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Sample records for glucose-inducible insulin secretion

  1. Sunitinib specifically augments glucose-induced insulin secretion.

    Science.gov (United States)

    Lutz, Stefan Z; Ullrich, Axel; Häring, Hans-Ulrich; Ullrich, Susanne; Gerst, Felicia

    2017-08-01

    The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting β-cells. Regulation of insulin secretion, of cellular cAMP levels and activation of signalling pathways were examined upon exposure of rat insulinoma INS-1E cells to sunitinib under specific stimulatory and inhibitory conditions. Secreted insulin and cellular cAMP levels were measured using RIA and ELISA, respectively. Protein phosphorylations were examined on western blots. Sunitinib enhanced glucose-induced insulin secretion (GIIS) concentration-dependently, reaching a maximal stimulation at 2μM. Sunitinib further augmented insulin secretion in the presence of elevated cAMP levels and the FFAR1 agonists. Adrenaline and the PKA inhibitor H89 counteracted the stimulatory effect of sunitinib on secretion. However, sunitinib altered neither the cellular levels of cAMP nor the phosphorylation of PKA. Sunitinib did not reduce IGF-1-induced phosphorylation of AKT/PKB and ERK1/2. In conclusion, these results suggest that sunitinib stimulates GIIS by a direct effect on β-cells, which may contribute to the glucose-lowering action of the tyrosine kinase inhibitor in humans. Copyright © 2017. Published by Elsevier Inc.

  2. Mitochondrial GTP Regulates Glucose-Induced Insulin Secretion

    OpenAIRE

    Kibbey, Richard G.; Pongratz, Rebecca L.; Romanelli, Anthony J.; Wollheim, Claes B.; Cline, Gary W.; Shulman, Gerald I.

    2007-01-01

    Substrate-level mitochondrial GTP (mtGTP) and ATP (mtATP) synthesis occurs by nucleotide-specific isoforms of the tricarboxylic acid (TCA) cycle enzyme succinyl CoA synthetase (SCS). Unlike mtATP, each molecule of glucose metabolized produces approximately one mtGTP in pancreatic β-cells independent of coupling with oxidative phosphorylation making mtGTP a potentially important fuel signal. siRNA suppression of the GTP-producing pathway (ΔSCS-GTP) reduced glucose-stimulated insulin secretion ...

  3. Mitochondrial GTP Regulates Glucose-Induced Insulin Secretion

    Science.gov (United States)

    Kibbey, Richard G.; Pongratz, Rebecca L.; Romanelli, Anthony J.; Wollheim, Claes B.; Cline, Gary W.; Shulman, Gerald I.

    2007-01-01

    Summary Substrate-level mitochondrial GTP (mtGTP) and ATP (mtATP) synthesis occurs by nucleotide-specific isoforms of the tricarboxylic acid (TCA) cycle enzyme succinyl CoA synthetase (SCS). Unlike mtATP, each molecule of glucose metabolized produces approximately one mtGTP in pancreatic β-cells independent of coupling with oxidative phosphorylation making mtGTP a potentially important fuel signal. siRNA suppression of the GTP-producing pathway (ΔSCS-GTP) reduced glucose-stimulated insulin secretion (GSIS) by 50%, whereas suppression of the parallel ATP-producing isoform (ΔSCS-ATP) increased GSIS by two-fold in INS-1 832/13 cells and cultured rat islets. Insulin secretion correlated with increases in cytosolic calcium but not with changes in NAD(P)H or the ATP/ADP ratio. These data suggest an important role for mtGTP in mediating GSIS in β-cells by modulation of mitochondrial metabolism possibly via influencing mitochondrial calcium. Furthermore, by virtue of its tight coupling to TCA oxidation rates, mtGTP production may serve as an important molecular signal of TCA cycle activity. PMID:17403370

  4. Foxa2 (HNF3beta) controls multiple genes implicated in metabolism-secretion coupling of glucose-induced insulin release

    OpenAIRE

    Wang, Haiyan; Gauthier, Benoît; Hagenfeldt-Johansson, Kerstin Arlette; Iezzi-Bakhtiari, Mariella; Wollheim, Claes

    2002-01-01

    The transcription factor Foxa2 is implicated in blood glucose homeostasis. Conditional expression of Foxa2 or its dominant-negative mutant DN-Foxa2 in INS-1 cells reveals that Foxa2 regulates the expression of genes important for glucose sensing in pancreatic beta-cells. Overexpression of Foxa2 results in blunted glucose-stimulated insulin secretion, whereas induction of DN-Foxa2 causes a left shift of glucose-induced insulin release. The mRNA levels of GLUT2 and glucokinase are drastically d...

  5. Glycated albumin suppresses glucose-induced insulin secretion by impairing glucose metabolism in rat pancreatic β-cells

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    Muto Takashi

    2011-04-01

    Full Text Available Abstract Background Glycated albumin (GA is an Amadori product used as a marker of hyperglycemia. In this study, we investigated the effect of GA on insulin secretion from pancreatic β cells. Methods Islets were collected from male Wistar rats by collagenase digestion. Insulin secretion in the presence of non-glycated human albumin (HA and GA was measured under three different glucose concentrations, 3 mM (G3, 7 mM (G7, and 15 mM (G15, with various stimulators. Insulin secretion was measured with antagonists of inducible nitric oxide synthetase (iNOS, and the expression of iNOS-mRNA was investigated by real-time PCR. Results Insulin secretion in the presence of HA and GA was 20.9 ± 3.9 and 21.6 ± 5.5 μU/3 islets/h for G3 (P = 0.920, and 154 ± 9.3 and 126.1 ± 7.3 μU/3 islets/h (P = 0.046, for G15, respectively. High extracellular potassium and 10 mM tolbutamide abrogated the inhibition of insulin secretion by GA. Glyceraldehyde, dihydroxyacetone, methylpyruvate, GLP-1, and forskolin, an activator of adenylate cyclase, did not abrogate the inhibition. Real-time PCR showed that GA did not induce iNOS-mRNA expression. Furthermore, an inhibitor of nitric oxide synthetase, aminoguanidine, and NG-nitro-L-arginine methyl ester did not abrogