariensis has an anti-hyperglycemic potential role able to improve the diabetic status and is probably a source of multiple hypoglycemic compounds. PMID:22795927

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

    PubMed Central

    Qinna, Nidal A; Badwan, Adnan A

    2015-01-01

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

  19. TDP-43, an ALS linked protein, regulates fat deposition and glucose homeostasis.

    PubMed

    Stallings, Nancy R; Puttaparthi, Krishna; Dowling, Katherine J; Luther, Christina M; Burns, Dennis K; Davis, Kathryn; Elliott, Jeffrey L

    2013-01-01

    The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism. Here we report, that over-expression of TDP-43 in transgenic mice can result in a phenotype characterized by increased fat deposition and adipocyte hypertrophy. In addition, TDP-43 over-expression in skeletal muscle results in increased steady state levels of Tbc1d1, a RAB-GTPase activating protein involved in Glucose 4 transporter (Glut4) translocation. Skeletal muscle fibers isolated from TDP-43 transgenic mice show altered Glut4 translocation in response to insulin and impaired insulin mediated glucose uptake. These results indicate that levels of TDP-43 regulate body fat composition and glucose homeostasis in vivo.

  20. TDP-43, an ALS Linked Protein, Regulates Fat Deposition and Glucose Homeostasis

    PubMed Central

    Stallings, Nancy R.; Puttaparthi, Krishna; Dowling, Katherine J.; Luther, Christina M.; Burns, Dennis K.; Davis, Kathryn; Elliott, Jeffrey L.

    2013-01-01

    The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism. Here we report, that over-expression of TDP-43 in transgenic mice can result in a phenotype characterized by increased fat deposition and adipocyte hypertrophy. In addition, TDP-43 over-expression in skeletal muscle results in increased steady state levels of Tbc1d1, a RAB-GTPase activating protein involved in Glucose 4 transporter (Glut4) translocation. Skeletal muscle fibers isolated from TDP-43 transgenic mice show altered Glut4 translocation in response to insulin and impaired insulin mediated glucose uptake. These results indicate that levels of TDP-43 regulate body fat composition and glucose homeostasis in vivo. PMID:23967244

  1. GABA promotes human β-cell proliferation and modulates glucose homeostasis.

    PubMed

    Purwana, Indri; Zheng, Juan; Li, Xiaoming; Deurloo, Marielle; Son, Dong Ok; Zhang, Zhaoyun; Liang, Christie; Shen, Eddie; Tadkase, Akshaya; Feng, Zhong-Ping; Li, Yiming; Hasilo, Craig; Paraskevas, Steven; Bortell, Rita; Greiner, Dale L; Atkinson, Mark; Prud'homme, Gerald J; Wang, Qinghua

    2014-12-01

    γ-Aminobutyric acid (GABA) exerts protective and regenerative effects on mouse islet β-cells. However, in humans it is unknown whether it can increase β-cell mass and improve glucose homeostasis. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-γ mice with streptozotocin-induced diabetes. GABA treatment increased grafted β-cell proliferation, while decreasing apoptosis, leading to enhanced β-cell mass. This was associated with increased circulating human insulin and reduced glucagon levels. Importantly, GABA administration lowered blood glucose levels and improved glucose excursion rates. We investigated GABA receptor expression and signaling mechanisms. In human islets, GABA activated a calcium-dependent signaling pathway through both GABA A receptor and GABA B receptor. This activated the phosphatidylinositol 3-kinase-Akt and CREB-IRS-2 signaling pathways that convey GABA signals responsible for β-cell proliferation and survival. Our findings suggest that GABA regulates human β-cell mass and may be beneficial for the treatment of diabetes or improvement of islet transplantation.

  2. Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population.

    PubMed

    Chang, Tien-Jyun; Chiu, Yen-Feng; Sheu, Wayne H-H; Shih, Kuang-Chung; Hwu, Chii-Min; Quertermous, Thomas; Jou, Yuh-Shan; Kuo, Shan-Shan; Chang, Yi-Cheng; Chuang, Lee-Ming

    2015-11-26

    Proprotein convertase subtilisin/kexin type 2 (PCSK2) is a prohormone processing enzyme involved in insulin and glucagon biosynthesis. We previously found the genetic polymorphism of PCSK2 on chromosome 20 was responsible for the linkage peak of several glucose homeostasis parameters. The aim of this study is to investigate the association between genetic variants of PCSK2 and glucose homeostasis parameters and incident diabetes. Total 1142 Chinese participants were recruited from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study, and 759 participants were followed up for 5 years. Ten SNPs of the PCSK2 gene were genotyped. Variants of rs6044695 and rs2284912 were associated with fasting plasma glucose, and variants of rs2269023 were associated with fasting plasma glucose and 1-hour plasma glucose during OGTT. Haplotypes of rs4814605/rs1078199 were associated with fasting plasma insulin levels and HOMA-IR. Haplotypes of rs890609/rs2269023 were also associated with fasting plasma glucose, fasting insulin and HOMA-IR. In the longitudinal study, we found individuals carrying TA/AA genotypes of rs6044695 or TC/CC genotypes of rs2284912 had lower incidence of diabetes during the 5-year follow-up. Our results indicated that PCSK2 gene polymorphisms are associated with pleiotropic effects on various traits of glucose homeostasis and incident diabetes.

  3. Distinct effects of aerobic exercise training and weight loss on glucose homeostasis in obese sedentary men.

    PubMed

    Dengel, D R; Pratley, R E; Hagberg, J M; Rogus, E M; Goldberg, A P

    1996-07-01

    The decline in glucose homeostasis with aging may be due to the physical deconditioning and obesity that often develop with aging. The independent and combined effects of aerobic exercise training (AEX) and weight loss (WL) on glucose metabolism were studied in 47 nondiabetic sedentary older men. There were 14 men in a weekly behavioral modification/WL program, 10 in a 3 times/wk AEX program, 14 in an AEX+WL program, and 9 in the control (Con) group. The 10-mo intervention increased maximal oxygen consumption (VO2max) in both the AEX and AEX+WL groups [0.33 +/- 0.05 and 0.37 +/- 0.09 (SE) l/min, respectively], but VO2max did not significantly change in the WL (0.01 +/- 0.06 l/min) and Con groups (-0.04 +/- 0.05 l/min; P > 0.05). The AEX+WL and WL groups had comparable reductions in body weight (-8.5 +/- 0.9 and -8.8 +/- 1.2 kg, respectively) and percent fat (-5.5 +/- 0.7 and -5.9 +/- 1.1%, respectively) that were significantly greater than those in the Con and AEX groups. Oral glucose tolerance tests showed significant reductions in insulin responses in the AEX, WL, and AEX+WL groups, but the decrease in insulin response in the AEX+WL group was significantly greater than that in the other three groups. The glucose area decreased significantly in the WL and AEX+WL groups but did not change in the Con or AEX groups. There were significant increases in insulin-mediated glucose disposal rates as measured by the hyperinsulinemic (600 pmol.m-2.min-1) euglycemic clamps in the AEX and AEX+WL groups [1.66 +/- 0.50 and 1.76 +/- 0.41 mg.kg fat-free mass (FFM)-1.min-1, respectively] that were significantly greater than those in the WL (0.13 +/- 0.31 mg.kg FFM-1.min-1) and Con groups (-0.05 +/- 0.51 mg.kg FFM-1.min-1; n = 5). These data suggest that AEX and WL improve glucose metabolism through different mechanisms and that the combined intervention of AEX+WL is necessary to improve both glucose tolerance and insulin sensitivity in older men.

  4. 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.

  5. 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

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

    PubMed

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

    2015-01-01

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

  7. 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

  8. Developmental exposure to di(2-ethylhexyl) phthalate impairs endocrine pancreas and leads to long-term adverse effects on glucose homeostasis in the rat.

    PubMed

    Lin, Yi; Wei, Jie; Li, Yuanyuan; Chen, Jun; Zhou, Zhao; Song, Liqiong; Wei, Zhengzheng; Lv, Ziquan; Chen, Xi; Xia, Wei; Xu, Shunqing

    2011-09-01

    -Di(2-ethylhexyl) phthalate (DEHP), a typical endocrine-disrupting chemical (EDC), is widely used as plasticizer. DEHP exposure in humans is virtually ubiquitous, and those undergoing certain medical procedures can be especially high. In this study, we investigated whether developmental DEHP exposure disrupted glucose homeostasis in the rat and whether this was associated with the early impairment in endocrine pancreas. Pregnant Wistar rats were administered DEHP (1.25 and 6.25 mg·kg(-1)·day(-1)) or corn oil throughout gestation and lactation by oral gavage. Body weight, glucose and insulin tolerance, and β-cell morphometry and function were examined in offspring during the growth. In this study, developmental DEHP exposure led to abnormal β-cell ultrastructure, reduced β-cell mass, and pancreatic insulin content as well as alterations in the expression of genes involved in pancreas development and β-cell function in offspring at weaning. At adulthood, female DEHP-exposed offspring exhibited elevated blood glucose, reduced serum insulin, impaired glucose tolerance, and insulin secretion. Male DEHP-exposed offspring had increased serum insulin, although there were no significant differences in blood glucose at fasting and during glucose tolerance test. In addition, both male and female DEHP-exposed offspring had significantly lower birth weight and maintained relatively lower body weight up to 27 wk of age. These results suggest that developmental exposure to DEHP gives rise to β-cell dysfunction and the whole body glucometabolic abnormalities in the rat. DEHP exposure in critical periods of development can be a potential risk factor, at least in part, for developing diabetes.

  9. Protective effect of methionine supplementation on arsenic-induced alteration of glucose homeostasis.

    PubMed

    Pal, Sudipta; Chatterjee, Ajay K

    2004-05-01

    Short term exposure of arsenic produces carbohydrate depletion and hypoglycemia. Dietary deficiency of methionine causes impaired biotransformation of arsenic which has been attributed to the pathogenesis of different diseases induced by arsenic. Accordingly, the effects of methionine supplementation on the altered glucose homeostasis induced by arsenic were studied. Arsenic (as sodium arsenite) treatment (i.p) of male Wistar rats (weighing 80-100 g) at a dose of 5.55 mg kg(-1) body weight (equivalent to 35% LD50) per day for a period of 21 days caused a significant diminution in blood glucose level and fall in liver glycogen and pyruvic acid contents. The free amino acid nitrogen content of liver was elevated while that of kidney was decreased after arsenic treatment. Transaminase activities in liver and kidney were not significantly altered except that glutamate-pyruvate transaminase activity of kidney decreased significantly after arsenic treatment. Methionine supplementation reversed the above changes except decreased liver glycogen due to arsenic treatment. It may be suggested that hypoglycemia with associated decreased glycolytic activity induced by arsenic treatment at the present dose and duration can be partially counteracted by dietary methionine supplementation.

  10. 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...

  11. 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.

  12. Tsc2 is a molecular checkpoint controlling osteoblast development and glucose homeostasis.

    PubMed

    Riddle, Ryan C; Frey, Julie L; Tomlinson, Ryan E; Ferron, Mathieu; Li, Yuanyuan; DiGirolamo, Douglas J; Faugere, Marie-Claude; Hussain, Mehboob A; Karsenty, Gerard; Clemens, Thomas L

    2014-05-01

    Insulin signaling in osteoblasts regulates global energy balance by stimulating the production of osteocalcin, a bone-derived protein that promotes insulin production and action. To identify the signaling pathways in osteoblasts that mediate insulin's effects on bone and energy metabolism, we examined the function of the tuberous sclerosis 2 (Tsc2) protein, a key target important in coordinating nutrient signaling. Here, we show that loss of Tsc2 in osteoblasts constitutively activates mTOR and destabilizes Irs1, causing osteoblasts to differentiate poorly and become resistant to insulin. Young Tsc2 mutant mice demonstrate hypoglycemia with increased levels of insulin and undercarboxylated osteocalcin. However, with age, Tsc2 mutants develop metabolic features similar to mice lacking the insulin receptor in the osteoblast, including peripheral adiposity, hyperglycemia, and decreased pancreatic β cell mass. These metabolic abnormalities appear to result from chronic elevations in undercarboxylated osteocalcin that lead to downregulation of the osteocalcin receptor and desensitization of the β cell to this hormone. Removal of a single mTOR allele from the Tsc2 mutant mice largely normalizes the bone and metabolic abnormalities. Together, these findings suggest that Tsc2 serves as a key checkpoint in the osteoblast that is required for proper insulin signaling and acts to ensure normal bone acquisition and energy homeostasis. PMID:24591652

  13. TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation

    PubMed Central

    Jansen, Jos C.; Timal, Sharita; van Scherpenzeel, Monique; Michelakakis, Helen; Vicogne, Dorothée; Ashikov, Angel; Moraitou, Marina; Hoischen, Alexander; Huijben, Karin; Steenbergen, Gerry; van den Boogert, Marjolein A.W.; Porta, Francesco; Calvo, Pier Luigi; Mavrikou, Mersyni; Cenacchi, Giovanna; van den Bogaart, Geert; Salomon, Jody; Holleboom, Adriaan G.; Rodenburg, Richard J.; Drenth, Joost P.H.; Huynen, Martijn A.; Wevers, Ron A.; Morava, Eva; Foulquier, François; Veltman, Joris A.; Lefeber, Dirk J.

    2016-01-01

    Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation. PMID:26833330

  14. TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation.

    PubMed

    Jansen, Jos C; Timal, Sharita; van Scherpenzeel, Monique; Michelakakis, Helen; Vicogne, Dorothée; Ashikov, Angel; Moraitou, Marina; Hoischen, Alexander; Huijben, Karin; Steenbergen, Gerry; van den Boogert, Marjolein A W; Porta, Francesco; Calvo, Pier Luigi; Mavrikou, Mersyni; Cenacchi, Giovanna; van den Bogaart, Geert; Salomon, Jody; Holleboom, Adriaan G; Rodenburg, Richard J; Drenth, Joost P H; Huynen, Martijn A; Wevers, Ron A; Morava, Eva; Foulquier, François; Veltman, Joris A; Lefeber, Dirk J

    2016-02-01

    Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation.

  15. Effects of Tai Chi on adiponectin and glucose homeostasis in individuals with cardiovascular risk factors.

    PubMed

    Chang, Rei-Yeuh; Koo, Malcolm; Ho, Meng-Ying; Lin, Zi-Zi; Yu, Zer-Ran; Lin, Yen-Fen; Wang, Be-Jen

    2011-01-01

    The aim of this study was to evaluate the acute effect of a single bout of Tai Chi (TC) exercise on adiponectin and glucose homeostasis in individuals with cardiovascular risk factors. Twenty-six individuals (mean age 60.2 years) with at least one cardiovascular risk factor who had been practicing Yang's style TC exercise for at least 3 months were recruited from a regional hospital in Taiwan. A one-group repeated measured quasi-experimental design was used. Participants completed a 60-min Yang's style TC exercise routine including warm up, stretching exercises, and TC followed by a 30-min resting period. After a 1-week washout period, the same group of participants underwent a control condition in which they were instructed to remain seated for 90 min at the study location. Blood samples were collected both before and after the TC intervention or the sitting condition. The difference between pre-post measurements for adiponectin was 0.58 ± 1.42 μg/ml in the TC trial and -0.46 ± 0.99 μg/ml in the sitting trial. The differences between the two trials were statistically significant (P = 0.004). The changes from pretrial to posttrial were significantly greater for glycerol (P < 0.001), cholesterol (P = 0.046), and LDL-C (P = 0.038) in the TC trial compared with those in the sitting trial. Conversely, the changes were significantly lesser for HOMA-IR (P = 0.004), log (HOMA-IR) (P = 0.001), and glucose (P = 0.003) in TC trial compared with those in the sitting trial. In conclusion, a single bout of TC exercise had a significant positive effect on blood adiponectin concentrations in individuals with cardiovascular risk factors. PMID:20809228

  16. 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. PMID:26394664

  17. 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

  18. Knockout Mice Challenge our Concepts of Glucose Homeostasis and the Pathogenesis of Diabetes

    PubMed Central

    2003-01-01

    A central component of type 2 diabetes and the metabolic syndrome is insulin resistance. Insulin exerts a multifaceted and highly integrated series of actions via its intracellular signaling systems. Generation of mice carrying null mutations of the genes encoding proteins in the insulin signaling pathway provides a unique approach to determining the role of individual proteins in the molecular mechanism of insulin action and the pathogenesis of insulin resistance and diabetes. The role of the four major insulin receptor substrates (IRS1-4) in insulin and IGF-1 signaling have been examined by creating mice with targeted gene knockouts. Each produces a unique phenotype, indicating the complementary role of these signaling components. Combined heterozygous defects often produce synergistic or epistatic effects, although the final severity of the phenotype depends on the genetic background of the mice. Conditional knockouts of the insulin receptor have also been created using the Cre-lox system. These tissue specific knockouts have provide unique insights into the control of glucose homeostasis and the pathogenesis of type 2 diabetes, and have led to development of new hypotheses about the nature of the insulin action and development of diabetes. PMID:15061645

  19. Involvement of SIK3 in Glucose and Lipid Homeostasis in Mice

    PubMed Central

    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. PMID:22662228

  20. [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.

  1. [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

    2014-01-01

    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. PMID:25238823

  2. Low-level subchronic arsenic exposure from prenatal developmental stages to adult life results in an impaired glucose homeostasis.

    PubMed

    Dávila-Esqueda, M E; Morales, J M V; Jiménez-Capdeville, M E; De la Cruz, E; Falcón-Escobedo, R; Chi-Ahumada, E; Martin-Pérez, S

    2011-11-01

    We evaluated how low-level (3 ppm) subchronic inorganic arsenic (iAs) exposure from prenatal developmental stages until adult life affects glucose homeostasis. Biochemical parameters of glucose and lipid metabolism, pancreatic insulin and glycosylated haemoglobin were determined in 4-month-old female offspring of adult Wistar rats. Pancreatic histology was also performed. Statistical comparisons between control and iAs-treated groups were performed by unpaired two-tailed Student's t-test. Statistical significance was set at p<0.05. We found that iAs treatment resulted in an impaired glucose tolerance test, suggestive of impaired glucose metabolism. This group was found to have hyperglycaemia and high levels of HOMA-IR, glycosylated haemoglobin, cholesterol and pancreatic insulin compared to control rats. However, plasma insulin, triglycerides and high-density lipoprotein cholesterol were not different from control rats. Moreover, β-cell damage found in iAs-treated rats consisted of cells with a nucleus with dense chromatin and predominance of eosinophilic cytoplasm, as well as changes in the pancreatic vasculature. The current study provided evidence that subchronic iAs exposure at 3 ppm from prenatal developmental stages to adult life resulted in damage to pancreatic β cells, affected insulin secretion and demonstrated altered glucose homeostasis, thus supporting a causal association between iAs exposure and diabetes.

  3. High Physiological Omega-3 Fatty Acid Supplementation Affects Muscle Fatty Acid Composition and Glucose and Insulin Homeostasis in Obese Adolescents

    PubMed Central

    Dangardt, Frida; Chen, Yun; Gronowitz, Eva; Dahlgren, Jovanna; Friberg, Peter; Strandvik, Birgitta

    2012-01-01

    Obese adolescents have high concentrations of saturated fatty acids and low omega-3 long-chain polyunsaturated fatty acids (LCUFAs) in plasma phospholipids. We aimed to investigate effects of omega-3 LCPUFA supplementation to obese adolescents on skeletal muscle lipids and glucose and insulin homeostasis. Twenty-five obese adolescents (14–17 years old, 14 females) completed a randomized double-blind crossover study supplying capsules containing either 1.2 g omega-3 LCPUFAs or placebo, for 3 months each with a six-week washout period. Fasting blood glucose, insulin, leptin, adiponectin, and lipids were measured. Intravenous glucose tolerance test (IVGTT) and euglycemic-hyperinsulinemic clamp were performed, and skeletal muscle biopsies were obtained at the end of each period. The concentrations of EPA, DHA, and total omega-3 PUFA in muscle phospholipids increased in both sexes. In the females, omega-3 LCPUFA supplementation improved glucose tolerance by 39% (P = 0.04) and restored insulin concentration by 34% (P = 0.02) during IVGTT. Insulin sensitivity improved 17% (P = 0.07). In males, none of these parameters was influenced by omega-3 supplementation. Thus, three months of supplementation of omega-3 LCPUFA improved glucose and insulin homeostasis in obese girls without influencing body weight. PMID:22523671

  4. Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice.

    PubMed

    Seo, Kwon-Il; Choi, Myung-Sook; Jung, Un Ju; Kim, Hye-Jin; Yeo, Jiyoung; Jeon, Seon-Min; Lee, Mi-Kyung

    2008-09-01

    We investigated the effect of curcumin on insulin resistance and glucose homeostasis in male C57BL/KsJ-db/db mice and their age-matched lean non-diabetic db/+ mice. Both db/+ and db/db mice were fed with or without curcumin (0.02%, wt/wt) for 6 wks. Curcumin significantly lowered blood glucose and HbA 1c levels, and it suppressed body weight loss in db/db mice. Curcumin improved homeostasis model assessment of insulin resistance and glucose tolerance, and elevated the plasma insulin level in db/db mice. Hepatic glucokinase activity was significantly higher in the curcumin-supplemented db/db group than in the db/db group, whereas glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly lower. In db/db mice, curcumin significantly lowered the hepatic activities of fatty acid synthase, beta-oxidation, 3-hydroxy-3-methylglutaryl coenzyme reductase, and acyl-CoA: cholesterol acyltransferase. Curcumin significantly lowered plasma free fatty acid, cholesterol, and triglyceride concentrations and increased the hepatic glycogen and skeletal muscle lipoprotein lipase in db/db mice. Curcumin normalized erythrocyte and hepatic antioxidant enzyme activities (superoxide dismutase, catalase, gluthathione peroxidase) in db/db mice that resulted in a significant reduction in lipid peroxidation. However, curcumin showed no effect on the blood glucose, plasma insulin, and glucose regulating enzyme activities in db/+ mice. These results suggest that curcumin seemed to be a potential glucose-lowering agent and antioxidant in type 2 diabetic db/db mice, but had no affect in non-diabetic db/+ mice.

  5. 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

  6. 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.

  7. Deletion of glutamate dehydrogenase in beta-cells abolishes part of the insulin secretory response not required for glucose homeostasis.

    PubMed

    Carobbio, Stefania; Frigerio, Francesca; Rubi, Blanca; Vetterli, Laurène; Bloksgaard, Maria; Gjinovci, Asllan; Pournourmohammadi, Shirin; Herrera, Pedro L; Reith, Walter; Mandrup, Susanne; Maechler, Pierre

    2009-01-01

    Insulin exocytosis is regulated in pancreatic ss-cells by a cascade of intracellular signals translating glucose levels into corresponding secretory responses. The mitochondrial enzyme glutamate dehydrogenase (GDH) is regarded as a major player in this process, although its abrogation has not been tested yet in animal models. Here, we generated transgenic mice, named betaGlud1(-/-), with ss-cell-specific GDH deletion. Our results show that GDH plays an essential role in the full development of the insulin secretory response. In situ pancreatic perfusion revealed that glucose-stimulated insulin secretion was reduced by 37% in betaGlud1(-/-). Furthermore, isolated islets with either constitutive or acute adenovirus-mediated knock-out of GDH showed a 49 and 38% reduction in glucose-induced insulin release, respectively. Adenovirus-mediated re-expression of GDH in betaGlud1(-/-) islets fully restored glucose-induced insulin release. Thus, GDH appears to account for about 40% of glucose-stimulated insulin secretion and to lack redundant mechanisms. In betaGlud1(-/-) mice, the reduced secretory capacity resulted in lower plasma insulin levels in response to both feeding and glucose load, while body weight gain was preserved. The results demonstrate that GDH is essential for the full development of the secretory response in beta-cells. However, maximal secretory capacity is not required for maintenance of glucose homeostasis in normo-caloric conditions.

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

    PubMed Central

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

    2008-01-01

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

  9. 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

    2014-10-01

    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.

  10. 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. PMID:25535832

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

    PubMed

    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

  12. 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

  13. Green tea leaf extract improves lipid and glucose homeostasis in a fructose-fed insulin-resistant hamster model.

    PubMed

    Li, Rachel W; Douglas, Teresa D; Maiyoh, Geoffrey K; Adeli, Khosrow; Theriault, Andre G

    2006-03-01

    The present study evaluated the effect of green tea (Camellia sinensis L.) leaf extract on triglyceride and glucose homeostasis in a fructose-fed hypertriglyceridemic, insulin-resistant hamster model. There was a significant decrease in plasma triglyceride levels following supplementation of the green tea epigallocatechin gallate-enriched extract (42% at 150 mg/(kg day) to 62% at 300 mg/(kg day) for 4 weeks). Compared to baseline, the fructose control group at the end of the study showed elevated serum insulin and apolipoprotein B levels, and decreased serum adiponectin levels. The fructose/green tea extract group showed a reversal in all of these metabolic defects, including an improvement in glucose levels during a glucose tolerance test. Triglyceride content was also examined in various tissues and compared to the control fructose group; supplementation of the green tea extract (300 mg/kg) reduced triglyceride content in liver and heart tissues. There was molecular evidence of improved lipid and glucose homeostasis based on peroxisome proliferator-activated receptor (PPAR) protein expression. Compared to the control fructose group, supplementation of the green tea extract (300 mg/kg) significantly increased PPARalpha and PPARgamma protein expression. In summary, the data suggest that intake of the green tea extract ameliorated the fructose-induced hypertriglyceridemia and the insulin-resistant state in part through PPAR.

  14. 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

  15. 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

  16. Effect of a single dose of dexamethasone on glucose homeostasis in healthy horses by using the combined intravenous glucose and insulin test.

    PubMed

    Haffner, J C; Eiler, H; Hoffman, R M; Fecteau, K A; Oliver, J W

    2009-01-01

    Sustained dexamethasone administration to horses results in insulin resistance, which may predispose them to laminitis. A single dose of dexamethasone is commonly used as a diagnostic aid, yet the effect of a single dose of dexamethasone on glucose homeostasis in horses is not well defined. The objective of this study was to characterize the change in glucose dynamics over time in response to a single dose of dexamethasone. A combined glucose-insulin tolerance test (CGIT) was performed on 6 adult geldings before and at 2, 24, and 72 h postdexamethasone (40 microg/kg of BW, i.v.); a minimum of 1 wk of rest was allowed between treatments. Before any treatment, the CGIT resulted in a hyperglycemic phase followed by a hypoglycemic phase. Dexamethasone affected glucose dynamics in 3 ways: 1) at 2 h, dexamethasone shortened the ascending branch of the negative phase (P < 0.001) of the test, indicating moderate insulin resistance; 2) at 24 h, dexamethasone impaired glucose clearance by extending the positive phase and eliminating the negative phase while insulin was elevated before the CGIT, indicating a decreased response to insulin; and 3) at 72 h, dexamethasone caused a deeper nadir value (P < 0.001) compared with predexamethasone, indicating an increased response to insulin. It was concluded that dexamethasone decreased the response to insulin as early as 2 h and maximally at 24 h. At 72 h, dexamethasone caused an increased response to insulin, which was unexpected.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2012-01-01

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

  19. Effects of dietary beef tallow and soy oil on glucose and cholesterol homeostasis in normal and diabetic pigs

    SciTech Connect

    Woollett, L.A.

    1987-01-01

    Toe valuate whether dietary fats of different degrees of unsaturation alter glucose and very low density lipoprotein-cholesterol (VLDL-CH) homeostasis, normal and alloxan-diabetic pigs were fed diets containing either beef tallow or soy oil as the primary source of fat for 6 weeks. After intra-arterial and oral doses of glucose, pigs fed soy oil had similar glucose and greater insulin concentrations in plasma when compared with pigs fed beef tallow. Beef tallow-fed pigs additionally were 40% more glucose effective than were soy oil-fed pigs. Disappearance of injected autologous /sup 14/C-VLDL-CH was analyzed in pigs using a two-pool model. Diabetes resulted in a twofold increase in half-lives and a 60-fold increase in pool sizes of the primary and secondary components of VLDL-CH disappearance when compared with those of normal pigs. In normal pigs, feeding beef tallow resulted in longer half-lives of both components of VLDL-CH disappearance and no effect in pool size of both components of VLDL-CH disappearance than did feeding soy oil. In comparison, diabetic pigs fed beef tallow had a similar half-life of the primary component, a twofold shorter half-life of the secondary component, and threefold larger pool size of the primary component, and a similar pool size of the secondary component of VLDL-CH disappearance than did diabetic pigs fed soy oil. Thus, dietary fat seems to play an important role in regulation of glucose and VLDL-CH homeostasis in normal and diabetic animals.

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

    PubMed Central

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

    2013-01-01

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

  1. Abnormal Glucose Tolerance Is Associated with a Reduced Myocardial Metabolic Flexibility in Patients with Dilated Cardiomyopathy

    PubMed Central

    Tricò, Domenico; Baldi, Simona; Frascerra, Silvia; Venturi, Elena; Marraccini, Paolo; Neglia, Danilo; Natali, Andrea

    2016-01-01

    Dilated cardiomyopathy (DCM) is characterized by a metabolic shift from fat to carbohydrates and failure to increase myocardial glucose uptake in response to workload increments. We verified whether this pattern is influenced by an abnormal glucose tolerance (AGT). In 10 patients with DCM, 5 with normal glucose tolerance (DCM-NGT) and 5 with AGT (DCM-AGT), and 5 non-DCM subjects with AGT (N-AGT), we measured coronary blood flow and arteriovenous differences of oxygen and metabolites during Rest, Pacing (at 130 b/min), and Recovery. Myocardial lactate exchange and oleate oxidation were also measured. At Rest, DCM patients showed a reduced nonesterified fatty acids (NEFA) myocardial uptake, while glucose utilization increased only in DCM-AGT. In response to Pacing, glucose uptake promptly rose in N-AGT (from 72 ± 21 to 234 ± 73 nmol/min/g, p < 0.05), did not change in DCM-AGT, and slowly increased in DCM-NGT. DCM-AGT sustained the extra workload by increasing NEFA oxidation (from 1.3 ± 0.2 to 2.9 ± 0.1 μmol/min/gO2 equivalents, p < 0.05), while DCM-NGT showed a delayed increase in glucose uptake. Substrate oxidation rates paralleled the metabolites data. The presence of AGT in patients with DCM exacerbates both the shift from fat to carbohydrates in resting myocardial metabolism and the reduced myocardial metabolic flexibility in response to an increased workload. This trial is registered with ClinicalTrial.gov NCT02440217. PMID:26798650

  2. Abnormal Glucose Tolerance Is Associated with a Reduced Myocardial Metabolic Flexibility in Patients with Dilated Cardiomyopathy.

    PubMed

    Tricò, Domenico; Baldi, Simona; Frascerra, Silvia; Venturi, Elena; Marraccini, Paolo; Neglia, Danilo; Natali, Andrea

    2016-01-01

    Dilated cardiomyopathy (DCM) is characterized by a metabolic shift from fat to carbohydrates and failure to increase myocardial glucose uptake in response to workload increments. We verified whether this pattern is influenced by an abnormal glucose tolerance (AGT). In 10 patients with DCM, 5 with normal glucose tolerance (DCM-NGT) and 5 with AGT (DCM-AGT), and 5 non-DCM subjects with AGT (N-AGT), we measured coronary blood flow and arteriovenous differences of oxygen and metabolites during Rest, Pacing (at 130 b/min), and Recovery. Myocardial lactate exchange and oleate oxidation were also measured. At Rest, DCM patients showed a reduced nonesterified fatty acids (NEFA) myocardial uptake, while glucose utilization increased only in DCM-AGT. In response to Pacing, glucose uptake promptly rose in N-AGT (from 72 ± 21 to 234 ± 73 nmol/min/g, p < 0.05), did not change in DCM-AGT, and slowly increased in DCM-NGT. DCM-AGT sustained the extra workload by increasing NEFA oxidation (from 1.3 ± 0.2 to 2.9 ± 0.1 μmol/min/gO2 equivalents, p < 0.05), while DCM-NGT showed a delayed increase in glucose uptake. Substrate oxidation rates paralleled the metabolites data. The presence of AGT in patients with DCM exacerbates both the shift from fat to carbohydrates in resting myocardial metabolism and the reduced myocardial metabolic flexibility in response to an increased workload. This trial is registered with ClinicalTrial.gov NCT02440217.

  3. Dysregulation of Glucose Homeostasis Following Chronic Exogenous Administration of Leptin in Healthy Sprague-Dawley Rats

    PubMed Central

    Wjidan, Khalil; Ibrahim, Effendi; Caszo, Brinnell; Gnanou, Justin

    2015-01-01

    Introduction Impaired glucose utilization is seen in chronic hyperleptinaemia associated conditions such as obesity and type 2 diabetes mellitus. It is unclear if this impaired glucose utilization is due to the effect of persistent hyperleptinaemia on insulin secretion from the beta cells of pancreas. Aim To examine the effects of chronic leptin administration on plasma glucose regulation in rats. Materials and Methods Glucose challenge curves were plotted for male Sprague-Dawley rats treated with either normal saline (Control; n=8) or subcutaneous leptin injection for 42 days (60 μg/kg body weight/day; n=8). Plasma glucose and plasma insulin levels were measured at 0, 5, 10, 15, 20 and 25 minutes after glucose challenege. Skeletal muscle tissue was collected at the end of a glucose challenge for glucose transporter-4 protein content, insulin receptor and glucose transporter-4 mRNA expression. Data were analysed using repeated measures and one-way ANOVA with post-hoc analysis. Results Chronic leptin treatment caused significantly higher fasting insulin level. Post glucose challenge, there was a significant increase in blood glucose levels and insulin level in the leptin treated rats. There was no significant difference in the skeletal muscle glucose transporter-4 content. However, leptin treated rats showed decreased mRNA expression of Insulin Receptor and glucose transporter-4 in the skeletal muscle. Conclusion Leptin administration for 42 days caused hyperinsulinaemia and decreased the expression of insulin receptors in insulin sensitive tissues leading to the development of an insulin resistance-like state in the rats. PMID:26816939

  4. Detection of Abnormal Glucose Tolerance in Africans Is Improved by Combining A1C With Fasting Glucose: The Africans in America Study

    PubMed Central

    Thoreson, Caroline K.; O'Connor, Michelle Y.; Ricks, Madia; Chung, Stephanie T.; Tulloch-Reid, Marshall K.; Lozier, Jay N.; Sacks, David B.

    2015-01-01

    OBJECTIVE Abnormal glucose tolerance is rising in sub-Saharan Africa. Hemoglobin A1c by itself and in combination with fasting plasma glucose (FPG) is used to diagnose abnormal glucose tolerance. The diagnostic ability of A1C in Africans with heterozygous variant hemoglobin, such as sickle cell trait or hemoglobin C trait, has not been rigorously evaluated. In U.S.-based Africans, we determined by hemoglobin status the sensitivities of 1) FPG ≥5.6 mmol/L, 2) A1C ≥ 5.7% (39 mmol/mol), and 3) FPG combined with A1C (FPG ≥5.6 mmol/L and/or A1C ≥5.7% [39 mmol/mol]) for the detection of abnormal glucose tolerance. RESEARCH DESIGN AND METHODS An oral glucose tolerance test (OGTT) was performed in 216 African immigrants (68% male, age 37 ± 10 years [mean ± SD], range 20–64 years). Abnormal glucose tolerance was defined as 2-h glucose ≥7.8 mmol/L. RESULTS Variant hemoglobin was identified in 21% (46 of 216). Abnormal glucose tolerance occurred in 33% (72 of 216). When determining abnormal glucose tolerance from the OGTT (2-h glucose ≥7.8 mmol/L), sensitivities of FPG for the total, normal, and variant hemoglobin groups were 32%, 32%, and 33%, respectively. Sensitivities for A1C were 53%, 54%, and 47%. For FPG and A1C combined, sensitivities were 64%, 63%, and 67%. Sensitivities for FPG and A1C and the combination did not vary by hemoglobin status (all P > 0.6). For the entire cohort, sensitivity was higher for A1C than FPG and for both tests combined than for either test alone (all P values ≤ 0.01). CONCLUSIONS No significant difference in sensitivity of A1C by variant hemoglobin status was detected. For the diagnosis of abnormal glucose tolerance in Africans, the sensitivity of A1C combined with FPG is significantly superior to either test alone. PMID:25338926

  5. Physically active vs. inactive lifestyle, muscle properties, and glucose homeostasis in middle-aged and older twins.

    PubMed

    Leskinen, T; Sipilä, S; Kaprio, J; Kainulainen, H; Alen, M; Kujala, U M

    2013-10-01

    Exercise-induced positive changes in skeletal muscle properties and metabolism decrease the risk for disability, cardiometabolic diseases and mortality. Here, we studied muscle properties and glucose homeostasis in a non-exercise stage in twin pairs with co-twins discordant for physical activity habits for at least 32 years of their adult lives. Isometric knee extension force, MR imaging of midthigh tissue composition and muscle volume, and fasting blood samples were acquired from 16 same-sex (seven monozygotic, nine dizygotic) middle-aged and older twin pairs. The consistently active twins had 20 % higher knee extension forces than their inactive co-twins (p = 0.006) although the active twins had only 4 % higher midthigh muscle cross-sectional areas (p = 0.072). These results were similar in intrapair analysis in which only the seven identical twin pairs were included. The ratio between the area of midthigh fat and muscle tissues was significantly lower among the active twins (0.65 vs. 0.48, p = 0.006). The active twins had also lower fasting plasma glucose levels (5.1 vs 5.6 mmol/l, p = 0.041). The area of midthigh intramuscular (extramyocellular) fat was associated with the markers of glucose homeostasis, especially with glycated hemoglobin, and these associations were emphasized by the diabetic and inactive twins. Regular exercise throughout the adult life retains muscle strength and quality but not necessarily mass. The regular use of muscles also prevents from the accumulation of intramuscular fat which might be related to maintained glucose metabolism and, thus, prevention of metabolic disorders. PMID:23124702

  6. Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect

    PubMed Central

    Zhang, Shiwu; Yang, Chuanwei; Yang, Zhenduo; Zhang, Dan; Ma, Xiaoping; Mills, Gordon; Liu, Zesheng

    2015-01-01

    Glucose metabolism in mitochondria through oxidative phosphorylation (OXPHOS) for generation of adenosine triphosphate (ATP) is vital for cell function. However, reactive oxygen species (ROS), a by-product from OXPHOS, is a major source of endogenously produced toxic stressors on the genome. In fact, ATP could be efficiently produced in a high throughput manner without ROS generation in cytosol through glycolysis, which could be a unique and critical metabolic pathway to prevent spontaneous mutation during DNA replication. Therefore glycolysis is dominant in robust proliferating cells. Indeed, aerobic glycolysis, or the Warburg effect, in normal proliferating cells is an example of homeostasis of redox status by transiently shifting metabolic flux from OXPHOS to glycolysis to avoid ROS generation during DNA synthesis and protect genome integrity. The process of maintaining redox homeostasis is driven by genome wide transcriptional clustering with mitochondrial retrograde signaling and coupled with the glucose metabolic pathway and cell division cycle. On the contrary, the Warburg effect in cancer cells is the results of the alteration of redox status from a reprogramed glucose metabolic pathway caused by the dysfunctional OXPHOS. Mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) disrupt mitochondrial structural integrity, leading to reduced OXPHOS capacity, sustained glycolysis and excessive ROS leak, all of which are responsible for tumor initiation, progression and metastasis. A “plumbing model” is used to illustrate how redox status could be regulated through glucose metabolic pathway and provide a new insight into the understanding of the Warburg effect in both normal and cancer cells. PMID:26101696

  7. Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect

    PubMed Central

    Zhang, Shiwu; Yang, Chuanwei; Yang, Zhenduo; Zhang, Dan; Ma, Xiaoping; Mills, Gordon; Liu, Zesheng

    2015-01-01

    Glucose metabolism in mitochondria through oxidative phosphorylation (OXPHOS) for generation of adenosine triphosphate (ATP) is vital for cell function. However, reactive oxygen species (ROS), a by-product from OXPHOS, is a major source of endogenously produced toxic stressors on the genome. In fact, ATP could be efficiently produced in a high throughput manner without ROS generation in cytosol through glycolysis, which could be a unique and critical metabolic pathway to prevent spontaneous mutation during DNA replication. Therefore glycolysis is dominant in robust proliferating cells. Indeed, aerobic glycolysis, or the Warburg effect, in normal proliferating cells is an example of homeostasis of redox status by transiently shifting metabolic flux from OXPHOS to glycolysis to avoid ROS generation during DNA synthesis and protect genome integrity. The process of maintaining redox homeostasis is driven by genome wide transcriptional clustering with mitochondrial retrograde signaling and coupled with the glucose metabolic pathway and cell division cycle. On the contrary, the Warburg effect in cancer cells is the results of the alteration of redox status from a reprogramed glucose metabolic pathway caused by the dysfunctional OXPHOS. Mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) disrupt mitochondrial structural integrity, leading to reduced OXPHOS capacity, sustained glycolysis and excessive ROS leak, all of which are responsible for tumor initiation, progression and metastasis. A “plumbing model” is used to illustrate how redox status could be regulated through glucose metabolic pathway and provide a new insight into the understanding of the Warburg effect in both normal and cancer cells. PMID:26045978

  8. Zinc status affects glucose homeostasis and insulin secretion in patients with thalassemia.

    PubMed

    Fung, Ellen B; Gildengorin, Ginny; Talwar, Siddhant; Hagar, Leah; Lal, Ashutosh

    2015-06-02

    Up to 20% of adult patients with Thalassemia major (Thal) live with diabetes, while 30% may be zinc deficient. The objective of this study was to explore the relationship between zinc status, impaired glucose tolerance and insulin sensitivity in Thal patients. Charts from thirty subjects (16 male, 27.8 ± 9.1 years) with Thal were reviewed. Patients with low serum zinc had significantly lower fasting insulin, insulinogenic and oral disposition indexes (all p < 0.05) and elevated glucose response curve, following a standard 75 g oral load of glucose compared to those with normal serum zinc after controlling for baseline (group × time interaction p = 0.048). Longitudinal data in five patients with a decline in serum zinc over a two year follow up period (-19.0 ± 9.6 μg/dL), showed consistent increases in fasting glucose (3.6 ± 3.2 mg/dL) and insulin to glucose ratios at 120 min post glucose dose (p = 0.05). Taken together, these data suggest that the frequently present zinc deficiency in Thal patients is associated with decreased insulin secretion and reduced glucose disposal. Future zinc trials will require modeling of oral glucose tolerance test data and not simply measurement of static indices in order to understand the complexities of pancreatic function in the Thal patient.

  9. Zinc Status Affects Glucose Homeostasis and Insulin Secretion in Patients with Thalassemia

    PubMed Central

    Fung, Ellen B.; Gildengorin, Ginny; Talwar, Siddhant; Hagar, Leah; Lal, Ashutosh

    2015-01-01

    Up to 20% of adult patients with Thalassemia major (Thal) live with diabetes, while 30% may be zinc deficient. The objective of this study was to explore the relationship between zinc status, impaired glucose tolerance and insulin sensitivity in Thal patients. Charts from thirty subjects (16 male, 27.8 ± 9.1 years) with Thal were reviewed. Patients with low serum zinc had significantly lower fasting insulin, insulinogenic and oral disposition indexes (all p < 0.05) and elevated glucose response curve, following a standard 75 g oral load of glucose compared to those with normal serum zinc after controlling for baseline (group × time interaction p = 0.048). Longitudinal data in five patients with a decline in serum zinc over a two year follow up period (−19.0 ± 9.6 μg/dL), showed consistent increases in fasting glucose (3.6 ± 3.2 mg/dL) and insulin to glucose ratios at 120 min post glucose dose (p = 0.05). Taken together, these data suggest that the frequently present zinc deficiency in Thal patients is associated with decreased insulin secretion and reduced glucose disposal. Future zinc trials will require modeling of oral glucose tolerance test data and not simply measurement of static indices in order to understand the complexities of pancreatic function in the Thal patient. PMID:26043030

  10. Chronic Exposure to Aroclor 1254 Disrupts Glucose Homeostasis in Male Mice via Inhibition of the Insulin Receptor Signal Pathway.

    PubMed

    Zhang, Shiqi; Wu, Tian; Chen, Meng; Guo, Zhizhun; Yang, Zhibin; Zuo, Zhenghong; Wang, Chonggang

    2015-08-18

    Epidemiological studies demonstrate that polychlorinated biphenyls (PCBs) induce diabetes and insulin resistance. However, the development of diabetes caused by PCBs and its underlying mechanisms are still unclear. In the present study, male C57BL/6 mice were orally administered with Aroclor 1254 (0.5, 5, 50, and 500 μg/kg) once every 3 days for 60 days. The body weight and the fasting blood glucose levels were significantly elevated; the levels of serum insulin, resistin, tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) increased, while glucagon levels decreased in the animals treated with Aroclor 1254. Pancreatic β-cell mass significantly increased, while α-cell mass was reduced. Aroclor 1254 inhibited the expression of the insulin receptor signaling cascade, including insulin receptor, insulin receptor substrate, phosphatidylinositol 3-kinase-Akt, and protein kinase B and glucose transporter 4, both in the skeletal muscle and the liver. The results suggested that chronic exposure to Aroclor 1254 disrupted glucose homeostasis and induced hyperinsulinemia. The significant elevation of serum resistin, TNFα and IL-6 indicated that obesity caused by Aroclor 1254 is associated with insulin resistance. The elevation of blood glucose levels could have been mainly as a result of insulin receptor signals pathway suppression in skeletal muscle and liver, and a decrease in pancreatic α-cells, accompanied by a reduction of serum glucagon levels, may play an important role in the development of type 2 diabetes.

  11. Long-term disruption of maternal glucose homeostasis induced by prenatal glucocorticoid treatment correlates with miR-29 upregulation.

    PubMed

    Gomes, Patrícia R; Graciano, Maria F; Pantaleão, Lucas C; Rennó, André L; Rodrigues, Sandra C; Velloso, Licio A; Latorraca, Márcia Q; Carpinelli, Angelo R; Anhê, Gabriel F; Bordin, Silvana

    2014-01-01

    Excess of glucocorticoids (GCs) during pregnancy is strongly associated with the programming of glucose intolerance in the offspring. However, the impact of high GC levels on maternal metabolism is not clearly documented. This study aimed to test the hypothesis that mothers exposed to elevated levels of GCs might also display long-term disturbances in glucose homeostasis. Dexamethasone (DEX) was administered noninvasively to the mothers via drinking water between the 14th and the 19th days of pregnancy. Mothers were subjected to glucose and insulin tolerance tests at 1, 2, 3, 6, and 12 mo postweaning. Pregnant rats not treated with DEX and age-matched virgin rats were used as controls. Pancreatic islets were isolated at the 20th day of pregnancy and 12 mo postweaning in order to evaluate glucose-stimulated insulin secretion. The expression of the miR-29 family was also studied due to its responsiveness to GCs and its well-documented role in the regulation of pancreatic β-cell function. Rats treated with DEX during pregnancy presented long-term glucose intolerance and impaired insulin secretion. These changes correlated with 1) increased expression of miR-29 and its regulator p53, 2) reduced expression of syntaxin-1a, a direct target of miR-29, and 3) altered expression of genes related to cellular senescence. Our data demonstrate that the use of DEX during pregnancy results in deleterious outcomes to the maternal metabolism, hallmarked by reduced insulin secretion and glucose intolerance. This maternal metabolic programming might be a consequence of time-sustained upregulation of miR-29s in maternal pancreatic islets. PMID:24253049

  12. 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

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

    PubMed

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

    2016-04-01

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

  14. 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

  15. Differential role of SH2-B and APS in regulating energy and glucose homeostasis.

    PubMed

    Li, Minghua; Ren, Decheng; Iseki, Masanori; Takaki, Satoshi; Rui, Liangyou

    2006-05-01

    SH2-B and APS, two members of a pleckstrin homology and SH2 domain-containing adaptor family, promote both insulin and leptin signaling in a similar fashion in cultured cells. In addition, APS mediates insulin-stimulated activation of the c-Cbl/CAP/TC10 pathway in cultured adipocytes. Here we characterized genetically modified mice lacking SH2-B, APS, or both to determine the physiological roles of these two proteins in animals. Disruption of the SH2-B gene resulted in obesity, hyperglycemia, hyperinsulinemia, and glucose intolerance. Conversely, deletion of the APS gene did not alter adiposity, energy balance, and glucose metabolism. Energy intake, energy expenditure, fat content, body weight, and plasma insulin, leptin, glucose, and lipid levels were similar between APS(-/-) and WT littermates fed either normal chow or a high-fat diet. Moreover, deletion of APS failed to alter insulin and glucose tolerance. APS(-/-)/SH2-B(-/-) double knockout mice also developed energy imbalance, obesity, hyperleptinemia, hyperinsulinemia, hyperglycemia, and glucose intolerance; however, plasma leptin and insulin levels were significantly lower in APS(-/-)/SH2-B(-/-) than in SH2-B(-/-) mice. These results suggest that SH2-B, but not APS, is a key positive regulator of energy and glucose metabolism in mice.

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

    PubMed

    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

  17. 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

  18. Preventive effects of procyanidin A2 on glucose homeostasis, pancreatic and duodenal homebox 1, and glucose transporter 2 gene expression disturbance induced by bisphenol A in male mice.

    PubMed

    Ahangarpour, A; Afshari, G; Mard, S A; Khodadadi, A; Hashemitabar, M

    2016-04-01

    Procyanidins (PCs) as oligomeric compounds with antidiabetic properties formed from catechin and epicatechin molecules. Bisphenol A(BPA) is a common chemical material use in food and beverage packaging. The aim of this study was to explore the protective effects of procyanidin A2 (PCA2) against glucose homeostasis disturbance and gene expression of pancreatic and duodenal homebox 1 (Pdx1) as well as glucose transporter 2 (Glut2) induced by BPA in male mice. First tested these five concentrations of PCA2 (3 - 300 μM) alone and in combination with BPA(100 μg/L), on insulin secretion from isolated islets at in vitro condition. Next, examined the influence of BPA and PCA2 on islet apoptosis using flowcytometry. At in vivo condition, the BPA (100 μg/kg) and PCA2 (10 μmol/kg) administered for 20 days then, blood glucose and insulin, Pdx1 and, Glut2 genes expression, and oxidative stress markers examined. The results indicated that PCA2 strongly prevents islet cells apoptosis induced by BPA and, co-administration of PCA2 and BPA modified hyperglycemia. BPA reduced Pdx1 and Glut2 mRNA expression and antioxidant level in pancreas tissue, whereas PCA2 prevented from these effects. The findings from these studies suggest that use of PCA2 rich plants have preventive effects on hyperglycemia, and type 2 diabetes. PMID:27226184

  19. Prenatal depressive symptoms and abnormalities of glucose tolerance during pregnancy among Hispanic women.

    PubMed

    Ertel, Karen A; Silveira, Marushka; Pekow, Penelope; Braun, Barry; Manson, JoAnn E; Solomon, Caren G; Markenson, Glenn; Chasan-Taber, Lisa

    2014-02-01

    The aim of this study is to prospectively examine the association between maternal depressive symptoms in early pregnancy and risk of abnormal glucose tolerance (AGT) and impaired glucose tolerance (IGT) in mid-pregnancy. We evaluated this association among 934 participants in Proyecto Buena Salud, a prospective cohort study of Hispanic (predominantly Puerto Rican) women in Western Massachusetts. Depressive symptoms were assessed in early pregnancy using the 10-item Edinburgh Postnatal Depression Scale. Scores ≥13 indicated at least probable minor depression and scores ≥15 indicated probable major depression. AGT and IGT were diagnosed using American Diabetes Association criteria. In early pregnancy, 247 (26.5 %) participants experienced at least minor depression and 163 (17.4 %) experienced major depression. A total of 123 (13.2 %) were classified with AGT and 56 (6.0 %) were classified with IGT. In fully-adjusted models, the odds ratio for AGT associated with minor depression was 1.20 (95 % CI 0.77-1.89) and for major depression was 1.34 (95 % CI 0.81-2.23). The odds ratio for IGT associated with minor depression was 1.22 (95 % CI 0.62-2.40) and for major depression was 1.53 (95 % CI 0.73-3.22). We did not observe an association with continuous screening glucose measures. Findings in this prospective cohort of Hispanic women did not indicate a statistically significant association between minor or major depression in early pregnancy and AGT or screening glucose values in mid-pregnancy. Due to the small number of cases of IGT, our ability to evaluate the association between depression and IGT risk was constrained.

  20. Cocoa-rich diet ameliorates hepatic insulin resistance by modulating insulin signaling and glucose homeostasis in Zucker diabetic fatty rats.

    PubMed

    Cordero-Herrera, Isabel; Martín, María Ángeles; Escrivá, Fernando; Álvarez, Carmen; Goya, Luis; Ramos, Sonia

    2015-07-01

    Insulin resistance is the primary characteristic of type 2 diabetes and results from insulin signaling defects. Cocoa has been shown to exert anti-diabetic effects by lowering glucose levels. However, the molecular mechanisms responsible for this preventive activity and whether cocoa exerts potential beneficial effects on the insulin signaling pathway in the liver remain largely unknown. Thus, in this study, the potential anti-diabetic properties of cocoa on glucose homeostasis and insulin signaling were evaluated in type 2 diabetic Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed a significant decrease in body weight gain, glucose and insulin levels, as well as an improved glucose tolerance and insulin resistance. Cocoa-rich diet further ameliorated the hepatic insulin resistance by abolishing the increased serine-phosphorylated levels of the insulin receptor substrate 1 and preventing the inactivation of the glycogen synthase kinase 3/glycogen synthase pathway in the liver of cocoa-fed ZDF rats. The anti-hyperglycemic effect of cocoa appeared to be at least mediated through the decreased levels of hepatic phosphoenolpyruvate carboxykinase and increased values of glucokinase and glucose transporter 2 in the liver of ZDF-Co rats. Moreover, cocoa-rich diet suppressed c-Jun N-terminal kinase and p38 activation caused by insulin resistance. These findings suggest that cocoa has the potential to alleviate both hyperglycemia and hepatic insulin resistance in type 2 diabetic ZDF rats.

  1. The tumor suppressor gene lkb1 is essential for glucose homeostasis during zebrafish early development.

    PubMed

    Kuang, Xia; Liu, Chao; Fang, Junshun; Ma, Weirui; Zhang, Jian; Cui, Sheng

    2016-07-01

    The liver kinase B1 (LKB1) is encoded by tumor suppressor gene STK11, which is mutated in Peutz-Jeghers syndrome patients. Lkb1 plays indispensable roles in energy homeostasis. However, how Lkb1 regulates energy homeostasis in vivo remains to be fully understood. We found that inactivation of zebrafish Lkb1 upregulates pyruvate dehydrogenase kinase 2 expression and inactivates pyruvate dehydrogenase complex by increasing phosphorylation of pyruvate dehydrogenase. As a result, glycolysis is significantly enhanced as indicated by increased lactate production, which resembles the Warburg effect in cancer cells. Inhibition of Pdk2 in lkb1 mutants with dichloroacetate, a promising anticancer drug, rescued the lactate production to wild-type level, suggesting the lkb1 mutant may be used to screen compounds targeting aerobic glycolysis in cancer therapy. PMID:27264935

  2. Restraint Stress Impairs Glucose Homeostasis Through Altered Insulin Signalling in Sprague-Dawley Rat.

    PubMed

    Morakinyo, Ayodele O; Ajiboye, Kolawole I; Oludare, Gabriel O; Samuel, Titilola A

    2016-01-01

    The study investigated the potential alteration in the level of insulin and adiponectin, as well as the expression of insulin receptors (INSR) and glucose transporter 4 GLUT-4 in chronic restraint stress rats. Sprague-Dawley rats were randomly divided into two groups: the control group and stress group in which the rats were exposed to one of the four different restraint stressors; 1 h, twice daily for a period of 7 days (S7D), 14 days (S14D) and 28 days (S28D). Glucose tolerance and insulin sensitivity were evaluated following the final stress exposure. ELISA were performed to assess the level of insulin and adiponectin as well as expression of INSR and GLUT4 protein in skeletal muscle. Plasma corticosterone level was also determined as a marker of stress exposure. Restraint stress for 7 days caused transient glucose intolerance, while S14D rats demonstrated increased glucose intolerance and insulin insensitivity. However, restraint stress for 28 days had no effect on glucose tolerance, but did cause an increase in glucose response to insulin challenge. The serum level of adiponectin was significantly (p< 0.05) lower compared with the control value while insulin remained unchanged except at in S28D rats that had a significant (p<0.05) increase. The expression of INSR and GLUT4 receptors were significantly (p< 0.05) decreased in the skeletal muscle of restraint stress exposed rats. There was a significant (p< 0.05) increase in the plasma corticosterone level of the stress rats compared with their control counterparts. Restraint stress caused glucose intolerance and insulin insensitivity in male Sprague-Dawley rats, which becomes accommodated with prolonged exposure and was likely related to the blunted insulin signalling in skeletal muscle. PMID:27574760

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

    PubMed Central

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

    2015-01-01

    Summary Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the central nervous system are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human diphtheria toxin receptor was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1bf/f/p mice, in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes. PMID:25955206

  4. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs.

    PubMed

    Frost, Robert J A; Olson, Eric N

    2011-12-27

    Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. MicroRNAs are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. Here we show that the Let-7 family of microRNAs regulates glucose metabolism in multiple organs. Global and pancreas-specific overexpression of Let-7 in mice resulted in impaired glucose tolerance and reduced glucose-induced pancreatic insulin secretion. Mice overexpressing Let-7 also had decreased fat mass and body weight, as well as reduced body size. Global knockdown of the Let-7 family with an antimiR was sufficient to prevent and treat impaired glucose tolerance in mice with diet-induced obesity, at least in part by improving insulin sensitivity in liver and muscle. AntimiR treatment of mice on a high-fat diet also resulted in increased lean and muscle mass, but not increased fat mass, and prevented ectopic fat deposition in the liver. These findings demonstrate that Let-7 regulates multiple aspects of glucose metabolism and suggest antimiR-induced Let-7 knockdown as a potential treatment for type 2 diabetes mellitus. Furthermore, our Cre-inducible Let-7-transgenic mice provide a unique model for studying tissue-specific aspects of body growth and type 2 diabetes. PMID:22160727

  5. 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

  6. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs.

    PubMed

    Frost, Robert J A; Olson, Eric N

    2011-12-27

    Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. MicroRNAs are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. Here we show that the Let-7 family of microRNAs regulates glucose metabolism in multiple organs. Global and pancreas-specific overexpression of Let-7 in mice resulted in impaired glucose tolerance and reduced glucose-induced pancreatic insulin secretion. Mice overexpressing Let-7 also had decreased fat mass and body weight, as well as reduced body size. Global knockdown of the Let-7 family with an antimiR was sufficient to prevent and treat impaired glucose tolerance in mice with diet-induced obesity, at least in part by improving insulin sensitivity in liver and muscle. AntimiR treatment of mice on a high-fat diet also resulted in increased lean and muscle mass, but not increased fat mass, and prevented ectopic fat deposition in the liver. These findings demonstrate that Let-7 regulates multiple aspects of glucose metabolism and suggest antimiR-induced Let-7 knockdown as a potential treatment for type 2 diabetes mellitus. Furthermore, our Cre-inducible Let-7-transgenic mice provide a unique model for studying tissue-specific aspects of body growth and type 2 diabetes.

  7. Effects of Bisphenol A on glucose homeostasis and brain insulin signaling pathways in male mice.

    PubMed

    Fang, Fangfang; Chen, Donglong; Yu, Pan; Qian, Wenyi; Zhou, Jing; Liu, Jingli; Gao, Rong; Wang, Jun; Xiao, Hang

    2015-02-01

    The potential effects of Bisphenol A (BPA) on peripheral insulin resistance have recently gained more attention, however, its functions on brain insulin resistance are still unknown. The aim of the present study was to investigate the effects of BPA on insulin signaling and glucose transport in mouse brain. The male mice were administrated of 100 μg/kg/day BPA or vehicle for 15 days then challenged with glucose and insulin tolerance tests. The insulin levels were detected with radioimmunoassay (RIA), and the insulin signaling pathways were investigated by Western blot. Our results revealed that BPA significantly increased peripheral plasma insulin levels, and decreased the insulin signals including phosphorylated insulin receptor (p-IR), phosphorylated insulin receptor substrate 1 (p-IRS1), phosphorylated protein kinase B (p-AKT), phosphorylated glycogen synthase kinase 3β (p-GSK3β) and phosphorylated extracellular regulated protein kinases (p-ERK1/2) in the brain, though insulin expression in both hippocampus and profrontal cortex was increased. In parallel, BPA exposure might contribute to glucose transport disturbance in the brain since the expression of glucose transporters were markedly decreased. In conclusion, BPA exposure perturbs the insulin signaling and glucose transport in the brain, therefore, it might be a risk factor for brain insulin resistance.

  8. Steroid Receptor Coactivator 1 is an Integrator of Glucose and NAD+/NADH Homeostasis

    PubMed Central

    Motamed, Massoud; Rajapakshe, Kimal I.; Hartig, Sean M.; Coarfa, Cristian; Moses, Robb E.; Lonard, David M.

    2014-01-01

    Steroid receptor coactivator 1 (SRC-1) drives diverse gene expression programs necessary for the dynamic regulation of cancer metastasis, inflammation and gluconeogenesis, pointing to its overlapping roles as an oncoprotein and integrator of cell metabolic programs. Nutrient utilization has been intensely studied with regard to cellular adaptation in both cancer and noncancerous cells. Nonproliferating cells consume glucose through the citric acid cycle to generate NADH to fuel ATP generation via mitochondrial oxidative phosphorylation. In contrast, cancer cells undergo metabolic reprogramming to support rapid proliferation. To generate lipids, nucleotides, and proteins necessary for cell division, most tumors switch from oxidative phosphorylation to glycolysis, a phenomenon known as the Warburg Effect. Because SRC-1 is a key coactivator responsible for driving a hepatic gluconeogenic program under fasting conditions, we asked whether SRC-1 responds to alterations in nutrient availability to allow for adaptive metabolism. Here we show SRC-1 is stabilized by the 26S proteasome in the absence of glucose. RNA profiling was used to examine the effects of SRC-1 perturbation on gene expression in the absence or presence of glucose, revealing that SRC-1 affects the expression of complex I of the mitochondrial electron transport chain, a set of enzymes responsible for the conversion of NADH to NAD+. NAD+ and NADH were subsequently identified as metabolites that underlie SRC-1's response to glucose deprivation. Knockdown of SRC-1 in glycolytic cancer cells abrogated their ability to grow in the absence of glucose consistent with SRC-1's role in promoting cellular adaptation to reduced glucose availability. PMID:24438340

  9. Clustering of hypertension, abnormal glucose tolerance, hypercholesterolaemia and obesity in Malaysian adult population.

    PubMed

    Lim, T O; Ding, L M; Zaki, M; Merican, I; Kew, S T; Maimunah, A H; Rozita, H H; Rugayah, B

    2000-06-01

    We determine the prevalence and determinants of clustering of hypertension, abnormal glucose tolerance, hypercholesterolaemia and overweight in Malaysia. A national probability sample of 17,392 individuals aged 30 years or older had usable data. 61% of adults had at least one risk factor, 27% had 2 or more risk factors. The observed frequency of 4 factors cluster was 6 times greater than that expected by chance. Indian and Malay women were at particular high risk of risk factors clustering. Individuals with a risk factor had 1.5 to 3 times higher prevalence of other risk factors. Ordinal regression analyses show that higher income, urban residence and physical inactivity were independently associated with risk factors clustering, lending support to the hypotheses that risk factors clustering is related to lifestyle changes brought about by modernisation and urbanisation. In conclusion, risk factor clustering is highly prevalent among Malaysian adults. Treatment and prevention programme must emphasise the multiple risk factor approach.

  10. 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...

  11. 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...

  12. 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

  13. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis

    PubMed Central

    Jiao, Yang; Lu, Yan; Li, Xiao-ying

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia. PMID:25500875

  14. 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

  15. Magnesium deficiency improves glucose homeostasis in the rat: studies in vivo and in isolated islets in vitro.

    PubMed

    Reis, M A; Latorraca, M Q; Carneiro, E M; Boschero, A C; Saad, M J; Velloso, L A; Reyes, F G

    2001-05-01

    The serum mineral levels, glucose disappearance rate (kg), total area under the glucose (DeltaG) and insulin (DeltaI) curves, and static insulin secretion were compared among rats fed a Mg-deficient diet for 6 (DF-6) or 11 (DF-11) weeks, and rats fed a control diet for the same periods (CO-6 and CO-11 groups). No change in glucose homeostasis was observed among DF-6, CO-6 and CO-11 rats. DF-11 rats showed an elevated kg and a reduced DeltaG and DeltaI. For evaluating the effect of supplementation, rats fed a control or Mg-deficient diet for 6 weeks were then fed a Mg- supplemented diet for 5 weeks (SCO and SDF groups respectively). The serum Mg levels in SDF rats were similar to those in CO-11 and SCO rats, but higher than in the DF-11 group. SDF rats showed similar kg, DeltaG and DeltaI compared with the CO-11 and SCO groups. However, a significantly lower kg and higher DeltaG and DeltaI were observed in SDF compared with DF-11 rats. Basal and 8.3 mmol glucose/l-stimulated insulin secretion by islets from DF-11 rats were higher than by islets from CO-11 rats. These results indicate that moderate Mg depletion for a long period may increase the secretion and sensitivity to insulin, while Mg supplementation in formerly Mg-deficient rats may prevent the increase in sensitivity and secretion of insulin. PMID:11348569

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

    PubMed Central

    Dunn-Meynell, Ambrose A.; Levin, Barry E.

    2014-01-01

    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. PMID:25477422

  17. The Nuclear Orphan Receptor COUP-TFII Plays an Essential Role in Adipogenesis, Glucose Homeostasis, and Energy Metabolism

    PubMed Central

    Li, Luoping; Xie, Xin; Qin, Jun; Jeha, George S.; Saha, Pradip K.; Yan, Jun; Haueter, Claire Menoza; Chan, Lawrence; Tsai, Sophia Y.; Tsai, Ming-Jer.

    2009-01-01

    Summary Adipose tissue development and function play a central role in the pathogenesis and pathophysiology of metabolic syndromes. Here we show that Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) plays a pivotal role in adipogenesis and energy homeostasis. COUP-TFII is expressed in the early stages of white adipocyte (WAT) development. COUP-TFII heterozygous mice (COUP-TFII+/-) have much less WAT than wild type mice (COUP-TFII+/+). COUP-TFII+/- mice display a decreased expression of key regulators for WAT development. Knock down COUP-TFII in 3T3-L1 cells resulted in an increased expression of Wnt10b, while chromatin immunoprecipitation analysis revealed that Wnt10b is a direct target of COUP-TFII. Moreover, COUP-TFII+/− mice have increased mitochondrial biogenesis in WAT, and COUP-TFII+/− mice have improved glucose homeostasis and increased energy expenditure. Thus, COUP-TFII regulates adipogenesis by regulating the key molecules in adipocyte development, and can serve as a new target for regulating energy metabolism. PMID:19117548

  18. Taurine supplementation ameliorates glucose homeostasis, prevents insulin and glucagon hypersecretion, and controls β, α, and δ-cell masses in genetic obese mice.

    PubMed

    Santos-Silva, Junia C; Ribeiro, Rosane Aparecida; Vettorazzi, Jean F; Irles, Esperanza; Rickli, Sarah; Borck, Patrícia C; Porciuncula, Patricia M; Quesada, Ivan; Nadal, Angel; Boschero, Antonio C; Carneiro, Everardo M

    2015-08-01

    Taurine (Tau) regulates β-cell function and glucose homeostasis under normal and diabetic conditions. Here, we assessed the effects of Tau supplementation upon glucose homeostasis and the morphophysiology of endocrine pancreas, in leptin-deficient obese (ob) mice. From weaning until 90-day-old, C57Bl/6 and ob mice received, or not, 5% Tau in drinking water (C, CT, ob and obT). Obese mice were hyperglycemic, glucose intolerant, insulin resistant, and exhibited higher hepatic glucose output. Tau supplementation did not prevent obesity, but ameliorated glucose homeostasis in obT. Islets from ob mice presented a higher glucose-induced intracellular Ca(2+) influx, NAD(P)H production and insulin release. Furthermore, α-cells from ob islets displayed a higher oscillatory Ca(2+) profile at low glucose concentrations, in association with glucagon hypersecretion. In Tau-supplemented ob mice, insulin and glucagon secretion was attenuated, while Ca(2+) influx tended to be normalized in β-cells and Ca(2+) oscillations were increased in α-cells. Tau normalized the inhibitory action of somatostatin (SST) upon insulin release in the obT group. In these islets, expression of the glucagon, GLUT-2 and TRPM5 genes was also restored. Tau also enhanced MafA, Ngn3 and NeuroD mRNA levels in obT islets. Morphometric analysis demonstrated that the hypertrophy of ob islets tends to be normalized by Tau with reductions in islet and β-cell masses, but enhanced δ-cell mass in obT. Our results indicate that Tau improves glucose homeostasis, regulating β-, α-, and δ-cell morphophysiology in ob mice, indicating that Tau may be a potential therapeutic tool for the preservation of endocrine pancreatic function in obesity and diabetes.

  19. 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.

  20. 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

  1. 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. PMID:26463117

  2. 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. PMID:9291828

  3. Soluble CLEC2 Extracellular Domain Improves Glucose and Lipid Homeostasis by Regulating Liver Kupffer Cell Polarization

    PubMed Central

    Wu, Xinle; Zhang, Jun; Ge, Hongfei; Gupte, Jamila; Baribault, Helene; Lee, Ki Jeong; Lemon, Bryan; Coberly, Suzanne; Gong, Yan; Pan, Zheng; Rulifson, Ingrid C.; Gardner, Jonitha; Richards, William G.; Li, Yang

    2015-01-01

    The polarization of tissue resident macrophages toward the alternatively activated, anti-inflammatory M2 phenotype is believed to positively impact obesity and insulin resistance. Here we show that the soluble form of the extracellular domain (ECD) of C-type lectin-like receptor 2, CLEC2, regulates Kupffer cell polarization in the liver and improves glucose and lipid parameters in diabetic animal models. Over-expression of Fc-CLEC2(ECD) in mice via in vivo gene delivery, or injection of recombinant Fc-CLEC2(ECD) protein, results in a reduction of blood glucose and liver triglyceride levels and improves glucose tolerance. Furthermore, Fc-CLEC2(ECD) treatment improves cytokine profiles and increases both the M2 macrophage population and the genes involved in the oxidation of lipid metabolism in the liver. These data reveal a previously unidentified role for CLEC2 as a regulator of macrophage polarity, and establish CLEC2 as a promising therapeutic target for treatment of diabetes and liver disease. PMID:26151067

  4. Phloretin promotes adipocyte differentiation in vitro and improves glucose homeostasis in vivo.

    PubMed

    Shu, Gang; Lu, Nai-Sheng; Zhu, Xiao-Tong; Xu, Yong; Du, Min-Qing; Xie, Qiu-Ping; Zhu, Can-Jun; Xu, Qi; Wang, Song-Bo; Wang, Li-Na; Gao, Ping; Xi, Qian-Yun; Zhang, Yong-Liang; Jiang, Qing-Yan

    2014-12-01

    Adipocyte dysfunction is associated with many metabolic diseases such as obesity, insulin resistance and diabetes. Previous studies found that phloretin promotes 3T3-L1 cells differentiation, but the underlying mechanisms for phloretin's effects on adipogenesis remain unclear. In this study, we demonstrated that phloretin enhanced the lipid accumulation in porcine primary adipocytes in a time-dependent manner. Furthermore, phloretin increased the utilization of glucose and nonesterified fatty acid, while it decreased the lactate output. Microarray analysis revealed that genes associated with peroxisome proliferator-activated receptor-γ (PPARγ), mitogen-activated protein kinase and insulin signaling pathways were altered in response to phloretin. We further confirmed that phloretin enhanced expression of PPARγ, CAAT enhancer binding protein-α (C/EBPα) and adipose-related genes, such as fatty acids translocase and fatty acid synthase. In addition, phloretin activated the Akt (Thr308) and extracellular signal-regulated kinase, and therefore, inactivated Akt targets protein. Wortmannin effectively blocked the effect of phloretin on Akt activity and the protein levels of PPARγ, C/EBPα and fatty acid binding protein-4 (FABP4/aP2). Oral administration of 5 or 10 mg/kg phloretin to C57BL BKS-DB mice significantly decreased the serum glucose level and improved glucose tolerance. In conclusion, phloretin promotes the adipogenesis of porcine primary preadipocytes through Akt-associated signaling pathway. These findings suggested that phloretin might be able to increase insulin sensitivity and alleviate the metabolic diseases. PMID:25283330

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

    PubMed Central

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

    2011-01-01

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

  6. PPARα-independent actions of omega-3 PUFAs contribute to their beneficial effects on adiposity and glucose homeostasis

    PubMed Central

    Liu, Menghan; Montgomery, Magdalene K.; Fiveash, Corrine E.; Osborne, Brenna; Cooney, Gregory J.; Bell-Anderson, Kim; Turner, Nigel

    2014-01-01

    Excess dietary lipid generally leads to fat deposition and impaired glucose homeostasis, but consumption of fish oil (FO) alleviates many of these detrimental effects. The beneficial effects of FO are thought to be mediated largely via activation of the nuclear receptor peroxisomal-proliferator-activated receptor α (PPARα) by omega-3 polyunsaturated fatty acids and the resulting upregulation of lipid catabolism. However, pharmacological and genetic PPARα manipulations have yielded variable results. We have compared the metabolic effects of FO supplementation and the synthetic PPARα agonist Wy-14,643 (WY) in mice fed a lard-based high-fat diet. In contrast to FO, WY treatment resulted in little protection against diet-induced obesity and glucose intolerance, despite upregulating many lipid metabolic pathways. These differences were likely due to differential effects on hepatic lipid synthesis, with FO decreasing and WY amplifying hepatic lipid accumulation. Our results highlight that the beneficial metabolic effects of FO are likely mediated through multiple independent pathways. PMID:24986106

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

    PubMed

    Pillai, Sneha S; Mini, S

    2016-03-01

    The prevalence of diabetes mellitus is becoming more and more serious and reaches epidemic proportions worldwide. Scientific research is constantly looking for new agents that could be used as dietary functional ingredients in the fight against diabetes. The objective of the present study was to evaluate the effect of ethyl acetate fraction of Hibiscus rosa sinensis Linn. petals on experimental diabetes at a dose of 25 mg/kg body weight and it was compared with standard anti-diabetic drug metformin. The elevated levels of serum glucose (398.56 ± 35.78) and glycated haemoglobin (12.89 ± 1.89) in diabetic rats were significantly decreased (156.89 ± 14.45 and 6.12 ± 0.49, respectively) by Hibiscus rosa sinensis petals (EHRS) administration. Hepatotoxicity marker enzyme levels in serum were normalized. The fraction supplementation restored the glycogen content by regulating the activities of glycogen metabolizing enzymes. It significantly modulated the expressions of marker genes involved in glucose homeostasis signalling pathway. Histopathological analysis of liver and pancreas supported our findings. The overall effect was comparable with metformin. Hence, our study reveals the role of hibiscus petals for alleviation of diabetes complications, thus it can be propagated as a nutraceutical agent. PMID:26590603

  8. 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

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

    PubMed

    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

    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.

  10. Pregnancy-induced changes in the circadian expression of hepatic clock genes: implications for maternal glucose homeostasis.

    PubMed

    Wharfe, Michaela D; Wyrwoll, Caitlin S; Waddell, Brendan J; Mark, Peter J

    2016-09-01

    Adaptations in maternal carbohydrate metabolism are particularly important in pregnancy because glucose is the principal energy substrate used by the fetus. As metabolic homeostasis is intricately linked to the circadian system via the rhythmic expression of clock genes, it is likely that metabolic adaptations during pregnancy also involve shifts in maternal circadian function. We hypothesized that maternal adaptation in pregnancy involves changes in the hepatic expression of clock genes, which drive downstream shifts in circadian expression of glucoregulatory genes. Maternal liver and plasma (n = 6-8/group) were collected across 24-h periods (0800, 1200, 1600, 2000, 0000, 0400) from C57Bl/6J mice under isoflurane-nitrous oxide anesthesia prior to and on days 6, 10, 14 and 18 of pregnancy (term = day 19). Hepatic expression of clock genes and glucoregulatory genes was determined by RT-qPCR. Hepatic clock gene expression was substantially altered across pregnancy, most notably in late gestation when the circadian rhythmicity of several clock genes was attenuated (≤64% reduced amplitude on day 18). These changes were associated with a similar decline in rhythmicity of the key glucoregulatory genes Pck1, G6Pase, and Gk, and by day 18, Pck1 was no longer rhythmic. Overall, our data show marked adaptations in the liver clock during mouse pregnancy, changes that may contribute to the altered circadian variation in glucoregulatory genes near term. We propose that the observed reduction of daily oscillations in glucose metabolism ensure a sustained supply of glucose to meet the high demands of fetal growth. PMID:27406739

  11. Caffeic acid phenethyl amide improves glucose homeostasis and attenuates the progression of vascular dysfunction in Streptozotocin-induced diabetic rats

    PubMed Central

    2013-01-01

    Background Glucose intolerance and cardiovascular complications are major symptoms in patients with diabetes. Many therapies have proven beneficial in treating diabetes in animals by protecting the cardiovascular system and increasing glucose utilization. In this study, we evaluated the effects of caffeic acid phenethyl amide (CAPA) on glucose homeostasis and vascular function in streptozotocin (STZ)-induced type 1 diabetic rats. Methods Diabetes (blood glucose levels > 350 mg/dL), was induced in Wistar rats by a single intravenous injection of 60 mg/kg STZ. Hypoglycemic effects were then assessed in normal and type 1 diabetic rats. In addition, coronary blood flow in Langendorff-perfused hearts was evaluated in the presence or absence of nitric oxide synthase (NOS) inhibitor. The thoracic aorta was used to measure vascular response to phenylephrine. Finally, the effect of chronic treatment of CAPA and insulin on coronary artery flow and vascular response to phenylephrine were analyzed in diabetic rats. Results Oral administration of 0.1 mg/kg CAPA decreased plasma glucose in normal (32.9 ± 2.3% decrease, P < 0.05) and diabetic rats (11.8 ± 5.5% decrease, P < 0.05). In normal and diabetic rat hearts, 1–10 μM CAPA increased coronary flow rate, and this increase was abolished by 10 μM NOS inhibitor. In the thoracic aorta, the concentration/response curve of phenylephrine was right-shifted by administration of 100 μM CAPA. Coronary flow rate was reduced to 7.2 ± 0.2 mL/min at 8 weeks after STZ-induction. However, 4 weeks of treatment with CAPA (3 mg/kg, intraperitoneal, twice daily) started at 4 weeks after STZ induction increased flow rate to 11.2 ± 0.5 mL/min (P < 0.05). In addition, the contractile response induced by 1 μM phenylephrine increased from 6.8 ± 0.6 mN to 11.4 ± 0.4 mN (P < 0.05) and 14.9 ± 1.4 mN (P < 0.05) by insulin (1 IU/kg, intraperitoneal) or CAPA treatment, respectively. Conclusions CAPA induced hypoglycemic activity, increased

  12. Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM

    PubMed Central

    Ma, Dan; Shield, Julian P.H.; Dean, Wendy; Leclerc, Isabelle; Knauf, Claude; Burcelin, Rémy; Rutter, Guy A.; Kelsey, Gavin

    2004-01-01

    Transient neonatal diabetes mellitus (TNDM) is a rare inherited diabetic syndrome apparent in the first weeks of life and again during early adulthood. The relative contributions of reduced islet β cell number and impaired β cell function to the observed hypoinsulinemia are unclear. The inheritance pattern of this imprinted disorder implicates overexpression of one or both genes within the TNDM locus: ZAC, which encodes a proapoptotic zinc finger protein, and HYMAI, which encodes an untranslated mRNA. To investigate the consequences for pancreatic function, we have developed a high-copy transgenic mouse line, TNDM29, carrying the human TNDM locus. TNDM29 neonates display hyperglycemia, and older adults, impaired glucose tolerance. Neonatal hyperglycemia occurs only on paternal transmission, analogous to paternal dependence of TNDM in humans. Embryonic pancreata of TNDM29 mice showed reductions in expression of endocrine differentiation factors and numbers of insulin-staining structures. By contrast, β cell mass was normal or elevated at all postnatal stages, whereas pancreatic insulin content in neonates and peak serum insulin levels after glucose infusion in adults were reduced. Expression of human ZAC and HYMAI in these transgenic mice thus recapitulates key features of TNDM and implicates impaired development of the endocrine pancreas and β cell function in disease pathogenesis. PMID:15286800

  13. Abnormal transient rise in hepatic glucose production after oral glucose in non-insulin-dependent diabetic subjects.

    PubMed

    Thorburn, A; Litchfield, A; Fabris, S; Proietto, J

    1995-05-01

    A transient rise in hepatic glucose production (HGP) after an oral glucosa load has been reported in some insulin-resistant states such as in obese fa/fa Zucker rats. The aim of this study was to determine whether this rise in HGP also occurs in subjects with established non-insulin-dependent diabetes mellitus (NIDDM). Glucose kinetics were measured basally and during a double-label oral glucose tolerance test (OGTT) in 12 NIDDM subjects and 12 non-diabetic 'control' subjects. Twenty minutes after the glucose load, HGP had increased 73% above basal in the NIDDM subjects (7.29 +/- 0.52 to 12.58 +/- 1.86 mumol/kg/min, P < 0.02). A transient rise in glucagon (12 pg/ml above basal, P < 0.004) occurred at a similar time. In contrast, the control subjects showed no rise in HGP or plasma glucagon. HGP began to suppress 40-50 min after the OGTT in both the NIDDM and control subjects. A 27% increase in the rate of gut-derived glucose absorption was also observed in the NIDDM group, which could be the result of increased gut glucose absorption or decreased first pass extraction of glucose by the liver. Therefore, in agreement with data in animal models of NIDDM, a transient rise in HGP partly contributes to the hyperglycemia observed after an oral glucose load in NIDDM subjects. PMID:7587920

  14. Internalized racism, body fat distribution, and abnormal fasting glucose among African-Caribbean women in Dominica, West Indies.

    PubMed

    Butler, Cleve; Tull, Eugene S; Chambers, Earle C; Taylor, Jerome

    2002-03-01

    The current study examined the relationship of internalized racism to glucose intolerance in a population of Afro-Caribbean women aged 18 to 55. Also of interest was whether this relationship would be differentially influenced by the type of body fat distribution or confounded by the level of hostility. A total of 244 women were selected from a systematic sample of households on the island of Dominica, West Indies. Demographic data together with information on internalized racism were collected by questionnaire. Anthropometric information and fasting blood glucose were also measured. Women with high levels of internalized racism exhibited an increased risk of elevated fasting glucose compared to those with low levels of internalized racism (odds ratio (OR) = 2.4; 95% confidence interval (CI) = 1.1-5.5). There was no difference in mean body mass index (BMI) by level of internalized racism. However those with high internalized racism had a significantly larger waist circumference after adjusting for age, education, hostility, and elevated fasting glucose status. In multivariate analyses controlling for age, education, hostility, and either weight or BMI, internalized racism remained independently associated with elevated fasting glucose. However, once waist circumference was included in the model, the relationship of internalized racism to elevated fasting glucose was not statistically significant. This study demonstrates a significant relationship between internalized racism and abnormal levels of fasting glucose which may be mediated through abdominal fat. The exact nature of the relationship of internalized racism to glucose intolerance may be an important area of future study.

  15. 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

  16. Class IIa Histone Deacetylases are Hormone-activated regulators of FOXO and Mammalian Glucose Homeostasis

    PubMed Central

    Mihaylova, Maria M.; Vasquez, Debbie S.; Ravnskjaer, Kim; Denechaud, Pierre-Damien; Yu, Ruth T.; Alvarez, Jacqueline G.; Downes, Michael; Evans, Ronald M.; Montminy, Marc; Shaw, Reuben J.

    2011-01-01

    SUMMARY Class IIa histone deacetylases (HDACs) are signal-dependent modulators of transcription with established roles in muscle differentiation and neuronal survival. We show here that in liver, Class IIa HDACs (HDAC4, 5, and 7) are phosphorylated and excluded from the nucleus by AMPK family kinases. In response to the fasting hormone glucagon, Class IIa HDACs are rapidly dephosphorylated and translocated to the nucleus where they associate with the promoters of gluconeogenic enzymes such as G6Pase. In turn, HDAC4/5 recruit HDAC3, which results in the acute transcriptional induction of these genes via deacetylation and activation of Foxo family transcription factors. Loss of Class IIa HDACs in murine liver results in inhibition of FOXO target genes and lowers blood glucose, resulting in increased glycogen storage. Finally, suppression of Class IIa HDACs in mouse models of Type 2 Diabetes ameliorates hyperglycemia, suggesting that inhibitors of Class I/II HDACs may be potential therapeutics for metabolic syndrome. PMID:21565617

  17. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions.

    PubMed

    Kaneko, Kentaro; Xu, Pingwen; Cordonier, Elizabeth L; Chen, Siyu S; Ng, Amy; Xu, Yong; Morozov, Alexei; Fukuda, Makoto

    2016-09-13

    The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment. PMID:27626668

  18. Remote regulation of glucose homeostasis in mice using genetically encoded nanoparticles

    PubMed Central

    Kane, Ravi S; Dordick, Jonathan S; Friedman, Jeffrey M

    2016-01-01

    Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP–transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics. PMID:25501906

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

    PubMed Central

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

    2015-01-01

    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. PMID:25628336

  20. Oral vanadate and Tiron in treatment of diabetes mellitus in rats: improvement of glucose homeostasis and negative side-effects.

    PubMed

    Domingo, J L; Sanchez, D J; Gomez, M; Llobet, J M; Corbella, J

    1993-12-01

    It has been shown that improvement of glucose homeostasis by oral vanadate or vanadyl treatment in streptozotocin-induced diabetic rats is accompanied by severe negative side effects (some deaths, decreased weight gain, alteration in renal function as well as tissue vanadium accumulation) which argue against the use of vanadium compounds in diabetes treatment. The present study was undertaken to assess the effectiveness in alleviating some signs of diabetes in streptozotocin-treated rats with oral therapy with sodium metavanadate (NaVO3) and sodium 4,5 dihydroxybenzene-1,3-disulfonate (Tiron), a chelating agent effective in mobilizing vanadium. In a preliminary experiment, diabetic rats were given aqueous solutions of 0.20 mg NaVO3/ml for 4 days. Vanadium-treated rats which showed blood glucose levels significantly lower (p < 0.001) than vanadate-untreated diabetic rats were selected for subsequent experiments. These animals were given 0.20 mg NaVO3/ml in drinking water and 0, 125.6, 314 or 628 mg Tiron/kg/d by gavage for 2 w. Although most of the animals did not become normoglycemic, several characteristic signs of diabetes (hyperglycemia, hyperphagia and polydipsia) were alleviated by the NaVO3 treatment. The administration of 314 mg Tiron/kg/d (approximately 1 NaVO3: 5 Tiron, mole ratio) did not diminish the ameliorative effects of NaVO3 with respect to diabetes, but significantly decreased the level of vanadium accumulation in target organs. These results show that some of the beneficial effects of NaVO3 are maintained in diabetic animals given Tiron, while the administration of the chelator results in a significant decrease in tissue vanadium accumulation. Accordingly, this would diminish the possibility of toxic side effects derived from prolonged oral vanadium administration.

  1. 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

  2. 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. PMID:27035649

  3. 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. PMID:25628336

  4. 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

  5. Abnormal calcium homeostasis in heart failure with preserved ejection fraction is related to both reduced contractile function and incomplete relaxation: an electromechanically detailed biophysical modeling study

    PubMed Central

    Adeniran, Ismail; MacIver, David H.; Hancox, Jules C.; Zhang, Henggui

    2015-01-01

    Heart failure with preserved ejection fraction (HFpEF) accounts for about 50% of heart failure cases. It has features of incomplete relaxation and increased stiffness of the left ventricle. Studies from clinical electrophysiology and animal experiments have found that HFpEF is associated with impaired calcium homeostasis, ion channel remodeling and concentric left ventricle hypertrophy (LVH). However, it is still unclear how the abnormal calcium homeostasis, ion channel and structural remodeling affect the electro-mechanical dynamics of the ventricles. In this study we have developed multiscale models of the human left ventricle from single cells to the 3D organ, which take into consideration HFpEF-induced changes in calcium handling, ion channel remodeling and concentric LVH. Our simulation results suggest that at the cellular level, HFpEF reduces the systolic calcium level resulting in a reduced systolic contractile force, but elevates the diastolic calcium level resulting in an abnormal residual diastolic force. In our simulations, these abnormal electro-mechanical features of the ventricular cells became more pronounced with the increase of the heart rate. However, at the 3D organ level, the ejection fraction of the left ventricle was maintained due to the concentric LVH. The simulation results of this study mirror clinically observed features of HFpEF and provide new insights toward the understanding of the cellular bases of impaired cardiac electromechanical functions in heart failure. PMID:25852567

  6. The Hijacking of Cellular Signaling and the Diabetes Epidemic: Mechanisms of Environmental Disruption of Insulin Action and Glucose Homeostasis

    PubMed Central

    2014-01-01

    The burgeoning epidemic of metabolic disease causes significant societal and individual morbidity and threatens the stability of health care systems around the globe. Efforts to understand the factors that contribute to metabolic derangements are critical for reversing these troubling trends. While excess caloric consumption and physical inactivity superimposed on a susceptible genetic background are central drivers of this crisis, these factors alone fail to fully account for the magnitude and rapidity with which metabolic diseases have increased in prevalence worldwide. Recent epidemiological evidence implicates endocrine disrupting chemicals in the pathogenesis of metabolic diseases. These compounds represent a diverse array of chemicals to which humans are exposed via multiple routes in adulthood and during development. Furthermore, a growing ensemble of animal- and cell-based studies provides preclinical evidence supporting the hypothesis that environmental contaminants contribute to the development of metabolic diseases, including diabetes. Herein are reviewed studies linking specific endocrine disruptors to impairments in glucose homeostasis as well as tying these compounds to disturbances in insulin secretion and impairments in insulin signal transduction. While the data remains somewhat incomplete, the current body of evidence supports the hypothesis that our chemically polluted environment may play a contributing role in the current metabolic crisis. PMID:24627823

  7. Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis.

    PubMed

    Sadagurski, Marianna; Dong, X Charlie; Myers, Martin G; White, Morris F

    2014-02-01

    Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although Irs4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because Irs4-null mice barely distinguishable from controls. We postulated that Irs2 and Irs4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body Irs4(-/y) mice that lacked Irs2 in the CNS (bIrs2(-/-)·Irs4(-/y)) or only in LepRb-neurons (Lepr (∆Irs2) ·Irs4 (-/y) ). bIrs2(-/-)·Irs4(-/y) mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr (∆Irs2) ·Irs4 (-/y) mice were not different from Lepr (∆Irs2) mice, suggesting that the functions of Irs2 and Irs4 converge upon neurons that are distinct from those expressing LepRb.

  8. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM

    SciTech Connect

    Mitrakou, A.; Kelley, D.; Veneman, T.; Jenssen, T.; Pangburn, T.; Reilly, J.; Gerich, J. )

    1990-11-01

    To assess the role of muscle and liver in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), we administered an oral glucose load enriched with (14C)glucose to 10 NIDDM subjects and 10 age- and weight-matched nondiabetic volunteers and compared muscle glucose disposal by measuring forearm balance of glucose, lactate, alanine, O2, and CO2. In addition, we used the dual-lable isotope method to compare overall rates of glucose appearance (Ra) and disappearance (Rd), suppression of endogenous glucose output, and splanchnic glucose sequestration. During the initial 1-1.5 h after glucose ingestion, plasma glucose increased by approximately 8 mM in NIDDM vs. approximately 3 mM in nondiabetic subjects (P less than 0.01); overall glucose Ra was nearly 11 g greater in NIDDM than nondiabetic subjects, but glucose Rd was not significantly different in NIDDM and nondiabetic subjects. The greater overall glucose Ra of NIDDM subjects was due to 6.8 g greater endogenous glucose output (13.7 +/- 1.1 vs. 6.8 +/- 1.0 g, P less than 0.01) and 3.8 g less oral glucose splanchnic sequestration of the oral load (31.4 +/- 1.5 vs. 27.5 +/- 0.9 g, P less than 0.05). Although glucose taken up by muscle was not significantly different in NIDDM and nondiabetic subjects (39.3 +/- 3.5 vs. 41.0 +/- 2.5 g/5 h), a greater amount of the glucose taken up by muscle in NIDDM was released as lactate and alanine (11.7 +/- 1.0 vs. 5.2 +/- 0.3 g in nondiabetic subjects, P less than 0.01), and less was stored (11.7 +/- 1.3 vs. 16.9 +/- 1.5 g, P less than 0.05). We conclude that increased systemic glucose delivery, due primarily to reduced suppression of endogenous hepatic glucose output and, to a lesser extent, reduced splanchnic glucose sequestration, is the predominant factor responsible for postprandial hyperglycemia in NIDDM.

  9. Autocrine/paracrine function of nicotinic acid adenine dinucleotide phosphate (NAADP) for glucose homeostasis in pancreatic β-cells and adipocytes.

    PubMed

    Park, Kwang-Hyun; Kim, Byung-Ju; Shawl, Asif Iqbal; Han, Myung-Kwan; Lee, Hon Cheung; Kim, Uh-Hyun

    2013-12-01

    Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger for mobilizing Ca(2+) from intracellular stores in various cell types. Extracellular application of NAADP has been shown to elicit intracellular Ca(2+) signals, indicating that it is readily transported into cells. However, little is known about the functional role of this NAADP uptake system. Here, we show that NAADP is effectively transported into selected cell types involved in glucose homeostasis, such as adipocytes and pancreatic β-cells, but not the acinar cells, in a high glucose-dependent manner. NAADP uptake was inhibitable by Ned-19, a NAADP mimic; dipyridamole, a nucleoside inhibitor; or NaN3, a metabolic inhibitor or under Ca(2+)-free conditions. Furthermore, NAADP was found to be released from pancreatic islets upon stimulation by high glucose. Consistently, administration of NAADP to type 2 diabetic mice improved glucose tolerance. We propose that NAADP is functioning as an autocrine/paracrine hormone important in glucose homeostasis. NAADP is thus a potential antidiabetic agent with therapeutic relevance.

  10. Associations between Obstructive Sleep Apnea, Sleep Duration, and Abnormal Fasting Glucose. The Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Weng, Jia; Wang, Rui; Redline, Susan; Punjabi, Naresh M.; Patel, Sanjay R.

    2015-01-01

    Rationale: No data exist as to the role of ethnicity in the associations between obstructive sleep apnea (OSA), sleep duration, and metabolic dysfunction. Objectives: To examine links between OSA, objectively measured habitual sleep duration, and fasting glucose in U.S. ethnic groups. Methods: The Multi-Ethnic Study of Atherosclerosis is a multisite community-based study that conducted polysomnography and wrist actigraphy. In 2,151 subjects (1,839 in fully adjusted models), the apnea–hypopnea index was used to classify OSA as none (0–4.9/h), mild (5–14.9/h), or moderate to severe (≥15/h). Actigraphic sleep duration was classified as short (≤5 h/night), intermediate (>5 and <8 h/night), or long (≥8 h/night). Subjects were classified as having normal fasting glucose (<100 mg/dl and no hypoglycemic medication use) or abnormal fasting glucose (≥100 mg/dl and/or hypoglycemic medication use). Measurements and Main Results: The sample was 45.8% male, age 68.5 ± 9.2 (mean ± SD) years, and 27.3% African American, 37.2% white, 11.8% Chinese, and 23.8% Hispanic. The prevalence of abnormal fasting glucose was 40.2%. Relative to subjects without apnea, moderate-to-severe OSA was significantly associated with abnormal fasting glucose in African Americans (odds ratio, 2.14; 95% confidence interval, 1.12–4.08) and white participants (odds ratio, 2.85; 95% confidence interval, 1.20–6.75), but not among Chinese or Hispanic subjects, after adjusting for site, age, sex, waist circumference, and sleep duration (P = 0.06 for ethnicity-by-OSA severity interaction). In contrast, sleep duration was not significantly associated with abnormal fasting glucose after considering the influence of OSA. Conclusions: This large multiethnic study confirmed previous reports of an independent association between OSA and metabolic dysfunction, and suggested that this association may vary by ethnicity. PMID:26084035

  11. 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.

  12. A role for adipose tissue de novo lipogenesis in glucose homeostasis during catch-up growth: a Randle cycle favoring fat storage.

    PubMed

    Marcelino, Helena; Veyrat-Durebex, Christelle; Summermatter, Serge; Sarafian, Delphine; Miles-Chan, Jennifer; Arsenijevic, Denis; Zani, Fabio; Montani, Jean-Pierre; Seydoux, Josiane; Solinas, Giovanni; Rohner-Jeanrenaud, Françoise; Dulloo, Abdul G

    2013-02-01

    Catch-up growth, a risk factor for type 2 diabetes, is characterized by hyperinsulinemia and accelerated body fat recovery. Using a rat model of semistarvation-refeeding that exhibits catch-up fat, we previously reported that during refeeding on a low-fat diet, glucose tolerance is normal but insulin-dependent glucose utilization is decreased in skeletal muscle and increased in adipose tissue, where de novo lipogenic capacity is concomitantly enhanced. Here we report that isocaloric refeeding on a high-fat (HF) diet blunts the enhanced in vivo insulin-dependent glucose utilization for de novo lipogenesis (DNL) in adipose tissue. These are shown to be early events of catch-up growth that are independent of hyperphagia and precede the development of overt adipocyte hypertrophy, adipose tissue inflammation, or defective insulin signaling. These results suggest a role for enhanced DNL as a glucose sink in regulating glycemia during catch-up growth, which is blunted by exposure to an HF diet, thereby contributing, together with skeletal muscle insulin resistance, to the development of glucose intolerance. Our findings are presented as an extension of the Randle cycle hypothesis, whereby the suppression of DNL constitutes a mechanism by which dietary lipids antagonize glucose utilization for storage as triglycerides in adipose tissue, thereby impairing glucose homeostasis during catch-up growth.

  13. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications

    PubMed Central

    Gerich, J E

    2010-01-01

    Abstract Considerable data have accumulated over the past 20 years, indicating that the human kidney is involved in the regulation of glucose via gluconeogenesis, taking up glucose from the circulation, and by reabsorbing glucose from the glomerular filtrate. In light of the development of glucose-lowering drugs involving inhibition of renal glucose reabsorption, this review summarizes these data. Medline was searched from 1989 to present using the terms ‘renal gluconeogenesis’, ‘renal glucose utilization’, ‘diabetes mellitus’ and ‘glucose transporters’. The human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the post-absorptive state. In the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis increases by approximately twofold. Glucose utilization by the kidneys after an overnight fast accounts for ∼10% of glucose utilized by the body. Following a meal, glucose utilization by the kidney increases. Normally each day, ∼180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium–glucose co-transporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and, when plasma glucose concentrations exceed a threshold, glucose appears in the urine. Handling of glucose by the kidney is altered in Type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the post-absorptive and postprandial states, and renal glucose reabsorption is increased. Specific SGLT2 inhibitors are being developed as a novel means of controlling hyperglycaemia in T2DM. Diabet. Med. 27, 136–142 (2010) PMID:20546255

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

    PubMed Central

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

    2015-01-01

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

  15. 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.

  16. The Effects of Empagliflozin, an SGLT2 Inhibitor, on Pancreatic β-Cell Mass and Glucose Homeostasis in Type 1 Diabetes.

    PubMed

    Cheng, Sam Tsz Wai; Chen, Lihua; Li, Stephen Yu Ting; Mayoux, Eric; Leung, Po Sing

    2016-01-01

    The novel sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has recently been reported to improve glycemic control in streptozotocin-induced type 1 diabetic rats in an insulin-independent manner, via an increase in urinary glucose output. We investigated the potential of empagliflozin to recover insulin pathways in type 1 diabetes by improving pancreatic β-cell mass. Blood glucose homeostasis was assessed by an intraperitoneal glucose tolerance test. Serum insulin levels and insulin mRNA expression were determined using commercial insulin ELISA kits and real-time quantitative polymerase chain reaction, respectively. Immunohistochemistry was used to investigate β-cell areas, β-cell proliferation, apoptosis of pancreatic β-cells, and reactive oxygen species production in the pancreatic β-cells. Results showed that glucose tolerance was significantly improved in streptozotocin-induced type 1 diabetic mice treated with empagliflozin. Empagliflozin-treated mice also showed an increase in insulin mRNA expression. Higher serum insulin levels were detected in mice treated with empagliflozin compared with the vehicle group. Immunohistochemistry indicated that β-cell area/total pancreatic area and the expression of cell proliferation marker Ki-67 (co-stained with insulin) were significantly enhanced by empagliflozin treatment. These effects were due, probably, to a reduction in apoptosis and reactive oxygen species in the pancreatic β-cells. Taken together, the results of this study indicate that empagliflozin may have a beneficial effect on preserving β-cell regeneration, thus improving blood glucose homeostasis in type 1 diabetes mellitus, probably via the protection of pancreatic β-cell from glucotoxicity-induced oxidative stress. PMID:26807719

  17. Dietary intake, food pattern, and abnormal blood glucose status of middle-aged adults: a cross-sectional community-based study in Myanmar

    PubMed Central

    Hlaing, Hlaing Hlaing; Liabsuetrakul, Tippawan

    2016-01-01

    Background Lifestyle changes, particularly dietary intake, had resulted in increasing trends of type-2 diabetes mellitus worldwide. However, dietary intake is diverse across country contexts. This study aimed to compare the dietary intake, food patterns, and blood glucose among middle-aged adults living in urban and suburban areas in Mandalay city, Myanmar, and explore their relationships. Methods A cross-sectional community-based study was conducted during June–November 2014. Adults aged 35–64 were randomly selected and requested to record all food they ate in a 4-day diary. Fasting and 2-hour postprandial blood glucose values were measured over two consecutive days. Dietary intakes were calculated in terms of energy, macronutrients, glycemic index, and glycemic load, and food patterns were identified by factor analysis. The relationships between food pattern, dietary intake, and blood glucose were assessed. Results Of 440 participants, dietary intake between urban and suburban residents was significantly different. Six food patterns were identified. There was no difference in fasting and 2-hour postprandial blood glucose between urban and suburban residents, but a strong correlation between fasting blood glucose and 2-hour postprandial blood glucose was found (correlation coefficient=0.8). Identification of abnormal blood glucose status using original fasting and converted 2-hour postprandial values showed substantial agreement (prevalence-adjusted bias-adjusted Kappa=0.8). Relationships between food patterns and blood glucose or abnormal blood glucose status were not found. Conclusion Food patterns were associated with dietary intake, not with abnormal blood glucose status. Two-hour postprandial blood glucose was highly correlated with fasting blood glucose and may be used for identifying abnormal blood glucose status. PMID:27150795

  18. Clinical and biochemical characteristics of acromegalic patients with different abnormalities in glucose metabolism.

    PubMed

    Espinosa-de-los-Monteros, Ana Laura; González, Baldomero; Vargas, Guadalupe; Sosa, Ernesto; Mercado, Moisés

    2011-09-01

    To determine the prevalence of diabetes, glucose intolerance and impaired fasting glucose in Mexican patients with acromegaly and establish associations with clinical, anthropometric and biochemical variables. 257 patients with acromegaly were evaluated by a 75 g-oral glucose tolerance test with measurements of both GH and glucose (0, 30, 60, 90 120 min) as well as baseline IGF-1. Normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes (DM) were defined based on the 2003 ADA criteria. NGT, IFG, IGT and DM were found in 27.6, 8.9, 31.6 and 31.9% of the subjects, respectively; 42 of the DM patients were unaware of the diagnosis. Patients with diabetes were older than subjects in the other 3 categories (P = 0.001), and the proportion of women was significantly higher in the DM (74%) and IGT (68%) groups than in the NGT group (52%) (P = 0.004). Odds ratio for the development of DM was 3.29 (95% CI 3.28-3.3). GH and IGF-1 levels were comparable among the different groups. In a multivariable analysis DM was significantly associated with age, presence of a macroadenoma, disease duration and a basal GH > 30 μg/dl. DM and probably IGT are more prevalent in acromegaly than in the general Mexican population. DM was more frequent in females of all ages, in subjects with severely elevated GH concentrations, in patients with macroadenomas, and long-standing disease duration. The odds ratio for DM in our subjects with acromegaly is more than 3 times higher than in the general population.

  19. 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.

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

    PubMed

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

    2016-02-01

    At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a noncoding 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, while 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 control subjects. Compared with control subjects, 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 demonstrated 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.

  2. 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

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

    PubMed

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

    2016-09-01

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

  4. 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.

  5. Westernized-like-diet-fed rats: effect on glucose homeostasis, lipid profile, and adipocyte hormones and their modulation by rosiglitazone and glimepiride.

    PubMed

    Schaalan, Mona; El-Abhar, Hanan S; Barakat, Maged; El-Denshary, Ezzedin S

    2009-01-01

    Wersternized diet, containing high fat diet intake combined with high consumption of softdrinks, is accused with the emerge of modern epidemic obesity and diabesity. Therefore, we aimed to study the effect of this diet combination on the homeostasis of glucose, lipids, and some adipohormones in rats and to simulate the metabolic perturbations induced by the unhealthy Westernized diet intake, leading to the development of type 2 diabetes. To achieve this, we divided male Wistar rats (80-120 g) into two main groups: the first was fed commercial normal fat diet and the second received an in-house-prepared high-fat diet (HFD), combined with fructose in drinking water for a period of 6 weeks, followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg) to produce frank hyperglycemia. The effect of this diet alone or after 2 weeks of treatment with rosiglitazone or glimepiride on glucose homeostasis, lipid profile, and levels of resistin and leptin was studied. The HFD/fructose/STZ diet elevated fasting plasma glucose, fructosamine, insulin, and homeostasis model assessment (HOMA) index, as well as serum triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol, with a decrease in high-density lipoprotein cholesterol. Hepatic TG and TC levels, as well as serum activities of aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH), were increased, suggesting a diet-induced hepatic steatosis, beside the increased levels of serum resistin and leptin. Rosiglitazone corrected the altered parameters measured, except for liver TGs; similarly, glimepiride reinstated the inverted parameters but raised insulin level and, consequently, the HOMA index. These results show that this diet could be used to induce an effect that mimics human type 2 diabetes with its metabolic disturbances and is suitable for screening the antidiabetic agents used for management of this disease.

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

    PubMed

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

    2014-01-01

    Little is known about longitudinal associations between added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis among youth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n = 564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes were examined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage, energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer). Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fat mass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of added sugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higher fasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4 unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P < 0.01). No associations were observed with consumption of added sugars from solid sources. Overweight/obese children at baseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases in Matsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid or solid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor for the development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk of obesity. PMID:24198307

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

    PubMed

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

    2014-01-01

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

  8. Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.

    PubMed

    Blanco, Cynthia L; McGill-Vargas, Lisa L; Gastaldelli, Amalia; Seidner, Steven R; McCurnin, Donald C; Leland, Michelle M; Anzueto, Diana G; Johnson, Marney C; Liang, Hanyu; DeFronzo, Ralph A; Musi, Nicolas

    2015-03-01

    Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

  9. Effects of 2-, 4- and 12-hour fasting intervals on preoperative gastric fluid pH and volume, and plasma glucose and lipid homeostasis in children.

    PubMed

    Maekawa, N; Mikawa, K; Yaku, H; Nishina, K; Obara, H

    1993-11-01

    We evaluated 105 randomly-selected unpremedicated children aged 1-14 years to determine the effects of a 2-, 4- and 12-h preoperative fasting interval on the preoperative gastric fluid pH and volume, and plasma glucose and lipid homeostasis. Each child undergoing elective surgery ingested a large volume (approximately 10 ml/kg b.w.) of apple juice and then fasted for 2, 4 or 12 h before the estimated induction of anaesthesia. After induction of anaesthesia, gastric fluid was aspirated through a large-bore, multiorifice orogastric tube. Plasma concentrations of glucose, total ketone bodies, non-esterified fatty acid (NEFA), triglycerides, and cortisol were measured at the time of induction to evaluate the fasting interval effects on preoperative plasma glucose and lipid homeostasis. There were no significant differences between the three groups in either gastric fluid volume or pH. In addition, there were no significant differences between the groups with respect to the proportion with a pH < 2.5 and volume > 0.4 ml/kg b.w. Neither plasma concentrations of glucose, triglycerides, nor cortisol at the time of anaesthetic induction differed between the three groups. Both 4 and 12 h nil per os (NPO) caused an increase in lipolysis, which was presumably a compensatory mechanism to maintain normoglycaemia. The plasma NEFA and total ketone bodies concentrations were therefore significantly higher in these two fasting intervals than in 2 h NPO. These data suggest that a 2-h NPO, after a large volume of ingested apple juice, may offer additional benefits by preventing an increase in lipolysis during the fasting interval without either increasing the volume of gastric fluid or decreasing the gastric pH.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Alteration of JNK-1 Signaling in Skeletal Muscle Fails to Affect Glucose Homeostasis and Obesity-Associated Insulin Resistance in Mice

    PubMed Central

    Spohn, Gabriele; Brönneke, Hella S.; Schmidt-Supprian, Marc; Wunderlich, F. Thomas

    2013-01-01

    Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNKC). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNKC mice were crossed to Mck-Cre mice yielding JNKSM-C mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNKSM-C mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance. PMID:23349837

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

    PubMed

    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.

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

    PubMed

    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

  13. 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

  14. Possibility to predict early postpartum glucose abnormality following gestational diabetes mellitus based on the results of routine mid-gestational screening

    PubMed Central

    Bartáková, Vendula; Malúšková, Denisa; Mužík, Jan; Bělobrádková, Jana; Kaňková, Kateřina

    2015-01-01

    Introduction Women with previous gestational diabetes mellitus (GDM) have increased risk of developing glucose abnormality, but current diagnostic criteria are evidence-based for adverse pregnancy outcome. The aims of our study were: (i) to ascertain a frequency of early conversion of GDM into permanent glucose abnormality, (ii) to determine predictive potential of current GDM diagnostic criteria for prediction of postpartum glucose abnormality and (iii) to find optimal cut-off values of oral glucose tolerance test (oGTT) to stratify GDM population according to postpartum risk. Materials and methods Electronic medical records of an ethnically homogenous cohort of women diagnosed and treated for GDM in a single medical centre during the period 2005–2011 who completed postpartum oGTT up to 1 year after the index delivery were retrospectively analysed (N = 305). Results Postpartum glucose abnormality was detected in 16.7% subjects. Mid-trimester oGTT values, respective area under the curve and HbA1c were significantly associated with early postpartum glucose abnormality (P < 0.05, Mann-Whitney) and exhibited significant predictive potential for postpartum glucose abnormality risk assessment. Optimal cut-off values for discrimination of at-risk sub-population were identified using ROC analysis and their comparison with WHO and IADPSG criteria exhibited superiority of IADPSG for risk-stratification of GDM population. Conclusion Risk-based stratification at the time of GDM diagnosis could improve efficiency of the post-gestational screening for diabetes. IADPSG criteria seem to optimally capture both perinatal and maternal metabolic risks and are therefore medically and economically justified. PMID:26526166

  15. Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome

    PubMed Central

    Brown, Audrey E.; Jones, David E.; Walker, Mark; Newton, Julia L.

    2015-01-01

    Background Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects. Methods Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise. Results In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured. Conclusion EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets. PMID:25836975

  16. 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

  17. Diabetes mellitus type 2 and abnormal glucose metabolism in the setting of human immunodeficiency virus.

    PubMed

    Hadigan, Colleen; Kattakuzhy, Sarah

    2014-09-01

    As the modern era of combination antiretroviral therapy has increased life expectancy for individuals infected with the human immunodeficiency virus (HIV), type 2 diabetes mellitus and disorders of glucose metabolism have emerged as an important issue in the care of this population. Multiple mechanisms, both specific and nonspecific to HIV, underlie a significant prevalence. Although best-practice diagnostic testing remains unclear, the risks associated with diabetes in the setting of HIV are well characterized, ranging from organ-specific damage to socioeconomic decline. As population-specific treatment data are limited, current guidelines serve as a basis for ongoing management.

  18. 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.

  19. 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.

  20. Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson’s patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

    PubMed Central

    Ray, Nicola J.; Miyasaki, Janis M.; Zurowski, Mateusz; Ko, Ji Hyun; Cho, Sang Soo; Pellecchia, Giovanna; Antonelli, Francesca; Houle, Sylvain; Lang, Anthony E.; Strafella, Antonio P.

    2012-01-01

    Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson’s disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait. PMID:22766031

  1. Heart Rate Variability, Ambient Particulate Matter Air Pollution, and Glucose Homeostasis: The Environmental Epidemiology of Arrhythmogenesis in the Women's Health Initiative

    PubMed Central

    Quibrera, P. Miguel; Christ, Sharon L.; Liao, Duanping; Prineas, Ronald J.; Anderson, Garnet L.; Heiss, Gerardo

    2009-01-01

    Metabolic neuropathophysiology underlying the prediabetic state may confer susceptibility to the adverse health effects of ambient particulate matter <10 μm in diameter (PM10). The authors therefore examined whether impaired glucose homeostasis modifies the effect of PM10 on heart rate variability in a stratified, random sample of 4,295 Women's Health Initiative clinical trial participants, among whom electrocardiograms and fasting blood draws were repeated at 3-year intervals from 1993 to 2004. In multilevel, mixed models weighted for sampling design and adjusted for clinical and environmental covariables, PM10 exposure was inversely associated with heart rate variability. Inverse PM10–heart rate variability associations were strongest for the root mean square of successive differences in normal-to-normal RR intervals (RMSSD). Among participants with impaired fasting glucose, there were −8.3% (95% confidence interval: −13.9, −2.4) versus −0.6% (95% confidence interval: −2.4, 1.3), −8.4% (95% confidence interval: −13.8, −2.7) versus −0.3% (95% confidence interval: −2.1, 1.6), and −4.3% (95% confidence interval: −9.4, 1.0) versus −0.8% (95% confidence interval: −2.7, 1.0) decreases in the RMSSD per 10-μg/m3 increase in PM10 at high versus low levels of insulin (P < 0.01), insulin resistance (P < 0.01), and glucose (P = 0.16), respectively. These associations were stronger among participants with diabetes and weaker among those without diabetes or impaired fasting glucose. The findings suggest that insulin and insulin resistance exacerbate the adverse effect of PM10 on cardiac autonomic control and thus risk of coronary heart disease among nondiabetic, postmenopausal women with impaired fasting glucose. PMID:19208727

  2. 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

  3. 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.

  4. Dietary antioxidants: Do they have a role to play in the ongoing fight against abnormal glucose metabolism?

    PubMed

    Avignon, Antoine; Hokayem, Marie; Bisbal, Catherine; Lambert, Karen

    2012-07-01

    Overfeeding, an increased intake of saturated fatty acids, and sugary foods are key dietary changes that have occurred in recent decades in addition to the emergence of the obesity epidemic. In addition to an increase in energy storage as fat, these dietary changes are accompanied by an increase in mitochondrial macronutrient oxidation, leading to an excessive free radical production and, hence, oxidative stress. The latter has long been considered a central mechanism linking nutrient overload, insulin resistance, the metabolic syndrome, and diabetes. However, food, through fruit and vegetable consumption, also can be a great source of antioxidants that protect the body against oxidative damage and insulin resistance and thus help cope with the metabolic backlash of the energy-dense Westernized diet. Experimental data are in favor of the beneficial role conveyed by antioxidants in glucose metabolism, but clinical data in humans remain controversial. This review therefore aimed to sort out any underlying discrepancies and provide an overall clear view of the role of antioxidants in the ongoing fight against abnormal glucose metabolism.

  5. Quetiapine Inhibits Microglial Activation by Neutralizing Abnormal STIM1-Mediated Intercellular Calcium Homeostasis and Promotes Myelin Repair in a Cuprizone-Induced Mouse Model of Demyelination

    PubMed Central

    Wang, Hanzhi; Liu, Shubao; Tian, Yanping; Wu, Xiyan; He, Yangtao; Li, Chengren; Namaka, Michael; Kong, Jiming; Li, Hongli; Xiao, Lan

    2015-01-01

    Microglial activation has been considered as a crucial process in the pathogenesis of neuroinflammation and psychiatric disorders. Several antipsychotic drugs (APDs) have been shown to display inhibitory effects on microglial activation in vitro, possibly through the suppression of elevated intracellular calcium (Ca2+) concentration. However, the exact underlying mechanisms still remain elusive. In this study, we aimed to investigate the inhibitory effects of quetiapine (Que), an atypical APD, on microglial activation. We utilized a chronic cuprizone (CPZ)-induced demyelination mouse model to determine the direct effect of Que on microglial activation. Our results showed that treatment with Que significantly reduced recruitment and activation of microglia/macrophage in the lesion of corpus callosum and promoted remyelination after CPZ withdrawal. Our in vitro studies also confirmed the direct effect of Que on lipopolysaccharide (LPS)-induced activation of microglial N9 cells, whereby Que significantly inhibited the release of nitric oxide (NO) and tumor necrosis factor α (TNF-α). Moreover, we demonstrated that pretreatment with Que, neutralized the up-regulation of STIM1 induced by LPS and declined both LPS and thapsigargin (Tg)-induced store-operated Ca2+ entry (SOCE). Finally, we found that pretreatment with Que significantly reduced the translocation of nuclear factor kappa B (NF-κB) p65 subunit from cytoplasm to nuclei in LPS-activated primary microglial cells. Overall, our data suggested that Que may inhibit microglial activation by neutralization of the LPS-induced abnormal STIM1-mediated intercellular calcium homeostasis. PMID:26732345

  6. 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. PMID:26211813

  7. 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.

  8. 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.

  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

    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...

  10. Shifting from glucose diagnosis to the new HbA1c diagnosis reduces the capability of the Finnish Diabetes Risk Score (FINDRISC) to screen for glucose abnormalities within a real-life primary healthcare preventive strategy

    PubMed Central

    2013-01-01

    Background To investigate differences in the performance of the Finnish Diabetes Risk Score (FINDRISC) as a screening tool for glucose abnormalities after shifting from glucose-based diagnostic criteria to the proposed new hemoglobin (Hb)A1c-based criteria. Methods A cross-sectional primary-care study was conducted as the first part of an active real-life lifestyle intervention to prevent type 2 diabetes within a high-risk Spanish Mediterranean population. Individuals without diabetes aged 45-75 years (n = 3,120) were screened using the FINDRISC. Where feasible, a subsequent 2-hour oral glucose tolerance test and HbA1c test were also carried out (n = 1,712). The performance of the risk score was calculated by applying the area under the curve (AUC) for the receiver operating characteristic, using three sets of criteria (2-hour glucose, fasting glucose, HbA1c) and three diagnostic categories (normal, pre-diabetes, diabetes). Results Defining diabetes by a single HbA1c measurement resulted in a significantly lower diabetes prevalence (3.6%) compared with diabetes defined by 2-hour plasma glucose (9.2%), but was not significantly lower than that obtained using fasting plasma glucose (3.1%). The FINDRISC at a cut-off of 14 had a reasonably high ability to predict diabetes using the diagnostic criteria of 2-hour or fasting glucose (AUC = 0.71) or all glucose abnormalities (AUC = 0.67 and 0.69, respectively). When HbA1c was used as the primary diagnostic criterion, the AUC for diabetes detection dropped to 0.67 (5.6% reduction in comparison with either 2-hour or fasting glucose) and fell to 0.55 for detection of all glucose abnormalities (17.9% and 20.3% reduction, respectively), with a relevant decrease in sensitivity of the risk score. Conclusions A shift from glucose-based diagnosis to HbA1c-based diagnosis substantially reduces the ability of the FINDRISC to screen for glucose abnormalities when applied in this real-life primary-care preventive strategy. PMID

  11. Deficiency in apolipoprotein A-I ablates the pharmacological effects of metformin on plasma glucose homeostasis and hepatic lipid deposition.

    PubMed

    Karavia, Eleni A; Hatziri, Aikaterini; Kalogeropoulou, Christina; Papachristou, Nikolaos I; Xepapadaki, Eva; Constantinou, Caterina; Natsos, Anastasios; Petropoulou, Peristera-Ioanna; Sasson, Shlomo; Papachristou, Dionysios J; Kypreos, Kyriakos E

    2015-11-01

    Recently, we showed that deficiency in apolipoprotein A-I (ApoA-I) sensitizes mice to diet-induced obesity, glucose intolerance and NAFLD. Here we investigated the potential involvement of ApoA-I in the pharmacological effects of metformin on glucose intolerance and NAFLD development. Groups of apoa1-deficient (apoa1(-/-)) and C57BL/6 mice fed western-type diet were either treated with a daily dose of 300 mg/kg metformin for 18 weeks or left untreated for the same period. Then, histological and biochemical analyses were performed. Metformin treatment led to a comparable reduction in plasma insulin levels in both C57BL/6 and apoa1(-/-) mice following intraperitoneal glucose tolerance test. However, only metformin-treated C57BL/6 mice maintained sufficient peripheral insulin sensitivity to effectively clear glucose following the challenge, as indicated by a [(3)H]-2-deoxy-D-glucose uptake assay in isolated soleus muscle. Similarly, deficiency in ApoA-I ablated the effect of metformin on hepatic lipid deposition and NAFLD development. Gene expression analysis indicated that the effects of ApoA-I on metformin treatment may be independent of adenosine monophosphate-activated protein kinase (AMPK) activation and de novo lipogenesis. Interestingly, metformin treatment reduced mitochondrial oxidative phosphorylation function only in apoa1(-/-) mice. Our data show that the role of ApoA-I in diabetes extends to the modulation of the pharmacological actions of metformin, a common drug for the treatment of type 2 diabetes.

  12. 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. PMID:26827797

  13. L-asparaginase-induced abnormality in plasma glucose level in patients of acute lymphoblastic leukemia admitted to a tertiary care hospital of Odisha

    PubMed Central

    Panigrahi, Mousumee; Swain, Trupti Rekha; Jena, Rabindra Kumar; Panigrahi, Ashutosh

    2016-01-01

    Objectives: The objective of this study was to evaluate any abnormal change in plasma glucose levels in patients treated with L-asparaginase (L-Asp)-based chemotherapy regimen in patients of acute lymphoblastic leukemia (ALL). Materials and Methods: This retrospective, hospital-based study was conducted in patients of ALL, admitted to the Clinical Haematology Department of a tertiary care hospital of Odisha from August 2014 to July 2015. Indoor records of 146 patients on multi-centered protocol-841 were evaluated for any alteration in plasma glucose level, time of onset of hypo/hyperglycemia, and persistence of plasma glucose alteration. Results: Twenty-one percent of patients showed abnormal plasma glucose level. Most of these patients developed hypoglycemia and were of lower age group. Most of these patients developed hypoglycemia and were of lower age group, whereas a majority of higher age group patients developed hyperglycemia. In majority of the cases, abnormal glucose developed after three doses of L-Asp. Hypoglycemia subsided whereas hyperglycemia persisted till the end of our observation period. Conclusions: L-Asp produces more incidences of hypoglycemia than hyperglycemia in a good number of ALL patients towards which clinicians should be more vigilant. However, hyperglycemia persists for a longer duration than hypoglycemia. PMID:27721550

  14. 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.

  15. 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.

  16. Effects of the Soluble Fiber Complex PolyGlycopleX® on Glucose Homeostasis and Body Weight in Young Zucker Diabetic Rats

    PubMed Central

    Grover, Gary James; Koetzner, Lee; Wicks, Joan; Gahler, Roland J.; Lyon, Michael R.; Reimer, Raylene A.; Wood, Simon

    2011-01-01

    Dietary fiber can reduce insulin resistance, body weight, and hyperlipidemia depending on fiber type, water solubility, and viscosity. PolyGlycopleX® (PGX®) is a natural, novel water soluble, non-starch polysaccharide complex that with water forms a highly viscous gel compared to other naturally occurring dietary fiber. We determined the effect of dietary PGX® vs. cellulose and inulin on the early development of insulin resistance, body weight, hyperlipidemia, and glycemia-induced tissue damage in young Zucker diabetic rats (ZDFs) in fasted and non-fasted states. ZDFs (5 weeks old) were fed a diet containing 5% (wgt/wgt) cellulose, inulin, or PGX® for 8 weeks. Body weight, lipids, insulin, and glucose levels were determined throughout the study and homeostasis model assessment (HOMA) was used to measure insulin sensitivity throughout the study in fasted animals. At study termination, insulin sensitivity (oral glucose tolerance test, OGTT) and kidney, liver, and pancreatic histopathology were determined. Body weight and food intake were significantly reduced by PGX® vs. inulin and cellulose. Serum insulin in fasted and non-fasted states was significantly reduced by PGX® as was non-fasted blood glucose. Insulin resistance, measured as a HOMA score, was significantly reduced by PGX® in weeks 5 through 8 as well as terminal OGTT scores in fed and fasted states. Serum total cholesterol was also significantly reduced by PGX®. PGX® significantly reduced histological kidney and hepatic damage in addition to reduced hepatic steatosis and cholestasis. A greater mass of pancreatic β-cells was found in the PGX® group. PGX® therefore may be a useful dietary additive in the control of the development of the early development of the metabolic syndrome. PMID:21922008

  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

    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.

  18. Experimental study on effect of hydroalcoholic extract of Emblica officinalis fruits on glucose homeostasis and metabolic parameters.

    PubMed

    Patel, Snehal S; Goyal, Ramesh K; Shah, Rajendra S; Tirgar, Pravin R; Jadav, Pinakin D

    2013-10-01

    Polyphenols from natural source are potential therapeutics that act alone or supplement anti-diabetic drugs in the prevention and treatment of diabetes. The present investigation was undertaken to study the effect of hydroalcoholic extract (HE) of fruits of Emblica officinalis on type 1 diabetic rats. Diabetes was induced by streptozotocin (STZ) (45 mg/kg i.v.). HE (100 mg/kg, p.o.) was administered for 4 weeks and at the end of treatment, blood samples were collected and analyzed for various biochemical parameters. STZ produced a diabetic state exhibiting all the cardinal symptoms such as loss of body weight, polydipsia, polyuria, glucosuria, polyphagia, hypoinsulinemia, and hyperglycemia associated with hypercholesterolemia and hypertriglyceridemia. Treatment with HE prevented cardinal symptoms and caused significant decrease in fasting serum glucose, AUCglucose, cholesterol, triglyceride, low-density lipoprotein (LDL) and very LDL in diabetic rats. However, insulin, AUCinsulin, and serum high-density lipoprotein level were not significantly altered by treatment. Treatment also reduced lipid peroxidation and increased anti-oxidant parameters in the liver homogenates of diabetic rats. Polyphenol enriched fraction of HE significantly improved disarranged carbohydrate and lipid metabolism of chemically induced diabetes in rats. The mechanism of its anti-diabetic activity appears to be either improvement in peripheral glucose utilization, increased insulin sensitivity, or anti-oxidant property. PMID:24696584

  19. Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis.

    PubMed

    Jin, Tianru

    2016-06-01

    The role of the Wnt signaling pathway in metabolic homeostasis has drawn our intensive attention, especially after the genome-wide association study discovery that certain polymorphisms of its key effector TCF7L2 are strongly associated with the susceptibility to type 2 diabetes. For a decade, great efforts have been made in determining the function of TCF7L2 in various metabolic organs, which have generated both considerable achievements and disputes. In this review, I will briefly introduce the canonical Wnt signaling pathway, focusing on its effector β-catenin/TCF, including emphasizing the bidirectional feature of TCFs and β-catenin post-translational modifications. I will then summarize the observations on the association between TCF7L2 polymorphisms and type 2 diabetes risk. The main content, however, is on the intensive functional exploration of the metabolic role of TCF7L2, including the disputes generated on determining its role in the pancreas and liver with various transgenic mouse lines. Finally, I will discuss those achievements and disputes and present my future perspectives. PMID:27159876

  20. 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

  1. 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

  2. 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.

  3. 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 Central

    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.

    2013-01-01

    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 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. PMID:23255780

  4. Salidroside improves glucose homeostasis in obese mice by repressing inflammation in white adipose tissues and improving leptin sensitivity in hypothalamus

    PubMed Central

    Wang, Meihong; Luo, Lan; Yao, Lili; Wang, Caiping; Jiang, Ketao; Liu, Xiaoyu; Xu, Muchen; Shen, Ningmei; Guo, Shaodong; Sun, Cheng; Yang, Yumin

    2016-01-01

    Salidroside is a functionally versatile natural compound from the perennial flowering plant Rhodiola rosea L. Here, we examined obese mice treated with salidroside at the dosage of 50 mg/kg/day for 48 days. Mice treated with salidroside showed slightly decreased food intake, body weight and hepatic triglyceride content. Importantly, salidroside treatment significantly improved glucose and insulin tolerance. It also increased insulin singling in both liver and epididymal white adipose tissue (eWAT). In addition, salidroside markedly ameliorated hyperglycemia in treated mice, which is likely due to the suppression of gluconeogenesis by salidroside as the protein levels of a gluconeogenic enzyme G6Pase and a co-activator PGC-1α were all markedly decreased. Further analysis revealed that adipogenesis in eWAT was significantly decreased in salidroside treated mice. The infiltration of macrophages in eWAT and the productions of pro-inflammatory cytokines were also markedly suppressed by salidroside. Furthermore, the leptin signal transduction in hypothalamus was improved by salidroside. Taken together, these euglycemic effects of salidroside may due to repression of adipogenesis and inflammation in eWAT and stimulation of leptin signal transduction in hypothalamus. Thus, salidroside might be used as an effective anti-diabetic agent. PMID:27145908

  5. 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

  6. Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain β-Cell Function and Glucose Homeostasis.

    PubMed

    Han, Jaeseok; Song, Benbo; Kim, Jiun; Kodali, Vamsi K; Pottekat, Anita; Wang, Miao; Hassler, Justin; Wang, Shiyu; Pennathur, Subramaniam; Back, Sung Hoon; Katze, Michael G; Kaufman, Randal J

    2015-08-01

    Proinsulin misfolding in the endoplasmic reticulum (ER) initiates a cell death response, although the mechanism(s) remains unknown. To provide insight into how protein misfolding may cause β-cell failure, we analyzed mice with the deletion of P58(IPK)/DnajC3, an ER luminal co-chaperone. P58(IPK-/-) mice become diabetic as a result of decreased β-cell function and mass accompanied by induction of oxidative stress and cell death. Treatment with a chemical chaperone, as well as deletion of Chop, improved β-cell function and ameliorated the diabetic phenotype in P58(IPK-/-) mice, suggesting P58(IPK) deletion causes β-cell death through ER stress. Significantly, a diet of chow supplemented with antioxidant dramatically and rapidly restored β-cell function in P58(IPK-/-) mice and corrected abnormal localization of MafA, a critical transcription factor for β-cell function. Antioxidant feeding also preserved β-cell function in Akita mice that express mutant misfolded proinsulin. Therefore defective protein folding in the β-cell causes oxidative stress as an essential proximal signal required for apoptosis in response to ER stress. Remarkably, these findings demonstrate that antioxidant feeding restores cell function upon deletion of an ER molecular chaperone. Therefore antioxidant or chemical chaperone treatment may be a promising therapeutic approach for type 2 diabetes.

  7. 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

  8. GPR39, a receptor of the ghrelin receptor family, plays a role in the regulation of glucose homeostasis in a mouse model of early onset diet-induced obesity.

    PubMed

    Verhulst, P J; Lintermans, A; Janssen, S; Loeckx, D; Himmelreich, U; Buyse, J; Tack, J; Depoortere, I

    2011-06-01

    GPR39, which may function as a Zn(2+) sensor, is a member of the G protein-coupled receptor family that also includes the receptor for the hunger hormone ghrelin. The down-regulation of GPR39 mRNA in adipose tissue of obese type 2 diabetic patients suggests that GPR39 may contribute to the pathogenesis of the disease. The present study aimed to investigate the role of GPR39 in the regulation of energy balance and glucose homeostasis in wild-type (GPR39(+/+) ) and GPR39 knockout mice (GPR39(-/-) ) with obesity-related type 2 diabetes. GPR39 mRNA levels in adipose tissue of fasted GPR39(+/+) mice fed a high-fat diet (HFD) for 30 weeks were reduced and correlated positively with blood glucose levels. Body weight, fat percentage and energy intake were increased in the HFD group but did not differ between both genotypes. Within the HFD group, blood glucose levels were lower in GPR39(-/-) than in GPR39(+/+) mice, despite significant reductions in prandial plasma insulin levels. The latter may not be a result of changes in β-cell hyperplasia because immunohistochemical staining of pancreata of mice on a HFD showed no differences between genotypes. The lower blood glucose levels may involve alterations in insulin sensitivity as revealed by glucose tolerance tests and respiratory quotient measurements that showed a preference of obese GPR39(-/-) mice for the use of carbohydrates as metabolic fuel. The increase in plasma ghrelin levels in GPR39(-/-) mice fed a HFD may contribute to the alterations in glucose homeostasis, whereas changes in gastric emptying or intestinal Zn(2+) absorption are not involved. The results obtained in the present study suggest that GPR39 plays a role in the pathogenesis of obesity-related type 2 diabetes by affecting the regulation of glucose homeostasis. PMID:21470317

  9. Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis.

    PubMed

    Kumar, Divya P; Asgharpour, Amon; Mirshahi, Faridoddin; Park, So Hyun; Liu, Sichen; Imai, Yumi; Nadler, Jerry L; Grider, John R; Murthy, Karnam S; Sanyal, Arun J

    2016-03-25

    The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic β cells by bile acids induces insulin secretion. Glucagon released from pancreatic α cells and glucagon-like peptide 1 (GLP-1) released from intestinal L cells regulate insulin secretion. Both glucagon and GLP-1 are derived from alternate splicing of a common precursor, proglucagon by PC2 and PC1, respectively. We investigated whether TGR5 activation in pancreatic α cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases β cell mass and function in a paracrine manner. TGR5 activation augmented a hyperglycemia-induced switch from glucagon to GLP-1 synthesis in human and mouse islet α cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from α cells was via an Epac-mediated PKA-independent mechanism. Administration of the TGR5 agonist, INT-777, to db/db mice attenuated the increase in body weight and improved glucose tolerance and insulin sensitivity. INT-777 augmented PC1 expression in α cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic β cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from α cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between α and β cells by switching from glucagon to GLP-1 to restore β cell mass and function under hyperglycemic conditions. Thus, INT-777-mediated TGR5 activation could be leveraged as a novel way to treat type 2 diabetes mellitus. PMID:26757816

  10. Maternal flaxseed oil intake during lactation changes body fat, inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism.

    PubMed

    Guarda, Deysla Sabino; de Moura, Egberto Gaspar; Carvalho, Janaíne Cavalcanti; Reis, Adelina Martha Dos; Soares, Patricia Novaes; Lisboa, Patricia Cristina; Figueiredo, Mariana Sarto

    2016-09-01

    We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1β and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1β expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny.

  11. Maternal flaxseed oil intake during lactation changes body fat, inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism.

    PubMed

    Guarda, Deysla Sabino; de Moura, Egberto Gaspar; Carvalho, Janaíne Cavalcanti; Reis, Adelina Martha Dos; Soares, Patricia Novaes; Lisboa, Patricia Cristina; Figueiredo, Mariana Sarto

    2016-09-01

    We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1β and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1β expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny. PMID:27469994

  12. 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

  13. Burden and Socio-Behavioral Correlates of Uncontrolled Abnormal Glucose Metabolism in an Urban Population of India

    PubMed Central

    Mahapatra, Tanmay; Chakraborty, Kaushik; Mahapatra, Sanchita; Mahapatra, Umakanta; Pandey, Naren; Thomson, Peter L.; Musk, Arthur W.; Mitra, Ramendra N.

    2016-01-01

    Background Progressive burden of diabetes mellitus is a major concern in India. Data on the predictors of poor glycemic control among diabetics are scanty. A population-based cross-sectional study nested in an urban cohort was thus conducted in West Bengal, India to determine the burden and correlates of total and uncontrolled abnormalities in glucose metabolism (AGM) in a representative population. Methods From 9046 adult cohort-members, 269 randomly selected consenting subjects (non-response = 7.24%) were interviewed, examined [blood pressure (BP), anthropometry], tested for fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1C). Those having pre-diagnosed diabetes or FPG ≥126 or HbA1c≥6.5 were defined as diabetic. Among non-diabetics, subjects with FPG (mg/dl) = 100–125 or HbA1C(%) = 5.7–6.4 were defined as pre-diabetic. Pre-diagnosed cases with current FPG ≥126 were defined as uncontrolled AGM. Descriptive and regression analyses were conducted using SAS-9.3.2. Results Among participants, 28.62% [95% Confidence Interval (95%CI) = 23.19–34.06)] were overweight [body mass index(BMI) = (25–29.99)kg/meter2], 7.81% (4.58–11.03) were obese(BMI≥30kg/meter2), 20.82% (15.93–25.70) were current smokers, 12.64% (8.64–16.64) were current alcohol-drinkers and 46.32% of responders (39.16–53.47) had family history of diabetes. 17.84% (13.24–22.45) had stage-I [140≤average systolic BP (AvSBP in mm of mercury)<160 or 90≤average diastolic BP (AvDBP)<100] and 12.64% (8.64–16.64) had stage-II (AvSBP≥160 or AvDBP≥160) hypertension. Based on FPG and HbA1c, 10.41% (6.74–14.08) were diabetic and 27.88% (22.49–33.27) were pre-diabetic. Overall prevalence of diabetes was 15.61% (11.25–19.98). Among pre-diagnosed cases, 46.43% (26.74–66.12) had uncontrolled AGM. With one year increase in age [Odds Ratio(OR) = 1.05(1.03–1.07)], retired subjects [OR = 9.14(1.72–48.66)], overweight[OR = 2.78(1.37–5.64)], ex-drinkers [OR = 4

  14. 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

  15. Valine Pyrrolidide Preserves Intact Glucose-Dependent Insulinotropic Peptide and Improves Abnormal Glucose Tolerance in Minipigs With Reduced β-Cell Mass

    PubMed Central

    Rolin, Bidda; Ribel, Ulla; Wilken, Michael; Deacon, Carolyn F.; Svendsen, Ove; Gotfredsen, Carsten F.; Carr, Richard David

    2003-01-01

    The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation.However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced β-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)–treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg).VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 ± 1880 to 9208 ± 3267 pM × min; P<.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 ± 480 to 1582 ± 353 mM × min;P = .05).VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 ± 42 to 192 ± 108; P < .05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced β-cell mass. PMID:14630571

  16. Involvement of ABA- and H2O2-dependent cytosolic glucose-6-phosphate dehydrogenase in maintaining redox homeostasis in soybean roots under drought stress.

    PubMed

    Wang, Huahua; Yang, Lidan; Li, Yan; Hou, Junjie; Huang, Junjun; Liang, Weihong

    2016-10-01

    The roles of abscisic acid (ABA) and hydrogen peroxide (H2O2) in inducing glucose-6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49) activity and the possible roles of G6PDH in regulating ascorbate-glutathione (AsA-GSH) cycle were investigated in soybean (Glycine max L.) roots under drought stress. Drought caused a marked increase of the total and cytosolic G6PDH activities and triggered a rapid ABA and H2O2 accumulation in soybean roots. Exogenous ABA or H2O2 treatment elevated the total and cytosolic G6PDH activities, whereas suppressing ABA or H2O2 production inhibited the drought-induced increase in total and cytosolic G6PDH activities, suggesting that ABA and H2O2 are required for drought-induced increase of total G6PDH activity, namely cytosolic G6PDH activity. Furthermore, ABA induced H2O2 production by stimulating NADPH oxidase activity under drought stress. Moreover, drought significantly increased the contents of AsA and GSH and the activities of key enzymes in AsA-GSH cycle, while application of G6PDH inhibitor to seedlings significantly reduced the above effect induced by drought. Taken together, these results indicate that H2O2 acting as a downstream signaling molecule of ABA mediates drought-induced increase in cytosolic G6PDH activity, and that enhanced cytosolic G6PDH activity maintains cellular redox homeostasis by regulating AsA-GSH cycle in soybean roots. PMID:27285781

  17. Involvement of ABA- and H2O2-dependent cytosolic glucose-6-phosphate dehydrogenase in maintaining redox homeostasis in soybean roots under drought stress.

    PubMed

    Wang, Huahua; Yang, Lidan; Li, Yan; Hou, Junjie; Huang, Junjun; Liang, Weihong

    2016-10-01

    The roles of abscisic acid (ABA) and hydrogen peroxide (H2O2) in inducing glucose-6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49) activity and the possible roles of G6PDH in regulating ascorbate-glutathione (AsA-GSH) cycle were investigated in soybean (Glycine max L.) roots under drought stress. Drought caused a marked increase of the total and cytosolic G6PDH activities and triggered a rapid ABA and H2O2 accumulation in soybean roots. Exogenous ABA or H2O2 treatment elevated the total and cytosolic G6PDH activities, whereas suppressing ABA or H2O2 production inhibited the drought-induced increase in total and cytosolic G6PDH activities, suggesting that ABA and H2O2 are required for drought-induced increase of total G6PDH activity, namely cytosolic G6PDH activity. Furthermore, ABA induced H2O2 production by stimulating NADPH oxidase activity under drought stress. Moreover, drought significantly increased the contents of AsA and GSH and the activities of key enzymes in AsA-GSH cycle, while application of G6PDH inhibitor to seedlings significantly reduced the above effect induced by drought. Taken together, these results indicate that H2O2 acting as a downstream signaling molecule of ABA mediates drought-induced increase in cytosolic G6PDH activity, and that enhanced cytosolic G6PDH activity maintains cellular redox homeostasis by regulating AsA-GSH cycle in soybean roots.

  18. Abnormal glucose tolerance and insulin resistance in polycystic ovary syndrome amongst the Taiwanese population- not correlated with insulin receptor substrate-1 Gly972Arg/Ala513Pro polymorphism

    PubMed Central

    Lin, Ta-Chin; Yen, Jui-Mei; Gong, Kum-Bing; Kuo, Tsung-Cheng; Ku, Dong-Chi; Liang, Shu-Fen; Wu, Ming-Jiuan

    2006-01-01

    Background Insulin resistance and glucose dysmetabolism in polycystic ovary syndrome (PCOS) are related with the polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, especially Gly972Arg/Ala513Pro polymorphism being reported to be associated with type-2 diabetes and PCOS. We intended to assess the prevalence of abnormal glucose tolerance (AGT) and insulin resistance in Taiwanese PCOS women. We also tried to assess whether the particular identity of Gly972Arg/Ala513Pro polymorphic alleles of the IRS-1 gene mutation can be used as an appropriate diagnostic indicator for PCOS. Methods We designed a prospective clinical study. Forty-seven Taiwanese Hoklo and Hakka women, diagnosed with PCOS were enrolled in this study as were forty-five healthy Hoklo and Hakka women as the control group. Insulin resistance was evaluated with fasting insulin, fasting glucose/insulin ratio, and homeostasis model assessment index for insulin resistance (HOMAIR). The genomic DNA of the subjects was amplified by PCR and digested by restriction fragmented length polymorphism (RFLP) with Bst N1 used for codon 972 and Dra III for codon 513. Results AGT was found in 46.8% of these PCOS patients and was significantly related to high insulin resistance rather than the low insulin resistance. Those patients with either insulin resistance or AGT comprised the majority of PCOS affected patients (AGT + fasting insulin ≥17: 83%, AGT + glucose/insulin ratio ≥6.5: 85.1%, AGT + HOMAIR ≥ 2: 87.2%, and AGT + HOMAIR ≥ 3.8: 72.3%). None of the tested samples revealed any polymorphism due to the absence of any Dra III recognition site or any Bst N1 recognition site in the amplified PCR fragment digested by restriction fragmented length polymorphism. Conclusion There is significantly high prevalence of AGT and insulin resistance in PCOS women, but Gly972Arg and Ala513Pro polymorphic alleles of IRS-1 are rare and are not associated with the elevated risk of PCOS amongst

  19. Abnormal temporal lobe response in Alzheimer's disease during cognitive processing as measured by /sup 11/C-2-deoxy-D-glucose and PET

    SciTech Connect

    Miller, J.D.; de Leon, M.J.; Ferris, S.H.; Kluger, A.; George, A.E.; Reisberg, B.; Sachs, H.J.; Wolf, A.P.

    1987-04-01

    Elderly controls and probable Alzheimer's disease patients underwent serial positron emission tomography (PET) studies during a baseline condition and while performing a verbal memory task. For the temporal lobes, all 7 Alzheimer patients demonstrated a relative shift in glucose metabolic rates to the right hemisphere during the memory condition relative to baseline, and 5 of 7 controls showed a shift to the left hemisphere. Baseline absolute regional metabolic rates replicate previous findings and were somewhat less useful than the memory challenge in differentiating patients from controls. These results indicate that a temporal lobe abnormality in Alzheimer's disease is related to memory performance.

  20. 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

  1. Aqueous extract of tamarind seeds selectively increases glucose transporter-2, glucose transporter-4, and islets' intracellular calcium levels and stimulates β-cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes mellitus.

    PubMed

    Sole, Sushant Shivdas; Srinivasan, B P

    2012-08-01

    Tamarindus indica Linn. has been in use for a long time in Asian food and traditional medicine for different diseases including diabetes and obesity. However, the molecular mechanisms of these effects have not been fully understood. In view of the multidimensional activity of tamarind seeds due to their having high levels of polyphenols and flavonoids, we hypothesized that the insulin mimetic effect of aqueous tamarind seed extract (TSE) might increase glucose uptake through improvement in the expression of genes of the glucose transporter (GLUT) family and sterol regulatory element-binding proteins (SREBP) 1c messenger RNA (mRNA) in the liver. Daily oral administration of TSE to streptozotocin (STZ)-induced (90 mg/kg intraperitoneally) type 2 diabetic male Wistar rats at different doses (120 and 240 mg/kg body weight) for 4 weeks showed positive correlation with intracellular calcium and insulin release in isolated islets of Langerhans. Tamarind seed extract supplementation significantly improved the GLUT-2 protein and SREBP-1c mRNA expression in the liver and GLUT-4 protein and mRNA expression in the skeletal muscles of diabetic rats. The elevated levels of serum nitric oxide (NO), glycosylated hemoglobin level (hemoglobin (A1c)) and tumor necrosis factor α (TNF-α) decreased after TSE administration. Immunohistochemical findings revealed that TSE abrogated STZ-induced apoptosis and increased β-cell neogenesis, indicating its effect on islets and β-cell mass. In conclusion, it was found that the antidiabetic effect of TSE on STZ-induced diabetes resulted from complex mechanisms of β-cell neogenesis, calcium handling, GLUT-2, GLUT-4, and SREBP-1c. These findings show the scope for formulating a new herbal drug for diabetes therapy.

  2. Aqueous extract of tamarind seeds selectively increases glucose transporter-2, glucose transporter-4, and islets' intracellular calcium levels and stimulates β-cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes mellitus.

    PubMed

    Sole, Sushant Shivdas; Srinivasan, B P

    2012-08-01

    Tamarindus indica Linn. has been in use for a long time in Asian food and traditional medicine for different diseases including diabetes and obesity. However, the molecular mechanisms of these effects have not been fully understood. In view of the multidimensional activity of tamarind seeds due to their having high levels of polyphenols and flavonoids, we hypothesized that the insulin mimetic effect of aqueous tamarind seed extract (TSE) might increase glucose uptake through improvement in the expression of genes of the glucose transporter (GLUT) family and sterol regulatory element-binding proteins (SREBP) 1c messenger RNA (mRNA) in the liver. Daily oral administration of TSE to streptozotocin (STZ)-induced (90 mg/kg intraperitoneally) type 2 diabetic male Wistar rats at different doses (120 and 240 mg/kg body weight) for 4 weeks showed positive correlation with intracellular calcium and insulin release in isolated islets of Langerhans. Tamarind seed extract supplementation significantly improved the GLUT-2 protein and SREBP-1c mRNA expression in the liver and GLUT-4 protein and mRNA expression in the skeletal muscles of diabetic rats. The elevated levels of serum nitric oxide (NO), glycosylated hemoglobin level (hemoglobin (A1c)) and tumor necrosis factor α (TNF-α) decreased after TSE administration. Immunohistochemical findings revealed that TSE abrogated STZ-induced apoptosis and increased β-cell neogenesis, indicating its effect on islets and β-cell mass. In conclusion, it was found that the antidiabetic effect of TSE on STZ-induced diabetes resulted from complex mechanisms of β-cell neogenesis, calcium handling, GLUT-2, GLUT-4, and SREBP-1c. These findings show the scope for formulating a new herbal drug for diabetes therapy. PMID:22935346

  3. A community-based survey for different abnormal glucose metabolism among pregnant women in a random household study (SAUDI-DM)

    PubMed Central

    Al-Rubeaan, Khalid; Al-Manaa, Hamad A; Khoja, Tawfik A; Youssef, Amira M; Al-Sharqawi, Ahmad H; Siddiqui, Khalid; Ahmad, Najlaa A

    2014-01-01

    Objective To assess the prevalence and risk factors of gestational diabetes mellitus (GDM) in a population known to have a high prevalence of abnormal glucose metabolism. Methods A household random population-based cross-sectional study of 13 627 women in the childbearing age, who were subjected to fasting plasma glucose if they were not known to have been diagnosed before with any type of diabetes. GDM cases were diagnosed using the International Association of Diabetes and Pregnancy Study Group (IAPSG) criteria. Results The overall GDM prevalence was 36.6%, categorised into 32.4% new cases and 4.2% known cases. Another 3.6% had preconception type 1 or 2 diabetes. GDM cases were older and had a significantly higher body mass index, in addition to a higher rate of macrocosmic baby and history of GDM. Monthly income, educational level, living in urban areas and smoking were not found to be significantly different between normal and GDM cases. The most important and significant risk factors for GDM were history of GDM, macrosomic baby, obesity and age >30 years. However, hypertension, low high-density lipoprotein, family history of diabetes and increased triglycerides did not show any significant effect on GDM prevalence in this cohort. Conclusions This society is facing a real burden of abnormal glucose metabolism during pregnancy, where almost half of the pregnant women are subjected to maternal and neonatal complications. Early screening of pregnant women, especially those at a high risk for GDM, is mandatory to identify and manage those cases. PMID:25138813

  4. CSF glucose test

    MedlinePlus

    Glucose test - CSF; Cerebrospinal fluid glucose test ... The glucose level in the CSF should be 50 to 80 mg/100 mL (or greater than 2/3 ... Abnormal results include higher and lower glucose levels. Abnormal ... or fungus) Inflammation of the central nervous system Tumor

  5. Chronic Superantigen Exposure Induces Systemic Inflammation, Elevated Bloodstream Endotoxin, and Abnormal Glucose Tolerance in Rabbits: Possible Role in Diabetes

    PubMed Central

    Vu, Bao G.; Stach, Christopher S.; Kulhankova, Katarina; Salgado-Pabón, Wilmara; Klingelhutz, Aloysius J.

    2015-01-01

    ABSTRACT Excessive weight and obesity are associated with the development of diabetes mellitus type 2 (DMII) in humans. They also pose high risks of Staphylococcus aureus colonization and overt infections. S. aureus causes a wide range of severe illnesses in both healthy and immunocompromised individuals. Among S. aureus virulence factors, superantigens are essential for pathogenicity. In this study, we show that rabbits that are chronically exposed to S. aureus superantigen toxic shock syndrome toxin-1 (TSST-1) experience impaired glucose tolerance, systemic inflammation, and elevated endotoxin levels in the bloodstream, all of which are common findings in DMII. Additionally, such DMII-associated findings are also seen through effects of TSST-1 on isolated adipocytes. Collectively, our findings suggest that chronic exposure to S. aureus superantigens facilitates the development of DMII, which may lead to therapeutic targeting of S. aureus and its superantigens. PMID:25714716

  6. 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. PMID:24789008

  7. 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.

  8. Cytosolic NADPH homeostasis in glucose-starved procyclic Trypanosoma brucei relies on malic enzyme and the pentose phosphate pathway fed by gluconeogenic flux.

    PubMed

    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

    2013-06-21

    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/(RNAi)PGI double mutant when compared with the single mutants, and (iii) the (13)C enrichment of glycolytic and PPP intermediates from cells incubated with [U-(13)C]proline, in the absence of glucose. Gluconeogenesis-supported NADPH supply may also be important for nucleotide and glycoconjugate syntheses in the insect host.

  9. 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. PMID:26970045

  10. Bisphenol A impairs insulin signaling and glucose homeostasis and decreases steroidogenesis in rat testis: an in vivo and in silico study.

    PubMed

    D'Cruz, Shereen Cynthia; Jubendradass, Rajamanickam; Jayakanthan, Mannu; Rani, Sivaraj Judith Amala; Mathur, Premendu Prakash

    2012-03-01

    Bisphenol A (BPA) is a potential endocrine disruptor and testicular toxicant. Recently, we have reported that exposure to BPA increases plasma insulin and glucose levels and decreases the levels of glycolytic enzymes, glucose transporter-8 (GLUT-8) and insulin receptor substrate-2 (IRS-2) in rat testis. In the present study we sought to investigate the effects of low doses of BPA on insulin signaling molecules, glucose transporter-2 (GLUT-2) and steroidogenesis in rat testis. BPA was administered to rats by oral gavage at doses of 0.005, 0.5, 50 and 500 μg/kg body weight/day for 45 days. A positive control was maintained by administering 17-β-estradiol (50 μg/kg body weight/day). Decreased levels of insulin, insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI-3 kinase) and GLUT-2 were observed in rat testis following BPA administration. Dose-dependent decrease in the activities of antioxidant enzymes, 3-β-hydroxysteroid dehydrogenase (3β-HSD), 17-β-hydroxysteroid dehydrogenase (17β-HSD), Steroidogenic Acute Regulatory Protein (StAR) and testosterone were also observed. Molecular docking of BPA, 17-β-estradiol, cytochalasin B and glucose with GLUT-2 and GLUT-8 revealed the higher binding affinity of BPA with GLUT-2 and GLUT-8. Thus, BPA impairs insulin signaling and glucose transport in rat testis which could consequently lead to impairment of testicular functions.

  11. 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.

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

    PubMed

    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

  13. Involvement of glucagon-like peptide 1 in the glucose homeostasis regulation in obese and pituitary-dependent hyperadrenocorticism affected dogs.

    PubMed

    Miceli, D D; Cabrera Blatter, M F; Gallelli, M F; Pignataro, O P; Castillo, V A

    2014-10-01

    The incretin glucagon-like peptide 1 (GLP-1) enhances insulin secretion. The aim of this study was to assess GLP-1, glucose and insulin concentrations, Homeostatic Model Assessment (HOMA insulin sensitivity and HOMA β-cell function) in dogs with pituitary-dependent hyperadrenocorticism (PDH), and compare these values with those in normal and obese dogs. The Oral Glucose Tolerance Test was performed and the glucose, GLP-1 and insulin concentrations were evaluated at baseline, and after 15, 30, 60 and 120 minutes. Both basal concentration and those corresponding to the subsequent times, for glucose, GLP-1 and insulin, were statistically elevated in PDH dogs compared to the other groups. Insulin followed a similar behaviour together with variations of GLP-1. HOMA insulin sensitivity was statistically decreased and HOMA β-cell function increased in dogs with PDH. The higher concentrations of GLP-1 in PDH could play an important role in the impairment of pancreatic β-cells thus predisposing to diabetes mellitus.

  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. Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice

    PubMed Central

    Lemaire, K.; Ravier, M. A.; Schraenen, A.; Creemers, J. W. M.; Van de Plas, R.; Granvik, M.; Van Lommel, L.; Waelkens, E.; Chimienti, F.; Rutter, G. A.; Gilon, P.; Veld, P. A. in't; Schuit, F. C.

    2009-01-01

    Zinc co-crystallizes with insulin in dense core secretory granules, but its role in insulin biosynthesis, storage and secretion is unknown. In this study we assessed the role of the zinc transporter ZnT8 using ZnT8-knockout (ZnT8−/−) mice. Absence of ZnT8 expression caused loss of zinc release upon stimulation of exocytosis, but normal rates of insulin biosynthesis, normal insulin content and preserved glucose-induced insulin release. Ultrastructurally, mature dense core insulin granules were rare in ZnT8−/− beta cells and were replaced by immature, pale insulin “progranules,” which were larger than in ZnT8+/+ islets. When mice were fed a control diet, glucose tolerance and insulin sensitivity were normal. However, after high-fat diet feeding, the ZnT8−/− mice became glucose intolerant or diabetic, and islets became less responsive to glucose. Our data show that the ZnT8 transporter is essential for the formation of insulin crystals in beta cells, contributing to the packaging efficiency of stored insulin. Interaction between the ZnT8−/− genotype and diet to induce diabetes is a model for further studies of the mechanism of disease of human ZNT8 gene mutations. PMID:19706465

  16. The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes.

    PubMed

    Rajpathak, Swapnil N; Gunter, Marc J; Wylie-Rosett, Judith; Ho, Gloria Y F; Kaplan, Robert C; Muzumdar, Radhika; Rohan, Thomas E; Strickler, Howard D

    2009-01-01

    This review addresses the possible role of the insulin-like growth factor (IGF)-axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF-I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin-like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I and its binding proteins (IGFBPs). Administration of recombinant human IGF-I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF-I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic beta-cell mass and function. There is considerable inter-individual heterogeneity in endogenous levels of IGF-I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association.

  17. Sustained improvement in glucose homeostasis in lean and obese mice following chronic administration of the β3 agonist SR 58611A

    PubMed Central

    Williams, Celia A; Shih, Mei-Fen; Taberner, Peter V

    1999-01-01

    Acute SR 58611A (0.25 mg kg−1), was effective in reducing the blood glucose response to a glucose tolerance test (GTT) in normal lean (control) and spontaneously obese/diabetic CBA/Ca mice and to be equipotent to 1.25 mg kg−1 glibenclamide in lean mice.Neither brown (BAT) nor white (WAT) adipose tissue lipogenesis was altered by acute SR 58611A (2–8 mg kg−1) in lean mice, but both increased significantly at the higher doses in the obese mice.Acute SR 58611A produced a hypoglycaemia 40 min after dosing in lean and obese animals, the duration and potency of which was less than that of glibenclamide. Plasma insulin levels increased 20 min after acute SR 58611A and glibenclamide in lean and obese mice.Chronic treatment (0.25 mg kg−1, 15 days) with SR 58611A increased its effectiveness in improving glucose tolerance, but did not affect the body weight (BW) or food intake of either lean or obese mice.Acute and chronic SR 58611A prolonged the hypoglycaemic effect of exogenous insulin in lean but not obese mice.In fed and fasted lean mice and in fasted obese mice chronic SR 58611A produced an acute hypoglycaemia 30 min post administration which was greater than after a single dose.SR 58611A maintained its effectiveness in improving glucose tolerance in lean and obese mice over a dosing period of 15 days. The improvement in glucose tolerance was achieved at a dose less than that required to stimulate adipose tissue lipogenesis and which did not affect food intake or body weight. PMID:10602340

  18. The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome.

    PubMed

    Putnam, Kelly; Shoemaker, Robin; Yiannikouris, Frederique; Cassis, Lisa A

    2012-03-15

    The renin-angiotensin system (RAS) is an important therapeutic target in the treatment of hypertension. Obesity has emerged as a primary contributor to essential hypertension in the United States and clusters with other metabolic disorders (hyperglycemia, hypertension, high triglycerides, low HDL cholesterol) defined within the metabolic syndrome. In addition to hypertension, RAS blockade may also serve as an effective treatment strategy to control impaired glucose and insulin tolerance and dyslipidemias in patients with the metabolic syndrome. Hyperglycemia, insulin resistance, and/or specific cholesterol metabolites have been demonstrated to activate components required for the synthesis [angiotensinogen, renin, angiotensin-converting enzyme (ACE)], degradation (ACE2), or responsiveness (angiotensin II type 1 receptors, Mas receptors) to angiotensin peptides in cell types (e.g., pancreatic islet cells, adipocytes, macrophages) that mediate specific disorders of the metabolic syndrome. An activated local RAS in these cell types may contribute to dysregulated function by promoting oxidative stress, apoptosis, and inflammation. This review will discuss data demonstrating the regulation of components of the RAS by cholesterol and its metabolites, glucose, and/or insulin in cell types implicated in disorders of the metabolic syndrome. In addition, we discuss data supporting a role for an activated local RAS in dyslipidemias and glucose intolerance/insulin resistance and the development of hypertension in the metabolic syndrome. Identification of an activated RAS as a common thread contributing to several disorders of the metabolic syndrome makes the use of angiotensin receptor blockers and ACE inhibitors an intriguing and novel option for multisymptom treatment.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. Chronic administration of Angelica sinensis polysaccharide effectively improves fatty liver and glucose homeostasis in high-fat diet-fed mice

    PubMed Central

    Wang, Kaiping; Cao, Peng; Wang, Hanxiang; Tang, Zhuohong; Wang, Na; Wang, Jinglin; Zhang, Yu

    2016-01-01

    This study aimed to investigate the therapeutic effects of Angelica sinensis polysaccharide (ASP), an active component derived from a water extract of Angelica sinensis, in high-fat diet (HFD)-fed BALB/c mice. The potential mechanisms underlying the activity of this compound were also considered. Specifically, serum and hepatic biochemical parameters were evaluated, and key proteins involved in the lipid/glucose metabolism were analyzed. Long-term feeding with a HFD induced severe fatty liver and hyperglycemia. Histological examination clearly showed that ASP reduced lipid accumulation in the liver and attenuated hepatic steatosis in HFD-fed mice. In addition, ASP markedly alleviated serum and liver lipid disorders and fatty liver via the upregulation of PPARγ expression and the activation of adiponectin-SIRT1-AMPK signaling. Furthermore, ASP also significantly relieved severe oxidative stress, demonstrating that ASP might attenuate nonalcoholic fatty liver disease via a “two-hit” mechanism. In addition, ASP reduced blood glucose levels and ameliorated insulin resistance via the regulation of related metabolic enzymes and by activating the PI3K/Akt pathway in HFD-fed mice. Our findings revealed that ASP might be used as an alternative dietary supplement or health care product to ameliorate metabolic syndrome in populations that consistently consume HFDs. PMID:27189109

  4. 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. PMID:27354540

  5. Nicotinic acetylcholine receptors in glucose homeostasis: the acute hyperglycemic and chronic insulin-sensitive effects of nicotine suggest dual opposing roles of the receptors in male mice.

    PubMed

    Vu, Christine U; Siddiqui, Jawed A; Wadensweiler, Paul; Gayen, Jiaur R; Avolio, Ennio; Bandyopadhyay, Gautam K; Biswas, Nilima; Chi, Nai-Wen; O'Connor, Daniel T; Mahata, Sushil K

    2014-10-01

    Cigarette smoking causes insulin resistance. However, nicotine induces anti-inflammation and improves glucose tolerance in insulin-resistant animal models. Here, we determined the effects of nicotine on glucose metabolism in insulin-sensitive C57BL/J6 mice. Acute nicotine administration (30 min) caused fasting hyperglycemia and lowered insulin sensitivity acutely, which depended on the activation of nicotinic-acetylcholine receptors (nAChRs) and correlated with increased catecholamine secretion, nitric oxide (NO) production, and glycogenolysis. Chlorisondamine, an inhibitor of nAChRs, reduced acute nicotine-induced hyperglycemia. qRT-PCR analysis revealed that the liver and muscle express predominantly β4 > α10 > α3 > α7 and β4 > α10 > β1 > α1 mRNA for nAChR subunits respectively, whereas the adrenal gland expresses β4 > α3 > α7 > α10 mRNA. Chronic nicotine treatment significantly suppressed expression of α3-nAChR (predominant peripheral α-subunit) in liver. Whereas acute nicotine treatment raised plasma norepinephrine (NE) and epinephrine (Epi) levels, chronic nicotine exposure raised only Epi. Acute nicotine treatment raised both basal and glucose-stimulated insulin secretion (GSIS). After chronic nicotine treatment, basal insulin level was elevated, but GSIS after acute saline or nicotine treatment was blunted. Chronic nicotine exposure caused an increased buildup of NO in plasma and liver, leading to decreased glycogen storage, along with a concomitant suppression of Pepck and G6Pase mRNA, thus preventing hyperglycemia. The insulin-sensitizing effect of chronic nicotine was independent of weight loss. Chronic nicotine treatment enhanced PI-3-kinase activities and increased Akt and glycogen synthase kinase (GSK)-3β phosphorylation in an nAChR-dependent manner coupled with decreased cAMP response element-binding protein (CREB) phosphorylation. The latter effects caused suppression of Pepck and G6Pase gene expression. Thus, nicotine causes both

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

    PubMed Central

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

    2015-01-01

    Objective Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown. Methods We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies. Results We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lepob/ob mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lepob/ob mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions. Conclusions GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action. PMID:26500840

  7. 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. PMID:26239056

  8. 55-week treatment of mice with the unani and ayurvedic medicine pomegranate flower ameliorates ageing-associated insulin resistance and skin abnormalities.

    PubMed

    Wang, Jianwei; Rong, Xianglu; Um, Irene S I; Yamahara, Johji; Li, Yuhao

    2012-01-01

    PPARs play a pivotal role in regulating lipid and glucose homeostasis and are involved in diverse biological activities in skin. Pomegranate flower (PGF, an antidiabetic therapy in Unani and Ayurvedic medicines) has been previously demonstrated to activate both PPARalpha/gamma. Here, we found that treatment of mice with the diet containing PGF powder over 55 weeks attenuated ageing-induced abnormal increases in the homeostasis model assessment of insulin resistance, glucose concentrations during oral glucose tolerance test, and adipose insulin resistance index. The diet tended to decrease the excessive peri-ovary fat mass. It, however, increased the thinned subcutaneous fat thickness. In addition, the diet restored decreases in skin water content, epidermis thickness, and collagen density in corium. Thus, our results demonstrate that long-term treatment with the Unani and Ayurvedic therapy ameliorates ageing-induced insulin resistance, which is associated with reversal of ageing-induced fat redistribution. Further, PGF attenuates ageing-mediated undesirable skin abnormalities. PMID:22253646

  9. Pregnancy Hyperglycemia in Prolactin Receptor Mutant, but Not Prolactin Mutant, Mice and Feeding-Responsive Regulation of Placental Lactogen Genes Implies Placental Control of Maternal Glucose Homeostasis1

    PubMed Central

    Rawn, Saara M.; Huang, Carol; Hughes, Martha; Shaykhutdinov, Rustem; Vogel, Hans J.; Cross, James C.

    2015-01-01

    Pregnancy is often viewed as a conflict between the fetus and mother over metabolic resources. Insulin resistance occurs in mothers during pregnancy but does not normally lead to diabetes because of an increase in the number of the mother's pancreatic beta cells. In mice, this increase is dependent on prolactin (Prl) receptor signaling but the source of the ligand has been unclear. Pituitary-derived Prl is produced during the first half of pregnancy in mice but the placenta produces Prl-like hormones from implantation to term. Twenty-two separate mouse genes encode the placenta Prl-related hormones, making it challenging to assess their roles in knockout models. However, because at least four of them are thought to signal through the Prl receptor, we analyzed Prlr mutant mice and compared their phenotypes with those of Prl mutants. We found that whereas Prlr mutants develop hyperglycemia during gestation, Prl mutants do not. Serum metabolome analysis showed that Prlr mutants showed other changes consistent with diabetes. Despite the metabolic changes, fetal growth was normal in Prlr mutants. Of the four placenta-specific, Prl-related hormones that have been shown to interact with the Prlr, their gene expression localizes to different endocrine cell types. The Prl3d1 gene is expressed by trophoblast giant cells both in the labyrinth layer, sitting on the arterial side where maternal blood is highest in oxygen and nutrients, and in the junctional zone as maternal blood leaves the placenta. Expression increases during the night, though the increase in the labyrinth is circadian whereas it occurs only after feeding in the junctional zone. These data suggest that the placenta has a sophisticated endocrine system that regulates maternal glucose metabolism during pregnancy. PMID:26269505

  10. Pregnancy Hyperglycemia in Prolactin Receptor Mutant, but Not Prolactin Mutant, Mice and Feeding-Responsive Regulation of Placental Lactogen Genes Implies Placental Control of Maternal Glucose Homeostasis.

    PubMed

    Rawn, Saara M; Huang, Carol; Hughes, Martha; Shaykhutdinov, Rustem; Vogel, Hans J; Cross, James C

    2015-09-01

    Pregnancy is often viewed as a conflict between the fetus and mother over metabolic resources. Insulin resistance occurs in mothers during pregnancy but does not normally lead to diabetes because of an increase in the number of the mother's pancreatic beta cells. In mice, this increase is dependent on prolactin (Prl) receptor signaling but the source of the ligand has been unclear. Pituitary-derived Prl is produced during the first half of pregnancy in mice but the placenta produces Prl-like hormones from implantation to term. Twenty-two separate mouse genes encode the placenta Prl-related hormones, making it challenging to assess their roles in knockout models. However, because at least four of them are thought to signal through the Prl receptor, we analyzed Prlr mutant mice and compared their phenotypes with those of Prl mutants. We found that whereas Prlr mutants develop hyperglycemia during gestation, Prl mutants do not. Serum metabolome analysis showed that Prlr mutants showed other changes consistent with diabetes. Despite the metabolic changes, fetal growth was normal in Prlr mutants. Of the four placenta-specific, Prl-related hormones that have been shown to interact with the Prlr, their gene expression localizes to different endocrine cell types. The Prl3d1 gene is expressed by trophoblast giant cells both in the labyrinth layer, sitting on the arterial side where maternal blood is highest in oxygen and nutrients, and in the junctional zone as maternal blood leaves the placenta. Expression increases during the night, though the increase in the labyrinth is circadian whereas it occurs only after feeding in the junctional zone. These data suggest that the placenta has a sophisticated endocrine system that regulates maternal glucose metabolism during pregnancy.

  11. 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 Central

    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.

    2015-01-01

    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. PMID:25830341

  12. 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. PMID:25830341

  13. Deletion of Apoptosis Signal-Regulating Kinase 1 (ASK1) Protects Pancreatic Beta-Cells from Stress-Induced Death but Not from Glucose Homeostasis Alterations under Pro-Inflammatory Conditions

    PubMed Central

    Pepin, Emilie; Higa, Arisa; Schuster-Klein, Carole; Bernard, Catherine; Sulpice, Thierry; Guardiola, Beatrice; Chevet, Eric; Alquier, Thierry

    2014-01-01

    Background Type 2 diabetes is characterized by pancreatic beta-cell dysfunction and is associated with low-grade inflammation. Recent observations suggest that apoptosis signal-regulating kinase 1 (ASK1) is involved in beta-cell death in response to different stressors. In this study, we tested whether ASK1 deficiency protects beta-cells from glucolipotoxic conditions and cytokines treatment or from glucose homeostasis alteration induced by endotoxemia. Methodology/Principal Findings Insulin secretion was neither affected upon shRNA-mediated downregulation of ASK1 in MIN6 cells nor in islets from ASK1-deficient mice. ASK1 silencing in MIN6 cells and deletion in islets did not prevent the deleterious effect of glucolipotoxic conditions or cytokines on insulin secretion. However, it protected MIN6 cells from death induced by ER stress or palmitate and islets from short term caspase activation in response to cytokines. Moreover, endotoxemia induced by LPS infusion increased insulin secretion during hyperglycemic clamps but the response was similar in wild-type and ASK1-deficient mice. Finally, insulin sensitivity in the presence of LPS was not affected by ASK1-deficiency. Conclusions/Significance Our study demonstrates that ASK1 is not involved in beta-cell function and dysfunction but controls stress-induced beta-cell death. PMID:25383781

  14. 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 Central

    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

    2010-01-01

    ) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates. PMID:21107780

  15. Mechanisms of mammalian iron homeostasis.

    PubMed

    Pantopoulos, Kostas; Porwal, Suheel Kumar; Tartakoff, Alan; Devireddy, L

    2012-07-24

    Iron is vital for almost all organisms because of its ability to donate and accept electrons with relative ease. It serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism, as well as for several other essential processes. Mammalian cells utilize multiple mechanisms to acquire iron. Disruption of iron homeostasis is associated with various human diseases: iron deficiency resulting from defects in the acquisition or distribution of the metal causes anemia, whereas iron surfeit resulting from excessive iron absorption or defective utilization causes abnormal tissue iron deposition, leading to oxidative damage. Mammals utilize distinct mechanisms to regulate iron homeostasis at the systemic and cellular levels. These involve the hormone hepcidin and iron regulatory proteins, which collectively ensure iron balance. This review outlines recent advances in iron regulatory pathways as well as in mechanisms underlying intracellular iron trafficking, an important but less studied area of mammalian iron homeostasis.

  16. Placental weight and placental weight-to-birth weight ratio are increased in diet- and exercise-treated gestational diabetes mellitus subjects but not in subjects with one abnormal value on 100-g oral glucose tolerance test.

    PubMed

    Kucuk, Mert; Doymaz, Fadime

    2009-01-01

    The aim of the present study was to determine whether the placental weight and placental weight-to-birth weight ratio (PW/BW) increased in pregnant women with one abnormal value (OAV) on 100-g oral glucose tolerance test (OGTT) and diet- and exercise-treated, non-insulin-requiring gestational diabetes mellitus (GDM) subjects. The 50-g glucose challenge test (GCT) was administered to 324 pregnant women. Women with abnormal 50-g test received a 100-g, 3-h OGTT using National Diabetes Data Group criteria. Women with GDM and OAV were treated with diet and exercise. Twenty subjects who required insulin or met exclusion criteria were excluded from the study. After the exclusion of 20 subjects, the GDM group consisted of 30 (9.7%) pregnant women and the OAV group consisted of 32 (9.9%) pregnant women. The control group consisted of 242 pregnant women. Birth weight (GDM: 3288.3+/-364.2 g; OAV: 3278.1+/-409.9 g; control group: 3270.6+/-346.5 g) did not differ significantly between groups (P>.05). Significantly higher placental weights (GDM: 694.8+/-152.1 g; OAV: 622.2+/-105.3 g; control group: 610.2+/-116.6 g; P<.01) and PW/BW (GDM: 0.21+/-0.03; OAV: 0.193+/-0.04; control group: 0.188+/-0.04; P<.01) were observed in GDM group compared to OAV and control group. No significant difference was found for OAV group in terms of placental weight and PW/BW compared to the control group. Our data indicated that women with OAV delivered infants and placenta of similar weight to those of normal pregnancies.

  17. Glucose disturbances in first-episode drug-naïve schizophrenia: Relationship to psychopathology.

    PubMed

    Zhang, Xiang Yang; Chen, Da-Chun; Tan, Yun-Long; An, Hui-Mei; Zunta-Soares, Giovana B; Huang, Xu-Feng; Soares, Jair C

    2015-12-01

    Accumulating evidence shows abnormal glucose metabolism in schizophrenia, even at the onset of psychosis. This study aims to examine the glucose and lipid metabolism in first-episode and drug naïve (FEDN) patients with schizophrenia and to explore their relationships with psychopathology, which have been under-investigated. Fasting glucose and lipid profiles, as well as homeostasis model of assessment-insulin resistance (HOMA-IR) index were determined in 120 never-medicated first-episode and 31 healthy control subjects matched for gender and age. The schizophrenia symptomatology was assessed by the positive and negative syndrome scale (PANSS). Our results showed that schizophrenia patients had a significantly higher level of fasting plasma glucose (p<0.0001) and insulin (p=0.038). HOMA, an indicator of insulin resistance was higher in the patients than in the healthy controls (p=0.008). No differences were found between the patients and healthy subjects in the levels of plasma triglycerides, high-density lipoprotein, and low-density lipoprotein, except that the cholesterol level was higher in the patients than health subjects (p=0.016). A significant negative association between plasma glucose levels and the PANSS positive symptom subscores was observed (p=0.013). Stepwise multiple regression analysis identified insulin resistance, insulin and the PANSS positive symptom subscore as significant predictor factors for glucose level. These results suggest that abnormal glucose metabolism may be associated with the pathogenesis and psychopathology of schizophrenia in the early phases of the disease process.

  18. Glucose Tolerance and Hyperkinesis.

    ERIC Educational Resources Information Center

    Langseth, Lillian; Dowd, Judith

    Examined were medical records of 265 hyperkinetic children (7-9 years old). Clinical blood chemistries, hematology, and 5-hour glucose tolerance test (GTT) results indicated that hematocrit levels were low in 27% of the Ss, eosinophil levels were abnormally high in 86% of the Ss, and GTT results were abnormal in a maority of Ss. (CL)

  19. Antihypertensive drugs and glucose metabolism

    PubMed Central

    Rizos, Christos V; Elisaf, Moses S

    2014-01-01

    Hypertension plays a major role in the development and progression of micro- and macrovascular disease. Moreover, increased blood pressure often coexists with additional cardiovascular risk factors such as insulin resistance. As a result the need for a comprehensive management of hypertensive patients is critical. However, the various antihypertensive drug categories have different effects on glucose metabolism. Indeed, angiotensin receptor blockers as well as angiotensin converting enzyme inhibitors have been associated with beneficial effects on glucose homeostasis. Calcium channel blockers (CCBs) have an overall neutral effect on glucose metabolism. However, some members of the CCBs class such as azelnidipine and manidipine have been shown to have advantageous effects on glucose homeostasis. On the other hand, diuretics and β-blockers have an overall disadvantageous effect on glucose metabolism. Of note, carvedilol as well as nebivolol seem to differentiate themselves from the rest of the β-blockers class, being more attractive options regarding their effect on glucose homeostasis. The adverse effects of some blood pressure lowering drugs on glucose metabolism may, to an extent, compromise their cardiovascular protective role. As a result the effects on glucose homeostasis of the various blood pressure lowering drugs should be taken into account when selecting an antihypertensive treatment, especially in patients which are at high risk for developing diabetes. PMID:25068013

  20. Insulin and glucose regulation.

    PubMed

    Ralston, Sarah L

    2002-08-01

    Abnormally high or low blood glucose and insulin concentrations after standardized glucose tolerance tests can reflect disorders such as pituitary dysfunction, polysaccharide storage myopathies, and other clinical disorders. Glucose and insulin responses, however, are modified by the diet to which the animal has adapted, time since it was last fed, and what it was fed. Body fat (obesity), fitness level, physiologic status, and stress also alter glucose and insulin metabolism. Therefore, it is important to consider these factors when evaluating glucose and insulin tests, especially if only one sample it taken. This article describes the factors affecting glucose and insulin metabolism in horses and how they might influence the interpretation of standardized tests of glucose tolerance.

  1. Adiposity and Insufficient MVPA Predict Cardiometabolic Abnormalities in Adults

    PubMed Central

    Peterson, Mark D.; Snih, Soham Al; Stoddard, Jonathan; McClain, James; Lee, IMin

    2014-01-01

    Objectives To compare the extent to which different combinations of objectively measured sedentary behavior (SB) and physical activity contribute to cardiometabolic health. Design and Methods A population representative sample of 5,268 individuals, aged 20-85 years, was included from the combined 2003-2006 NHANES datasets. Activity categories were created on the combined basis of objectively measured SB and moderate-to-vigorous physical activity (MVPA) tertiles. Cardiometabolic abnormalities included elevated blood pressure, levels of triglycerides, fasting plasma glucose, C-reactive protein, homeostasis model assessment (HOMA) of insulin resistance value, and low HDL-cholesterol level. BMI, and DXA-derived percent body fat (% BF) and android adiposity were also compared across groups. Predictors for a metabolically abnormal phenotype (≥3 cardiometabolic abnormalities, or insulin resistance) were determined. Results Adults with the least SB and greatest MVPA exhibited the healthiest cardiometabolic profiles, whereas adults with the greatest SB and lowest MVPA were older and had elevated risk. Time spent in SB was not a predictor of the metabolically abnormal phenotype when MVPA was accounted for. Adults with the highest MVPA across SB tertiles did not differ markedly in prevalence of obesity, adiposity, and/or serum cardiometabolic risk factors; however, less MVPA was associated with substantial elevations of obesity and cardiometabolic risk. Android adiposity (per kilogram) was independently associated with the metabolically abnormal phenotype in both men (OR: 2.36 [95% CI, 1.76-3.17], p<0.001) and women (OR: 2.00 [95% CI, 1.63-2.45], p<0.001). Among women, greater SB, and less lifestyle moderate activity and MVPA were each independently associated with the metabolically abnormal phenotype, whereas only less MVPA was associated with it in men. Conclusions MVPA is a strong predictor of cardiometabolic health among adults, independent of time spent in SB. PMID

  2. Homeostasis and Biofeedback

    PubMed Central

    Kryspin, J.; Godfrey, C. M.

    1976-01-01

    Homeostasis of human organisms is the maintenance of a hierarchy of steady state conditions with little variation from, and prompt return to, a stabilized level during function. Any one of the information channels which informs the organism of the state of homeostasis can be used as ‘biofeedback’, i.e. to increase awareness of inadequate control and to teach new control mechanisms. If homeostasis is the basis of good health, disease may be considered a deviation from homeostasis. Through the use of biofeedback the subject may be made aware of poor health and learn to make adjustments to achieve homeostasis. Clinical application and results in several chronic disorders illustrate some successes and limitations of this approach. PMID:21304759

  3. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  4. Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism

    NASA Astrophysics Data System (ADS)

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

    2005-08-01

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

  5. Craniofacial Abnormalities

    MedlinePlus

    ... of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft ... palate, are among the most common of all birth defects. Others are very rare. Most of them affect ...

  6. Chromosome Abnormalities

    MedlinePlus

    ... decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal abnormalities without using a microscope. These newer methods compare the patient's DNA to a normal DNA ...

  7. Walking abnormalities

    MedlinePlus

    ... include: Arthritis of the leg or foot joints Conversion disorder (a psychological disorder) Foot problems (such as a ... injuries. For an abnormal gait that occurs with conversion disorder, counseling and support from family members are strongly ...

  8. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... Just like the skin, the fingernails tell a lot about your health: ... the fingernail. These lines can occur after illness, injury to ...

  9. Oxygen Sensing and Homeostasis.

    PubMed

    Prabhakar, Nanduri R; Semenza, Gregg L

    2015-09-01

    The discovery of carotid bodies as sensory receptors for detecting arterial blood oxygen levels, and the identification and elucidation of the roles of hypoxia-inducible factors (HIFs) in oxygen homeostasis have propelled the field of oxygen biology. This review highlights the gas-messenger signaling mechanisms associated with oxygen sensing, as well as transcriptional and non-transcriptional mechanisms underlying the maintenance of oxygen homeostasis by HIFs and their relevance to physiology and pathology.

  10. Plant-rich mixed meals based on Palaeolithic diet principles have a dramatic impact on incretin, peptide YY and satiety response, but show little effect on glucose and insulin homeostasis: an acute-effects randomised study.

    PubMed

    Bligh, H Frances J; Godsland, Ian F; Frost, Gary; Hunter, Karl J; Murray, Peter; MacAulay, Katrina; Hyliands, Della; Talbot, Duncan C S; Casey, John; Mulder, Theo P J; Berry, Mark J

    2015-02-28

    There is evidence for health benefits from 'Palaeolithic' diets; however, there are a few data on the acute effects of rationally designed Palaeolithic-type meals. In the present study, we used Palaeolithic diet principles to construct meals comprising readily available ingredients: fish and a variety of plants, selected to be rich in fibre and phyto-nutrients. We investigated the acute effects of two Palaeolithic-type meals (PAL 1 and PAL 2) and a reference meal based on WHO guidelines (REF), on blood glucose control, gut hormone responses and appetite regulation. Using a randomised cross-over trial design, healthy subjects were given three meals on separate occasions. PAL2 and REF were matched for energy, protein, fat and carbohydrates; PAL1 contained more protein and energy. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) concentrations were measured over a period of 180 min. Satiation was assessed using electronic visual analogue scale (EVAS) scores. GLP-1 and PYY concentrations were significantly increased across 180 min for both PAL1 (P= 0·001 and P< 0·001) and PAL2 (P= 0·011 and P= 0·003) compared with the REF. Concomitant EVAS scores showed increased satiety. By contrast, GIP concentration was significantly suppressed. Positive incremental AUC over 120 min for glucose and insulin did not differ between the meals. Consumption of meals based on Palaeolithic diet principles resulted in significant increases in incretin and anorectic gut hormones and increased perceived satiety. Surprisingly, this was independent of the energy or protein content of the meal and therefore suggests potential benefits for reduced risk of obesity. PMID:25661189

  11. Plant-rich mixed meals based on Palaeolithic diet principles have a dramatic impact on incretin, peptide YY and satiety response, but show little effect on glucose and insulin homeostasis: an acute-effects randomised study.

    PubMed

    Bligh, H Frances J; Godsland, Ian F; Frost, Gary; Hunter, Karl J; Murray, Peter; MacAulay, Katrina; Hyliands, Della; Talbot, Duncan C S; Casey, John; Mulder, Theo P J; Berry, Mark J

    2015-02-28

    There is evidence for health benefits from 'Palaeolithic' diets; however, there are a few data on the acute effects of rationally designed Palaeolithic-type meals. In the present study, we used Palaeolithic diet principles to construct meals comprising readily available ingredients: fish and a variety of plants, selected to be rich in fibre and phyto-nutrients. We investigated the acute effects of two Palaeolithic-type meals (PAL 1 and PAL 2) and a reference meal based on WHO guidelines (REF), on blood glucose control, gut hormone responses and appetite regulation. Using a randomised cross-over trial design, healthy subjects were given three meals on separate occasions. PAL2 and REF were matched for energy, protein, fat and carbohydrates; PAL1 contained more protein and energy. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) concentrations were measured over a period of 180 min. Satiation was assessed using electronic visual analogue scale (EVAS) scores. GLP-1 and PYY concentrations were significantly increased across 180 min for both PAL1 (P= 0·001 and P< 0·001) and PAL2 (P= 0·011 and P= 0·003) compared with the REF. Concomitant EVAS scores showed increased satiety. By contrast, GIP concentration was significantly suppressed. Positive incremental AUC over 120 min for glucose and insulin did not differ between the meals. Consumption of meals based on Palaeolithic diet principles resulted in significant increases in incretin and anorectic gut hormones and increased perceived satiety. Surprisingly, this was independent of the energy or protein content of the meal and therefore suggests potential benefits for reduced risk of obesity.

  12. Glucose disturbances in first-episode drug-naïve schizophrenia: Relationship to psychopathology.

    PubMed

    Zhang, Xiang Yang; Chen, Da-Chun; Tan, Yun-Long; An, Hui-Mei; Zunta-Soares, Giovana B; Huang, Xu-Feng; Soares, Jair C

    2015-12-01

    Accumulating evidence shows abnormal glucose metabolism in schizophrenia, even at the onset of psychosis. This study aims to examine the glucose and lipid metabolism in first-episode and drug naïve (FEDN) patients with schizophrenia and to explore their relationships with psychopathology, which have been under-investigated. Fasting glucose and lipid profiles, as well as homeostasis model of assessment-insulin resistance (HOMA-IR) index were determined in 120 never-medicated first-episode and 31 healthy control subjects matched for gender and age. The schizophrenia symptomatology was assessed by the positive and negative syndrome scale (PANSS). Our results showed that schizophrenia patients had a significantly higher level of fasting plasma glucose (p<0.0001) and insulin (p=0.038). HOMA, an indicator of insulin resistance was higher in the patients than in the healthy controls (p=0.008). No differences were found between the patients and healthy subjects in the levels of plasma triglycerides, high-density lipoprotein, and low-density lipoprotein, except that the cholesterol level was higher in the patients than health subjects (p=0.016). A significant negative association between plasma glucose levels and the PANSS positive symptom subscores was observed (p=0.013). Stepwise multiple regression analysis identified insulin resistance, insulin and the PANSS positive symptom subscore as significant predictor factors for glucose level. These results suggest that abnormal glucose metabolism may be associated with the pathogenesis and psychopathology of schizophrenia in the early phases of the disease process. PMID:26385108

  13. Prognosis of Pregnant Women with One Abnormal Value on 75g OGTT.

    PubMed

    Kozuma, Yutaka; Inoue, Shigeru; Horinouchi, Takashi; Shinagawa, Takaaki; Nakayama, Hitomi; Kawaguchi, Atsushi; Hori, Daizo; Kamura, Toshiharu; Yamada, Kentaro; Ushijima, Kimio

    2015-01-01

    The aim of this study was to identify risk factors to allow us to detect patients at high risk of requiring insulin therapy, among Japanese pregnant women with one abnormal value (OAV) on a 75-g oral glucose tolerance test (75-g OGTT). A total of 118 pregnant women with OAV on a previous 75-g OGTT between 1997 and 2010 were studied. We identified the factors which can predict patients at high risk of requiring insulin therapy among Japanese pregnant women with OAV, by comparing severe abnormal glucose tolerance (insulin treatment; n=17) with mild glucose tolerance patients (diet only; n=101). The following factors were examined; plasma level of glucose (PG) and immunoreactive insulin (IRI) at fasting, 0.5, 1 and 2 hours after loading glucose, insulinogenic index, homeostasis model assessment insulin resistance (HOMA-IR), insulin sensitivity index-composite (ISI composite), and HbA1c at the time of the 75-g OGTT. Univariate analysis showed a positive correlation between insulin therapy and 2-h PG value, 0.5-h and 1-h IRI values, AUC-IRI and insulinogenic index (p<0.05). Multivariate analysis showed that the PG 2-h value and insulinogenic index were independent predictive factors of insulin therapy. A 2-h PG ≥153 mg / dl and an insulinogenic index of <0.42 had a sensitivity of 81.8%, a specificity of 83.8%, a positive predictive value of 60.0% and a negative predictive value of 93.9% for the prediction of patients who required insulin therapy among pregnant women with OAV. These results suggest that a level of 2-h PG ≥153 mg/dl and an insulinogenic index of <0.42 on 75-g OGTT are predictive factors for insulin therapy in Japanese pregnant women with OAV.

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

    PubMed Central

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

    2015-01-01

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

  15. Redox regulated peroxisome homeostasis.

    PubMed

    Wang, Xiaofeng; Li, Shuo; Liu, Yu; Ma, Changle

    2015-01-01

    Peroxisomes are ubiquitous organelles present in nearly all eukaryotic cells. Conserved functions of peroxisomes encompass beta-oxidation of fatty acids and scavenging of reactive oxygen species generated from diverse peroxisomal metabolic pathways. Peroxisome content, number, and size can change quickly in response to environmental and/or developmental cues. To achieve efficient peroxisome homeostasis, peroxisome biogenesis and degradation must be orchestrated. We review the current knowledge on redox regulated peroxisome biogenesis and degradation with an emphasis on yeasts and plants.

  16. Redox regulated peroxisome homeostasis.

    PubMed

    Wang, Xiaofeng; Li, Shuo; Liu, Yu; Ma, Changle

    2015-01-01

    Peroxisomes are ubiquitous organelles present in nearly all eukaryotic cells. Conserved functions of peroxisomes encompass beta-oxidation of fatty acids and scavenging of reactive oxygen species generated from diverse peroxisomal metabolic pathways. Peroxisome content, number, and size can change quickly in response to environmental and/or developmental cues. To achieve efficient peroxisome homeostasis, peroxisome biogenesis and degradation must be orchestrated. We review the current knowledge on redox regulated peroxisome biogenesis and degradation with an emphasis on yeasts and plants. PMID:25545794

  17. Alcohol disrupts sleep homeostasis.

    PubMed

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  18. CFTR and lung homeostasis.

    PubMed

    Collawn, James F; Matalon, Sadis

    2014-12-15

    CFTR is a cAMP-activated chloride and bicarbonate channel that is critical for lung homeostasis. Decreases in CFTR expression have dire consequences in cystic fibrosis (CF) and have been suggested to be a component of the lung pathology in chronic obstructive pulmonary disease. Decreases or loss of channel function often lead to mucus stasis, chronic bacterial infections, and the accompanying chronic inflammatory responses that promote progressive lung destruction, and, eventually in CF, lung failure. Here we discuss CFTR's functional role airway surface liquid hydration and pH, in regulation of other channels such as the epithelial sodium channel, and in regulating inflammatory responses in the lung. PMID:25381027

  19. Alcohol disrupts sleep homeostasis

    PubMed Central

    Thakkar, Mahesh M.; Sharma, Rishi; Sahota, Pradeep

    2014-01-01

    Alcohol is a potent somnogen and one of the most commonly used “over the counter” sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to understand how and where alcohol acts to affect sleep. We have conducted a series of experiments using two different species, rats and mice, as animal models, and a combination of multi-disciplinary experimental methodologies to examine and understand anatomical and cellular substrates mediating the effects of acute and chronic alcohol exposure on sleep-wakefulness. The results of our studies suggest that the sleep-promoting effects of alcohol may be mediated via alcohol’s action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Lesions of the BF cholinergic neurons or blockade of AD A1 receptors results in attenuation of alcohol-induced sleep promotion, suggesting that AD and BF cholinergic neurons are critical for sleep-promoting effects of alcohol. Since binge alcohol consumption is a highly prevalent pattern

  20. Acid-Base Homeostasis.

    PubMed

    Hamm, L Lee; Nakhoul, Nazih; Hering-Smith, Kathleen S

    2015-12-01

    Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO3(-) is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys.

  1. Homeostasis in anorexia nervosa

    PubMed Central

    Södersten, Per; Bergh, Cecilia; Zandian, Modjtaba; Ioakimidis, Ioannis

    2014-01-01

    Brainstem and hypothalamic “orexigenic/anorexigenic” networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have shown that while a hypothalamic “orexigen” excites eating when food is abundant, it inhibits eating and stimulates foraging when food is in short supply. As the physical price of food approaches zero, eating and body weight increase without constraints. Conversely, in anorexia nervosa body weight is homeostatically regulated, the high level of physical activity in anorexia is displaced hoarding for food that keeps body weight constantly low. A treatment based on this point of view, providing patients with computerized mealtime support to re-establish normal eating behavior, has brought 75% of patients with eating disorders into remission, reduced the rate of relapse to 10%, and eliminated mortality. PMID:25147496

  2. Ageing and water homeostasis

    NASA Technical Reports Server (NTRS)

    Robertson, David; Jordan, Jens; Jacob, Giris; Ketch, Terry; Shannon, John R.; Biaggioni, Italo

    2002-01-01

    This review outlines current knowledge concerning fluid intake and volume homeostasis in ageing. The physiology of vasopressin is summarized. Studies have been carried out to determine orthostatic changes in plasma volume and to assess the effect of water ingestion in normal subjects, elderly subjects, and patients with dysautonomias. About 14% of plasma volume shifts out of the vasculature within 30 minutes of upright posture. Oral ingestion of water raises blood pressure in individuals with impaired autonomic reflexes and is an important source of noise in blood pressure trials in the elderly. On the average, oral ingestion of 16 ounces (473ml) of water raises blood pressure 11 mmHg in elderly normal subjects. In patients with autonomic impairment, such as multiple system atrophy, strikingly exaggerated pressor effects of water have been seen with blood pressure elevations greater than 75 mmHg not at all uncommon. Ingestion of water is a major determinant of blood pressure in the elderly population. Volume homeostasis is importantly affected by posture and large changes in plasma volume may occur within 30 minutes when upright posture is assumed.

  3. [The effects of DNA methylation on the homeostasis in vascular diseases].

    PubMed

    Xiaoying, Chen; Huadan, Ye; Qingxiao, Hong; Annan, Zhou; Linlin, Tang; Shiwei, Duan

    2015-03-01

    Homeostasis is fundamental to maintain normal physiological functions in our body. Internal and external physical, chemical and biologial changes can cause dysregulation of vascular homeostasis, which is closely associated with the homeostasis of oxygen supply, blood transportation and lipid metabolism. Subsequent epigenetic modifications are able to lead to abnormal structures and function of vessels. DNA methylation has been shown to play a vital role in the development of vascular diseases. In addition, 5-hydroxymethylcytosine (5hmC) and N(6)-methyladenine (m(6)A), as new epigenetic modifications, provide additional clues for vascular diseases. In this review, we summarize the effects of DNA methylation on the homeostasis dysregulation in the vascular diseases.

  4. Regulation of Potassium Homeostasis.

    PubMed

    Palmer, Biff F

    2015-06-01

    Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal clearance of potassium under normal circumstances can provide a framework for approaching disorders of potassium commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a resource for teaching trainees and medical students.

  5. Neuronal ubiquitin homeostasis

    PubMed Central

    Hallengren, Jada; Chen, Ping-Chung; Wilson, Scott M.

    2013-01-01

    Neurons have highly specialized intracellular compartments that facilitate the development and activity of the nervous system. Ubiquitination is a post-translational modification that controls many aspects of neuronal function by regulating protein abundance. Disruption of this signaling pathway has been demonstrated in neurological disorders such as Parkinson’s disease, Amyotrophic Lateral Sclerosis and Angleman Syndrome. Since many neurological disorders exhibit ubiquitinated protein aggregates, the loss of neuronal ubiquitin homeostasis may be an important contributor of disease. This review discusses the mechanisms utilized by neurons to control the free pool of ubiquitin necessary for normal nervous system development and function as well as new roles of protein ubiquitination in regulating synaptic activity. PMID:23686613

  6. Vescalagin from Pink Wax Apple [Syzygium samarangense (Blume) Merrill and Perry] Alleviates Hepatic Insulin Resistance and Ameliorates Glycemic Metabolism Abnormality in Rats Fed a High-Fructose Diet.

    PubMed

    Huang, Da-Wei; Chang, Wen-Chang; Wu, James Swi-Bea; Shih, Rui-Wen; Shen, Szu-Chuan

    2016-02-10

    This study investigates the ameliorative effect of vescalagin (VES) isolated from Pink wax apple fruit on hepatic insulin resistance and abnormal carbohydrate metabolism in high-fructose diet (HFD)-induced hyperglycemic rats. The results show that in HFD rats, VES significantly reduced the values of the area under the curve for glucose in an oral glucose tolerance test and the homeostasis model assessment of insulin resistance index. VES significantly enhanced the activity of hepatic antioxidant enzymes while reducing thiobarbituric acid-reactive substances in HFD rats. Western blot assay revealed that VES reduced hepatic protein expression involved in inflammation pathways while up-regulating expression of hepatic insulin signaling-related proteins. Moreover, VES up-regulated the expression of hepatic glycogen synthase and hepatic glycolysis-related proteins while down-regulating hepatic gluconeogenesis-related proteins in HFD rats. This study suggests some therapeutic potential of VES in preventing the progression of diabetes mellitus. PMID:26800576

  7. Vescalagin from Pink Wax Apple [Syzygium samarangense (Blume) Merrill and Perry] Alleviates Hepatic Insulin Resistance and Ameliorates Glycemic Metabolism Abnormality in Rats Fed a High-Fructose Diet.

    PubMed

    Huang, Da-Wei; Chang, Wen-Chang; Wu, James Swi-Bea; Shih, Rui-Wen; Shen, Szu-Chuan

    2016-02-10

    This study investigates the ameliorative effect of vescalagin (VES) isolated from Pink wax apple fruit on hepatic insulin resistance and abnormal carbohydrate metabolism in high-fructose diet (HFD)-induced hyperglycemic rats. The results show that in HFD rats, VES significantly reduced the values of the area under the curve for glucose in an oral glucose tolerance test and the homeostasis model assessment of insulin resistance index. VES significantly enhanced the activity of hepatic antioxidant enzymes while reducing thiobarbituric acid-reactive substances in HFD rats. Western blot assay revealed that VES reduced hepatic protein expression involved in inflammation pathways while up-regulating expression of hepatic insulin signaling-related proteins. Moreover, VES up-regulated the expression of hepatic glycogen synthase and hepatic glycolysis-related proteins while down-regulating hepatic gluconeogenesis-related proteins in HFD rats. This study suggests some therapeutic potential of VES in preventing the progression of diabetes mellitus.

  8. A Physiologist's View of Homeostasis

    ERIC Educational Resources Information Center

    Modell, Harold; Cliff, William; Michael, Joel; McFarland, Jenny; Wenderoth, Mary Pat; Wright, Ann

    2015-01-01

    Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of…

  9. 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. PMID:25392482

  10. 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

  11. 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.

  12. Water Homeostasis: Evolutionary Medicine

    PubMed Central

    Zeidel, Mark L.

    2012-01-01

    As a major component of homeostasis, all organisms regulate the water composition of various compartments. Through the selective use of barrier membranes and surface glycoproteins, as well as aquaporin water channels, organisms ranging from Archaebacteria to humans can vary water permeabilities across their cell membranes by 4 to 5 orders of magnitude. In barrier epithelia the outer, or exofacial, leaflet acts as the main resistor to water flow; this leaflet restricts water flow by minimizing the surface area of lipid molecules which is not covered by phosphate headgroups and by packing hydrocarbon chains at maximal density. Cells may enhance the barrier by expressing glycoproteins that augment the “thickness” of unstirred layers at their surfaces, reducing osmotic gradients at the lipid bilayer surface. Aquaporins markedly and highly selectively accelerate water flux and are “switched on” either by deployment into membranes or gating. This review summarizes these mechanisms in many species, and indicates potential roles for manipulating water permeabilities in treating disease. PMID:23303973

  13. Modeling Glucose Metabolism in the Kidney.

    PubMed

    Chen, Ying; Fry, Brendan C; Layton, Anita T

    2016-06-01

    The mammalian kidney consumes a large amount of energy to support the reabsorptive work it needs to excrete metabolic wastes and to maintain homeostasis. Part of that energy is supplied via the metabolism of glucose. To gain insights into the transport and metabolic processes in the kidney, we have developed a detailed model of the renal medulla of the rat kidney. The model represents water and solute flows, transmural fluxes, and biochemical reactions in the luminal fluid of the nephrons and vessels. In particular, the model simulates the metabolism of oxygen and glucose. Using that model, we have identified parameters concerning glucose transport and basal metabolism that yield predicted blood glucose concentrations that are consistent with experimental measurements. The model predicts substantial axial gradients in blood glucose levels along various medullary structures. Furthermore, the model predicts that in the inner medulla, owing to the relatively limited blood flow and low tissue oxygen tension, anaerobic metabolism of glucose dominates. PMID:27371260

  14. Spontaneous subarachnoid hemorrhage and glucose management.

    PubMed

    Schmutzhard, Erich; Rabinstein, Alejandro A

    2011-09-01

    Although metabolic abnormalities have been linked with poor outcome after subarachnoid hemorrhage, there are limited data addressing the impact of glycemic control or benefits of glucose management after aneurysmal subarachnoid hemorrhage. A systematic literature search was conducted of English-language articles describing original research on glycemic control in patients with subarachnoid hemorrhage. Case reports and case series were excluded. A total of 22 publications were selected for this review. Among the 17 studies investigating glucose as an outcome predictor, glucose levels during hospitalization were more likely to predict outcome than admission glucose. In general, hyperglycemia was linked to worse outcome. While insulin therapy in subarachnoid hemorrhage patients was shown to effectively control plasma glucose levels, plasma glucose control was not necessarily reflective of cerebral glucose such that very tight glucose control may lead to neuroglycopenia. Furthermore, tight glycemic control was associated with an increased risk for hypoglycemia which was linked to worse outcome. PMID:21850563

  15. Disorders of Phosphate Homeostasis and Tissue Mineralisation

    PubMed Central

    Bergwitz, Clemens; Jüppner, Harald

    2013-01-01

    Phosphate is absorbed from the diet in the gut, stored as hydroxyapatite in the skeleton, and excreted with the urine. The balance between these compartments determines the circulating phosphate concentration. Fibroblast growth factor 23 (FGF23) has recently been discovered and is part of a previously unrecognised hormonal bone-kidney axis. Phosphate-regulating gene with homologies to endopeptidases on the X chromosome, and dentin matrix protein 1 regulate the expression of FGF23 in osteocytes, which then is O-glycosylated by UDP-N-acetyl-alpha-d-galactosamine: poly-peptide N-acetylgalactosaminyl-transferase 3 and secreted into the circulation. FGF23 binds with high affinity to fibroblast growth factor receptor 1c in the presence of its co-receptor Klotho. It inhibits, either directly or indirectly, reabsorption of phosphate and the synthesis of 1,25-dihydroxy-vita-min-D by the renal proximal tubule and the secretion of parathyroid hormone by the parathyroid glands. Acquired or inborn errors affecting this newly discovered hormonal system can lead to abnormal phosphate homeostasis and/or tissue mineralisation. This chapter will provide an update on the current knowledge of the pathophysiology, the clinical presentation, diagnostic evaluation and therapy of the disorders of phosphate homeostasis and tissue mineralisation. PMID:19494665

  16. ASICs and cardiovascular homeostasis.

    PubMed

    Abboud, François M; Benson, Christopher J

    2015-07-01

    In this review we address primarily the role of ASICs in determining sensory signals from arterial baroreceptors, peripheral chemoreceptors, and cardiopulmonary and somatic afferents. Alterations in these sensory signals during acute cardiovascular stresses result in changes in sympathetic and parasympathetic activities that restore cardiovascular homeostasis. In pathological states, however, chronic dysfunctions of these afferents result in serious sympatho-vagal imbalances with significant increases in mortality and morbidity. We identified a role for ASIC2 in the mechano-sensitivity of aortic baroreceptors and of ASIC3 in the pH sensitivity of carotid bodies. In spontaneously hypertensive rats, we reported decreased expression of ASIC2 in nodose ganglia neurons and overexpression of ASIC3 in carotid bodies. This reciprocal expression of ASIC2 and ASIC3 results in reciprocal changes in sensory sensitivity of baro- and chemoreceptors and a consequential synergistic exaggeration sympathetic nerve activity. A similar reciprocal sensory dysautonomia prevails in heart failure and increases the risk of mortality. There is also evidence that ASIC heteromers in skeletal muscle afferents contribute significantly to the exercise pressor reflex. In cardiac muscle afferents of the dorsal root ganglia, they contribute to nociception and to the detrimental sympathetic activation during ischemia. Finally, we report that an inhibitory influence of ASIC2-mediated baroreceptor activity suppresses the sympatho-excitatory reflexes of the chemoreceptors and skeletal muscle afferents, as well as the ASIC1a-mediated excitation of central neurons during fear, threat, or panic. The translational potential of activation of ASIC2 in cardiovascular disease states may be a beneficial sympatho-inhibition and parasympathetic activation. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.

  17. Continuous glucose monitoring in small animals.

    PubMed

    Surman, Sean; Fleeman, Linda

    2013-03-01

    The use of continuous glucose monitoring systems in veterinary patients is summarized and discussed. The current clinical uses in veterinary medicine, including monitoring of hospitalized/sick diabetic patients, long-term monitoring of stable diabetic patients, anesthetized patients, and other patients with altered blood glucose homeostasis are presented. The most important advantage of these systems over intermittent blood glucose measurements is that they facilitate detection of brief periods of hypoglycemia and provide information overnight. The accuracy and advantages/disadvantages compared with traditional monitoring are addressed. The technology involved in the currently available monitoring systems is also discussed. PMID:23522178

  18. A balanced view of calcium and phosphate homeostasis in chronic kidney disease.

    PubMed

    Evenepoel, Pieter; Wolf, Myles

    2013-05-01

    The association of abnormalities of calcium and phosphate homeostasis with adverse clinical outcomes in chronic kidney disease (CKD) has generated interest in developing therapeutic strategies to target mineral metabolism early in the course of CKD. Hill et al. present results from a classic balance study of CKD stage 3-4 patients that challenge existing paradigms and suggest a need to rethink our understanding of calcium and phosphate homeostasis in CKD.

  19. Magnesium homeostasis and aging.

    PubMed

    Barbagallo, Mario; Belvedere, Mario; Dominguez, Ligia J

    2009-12-01

    Aging is very often associated with magnesium (Mg) deficit. Total plasma magnesium concentrations are remarkably constant in healthy subjects throughout life, while total body Mg and Mg in the intracellular compartment tend to decrease with age. Dietary Mg deficiencies are common in the elderly population. Other frequent causes of Mg deficits in the elderly include reduced Mg intestinal absorption, reduced Mg bone stores, and excess urinary loss. Secondary Mg deficit in aging may result from different conditions and diseases often observed in the elderly (i.e. insulin resistance and/or type 2 diabetes mellitus) and drugs (i.e. use of hypermagnesuric diuretics). Chronic Mg deficits have been linked to an increased risk of numerous preclinical and clinical outcomes, mostly observed in the elderly population, including hypertension, stroke, atherosclerosis, ischemic heart disease, cardiac arrhythmias, glucose intolerance, insulin resistance, type 2 diabetes mellitus, endothelial dysfunction, vascular remodeling, alterations in lipid metabolism, platelet aggregation/thrombosis, inflammation, oxidative stress, cardiovascular mortality, asthma, chronic fatigue, as well as depression and other neuropsychiatric disorders. Both aging and Mg deficiency have been associated to excessive production of oxygen-derived free radicals and low-grade inflammation. Chronic inflammation and oxidative stress are also present in several age-related diseases, such as many vascular and metabolic conditions, as well as frailty, muscle loss and sarcopenia, and altered immune responses, among others. Mg deficit associated to aging may be at least one of the pathophysiological links that may help to explain the interactions between inflammation and oxidative stress with the aging process and many age-related diseases.

  20. Brain iron homeostasis.

    PubMed

    Moos, Torben

    2002-11-01

    Iron is essential for virtually all types of cells and organisms. The significance of the iron for brain function is reflected by the presence of receptors for transferrin on brain capillary endothelial cells. The transport of iron into the brain from the circulation is regulated so that the extraction of iron by brain capillary endothelial cells is low in iron-replete conditions and the reverse when the iron need of the brain is high as in conditions with iron deficiency and during development of the brain. Whereas there is good agreement that iron is taken up by means of receptor-mediated uptake of iron-transferrin at the brain barriers, there are contradictory views on how iron is transported further on from the brain barriers and into the brain extracellular space. The prevailing hypothesis for transport of iron across the BBB suggests a mechanism that involves detachment of iron from transferrin within barrier cells followed by recycling of apo-transferrin to blood plasma and release of iron as non-transferrin-bound iron into the brain interstitium from where the iron is taken up by neurons and glial cells. Another hypothesis claims that iron-transferrin is transported into the brain by means of transcytosis through the BBB. This thesis deals with the topic "brain iron homeostasis" defined as the attempts to maintain constant concentrations of iron in the brain internal environment via regulation of iron transport through brain barriers, cellular iron uptake by neurons and glia, and export of iron from brain to blood. The first part deals with transport of iron-transferrin complexes from blood to brain either by transport across the brain barriers or by uptake and retrograde axonal transport in motor neurons projecting beyond the blood-brain barrier. The transport of iron and transport into the brain was examined using radiolabeled iron-transferrin. Intravenous injection of [59Fe-125]transferrin led to an almost two-fold higher accumulation of 59Fe than of

  1. Glucose and insulin metabolism in cirrhosis.

    PubMed

    Petrides, A S; DeFronzo, R A

    1989-01-01

    Glucose intolerance, overt diabetes mellitus, and insulin resistance are characteristic features of patients with cirrhosis. Insulin secretion, although increased in absolute terms, is insufficient to offset the presence of insulin resistance. The defect in insulin-mediated glucose disposal involves peripheral tissues, primarily muscle, and most likely reflects a disturbance in glycogen synthesis. Hepatic glucose production is normally sensitive to insulin; at present, it is unknown whether hepatic glucose uptake is impaired in cirrhosis. One of the more likely candidates responsible for the insulin-resistant state is insulin itself. The hyperinsulinemia results from three abnormalities: diminished hepatic extraction, portosystemic/intrahepatic shunting, and enhanced insulin secretion. PMID:2646365

  2. Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues.

    PubMed

    Xu, Cheng; Cai, Yu; Fan, Pengcheng; Bai, Bo; Chen, Jie; Deng, Han-Bing; Che, Chi-Ming; Xu, Aimin; Vanhoutte, Paul M; Wang, Yu

    2015-05-01

    Adipose tissue is a pivotal organ determining longevity, due largely to its role in maintaining whole-body energy homeostasis and insulin sensitivity. SIRT1 is a NAD-dependent protein deacetylase possessing antiaging activities in a wide range of organisms. The current study demonstrates that mice with adipose tissue-selective overexpression of hSIRT1(H363Y), a dominant-negative mutant that disrupts endogenous SIRT1 activity, show accelerated development of metabolic aging. These mice, referred to as Adipo-H363Y, exhibit hyperglycemia, dyslipidemia, ectopic lipid deposition, insulin resistance, and glucose intolerance at a much younger age than their wild-type littermates. The metabolic defects of Adipo-H363Y are associated with abnormal epigenetic modifications and chromatin remodeling in their adipose tissues, as a result of excess accumulation of biotin, which inhibits endogenous SIRT1 activity, leading to increased inflammation, cellularity, and collagen deposition. The enzyme acetyl-CoA carboxylase 2 plays an important role in biotin accumulation within adipose tissues of Adipo-H363Y. Calorie restriction prevents biotin accumulation, abolishes abnormal histone biotinylation, and completely restores the metabolic and adipose functions of Adipo-H363Y. The effects are mimicked by short-term restriction of biotin intake, an approach potentially translatable to humans for maintaining the epigenetic and chromatin remodeling capacity of adipose tissues and preventing aging-associated metabolic disorders.

  3. Glucose control.

    PubMed

    Preiser, Jean-Charles

    2013-01-01

    Stress-related hyperglycemia is a common finding in acutely ill patients, and is related to the severity and outcome of the critical illness. The pathophysiology of stress hyperglycemia includes hormonal and neural signals, leading to increased production of glucose by the liver and peripheral insulin resistance mediated by the translocation of transmembrane glucose transporters. In one pioneering study, tight glycemic control by intensive insulin therapy in critically ill patients was associated with improved survival. However, this major finding was not confirmed in several other prospective randomized controlled trials. The reasons underlying the discrepancy between the first and the subsequent studies could include nutritional strategy (amount of calories provided, use of parenteral nutrition), case-mix, potential differences in the optimal blood glucose level (BG) in different types of patients, hypoglycemia and its correction, and the magnitude of glucose variability. Therefore, an improved understanding of the physiology and pathophysiology of glycemic regulation during acute illness is needed. Safe and effective glucose control will need improvement in the definition of optimal BG and in the measurement techniques, perhaps including continuous monitoring of insulin algorithms and closed-loop systems. PMID:23075589

  4. General aspects of muscle glucose uptake.

    PubMed

    Alvim, Rafael O; Cheuhen, Marcel R; Machado, Silmara R; Sousa, André Gustavo P; Santos, Paulo C J L

    2015-03-01

    Glucose uptake in peripheral tissues is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. Studies have shown the existence of two major signaling pathways that lead to the translocation of GLUT4. The first, and widely investigated, is the insulin activated signaling pathway through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The second is the insulin-independent signaling pathway, which is activated by contractions. Individuals with type 2 diabetes mellitus have reduced insulin-stimulated glucose uptake in skeletal muscle due to the phenomenon of insulin resistance. However, those individuals have normal glucose uptake during exercise. In this context, physical exercise is one of the most important interventions that stimulates glucose uptake by insulin-independent pathways, and the main molecules involved are adenosine monophosphate-activated protein kinase, nitric oxide, bradykinin, AKT, reactive oxygen species and calcium. In this review, our main aims were to highlight the different glucose uptake pathways and to report the effects of physical exercise, diet and drugs on their functioning. Lastly, with the better understanding of these pathways, it would be possible to assess, exactly and molecularly, the importance of physical exercise and diet on glucose homeostasis. Furthermore, it would be possible to assess the action of drugs that might optimize glucose uptake and consequently be an important step in controlling the blood glucose levels in diabetic patients, in addition to being important to clarify some pathways that justify the development of drugs capable of mimicking the contraction pathway.

  5. The roles of peripheral serotonin in metabolic homeostasis.

    PubMed

    El-Merahbi, Rabih; Löffler, Mona; Mayer, Alexander; Sumara, Grzegorz

    2015-07-01

    Metabolic homeostasis in the organism is assured both by the nervous system and by hormones. Among a plethora of hormones regulating metabolism, serotonin presents a number of unique features. Unlike classical hormones serotonin is produced in different anatomical locations. In brain it acts as a neurotransmitter and in the periphery it can act as a hormone, auto- and/or paracrine factor, or intracellular signaling molecule. Serotonin does not cross the blood-brain barrier; therefore the two major pools of this bioamine remain separated. Although 95% of serotonin is produced in the periphery, its functions have been ignored until recently. Here we review the impact of the peripheral serotonin on the regulation of function of the organs involved in glucose and lipid homeostasis.

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

    PubMed

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

    2016-02-25

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

  7. Pharmacologic Approaches to Electrolyte Abnormalities in Heart Failure.

    PubMed

    Grodin, Justin L

    2016-08-01

    Electrolyte abnormalities are common in heart failure and can arise from a variety of etiologies. Neurohormonal activation from ventricular dysfunction, renal dysfunction, and heart failure medications can perturb electrolyte homeostasis which impact both heart failure-related morbidity and mortality. These include disturbances in serum sodium, chloride, acid-base, and potassium homeostasis. Pharmacological treatments differ for each electrolyte abnormality and vary from older, established treatments like the vaptans or acetazolamide, to experimental or theoretical treatments like hypertonic saline or urea, or to newer, novel agents like the potassium binders: patiromer and zirconium cyclosilicate. Pharmacologic approaches range from limiting electrolyte intake or directly repleting the electrolyte, to blocking or promoting their resorption, and to neurohormonal antagonism. Because of the prevalence and clinical impact of electrolyte abnormalities, understanding both the older and newer therapeutic options is and will continue to be necessity for the management of heart failure. PMID:27278221

  8. Targeting p97 to Disrupt Protein Homeostasis in Cancer

    PubMed Central

    Vekaria, Pratikkumar Harsukhbhai; Home, Trisha; Weir, Scott; Schoenen, Frank J.; Rao, Rekha

    2016-01-01

    Cancer cells are addicted to numerous non-oncogenic traits that enable them to thrive. Proteotoxic stress is one such non-oncogenic trait that is experienced by all tumor cells owing to increased genomic abnormalities and the resulting synthesis and accumulation of non-stoichiometric amounts of cellular proteins. This imbalance in the amounts of proteins ultimately culminates in proteotoxic stress. p97, or valosin-containing protein (VCP), is an ATPase whose function is essential to restore protein homeostasis in the cells. Working in concert with the ubiquitin proteasome system, p97 promotes the retrotranslocation from cellular organelles and/or degradation of misfolded proteins. Consequently, p97 inhibition has emerged as a novel therapeutic target in cancer cells, especially those that have a highly secretory phenotype. This review summarizes our current understanding of the function of p97 in maintaining protein homeostasis and its inhibition with small molecule inhibitors as an emerging strategy to target cancer cells. PMID:27536557

  9. WSB1: from homeostasis to hypoxia.

    PubMed

    Haque, Moinul; Kendal, Joseph Keith; MacIsaac, Ryan Matthew; Demetrick, Douglas James

    2016-01-01

    The wsb1 gene has been identified to be important in developmental biology and cancer. A complex transcriptional regulation of wsb1 yields at least three functional transcripts. The major expressed isoform, WSB1 protein, is a substrate recognition protein within an E3 ubiquitin ligase, with the capability to bind diverse targets and mediate ubiquitinylation and proteolytic degradation. Recent data suggests a new role for WSB1 as a component of a neuroprotective pathway which results in modification and aggregation of neurotoxic proteins such as LRRK2 in Parkinson's Disease, via an unusual mode of protein ubiquitinylation.WSB1 is also involved in thyroid hormone homeostasis, immune regulation and cellular metabolism, particularly glucose metabolism and hypoxia. In hypoxia, wsb1 is a HIF-1 target, and is a regulator of the degradation of diverse proteins associated with the cellular response to hypoxia, including HIPK2, RhoGDI2 and VHL. Major roles are to both protect HIF-1 function through degradation of VHL, and decrease apoptosis through degradation of HIPK2. These activities suggest a role for wsb1 in cancer cell proliferation and metastasis. As well, recent work has identified a role for WSB1 in glucose metabolism, and perhaps in mediating the Warburg effect in cancer cells by maintaining the function of HIF1. Furthermore, studies of cancer specimens have identified dysregulation of wsb1 associated with several types of cancer, suggesting a biologically relevant role in cancer development and/or progression.Recent development of an inducible expression system for wsb1 could aid in the further understanding of the varied functions of this protein in the cell, and roles as a potential oncogene and neuroprotective protein. PMID:27542736

  10. Minimal hepatic glucose-6-phosphatase-α activity required to sustain survival and prevent hepatocellular adenoma formation in murine glycogen storage disease type Ia.

    PubMed

    Lee, Young Mok; Kim, Goo-Young; Pan, Chi-Jiunn; Mansfield, Brian C; Chou, Janice Y

    2015-06-01

    Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. In a previous 70-90 week-study, we showed that a recombinant adeno-associated virus (rAAV) vector-mediated gene transfer that restores more than 3% of wild-type hepatic G6Pase-α activity in G6pc (-/-) mice corrects hepatic G6Pase-α deficiency with no evidence of HCA. We now examine the minimal hepatic G6Pase-α activity required to confer therapeutic efficacy. We show that rAAV-treated G6pc (-/-) mice expressing 0.2% of wild-type hepatic G6Pase-α activity suffered from frequent hypoglycemic seizures at age 63-65 weeks but mice expressing 0.5-1.3% of wild-type hepatic G6Pase-α activity (AAV-LL mice) sustain 4-6 h of fast and grow normally to age 75-90 weeks. Despite marked increases in hepatic glycogen accumulation, the AAV-LL mice display no evidence of hepatic abnormalities, hepatic steatosis, or HCA. Interprandial glucose homeostasis is maintained by the G6Pase-α/glucose-6-phosphate transporter (G6PT) complex, and G6PT-mediated microsomal G6P uptake is the rate-limiting step in endogenous glucose production. We show that hepatic G6PT activity is increased in AAV-LL mice. These findings are encouraging for clinical studies of G6Pase-α gene-based therapy for GSD-Ia.

  11. Glucose-lowering effects of intestinal bile acid sequestration through enhancement of splanchnic glucose utilization.

    PubMed

    Prawitt, Janne; Caron, Sandrine; Staels, Bart

    2014-05-01

    Intestinal bile acid (BA) sequestration efficiently lowers plasma glucose concentrations in type 2 diabetes (T2D) patients. Because BAs act as signaling molecules via receptors, including the G protein-coupled receptor TGR5 and the nuclear receptor FXR (farnesoid X receptor), to regulate glucose homeostasis, BA sequestration, which interrupts the entero-hepatic circulation of BAs, constitutes a plausible action mechanism of BA sequestrants. An increase of intestinal L-cell glucagon-like peptide-1 (GLP-1) secretion upon TGR5 activation is the most commonly proposed mechanism, but recent studies also argue for a direct entero-hepatic action to enhance glucose utilization. We discuss here recent findings on the mechanisms of sequestrant-mediated glucose lowering via an increase of splanchnic glucose utilization through entero-hepatic FXR signaling.

  12. Gravity and positional homeostasis of the cell

    NASA Astrophysics Data System (ADS)

    Nace, George W.

    Normally bilateralization takes place in the presence of the Earth's gravity which produces torque, shear, tension and compression acting upon the naked aggregates of cytoplasm in the zygote which is only stabilized by a weak cytoskeleton. In an initial examination of the effects of these quantities on development, an expression is derived to describe the tendency of torque to rotate the egg and reorganize its constituents. This expression yields the net torque resulting from buoyancy and gravity acting upon a dumbbell shaped cell with heavy and light masses at either end and ``floating'' in a medium. Using crude values for the variables, torques of 2.5 × 10-13 to 8.5 × 10-1 dyne-cm are found to act upon cells ranging from 6.4 μm to 31 mm (chicken egg). By way of comparison six microtubules can exert a torque of 5 × 10-9 dyne-cm. (1) Gravity imparts torque to cells; (2) torque is reduced to zero as gravity approaches zero; and (3) torque is sensitive to cell size and particulate distribution. Cells must expend energy to maintain positional homeostasis against gravity. Although not previously recognized, Skylab 3 results support this hypothesis: tissue cultures used 58% more glucose on Earth than in space. The implications for developmental biology, physiology, genetics, and evolution are considered. At the cellular and tissue level the concept of ``gravity receptors'' may be unnecessary.

  13. Gravity and positional homeostasis of the cell

    NASA Technical Reports Server (NTRS)

    Nace, G. W.

    1983-01-01

    The effect of gravity upon cytoplasmic aggregates of the size present in eggs and upon cells is investigated. An expression is developed to describe the tendency of torque to rotate the egg and reorganize its constituents. This expression provides the net torque resulting from buoyancy and gravity acting upon a dumbbell-shaped cell, with heavy and light masses at either end and floating in a medium. Torques of approximately 2.5 x 10 to the -13th to 0.85 dyne-cm are found to act upon cells ranging from 6.4 microns to 31 mm (chicken egg). It is noted that cells must expend energy to maintain positional homeostasis against gravity, as demonstrated by results from Skylab 3, where tissue cultures used 58 percent more glucose on earth than in space. The implications for developmental biology, physiology, genetics, and evolution are discussed. It is argued that at the cellular and tissue levels the concept of gravity receptors may be unnecessary.

  14. Evolution of glucose utilization: Glucokinase and glucokinase regulator protein

    PubMed Central

    Irwin, David M.; Tan, Huanran

    2014-01-01

    Glucose is an essential nutrient that must be distributed throughout the body to provide energy to sustain physiological functions. Glucose is delivered to distant tissues via be blood stream, and complex systems have evolved to maintain the levels of glucose within a narrow physiological range. Phosphorylation of glucose, by glucokinase, is an essential component of glucose homeostasis, both from the regulatory and metabolic point-of-view. Here we review the evolution of glucose utilization from the perspective of glucokinase. We discuss the origin of glucokinase, its evolution within the hexokinase gene family, and the evolution of its interacting regulatory partner, glucokinase regulatory protein (GCKR). Evolution of the structure and sequence of both glucokinase and GCKR have been necessary to optimize glucokinase in its role in glucose metabolism. PMID:24075984

  15. Dspp mutations disrupt mineralization homeostasis during odontoblast differentiation

    PubMed Central

    Jia, Jie; Bian, Zhuan; Song, Yaling

    2015-01-01

    The main pathological feature in isolated hereditary dentin disorders is the abnormality of dentin mineralization. Dentin sialophosphoprotein (DSPP) gene is the only identified causative gene for the disorders. The present study aims to explore the molecular association between Dspp mutations and the disrupted mineralization homeostasis during odontoblast differentiation. We generated lentivirus constructs with the mouse full-length wild type Dspp cDNA and 3 Dspp mutants and transfected them into mouse odontoblast-lineage cells (OLCs) which were then performed 21-day mineralization inducing differentiation. The formation of mineralized nodules was obviously fewer in mutants. Digital Gene Expression (DGE) showed that Dspp mutation affected the OLC differentiation in a degree. Further examination validated that Dspp (LV-Dspp) overexpressing OLCs possessed the ability to strictly orchestrate framework for mineralization inductors like Bmp2, Col1 and Runx2, and proliferative markers for mineralization like Alp and Ocn, as well as mineral homeostasis feedback regulators Mgp and Htra1. However, the missense mutation in Dspp signal peptide region (LV-M2) and the nonsense mutation (LV-M5) broke this orchestration. The results suggested that the mutant Dspp disrupt the dynamic homeostasis of mineralization during OLC differentiation. We are the first to use full-length mouse Dspp gene expression system to explore the mineralization mechanism by which inductors and inhibitors adjust each other during odontoblast differentiation. Our findings shed new light on association between Dspp and the dynamic homeostasis of mineralization inductors and inhibitors, and indicate the disruption of mineralization homeostasis might be a crucial reason for Dspp mutations resulting in dentin disorders. PMID:26807185

  16. Homeostasis: Beyond Curt Richter1

    PubMed Central

    Woods, Stephen C.; Ramsay, Douglas S.

    2007-01-01

    Curt Richter introduced behavioral control into the concept of homeostasis, thereby opening entire fields of research. The prevailing dogma, and the techniques he used, conspired to lead Richter and others to interpret regulation in strict negative feedback terms. Although this point of view continues to be embraced by many contemporary biologists, we believe that prevailing sentiment favors a broader view in which organisms integrate anticipatory pre-emptive control over regulated variables whenever possible. PMID:17524521

  17. Tensional homeostasis in single fibroblasts.

    PubMed

    Webster, Kevin D; Ng, Win Pin; Fletcher, Daniel A

    2014-07-01

    Adherent cells generate forces through acto-myosin contraction to move, change shape, and sense the mechanical properties of their environment. They are thought to maintain defined levels of tension with their surroundings despite mechanical perturbations that could change tension, a concept known as tensional homeostasis. Misregulation of tensional homeostasis has been proposed to drive disorganization of tissues and promote progression of diseases such as cancer. However, whether tensional homeostasis operates at the single cell level is unclear. Here, we directly test the ability of single fibroblast cells to regulate tension when subjected to mechanical displacements in the absence of changes to spread area or substrate elasticity. We use a feedback-controlled atomic force microscope to measure and modulate forces and displacements of individual contracting cells as they spread on a fibronectin-patterned atomic-force microscope cantilever and coverslip. We find that the cells reach a steady-state contraction force and height that is insensitive to stiffness changes as they fill the micropatterned areas. Rather than maintaining a constant tension, the fibroblasts altered their contraction force in response to mechanical displacement in a strain-rate-dependent manner, leading to a new and stable steady-state force and height. This response is influenced by overexpression of the actin crosslinker α-actinin, and rheology measurements reveal that changes in cell elasticity are also strain- rate-dependent. Our finding of tensional buffering, rather than homeostasis, allows cells to transition between different tensional states depending on how they are displaced, permitting distinct responses to slow deformations during tissue growth and rapid deformations associated with injury.

  18. Premenstrual changes. Impaired hormonal homeostasis.

    PubMed

    Halbreich, U; Alt, I H; Paul, L

    1988-03-01

    Premenstrual changes (PMCs) in mood and behavior are very prevalent. Nonetheless, their pathophysiology is still obscure and no proven treatment is yet available. Evaluation of the plethora of available data leads to the suggestion that PMCs may result from a temporary impairment of homeostasis among a multitude of systems. This impairment is triggered by a differential pace and magnitude of change-over-time in levels of several hormones and other substances during the luteal phase. PMID:3288473

  19. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... The appearance of normal teeth varies, especially the molars. ... conditions. Specific diseases can affect tooth shape, tooth ...

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  2. Impact of Glucose Tolerance Status, Sex, and Body Size on Glucose Absorption Patterns During OGTTs

    PubMed Central

    Færch, Kristine; Pacini, Giovanni; Nolan, John J.; Hansen, Torben; Tura, Andrea; Vistisen, Dorte

    2013-01-01

    OBJECTIVE We studied whether patterns of glucose absorption during oral glucose tolerance tests (OGTTs) were abnormal in individuals with impaired glucose regulation and whether they were related to sex and body size (height and fat-free mass). We also examined how well differences in insulin sensitivity and β-cell function measured by gold-standard tests were reflected in the corresponding OGTT-derived estimates. RESEARCH DESIGN AND METHODS With validated methods, various aspects of glucose absorption were estimated from 12-point, 3-h, 75-g OGTTs in 66 individuals with normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), or isolated impaired glucose tolerance (i-IGT). Insulin sensitivity and β-cell function were measured with the euglycemic-hyperinsulinemic clamp and intravenous glucose tolerance tests, respectively. Surrogate markers of both conditions were calculated from OGTTs. RESULTS More rapid glucose absorption (P ≤ 0.036) and reduced late glucose absorption (P ≤ 0.039) were observed in the i-IFG group relative to NGT and i-IGT groups. Women with i-IGT had a lower early glucose absorption than did men with i-IGT (P = 0.041); however, this difference did not persist when differences in body size were taken into account (P > 0.28). Faster glucose absorption was related to higher fasting (P = 0.001) and lower 2-h (P = 0.001) glucose levels and to greater height and fat-free mass (P < 0.001). All OGTT-derived measures of insulin sensitivity, but only one of three measures of β-cell function, reflected the differences for these parameters between those with normal and impaired glucose regulation as measured by gold-standard tests. CONCLUSIONS Glucose absorption patterns during an OGTT are significantly related to plasma glucose levels and body size, which should be taken into account when estimating β-cell function from OGTTs in epidemiological studies. PMID:24062321

  3. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

    PubMed Central

    Shen, Minqian; Shi, Haifei

    2015-01-01

    The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis. PMID:26491440

  4. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  5. Morphological abnormalities among lampreys

    USGS Publications Warehouse

    Manion, Patrick J.

    1967-01-01

    The experimental control of the sea lamprey (Petromyzon marinus) in the Great Lakes has required the collection of thousands of lampreys. Representatives of each life stage of the four species of the Lake Superior basin were examined for structural abnormalities. The most common aberration was the presence of additional tails. The accessory tails were always postanal and smaller than the normal tail. The point of origin varied; the extra tails occurred on dorsal, ventral, or lateral surfaces. Some of the extra tails were misshaped and curled, but others were normal in shape and pigment pattern. Other abnormalities in larval sea lampreys were malformed or twisted tails and bodies. The cause of the structural abnormalities is unknown. The presence of extra caudal fins could be genetically controlled, or be due to partial amputation or injury followed by abnormal regeneration. Few if any lampreys with structural abnormalities live to sexual maturity.

  6. Ca2+ homeostasis in microvascular endothelial cells from an insulin-dependent diabetic model: role of endosomes/lysosomes

    NASA Astrophysics Data System (ADS)

    Sanka, Shankar C.; Bennett, David C.; Rojas, Jose D.; Tasby, Geraldine B.; Meininger, Cynthia J.; Wu, Guoyao; Wesson, Donald E.; Pfarr, Curtis M.; Martinez-Zaguilan, Raul

    2000-04-01

    Cytosolic Ca2+ ([Ca2+]cyt) regulates several cellular functions, e.g. cell growth, contraction, secretion, etc. In many cell types, ion homeostasis appears to be coupled with glucose metabolism. In certain cell types, a strict coupling between glycolysis and the activity of Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPases (SERCA) has been suggested. Glucose metabolism is altered in diabetes. We hypothesize that: (1) Ca2+ homeostasis is altered in microvascular endothelial cells from diabetic animals due to the dysfunction of glycolysis coupling the activity of SERCA; (2) endosomal/lysosomal compartments expressing SERCA are involved in the dysfunction associated with diabetes.

  7. Sterol regulatory element-binding factor 2 (SREBF-2) predicts 7-year NAFLD incidence and severity of liver disease and lipoprotein and glucose dysmetabolism.

    PubMed

    Musso, Giovanni; Cassader, Maurizio; Bo, Simona; De Michieli, Franco; Gambino, Roberto

    2013-04-01

    We prospectively assessed the impact of a sterol regulatory element-binding factor-2 (SREBF-2) polymorphism on the risk of developing nonalcoholic fatty liver disease (NAFLD) and on liver histology and lipoprotein and glucose metabolism in biopsy-proven NAFLD. In a population-based study, we followed 175 nonobese, nondiabetic participants without NAFLD or metabolic syndrome at baseline, characterized for the SREBF-2 rs133291 C/T polymorphism, dietary habits, physical activity, adipokines, C-reactive protein (CRP), and endothelial adhesion molecules. A comparable cohort of NAFLD patients underwent liver biopsy, an oral glucose tolerance test with minimal model analysis to yield glucose homeostasis parameters, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, and cytokeratin-18 fragments. After 7 years, 27% of subjects developed NAFLD and 5% developed diabetes. SREBF-2 predicted incident NAFLD and diabetes and CRP and endothelial adhesion molecule changes. In biopsy-proven NAFLD patients, SREBF-2 predicted nonalcoholic steatohepatitis (odds ratio 2.92 [95% CI 2.08-4.18], P = 0.002) and the severity of tissue insulin resistance, β-cell dysfunction, and oral fat intolerance (characterized by higher postprandial lipemia, cholesterol enrichment of triglyceride-rich lipoproteins and oxidized LDLs, HDL cholesterol fall, adipokine imbalance, and postprandial apoptosis activation). An SREBF-2 polymorphism predisposes individuals to NAFLD and associated cardiometabolic abnormalities and affects liver histology and glucose and lipid metabolism in biopsy-proven NAFLD.

  8. Dysregulation of Glutathione Homeostasis Causes Oxido-reductive Stress and Cardiomyopathy in R120GCryAB Mice

    PubMed Central

    Rajasekaran, Namakkal S.; Connell, Patrice; Christians, Elisabeth S.; Yan, Liang-Jun; Taylor, Ryan P.; Orosz, Andras; Zhang, Xia Q.; Stevenson, Tamara J.; Peshock, Ronald M.; Leopold, Jane A.; Barry, William H.; Loscalzo, Joseph; Odelberg, Shannon J.; Benjamin, Ivor J.

    2008-01-01

    Summary Oxidative stress is widely implicated in pathogenic states including heart failure. In contrast, the role of ‘reductive stress,’ defined as the abnormal increase of reducing equivalents (e.g., glutathione, NADPH), remains controversial. Here we show that transgenic mice overexpressing cardiac-specific human R120G αB-crystallin (hR120GCryAB Tg) recapitulate protein aggregation cardiomyopathy and are under reductive stress linked to glutathione homeostasis. In myopathic hearts, increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH) and GSH/GSSG ratios were due to augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB Tg cardiomyopathic animals with G6PD-deficient (20% normal G6PD activity) mice rescues hR120GCryAB Tg/G6PDmut progeny from increased G6PD activity, cardiac hypertrophy, and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans. PMID:17693254

  9. The intestine as a regulator of cholesterol homeostasis in diabetes.

    PubMed

    Tomkin, Gerald H

    2008-09-01

    The chylomicron influences very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) composition but itself is atherogenic. Thus abnormalities of chylomicron production are of interest particularly in conditions such as diabetes which confer major cardiovascular risk. Intestinal function is abnormal in diabetes and is a major cause of the dyslipidaemia found in this condition. Studies have suggested that cholesterol absorption is decreased in diabetes and cholesterol synthesis increased. Molecular mechanisms involved in insulin resistance in the intestine and its effect on cholesterol homeostasis in diabetes are described. Abnormalities in triglyceride synthesis and alterations genes regulating cholesterol absorption and intestinal synthesis are discussed. In particular, increase in apolipoprotein B48 synthesis has been demonstrated in animal models of diabetes and insulin resistance. Intestinal mRNA expression of Niemann Pick C1-like 1, protein is increased in both experimental and human diabetes suggesting that an increase in cholesterol transportation does occur. mRNA expression of the ATP binding cassette proteins (ABC) G5 and G8, two proteins working in tandem to excrete cholesterol have been shown to be decreased suggesting increased delivery of cholesterol for absorption. Expression of microsomal triglyceride transfer protein, which assembles the chylomicron particle, is increased in diabetes leading to increase in both number and cholesterol content. In conclusion, diabetes is associated with considerable dysfunction of the intestine leading to abnormal chylomicron composition which may play a major part in the premature development of atherosclerosis.

  10. Regulation of glucose metabolism from a liver-centric perspective

    PubMed Central

    Han, Hye-Sook; Kang, Geon; Kim, Jun Seok; Choi, Byeong Hoon; Koo, Seung-Hoi

    2016-01-01

    Glucose homeostasis is tightly regulated to meet the energy requirements of the vital organs and maintain an individual's health. The liver has a major role in the control of glucose homeostasis by controlling various pathways of glucose metabolism, including glycogenesis, glycogenolysis, glycolysis and gluconeogenesis. Both the acute and chronic regulation of the enzymes involved in the pathways are required for the proper functioning of these complex interwoven systems. Allosteric control by various metabolic intermediates, as well as post-translational modifications of these metabolic enzymes constitute the acute control of these pathways, and the controlled expression of the genes encoding these enzymes is critical in mediating the longer-term regulation of these metabolic pathways. Notably, several key transcription factors are shown to be involved in the control of glucose metabolism including glycolysis and gluconeogenesis in the liver. In this review, we would like to illustrate the current understanding of glucose metabolism, with an emphasis on the transcription factors and their regulators that are involved in the chronic control of glucose homeostasis. PMID:26964834

  11. [Prevalence of abnormal glucose tolerance in hypertensive patients].

    PubMed

    Rubio-Guerra, Alberto Francisco; Rodríguez-López, Leticia; Lozano-Nuevo, José Juan; Vargas-Ayala, German; Beltrán-Soto, José Martín; Durán-Salgado, Montserrat Berenice

    2014-01-01

    Introducción: la hipertensión arterial y la diabetes mellitus tipo 2 tienden a coexistir en el mismo paciente. La hiperglucemia postprandial de dos horas es un predictor de enfermedad cardiovascular. Nuestro objetivo fue investigar la prevalencia de tolerancia a la glucosa alterada en sujetos hipertensos con glucosa de ayuno normal. Métodos: se incluyeron 65 pacientes hipertensos no diabéticos y con glucosa plasmática de ayuno < 100 mg/dL, en quienes se realizó una prueba de tolerancia a la glucosa. Resultados: encontramos tolerancia a la glucosa alterada en 32 pacientes (49.2 %), 29 en rango de intolerancia a la glucosa y tres casos en rango de diabetes mellitus. No hallamos relación entre glucosa postprandial con cifras de presión arterial ni con la edad, pero sí una correlación significativa entre intolerancia a la glucosa e índice de masa corporal > 32.6 (R = 0.59, p < 0.005, RR 4.2). Conclusión: nuestros resultados muestran que los pacientes hipertensos no diabéticos suelen cursar con tolerancia a la glucosa alterada, particularmente aquellos con índice de masa corporal aumentado, y que la glucosa de ayuno no es suficiente como prueba de monitoreo para diabetes mellitus tipo 2 en ese tipo de pacientes.

  12. Abnormal uterine bleeding.

    PubMed

    Jennings, J C

    1995-11-01

    Physicians who care for female patients cannot avoid the frequent complaint of abnormal uterine bleeding. Knowledge of the disorders that cause this problem can prevent serious consequences in many patients and improve the quality of life for many others. The availability of noninvasive and minimally invasive diagnostic studies and minimally invasive surgical treatment has revolutionized management of abnormal uterine bleeding. Similar to any other disorder, the extent to which a physician manages abnormal uterine bleeding depends on his or her own level of comfort. When limitations of either diagnostic or therapeutic capability are encountered, consultation and referral should be used to the best interest of patients.

  13. A physiologist's view of homeostasis.

    PubMed

    Modell, Harold; Cliff, William; Michael, Joel; McFarland, Jenny; Wenderoth, Mary Pat; Wright, Ann

    2015-12-01

    Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of "constancy" of the internal environment in an explicit and concrete way. In the 1960s, homeostatic regulatory mechanisms in physiology began to be described as discrete processes following the application of engineering control system analysis to physiological systems. Unfortunately, many undergraduate texts continue to highlight abstract aspects of the concept rather than emphasizing a general model that can be specifically and comprehensively applied to all homeostatic mechanisms. As a result, students and instructors alike often fail to develop a clear, concise model with which to think about such systems. In this article, we present a standard model for homeostatic mechanisms to be used at the undergraduate level. We discuss common sources of confusion ("sticky points") that arise from inconsistencies in vocabulary and illustrations found in popular undergraduate texts. Finally, we propose a simplified model and vocabulary set for helping undergraduate students build effective mental models of homeostatic regulation in physiological systems. PMID:26628646

  14. Homeostasis, Inflammation, and Disease Susceptibility

    PubMed Central

    Kotas, Maya E.; Medzhitov, Ruslan

    2015-01-01

    While modernization has dramatically increased lifespan, it has also witnessed the increasing prevalence of diseases such as obesity, hypertension and type 2 diabetes. Such chronic, acquired diseases result when normal physiologic control goes awry and may thus be viewed as failures of homeostasis. However, while nearly every process in human physiology relies on homeostatic mechanisms for stability, only some have demonstrated vulnerability to dysregulation. Additionally, chronic inflammation is a common accomplice of the diseases of homeostasis, yet the basis for this connection is not fully understood. Here we review the design of homeostatic systems and discuss universal features of control circuits that operate at the cellular, tissue and organismal levels. We suggest a framework for classification of homeostatic signals that is based on different classes of homeostatic variables they report on. Finally, we discuss how adaptability of homeostatic systems with adjustable set points creates vulnerability to dysregulation and disease. This framework highlights the fundamental parallels between homeostatic and inflammatory control mechanisms and provides a new perspective on the physiological origin of inflammation. PMID:25723161

  15. A physiologist's view of homeostasis.

    PubMed

    Modell, Harold; Cliff, William; Michael, Joel; McFarland, Jenny; Wenderoth, Mary Pat; Wright, Ann

    2015-12-01

    Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of "constancy" of the internal environment in an explicit and concrete way. In the 1960s, homeostatic regulatory mechanisms in physiology began to be described as discrete processes following the application of engineering control system analysis to physiological systems. Unfortunately, many undergraduate texts continue to highlight abstract aspects of the concept rather than emphasizing a general model that can be specifically and comprehensively applied to all homeostatic mechanisms. As a result, students and instructors alike often fail to develop a clear, concise model with which to think about such systems. In this article, we present a standard model for homeostatic mechanisms to be used at the undergraduate level. We discuss common sources of confusion ("sticky points") that arise from inconsistencies in vocabulary and illustrations found in popular undergraduate texts. Finally, we propose a simplified model and vocabulary set for helping undergraduate students build effective mental models of homeostatic regulation in physiological systems.

  16. PTPMT1 Inhibition Lowers Glucose Through Phosphorylation of SDH

    PubMed Central

    Nath, Anjali K.; Ryu, Justine H.; Jin, Youngnam N.; Roberts, Lee D.; Dejam, Andre; Gerszten, Robert E.; Peterson, Randall T.

    2015-01-01

    Summary Virtually all organisms seek to maximize fitness by matching fuel availability with energy expenditure. In vertebrates, glucose homeostasis is central to this process, with glucose levels finely tuned to match changing energy requirements. To discover new pathways regulating glucose levels in vivo, we performed a large-scale chemical screen in live zebrafish and identified the small molecule alexidine as a potent glucose-lowering agent. We found that alexidine inhibits the PTEN-like mitochondrial phosphatase PTPMT1, and that other pharmacological and genetic means of inactivating PTPMT1 also decrease glucose levels in zebrafish. Mutation of ptpmt1 eliminates the effect of alexidine, further confirming it as the glucose-lowering target of alexidine. We then identified succinate dehydrogenase (SDH) as a substrate of PTPMT1. Inactivation of PTPMT1 causes hyperphosphorylation and activation of SDH, providing a possible mechanism by which PTPMT1 coordinates glucose homeostasis. Therefore, PTPMT1 appears to be an important regulator of SDH phosphorylation status and glucose concentration. PMID:25660020

  17. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  18. Abnormal Uterine Bleeding

    MedlinePlus

    ... Abnormal uterine bleeding is any bleeding from the uterus (through your vagina) other than your normal monthly ... or fibroids (small and large growths) in the uterus can also cause bleeding. Rarely, a thyroid problem, ...

  19. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... as cancer of the uterus, cervix, or vagina • Polycystic ovary syndrome How is abnormal bleeding diagnosed? Your health care ... before the fetus can survive outside the uterus. Polycystic Ovary Syndrome: A condition characterized by two of the following ...

  20. Low Blood Glucose (Hypoglycemia)

    MedlinePlus

    ... Other Dental Problems Diabetic Eye Disease Low Blood Glucose (Hypoglycemia) What is hypoglycemia? Hypoglycemia, also called low ... actions can also help prevent hypoglycemia: Check blood glucose levels Knowing your blood glucose level can help ...

  1. Glucose test (image)

    MedlinePlus

    ... person with diabetes constantly manages their blood's sugar (glucose) levels. After a blood sample is taken and tested, it is determined whether the glucose levels are low or high. If glucose levels ...

  2. Homeostasis of peripheral immune effectors.

    PubMed

    Warrender, Christina; Forrest, Stephanie; Segel, Lee

    2004-11-01

    In this paper, we use both mathematical modeling and simulation to explore homeostasis of peripheral immune system effector cells, particularly alveolar macrophages. Our interest is in the distributed control mechanisms that allow such a population to maintain itself. We introduce a multi-purpose simulator designed to study individual cell responses to local molecular signals and their effects on population dynamics. We use the simulator to develop a model of growth factor regulation of macrophage proliferation and survival. We examine the effects of this form of regulation in the context of two competing hypotheses regarding the source of new alveolar macrophages. In one model, local cells divide to replenish the population; in the other, only cells migrating from circulation divide. We find that either scenario is plausible, although the influx-driven system is inherently more stable. The proliferation-driven system requires lower cell death and efflux rates than the influx-driven system.

  3. Copper Homeostasis in Mycobacterium tuberculosis

    PubMed Central

    Shi, Xiaoshan; Darwin, K. Heran

    2015-01-01

    Copper (Cu) is a trace element essential for the growth and development of almost all organisms, including bacteria. However, Cu overload in most systems is toxic. Studies show Cu accumulates in macrophage phagosomes infected with bacteria, suggesting Cu provides an innate immune mechanism to combat invading pathogens. To counteract the host-supplied Cu, increasing evidence suggests that bacteria have evolved Cu resistance mechanisms to facilitate their pathogenesis. In particular, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has evolved multiple pathways to respond to Cu. Here, we summarize what is currently known about Cu homeostasis in Mtb and discuss potential sources of Cu encountered by this and other pathogens in a mammalian host. PMID:25614981

  4. Oxygen sensing and metabolic homeostasis.

    PubMed

    Palmer, Biff F; Clegg, Deborah J

    2014-11-01

    Oxygen-sensing mechanisms have evolved to maintain cell and tissue homeostasis since the ability to sense and respond to changes in oxygen is essential for survival. The primary site of oxygen sensing occurs at the level of the carotid body which in response to hypoxia signals increased ventilation without the need for new protein synthesis. Chronic hypoxia activates cellular sensing mechanisms which lead to protein synthesis designed to alter cellular metabolism so cells can adapt to the low oxygen environment without suffering toxicity. The master regulator of the cellular response is hypoxia-inducible factor (HIF). Activation of this system under condition of hypobaric hypoxia leads to weight loss accompanied by increased basal metabolic rate and suppression of appetite. These effects are dose dependent, gender and genetic specific, and results in adverse effects if the exposure is extreme. Hypoxic adipose tissue may represent a unified cellular mechanism for variety of metabolic disorders, and insulin resistance in patients with metabolic syndrome.

  5. Activation of Short and Long Chain Fatty Acid Sensing Machinery in the Ileum Lowers Glucose Production in Vivo.

    PubMed

    Zadeh-Tahmasebi, Melika; Duca, Frank A; Rasmussen, Brittany A; Bauer, Paige V; Côté, Clémence D; Filippi, Beatrice M; Lam, Tony K T

    2016-04-15

    Evidence continues to emerge detailing the myriad of ways the gut microbiota influences host energy homeostasis. Among the potential mechanisms, short chain fatty acids (SCFAs), the byproducts of microbial fermentation of dietary fibers, exhibit correlative beneficial metabolic effects in humans and rodents, including improvements in glucose homeostasis. The underlying mechanisms, however, remain elusive. We here report that one of the main bacterially produced SCFAs, propionate, activates ileal mucosal free fatty acid receptor 2 to trigger a negative feedback pathway to lower hepatic glucose production in healthy rats in vivo We further demonstrate that an ileal glucagon-like peptide-1 receptor-dependent neuronal network is necessary for ileal propionate and long chain fatty acid sensing to regulate glucose homeostasis. These findings highlight the potential to manipulate fatty acid sensing machinery in the ileum to regulate glucose homeostasis.

  6. Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus.

    PubMed

    Urbano, Francesca; Filippello, Agnese; Di Pino, Antonino; Barbagallo, Davide; Di Mauro, Stefania; Pappalardo, Alessandro; Rabuazzo, Agata Maria; Purrello, Michele; Purrello, Francesco; Piro, Salvatore

    2016-04-01

    Glucagon-like peptide-1 (GLP-1) is a gut L-cell hormone that enhances glucose-stimulated insulin secretion. Several approaches that prevent GLP-1 degradation or activate the GLP-1 receptor are being used to treat type 2 diabetes mellitus (T2DM) patients. In T2DM, GLP-1 secretion has been suggested to be impaired, and this defect appears to be a consequence rather than a cause of impaired glucose homeostasis. However, although defective GLP-1 secretion has been correlated with insulin resistance, little is known about the direct effects of chronic high glucose concentrations, which are typical in diabetes patients, on GLP-1-secreting cell function. In the present study, we demonstrate that glucotoxicity directly affects GLP-1 secretion in GLUTag cells chronically exposed to high glucose. Our results indicate that this abnormality is associated with a decrease in ATP production due to the elevated expression of mitochondrial uncoupling protein 2 (UCP2). Furthermore, UCP2 inhibition using small interfering RNA (siRNA) and the application of glibenclamide, an ATP-sensitive potassium (KATP(+)) channel blocker, reverse the GLP-1 secretion defect induced by chronic high-glucose treatment. These results show that glucotoxicity diminishes the secretory responsiveness of GLP-1-secreting cells to acute glucose stimulation. We conclude that the loss of the incretin effect, as observed in T2DM patients, could at least partially depend on hyperglycemia, which is typical in diabetes patients. Such an understanding may not only provide new insight into diabetes complications but also ultimately contribute to the identification of novel molecular targets within intestinal L-cells for controlling and improving endogenous GLP-1 secretion.

  7. Targeting the NLRP3 Inflammasome to Reduce Diet-Induced Metabolic Abnormalities in Mice

    PubMed Central

    Chiazza, Fausto; Couturier-Maillard, Aurélie; Benetti, Elisa; Mastrocola, Raffaella; Nigro, Debora; Cutrin, Juan C; Serpe, Loredana; Aragno, Manuela; Fantozzi, Roberto; Ryffel, Bernard; Collino, Massimo

    2015-01-01

    Although the molecular links underlying the causative relationship between chronic low-grade inflammation and insulin resistance are not completely understood, compelling evidence suggests a pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Here we tested the hypothesis that either a selective pharmacological inhibition or a genetic downregulation of the NLRP3 inflammasome results in reduction of the diet-induced metabolic alterations. Male C57/BL6 wild-type mice and NLRP3−/− littermates were fed control diet or high-fat, high-fructose diet (HD). A subgroup of HD-fed wild-type mice was treated with the NLRP3 inflammasome inhibitor BAY 11-7082 (3 mg/kg intraperitoneally [IP]). HD feeding increased plasma and hepatic lipids and impaired glucose homeostasis and renal function. Renal and hepatic injury was associated with robust increases in profibrogenic markers, while only minimal fibrosis was recorded. None of these metabolic abnormalities were detected in HD-fed NLRP3−/− mice, and they were dramatically reduced in HD-mice treated with the NLRP3 inflammasome inhibitor. BAY 11-7082 also attenuated the diet-induced increase in NLRP3 inflammasome expression, resulting in inhibition of caspase-1 activation and interleukin (IL)-1β and IL-18 production (in liver and kidney). Interestingly, BAY 11-7082, but not gene silencing, inhibited nuclear factor (NF)-κB nuclear translocation. Overall, these results demonstrate that the selective pharmacological modulation of the NLRP3 inflammasome attenuates the metabolic abnormalities and the related organ injury/dysfunction caused by chronic exposure to HD, with effects similar to those obtained by NLRP3 gene silencing. PMID:26623925

  8. Regulation of. beta. -cell glucose transporter gene expression

    SciTech Connect

    Chen, Ling; Alam, Tausif; Johnson, J.H.; Unger, R.H. Department of Veterans Affairs Medical Center, Dallas, TX ); Hughes, S.; Newgard, C.B. )

    1990-06-01

    It has been postulated that a glucose transporter of {beta} cells (GLUT-2) may be important in glucose-stimulated insulin secretion. To determine whether this transporter is constitutively expressed or regulated, the authors subjected conscious unrestrained Wistar rats to perturbations in glucose homeostasis and quantitated {beta}-cell GLUT-2 mRNA by in situ hybridization. After 3 hr of hypoglycemia, GLUT-2 and proinsulin mRNA signal densities were reduced by 25% of the level in control rats. After 4 days, GLUT-2 and proinsulin mRNA densities were reduced by 85% and 65%, respectively. After 12 days of hypoglycemia, the K{sub m} for 3-O-methyl-D-glucose transport in isolated rat islets, normally 18-20 mM, was 2.5 mM. This provides functional evidence of a profound reduction of high K{sub m} glucose transporter in {beta} cells. In contrast, GLUT-2 was only slightly reduced by hypoglycemia in liver. To determine the effect of prolonged hyperglycemia, they also infused animals with 50% (wt/vol) glucose for 5 days. Hyperglycemic clamping increased GLUT-2 mRNA by 46% whereas proinsulin mRNA doubled. They conclude that GLUT-2 expression in {beta} cells, but not liver, is subject to regulation by certain perturbations in blood glucose homeostasis.

  9. Neuronal Expression of Glucosylceramide Synthase in Central Nervous System Regulates Body Weight and Energy Homeostasis

    PubMed Central

    Nordström, Viola; Willershäuser, Monja; Herzer, Silke; Rozman, Jan; von Bohlen und Halbach, Oliver; Meldner, Sascha; Rothermel, Ulrike; Kaden, Sylvia; Roth, Fabian C.; Waldeck, Clemens; Gretz, Norbert; de Angelis, Martin Hrabě; Draguhn, Andreas; Klingenspor, Martin

    2013-01-01

    Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis. PMID:23554574

  10. Spare mitochondrial respiratory capacity permits human adipocytes to maintain ATP homeostasis under hypoglycemic conditions.

    PubMed

    Keuper, Michaela; Jastroch, Martin; Yi, Chun-Xia; Fischer-Posovszky, Pamela; Wabitsch, Martin; Tschöp, Matthias H; Hofmann, Susanna M

    2014-02-01

    Mitochondrial dysfunction in white adipose tissue plays a key role in the pathogenesis of type 2 diabetes. Emerging evidence specifically suggests that altered oxidative phosphorylation in adipocytes may have a relevant effect on systemic glucose homeostasis, requiring understanding of adipocyte bioenergetics. We analyzed energetic flux of an intact human adipocyte cell model by plate-based respirometry and extracellular acidification. During differentiation, we discovered that glycolytic ATP production was increasingly replaced by mitochondrial oxidative metabolism (from 20 to 60%). This observation was corroborated by simultaneous up-regulation of canonical mitochondrial gene programs, such as peroxisome proliferator-activated receptor γ coactivator α (PGC1α; 150-fold) and cytochrome c-1 (CytC; 3-fold). Mimicking diabetic phenotypes by exposure to various glucose levels (0, 5, and 25 mM) resulted in immediate adjustments of glycolytic and mitochondrial activity that aimed to maintain intracellular ATP. We conclude that ATP deficits by mitochondrial failure are compensated by glycolytic ATP production, resulting in inefficient conversion of glucose to cellular ATP. Metabolic inefficiency may enhance glucose uptake, therefore improving systemic glucose homeostasis. Notably, mature adipocytes developed a high spare respiratory capacity (increased by 6-fold) permitting rapid adaptation to metabolic changes. Spare respiratory capacity may also allow additional metabolic scope for energy dissipation, potentially offering new therapeutic targets for the treatment of metabolic disease.

  11. [Hair shaft abnormalities].

    PubMed

    Itin, P H; Düggelin, M

    2002-05-01

    Hair shaft disorders may lead to brittleness and uncombable hair. In general the hair feels dry and lusterless. Hair shaft abnormalities may occur as localized or generalized disorders. Genetic predisposition or exogenous factors are able to produce and maintain hair shaft abnormalities. In addition to an extensive history and physical examination the most important diagnostic examination to analyze a hair shaft problem is light microscopy. Therapy of hair shaft disorders should focus to the cause. In addition, minimizing traumatic influences to hair shafts, such as dry hair with an electric dryer, permanent waves and dyes is important. A short hair style is more suitable for such patients with hair shaft disorders.

  12. Affected chromosome homeostasis and genomic instability of clonal yeast cultures.

    PubMed

    Adamczyk, Jagoda; Deregowska, Anna; Panek, Anita; Golec, Ewelina; Lewinska, Anna; Wnuk, Maciej

    2016-05-01

    Yeast cells originating from one single colony are considered genotypically and phenotypically identical. However, taking into account the cellular heterogeneity, it seems also important to monitor cell-to-cell variations within a clone population. In the present study, a comprehensive yeast karyotype screening was conducted using single chromosome comet assay. Chromosome-dependent and mutation-dependent changes in DNA (DNA with breaks or with abnormal replication intermediates) were studied using both single-gene deletion haploid mutants (bub1, bub2, mad1, tel1, rad1 and tor1) and diploid cells lacking one active gene of interest, namely BUB1/bub1, BUB2/bub2, MAD1/mad1, TEL1/tel1, RAD1/rad1 and TOR1/tor1 involved in the control of cell cycle progression, DNA repair and the regulation of longevity. Increased chromosome fragility and replication stress-mediated chromosome abnormalities were correlated with elevated incidence of genomic instability, namely aneuploid events-disomies, monosomies and to a lesser extent trisomies as judged by in situ comparative genomic hybridization (CGH). The tor1 longevity mutant with relatively balanced chromosome homeostasis was found the most genomically stable among analyzed mutants. During clonal yeast culture, spontaneously formed abnormal chromosome structures may stimulate changes in the ploidy state and, in turn, promote genomic heterogeneity. These alterations may be more accented in selected mutated genetic backgrounds, namely in yeast cells deficient in proper cell cycle regulation and DNA repair.

  13. Sleep restriction acutely impairs glucose tolerance in rats.

    PubMed

    Jha, Pawan K; Foppen, Ewout; Kalsbeek, Andries; Challet, Etienne

    2016-06-01

    Chronic sleep curtailment in humans has been related to impairment of glucose metabolism. To better understand the underlying mechanisms, the purpose of the present study was to investigate the effect of acute sleep deprivation on glucose tolerance in rats. A group of rats was challenged by 4-h sleep deprivation in the early rest period, leading to prolonged (16 h) wakefulness. Another group of rats was allowed to sleep during the first 4 h of the light period and sleep deprived in the next 4 h. During treatment, food was withdrawn to avoid a postmeal rise in plasma glucose. An intravenous glucose tolerance test (IVGTT) was performed immediately after the sleep deprivation period. Sleep deprivation at both times of the day similarly impaired glucose tolerance and reduced the early-phase insulin responses to a glucose challenge. Basal concentrations of plasma glucose, insulin, and corticosterone remained unchanged after sleep deprivation. Throughout IVGTTs, plasma corticosterone concentrations were not different between the control and sleep-deprived group. Together, these results demonstrate that independent of time of day and sleep pressure, short sleep deprivation during the resting phase favors glucose intolerance in rats by attenuating the first-phase insulin response to a glucose load. In conclusion, this study highlights the acute adverse effects of only a short sleep restriction on glucose homeostasis. PMID:27354542

  14. Ionic homeostasis in brain conditioning

    PubMed Central

    Cuomo, Ornella; Vinciguerra, Antonio; Cerullo, Pierpaolo; Anzilotti, Serenella; Brancaccio, Paola; Bilo, Leonilda; Scorziello, Antonella; Molinaro, Pasquale; Di Renzo, Gianfranco; Pignataro, Giuseppe

    2015-01-01

    Most of the current focus on developing neuroprotective therapies is aimed at preventing neuronal death. However, these approaches have not been successful despite many years of clinical trials mainly because the numerous side effects observed in humans and absent in animals used at preclinical level. Recently, the research in this field aims to overcome this problem by developing strategies which induce, mimic, or boost endogenous protective responses and thus do not interfere with physiological neurotransmission. Preconditioning is a protective strategy in which a subliminal stimulus is applied before a subsequent harmful stimulus, thus inducing a state of tolerance in which the injury inflicted by the challenge is mitigated. Tolerance may be observed in ischemia, seizure, and infection. Since it requires protein synthesis, it confers delayed and temporary neuroprotection, taking hours to develop, with a pick at 1–3 days. A new promising approach for neuroprotection derives from post-conditioning, in which neuroprotection is achieved by a modified reperfusion subsequent to a prolonged ischemic episode. Many pathways have been proposed as plausible mechanisms to explain the neuroprotection offered by preconditioning and post-conditioning. Although the mechanisms through which these two endogenous protective strategies exert their effects are not yet fully understood, recent evidence highlights that the maintenance of ionic homeostasis plays a key role in propagating these neuroprotective phenomena. The present article will review the role of protein transporters and ionic channels involved in the control of ionic homeostasis in the neuroprotective effect of ischemic preconditioning and post-conditioning in adult brain, with particular regards to the Na+/Ca2+ exchangers (NCX), the plasma membrane Ca2+-ATPase (PMCA), the Na+/H+ exchange (NHE), the Na+/K+/2Cl− cotransport (NKCC) and the acid-sensing cation channels (ASIC). Ischemic stroke is the third leading

  15. Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney.

    PubMed

    Palmer, Biff F; Clegg, Deborah J; Taylor, Simeon I; Weir, Matthew R

    2016-08-01

    Diabetic ketoacidosis is a serious metabolic condition that may occur in patients with either Type 1 or Type 2 diabetes. The accumulation of ketoacids in the serum is a consequence of insulin deficiency and glucagon excess. Sodium Glucose Transporter 2 (SGLT2) inhibitors are novel therapeutic treatments for improving glucose homeostasis in patients with diabetes. Through reductions in glucose reabsorption by the kidney, they lower serum glucose in patients with Type 2 diabetes and they improve glucose control whether used alone or in combination with other therapies. Mechanistically, these drugs increase serum ketoacids and increase glucagon production, which in some individuals, can lead to formation of diabetic ketoacidosis. This review will first focus in how the kidney normally handles ketoacids, and second will discuss how the SGLT2 inhibitors affect the kidney in such a way so as to enhance the risk for development of ketoacidosis in susceptible individuals. PMID:27240541

  16. Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney.

    PubMed

    Palmer, Biff F; Clegg, Deborah J; Taylor, Simeon I; Weir, Matthew R

    2016-08-01

    Diabetic ketoacidosis is a serious metabolic condition that may occur in patients with either Type 1 or Type 2 diabetes. The accumulation of ketoacids in the serum is a consequence of insulin deficiency and glucagon excess. Sodium Glucose Transporter 2 (SGLT2) inhibitors are novel therapeutic treatments for improving glucose homeostasis in patients with diabetes. Through reductions in glucose reabsorption by the kidney, they lower serum glucose in patients with Type 2 diabetes and they improve glucose control whether used alone or in combination with other therapies. Mechanistically, these drugs increase serum ketoacids and increase glucagon production, which in some individuals, can lead to formation of diabetic ketoacidosis. This review will first focus in how the kidney normally handles ketoacids, and second will discuss how the SGLT2 inhibitors affect the kidney in such a way so as to enhance the risk for development of ketoacidosis in susceptible individuals.

  17. Blood Test: Glucose

    MedlinePlus

    ... Things to Know About Zika & Pregnancy Blood Test: Glucose KidsHealth > For Parents > Blood Test: Glucose Print A A A Text Size What's in ... de sangre: glucosa What It Is A blood glucose test measures the amount of glucose (the main ...

  18. cAMP Sensor EPAC Proteins and Energy Homeostasis

    PubMed Central

    Almahariq, Muayad; Mei, Fang C.; Cheng, Xiaodong

    2013-01-01

    The pleotropic second messenger cAMP plays a critical role in mediating the effects of various hormones on metabolism. The major intracellular functions of cAMP are transduced by protein kinase A (PKA) and exchange proteins directly activated by cAMP (EPACs). The latter act as guanine nucleotide exchange factors for the RAS-like small G-proteins Rap1 and Rap2. While the role of PKA in regulating energy balance has been extensively studied, EPACs’ impact remains relatively enigmatic. This review summarizes recent genetic and pharmacological studies concerning EPACs’ involvement in glucose homeostasis and energy balance, through regulation of leptin and insulin signaling pathways. Additionally, the development of small molecule EPAC-specific modulators and their therapeutic potential for the treatment of diabetes and obesity are discussed. PMID:24231725

  19. Hypothalamic AMPK as a Regulator of Energy Homeostasis

    PubMed Central

    Huynh, My Khanh Q.; Kinyua, Ann W.; Yang, Dong Joo

    2016-01-01

    Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences. Here we explore the factors that affect hypothalamic AMPK activity and give the underlying mechanisms for the role of central AMPK in energy homeostasis together with the physiological effects of hypothalamic AMPK on energy balance restoration. PMID:27547453

  20. Lepidium peruvianum chacon restores homeostasis impaired by restraint stress.

    PubMed

    López-Fando, A; Gómez-Serranillos, M P; Iglesias, I; Lock, O; Upamayta, U P; Carretero, M E

    2004-06-01

    Lepidium peruvianum root has been traditionally utilized by native Peruvians, since before the time of the Incas, for both nutritional and putative medicinal purposes as an adaptogen and also to enhance fertility in humans and animals. The present research was conducted to evaluate the anti-stress activity of the methanolic extract of Lepidium peruvianum. The drug is capable of attenuating or even eliminating variations in homeostasis produced by stress since it reduces or abolishes stress-induced ulcers, elevated corticosterone levels, the reduction of glucose and the increase in the weight of adrenal glands produced by stress. It also eliminates the decrease in free fatty-acids (FFA) in plasma produced by stress and we obtain a positive result in the forced-swimming test. Thus, it did not appear to affect restraint stress-induced immunosuppression.

  1. Hypothalamic AMPK as a Regulator of Energy Homeostasis.

    PubMed

    Huynh, My Khanh Q; Kinyua, Ann W; Yang, Dong Joo; Kim, Ki Woo

    2016-01-01

    Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences. Here we explore the factors that affect hypothalamic AMPK activity and give the underlying mechanisms for the role of central AMPK in energy homeostasis together with the physiological effects of hypothalamic AMPK on energy balance restoration. PMID:27547453

  2. An acetylation rheostat for the control of muscle energy homeostasis

    PubMed Central

    Menzies, Keir; Auwerx, Johan

    2013-01-01

    In recent years the role of acetylation has gained ground as an essential modulator of intermediary metabolism in skeletal muscle. Imbalance in energy homeostasis or chronic cellular stress, due to diet, aging or disease, translate into alterations in the acetylation levels of key proteins which governs bioenergetics, cellular substrate use and/or changes in mitochondrial content and function. For example, cellular stress induced by exercise or caloric restriction can alter the coordinated activity of acetyltransferases and deacetylases to increase mitochondrial biogenesis and function in order to adapt to low energetic levels. The natural duality of these enzymes, as metabolic sensors and effector proteins, have helped biologists understand how the body can integrate seemingly distinct signaling pathways to control mitochondrial biogenesis, insulin sensitivity, glucose transport, reactive oxygen species handling, angiogenesis and muscle satellite cell proliferation/differentiation. Our review will summarize the recent developments related to acetylation dependent responses following metabolic stress in skeletal muscle. PMID:23999889

  3. An acetylation rheostat for the control of muscle energy homeostasis.

    PubMed

    Menzies, Keir; Auwerx, Johan

    2013-12-01

    In recent years, the role of acetylation has gained ground as an essential modulator of intermediary metabolism in skeletal muscle. Imbalance in energy homeostasis or chronic cellular stress, due to diet, aging, or disease, translate into alterations in the acetylation levels of key proteins which govern bioenergetics, cellular substrate use, and/or changes in mitochondrial content and function. For example, cellular stress induced by exercise or caloric restriction can alter the coordinated activity of acetyltransferases and deacetylases to increase mitochondrial biogenesis and function in order to adapt to low energetic levels. The natural duality of these enzymes, as metabolic sensors and effector proteins, has helped biologists to understand how the body can integrate seemingly distinct signaling pathways to control mitochondrial biogenesis, insulin sensitivity, glucose transport, reactive oxygen species handling, angiogenesis, and muscle satellite cell proliferation/differentiation. Our review will summarize the recent developments related to acetylation-dependent responses following metabolic stress in skeletal muscle. PMID:23999889

  4. Effect of Intermittent Cold Exposure on Brown Fat Activation, Obesity, and Energy Homeostasis in Mice

    PubMed Central

    Ravussin, Yann; Xiao, Cuiying; Gavrilova, Oksana; Reitman, Marc L.

    2014-01-01

    Homeotherms have specific mechanisms to maintain a constant core body temperature despite changes in thermal environment, food supply, and metabolic demand. Brown adipose tissue, the principal thermogenic organ, quickly and efficiently increases heat production by dissipating the mitochondrial proton motive force. It has been suggested that activation of brown fat, via either environmental (i.e. cold exposure) or pharmacologic means, could be used to increase metabolic rate and thus reduce body weight. Here we assess the effects of intermittent cold exposure (4°C for one to eight hours three times a week) on C57BL/6J mice fed a high fat diet. Cold exposure increased metabolic rate approximately two-fold during the challenge and activated brown fat. In response, food intake increased to compensate fully for the increased energy expenditure; thus, the mice showed no reduction in body weight or adiposity. Despite the unchanged adiposity, the cold-treated mice showed transient improvements in glucose homeostasis. Administration of the cannabinoid receptor-1 inverse agonist AM251 caused weight loss and improvements in glucose homeostasis, but showed no further improvements when combined with cold exposure. These data suggest that intermittent cold exposure causes transient, meaningful improvements in glucose homeostasis, but without synergy when combined with AM251. Since energy expenditure is significantly increased during cold exposure, a drug that dissociates food intake from metabolic demand during cold exposure may achieve weight loss and further metabolic improvements. PMID:24465761

  5. Hyperproinsulinemia in a three-generation Caucasian family due to mutant proinsulin (Arg{sup 65}{yields}His) not associated with impaired glucose tolerance: The contribution of mutant proinsulin to insulin bioactivity

    SciTech Connect

    Roder, M.E.; Vissing, H.; Nauck, M.A.

    1996-04-01

    Familial hyperproinsulinemia is a genetic abnormality characterized by an increased proportion of proinsulin immunoreactivity in the circulation due to mutations affecting the posttranslational processing of proinsulin. In affected Japanese families, this has been associated with noninsulin-dependent diabetes mellitus or impaired glucose tolerance. A three-generation Caucasian family with hyperproinsulinemia was identified through unexplained hyperinsulinemia in a normal volunteer participating in a metabolic study. High pressure liquid chromatography analysis of fasting plasma revealed a major peak eluting close to the position of proinsulin. Direct sequencing of the proinsulin gene exon 3 showed a heterozygous point mutation (CGT{yields}CAT) resulting in the substitution of Arg{yields}His in position 65 (corresponding to the AC cleavage site) in the index case, his mother, and his maternal grandmother. All affected subjects had normal oral glucose tolerance. In the basal state and after oral glucose administration, their proinsulin responses were slightly reduced. However, when calculating insulin bioactivity by assuming 9% activity for mutant Arg{sup 65}{yields}His proinsulin, responses in affected subjects were comparable to those in normal subjects. In conclusion, our data demonstrate hyperproinsulinemia in a three-generation Caucasian family due to heterozygous mutant Arg{sup 65}{yields}His proinsulin. This was not associated with impaired glucose tolerance. These results suggest that this mutation in the heterozygous state per se does not affect glucose tolerance and that the biological activity of mutant proinsulin contributes to glucose homeostasis in this family. The association of the same mutation with impaired glucose tolerance or diabetes in previous studies may be the result of selection bias or associated conditions (e.g. the genetic background of the kindreds examined). 29 refs., 5 figs., 3 tabs.

  6. Dual epithelial and immune cell function of Dvl1 regulates gut microbiota composition and intestinal homeostasis

    PubMed Central

    Belinson, Haim; Savage, Adam K.; Fadrosh, Douglas; Kuo, Yien-Ming; Lin, Din; Valladares, Ricardo; Nusse, Ysbrand; Wynshaw-Boris, Anthony; Lynch, Susan V.; Locksley, Richard M.; Klein, Ophir D.

    2016-01-01

    Homeostasis of the gastrointestinal (GI) tract is controlled by complex interactions between epithelial and immune cells and the resident microbiota. Here, we studied the role of Wnt signaling in GI homeostasis using Disheveled 1 knockout (Dvl1−/−) mice, which display an increase in whole gut transit time. This phenotype is associated with a reduction and mislocalization of Paneth cells and an increase in CD8+ T cells in the lamina propria. Bone marrow chimera experiments demonstrated that GI dysfunction requires abnormalities in both epithelial and immune cells. Dvl1−/− mice exhibit a significantly distinct GI microbiota, and manipulation of the gut microbiota in mutant mice rescued the GI transit abnormality without correcting the Paneth and CD8+ T cell abnormalities. Moreover, manipulation of the gut microbiota in wild-type mice induced a GI transit abnormality akin to that seen in Dvl1−/− mice. Together, these data indicate that microbiota manipulation can overcome host dysfunction to correct GI transit abnormalities. Our findings illustrate a mechanism by which the epithelium and immune system coregulate gut microbiota composition to promote normal GI function. PMID:27525310

  7. Dual epithelial and immune cell function of Dvl1 regulates gut microbiota composition and intestinal homeostasis

    PubMed Central

    Belinson, Haim; Savage, Adam K.; Fadrosh, Douglas; Kuo, Yien-Ming; Lin, Din; Valladares, Ricardo; Nusse, Ysbrand; Wynshaw-Boris, Anthony; Lynch, Susan V.; Locksley, Richard M.

    2016-01-01

    Homeostasis of the gastrointestinal (GI) tract is controlled by complex interactions between epithelial and immune cells and the resident microbiota. Here, we studied the role of Wnt signaling in GI homeostasis using Disheveled 1 knockout (Dvl1–/–) mice, which display an increase in whole gut transit time. This phenotype is associated with a reduction and mislocalization of Paneth cells and an increase in CD8+ T cells in the lamina propria. Bone marrow chimera experiments demonstrated that GI dysfunction requires abnormalities in both epithelial and immune cells. Dvl1–/– mice exhibit a significantly distinct GI microbiota, and manipulation of the gut microbiota in mutant mice rescued the GI transit abnormality without correcting the Paneth and CD8+ T cell abnormalities. Moreover, manipulation of the gut microbiota in wild-type mice induced a GI transit abnormality akin to that seen in Dvl1–/– mice. Together, these data indicate that microbiota manipulation can overcome host dysfunction to correct GI transit abnormalities. Our findings illustrate a mechanism by which the epithelium and immune system coregulate gut microbiota composition to promote normal GI function. PMID:27525310

  8. Cellular Links between Neuronal Activity and Energy Homeostasis

    PubMed Central

    Shetty, Pavan K.; Galeffi, Francesca; Turner, Dennis A.

    2012-01-01

    Neuronal activity, astrocytic responses to this activity, and energy homeostasis are linked together during baseline, conscious conditions, and short-term rapid activation (as occurs with sensory or motor function). Nervous system energy homeostasis also varies during long-term physiological conditions (i.e., development and aging) and with adaptation to pathological conditions, such as ischemia or low glucose. Neuronal activation requires increased metabolism (i.e., ATP generation) which leads initially to substrate depletion, induction of a variety of signals for enhanced astrocytic function, and increased local blood flow and substrate delivery. Energy generation (particularly in mitochondria) and use during ATP hydrolysis also lead to considerable heat generation. The local increases in blood flow noted following neuronal activation can both enhance local substrate delivery but also provides a heat sink to help cool the brain and removal of waste by-products. In this review we highlight the interactions between short-term neuronal activity and energy metabolism with an emphasis on signals and factors regulating astrocyte function and substrate supply. PMID:22470340

  9. Ketone body metabolism and sleep homeostasis in mice.

    PubMed

    Chikahisa, Sachiko; Shimizu, Noriyuki; Shiuchi, Tetsuya; Séi, Hiroyoshi

    2014-04-01

    A link has been established between energy metabolism and sleep homeostasis. The ketone bodies acetoacetate and β-hydroxybutyrate, generated from the breakdown of fatty acids, are major metabolic fuels for the brain under conditions of low glucose availability. Ketogenesis is modulated by the activity of peroxisome proliferator-activated receptor alpha (PPARα), and treatment with a PPAR activator has been shown to induce a marked increase in plasma acetoacetate and decreased β-hydroxybutyrate in mice, accompanied by increased slow-wave activity during non-rapid eye movement (NREM) sleep. The present study investigated the role of ketone bodies in sleep regulation. Six-hour sleep deprivation increased plasma ketone bodies and their ratio (acetoacetate/β-hydroxybutyrate) in 10-week-old male mice. Moreover, sleep deprivation increased mRNA expression of ketogenic genes such as PPARα and 3-hydroxy-3-methylglutarate-CoA synthase 2 in the brain and decreased ketolytic enzymes such as succinyl-CoA: 3-oxoacid CoA transferase. In addition, central injection of acetoacetate, but not β-hydroxybutyrate, markedly increased slow-wave activity during NREM sleep and suppressed glutamate release. Central metabolism of ketone bodies, especially acetoacetate, appears to play a role in the regulation of sleep homeostasis.

  10. Circadian clocks in fuel harvesting and energy homeostasis.

    PubMed

    Ramsey, K M; Bass, J

    2011-01-01

    Circadian systems have evolved in plants, eubacteria, neurospora, and the metazoa as a mechanism to optimize energy acquisition and storage in synchrony with the rotation of the Earth on its axis. In plants, circadian clocks drive the expression of genes involved in oxygenic photosynthesis during the light and nitrogen fixation during the dark, repeating this cycle each day. In mammals, the core clock in the suprachiasmatic nucleus (SCN) functions to entrain extra-SCN and peripheral clocks to the light cycle, including regions central to energy homeostasis and sleep, as well as peripheral tissues involved in glucose and lipid metabolism. Tissue-specific gene targeting has shown a primary role of clock genes in endocrine pancreas insulin secretion, indicating that local clocks play a cell-autonomous role in organismal homeostasis. A present focus is to dissect the consequences of clock disruption on modulation of nuclear hormone receptor signaling and on posttranscriptional regulation of intermediary metabolism. Experimental genetic studies have pointed toward extensive interplay between circadian and metabolic systems and offer a means to dissect the impact of local tissue molecular clocks on fuel utilization across the sleep-wake cycle.

  11. Effects of methyl mercury on the activity and gene expression of mouse Langerhans islets and glucose metabolism.

    PubMed

    Maqbool, Faheem; Bahadar, Haji; Niaz, Kamal; Baeeri, Maryam; Rahimifard, Mahban; Navaei-Nigjeh, Mona; Ghasemi-Niri, Seyedeh Farnaz; Abdollahi, Mohammad

    2016-07-01

    Mercury (Hg) is a well-known heavy metal and causes various toxic effects. It is abundantly present in fish in the form of methyl mercury (MeHg). Also, various other forms of mercury can enter human body either from environment like inhalation or through dental amalgams. The present study was designed to assess MeHg induced toxicity in mouse plasma and pancreatic islets with respect to insulin secretion, oxidative balance, glucose tolerance, gene expression, caspases 3 and 9 activities. MeHg was dissolved in tap water and administered at doses 2.5, 5 and 10 mg/kg/day, for 4 weeks. In mice, MeHg significantly caused increase in plasma insulin as well as C-peptides. Glucose intolerance, insulin resistance and hyperglycemia are main consequences of our study that correlate with the gene expression changes of glucose homeostasis as well. MeHg caused increase lipid peroxidation in a dose-dependent manner in plasma as well as pancreatic islets. In addition, total thiol molecules and ferrous reducing antioxidant power in MeHg treated group was decreased in plasma as well as pancreatic islets. Caspases 3 and 9 activities of pancreatic islets were upregulated in MeHg exposed animals. Reactive oxygen species were extremely high in pancreatic islets of MeHg treated groups. MeHg disrupted gluconeogenesis/glycogenolysis pathways and insulin secretory functions of islets by targeting GDH, GLUT2 and GCK genes of pancreatic islets. In conclusion, the current study revealed that insulin pathways, oxidative balance and glucose metabolism encoded genetic makeup are susceptible to MeHg toxicity and the subsequent oxidative stress and alternations in gene expression could lead toward functional abnormalities in other organs. PMID:27178136

  12. MicroRNA 33 Regulates Glucose Metabolism

    PubMed Central

    Ramírez, Cristina M.; Goedeke, Leigh; Rotllan, Noemi; Yoon, Je-Hyun; Cirera-Salinas, Daniel; Mattison, Julie A.; Suárez, Yajaira; de Cabo, Rafael; Gorospe, Myriam

    2013-01-01

    Metabolic diseases are characterized by the failure of regulatory genes or proteins to effectively orchestrate specific pathways involved in the control of many biological processes. In addition to the classical regulators, recent discoveries have shown the remarkable role of small noncoding RNAs (microRNAs [miRNAs]) in the posttranscriptional regulation of gene expression. In this regard, we have recently demonstrated that miR-33a and miR33b, intronic miRNAs located within the sterol regulatory element-binding protein (SREBP) genes, regulate lipid metabolism in concert with their host genes. Here, we show that miR-33b also cooperates with SREBP1 in regulating glucose metabolism by targeting phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), key regulatory enzymes of hepatic gluconeogenesis. Overexpression of miR-33b in human hepatic cells inhibits PCK1 and G6PC expression, leading to a significant reduction of glucose production. Importantly, hepatic SREBP1c/miR-33b levels correlate inversely with the expression of PCK1 and G6PC upon glucose infusion in rhesus monkeys. Taken together, these results suggest that miR-33b works in concert with its host gene to ensure a fine-tuned regulation of lipid and glucose homeostasis, highlighting the clinical potential of miR-33a/b as novel therapeutic targets for a range of metabolic diseases. PMID:23716591

  13. Modulation of cellular redox homeostasis by the endocannabinoid system

    PubMed Central

    2016-01-01

    The endocannabinoid system (ECS) and reactive oxygen species (ROS) constitute two key cellular signalling systems that participate in the modulation of diverse cellular functions. Importantly, growing evidence suggests that cross-talk between these two prominent signalling systems acts to modulate functionality of the ECS as well as redox homeostasis in different cell types. Herein, we review and discuss evidence pertaining to ECS-induced regulation of ROS generating and scavenging mechanisms, as well as highlighting emerging work that supports redox modulation of ECS function. Functionally, the studies outlined reveal that interactions between the ECS and ROS signalling systems can be both stimulatory and inhibitory in nature, depending on cell stimulus, the source of ROS species and cell context. Importantly, such cross-talk may act to maintain cell function, whereas abnormalities in either system may propagate and undermine the stability of both systems, thereby contributing to various pathologies associated with their dysregulation. PMID:27248801

  14. Diet-induced obesity impairs hypothalamic glucose sensing but not glucose hypothalamic extracellular levels, as measured by microdialysis

    PubMed Central

    de Andrade, I S; Zemdegs, J C S; de Souza, A P; Watanabe, R L H; Telles, M M; Nascimento, C M O; Oyama, L M; Ribeiro, E B

    2015-01-01

    Background/Objectives: Glucose from the diet may signal metabolic status to hypothalamic sites controlling energy homeostasis. Disruption of this mechanism may contribute to obesity but its relevance has not been established. The present experiments aimed at evaluating whether obesity induced by chronic high-fat intake affects the ability of hypothalamic glucose to control feeding. We hypothesized that glucose transport to the hypothalamus as well as glucose sensing and signaling could be impaired by high-fat feeding. Subjects/methods: Female Wistar rats were studied after 8 weeks on either control or high-lard diet. Daily food intake was measured after intracerebroventricular (i.c.v.) glucose. Glycemia and glucose content of medial hypothalamus microdialysates were measured in response to interperitoneal (i.p.) glucose or meal intake after an overnight fast. The effect of refeeding on whole hypothalamus levels of glucose transporter proteins (GLUT) 1, 2 and 4, AMPK and phosphorylated AMPK levels was determined by immunoblotting. Results: High-fat rats had higher body weight and fat content and serum leptin than control rats, but normal insulin levels and glucose tolerance. I.c.v. glucose inhibited food intake in control but failed to do so in high-fat rats. Either i.p. glucose or refeeding significantly increased glucose hypothalamic microdialysate levels in the control rats. These levels showed exacerbated increases in the high-fat rats. GLUT1 and 4 levels were not affected by refeeding. GLUT2 levels decreased and phosphor-AMPK levels increased in the high-fat rats but not in the controls. Conclusions: The findings suggest that, in the high-fat rats, a defective glucose sensing by decreased GLUT2 levels contributed to an inappropriate activation of AMPK after refeeding, despite increased extracellular glucose levels. These derangements were probably involved in the abolition of hypophagia in response to i.c.v. glucose. It is proposed that ‘glucose resistance

  15. Protein Homeostasis and Aging: the importance of exquisite quality control

    PubMed Central

    Koga, Hiroshi; Kaushik, Susmita; Cuervo, Ana Maria

    2010-01-01

    All cells count on precise mechanisms that regulate protein homeostasis to maintain a stable and functional proteome. A progressive deterioration in the ability of cells to preserve the stability of their proteome occurs with age and contributes to the functional loss characteristic of old organisms. Molecular chaperones and the proteolytic systems are responsible for this cellular quality control by assuring continuous renewal of intracellular proteins. When protein damage occurs, such as during cellular stress, the coordinated action of these cellular surveillance systems allows detection and repair of the damaged structures or, in many instances, leads to the complete elimination of the altered proteins from inside cells. Dysfunction of the quality control mechanisms and intracellular accumulation of abnormal proteins in the form of protein inclusions and aggregates occur in almost all tissues of an aged organism. Preservation or enhancement of the activity of these surveillance systems until late in life improves their resistance to stress and is sufficient to slow down aging. In this work, we review recent advances on our understanding of the contribution of chaperones and proteolytic systems to the maintenance of cellular homeostasis, the cellular response to stress and ultimately to longevity. PMID:20152936

  16. Health, homeostasis, and the situation-specificity of normality.

    PubMed

    Dussault, Antoine C; Gagné-Julien, Anne-Marie

    2015-02-01

    Christopher Boorse's Biostatistical Theory of Health has been the main contender among naturalistic accounts of health for the last 40 years. Yet, a recent criticism of this theory, presented by Elselijn Kingma, identifies a dilemma resulting from the BST's conceptual linking of health and statistical typicality. Kingma argues that the BST either cannot accommodate the situation-specificity of many normal functions (e.g., digestion) or cannot account for many situation-specific diseases (e.g., mountain sickness). In this article, we expand upon with Daniel Hausman's response to Kingma's dilemma. We propose that recalling Boorse's specification that health is an intrinsic property of its bearers and explicating this intrinsic property in relation to the concept of homeostasis can illuminate how proponents of naturalistic accounts of health should deal with the situation-specificity of normal functions. We argue that beyond what Boorse and Hausman have delineated, the situation-specificity of normal function cannot be fully captured in a simple dichotomy between normal and abnormal environment or between relevant and irre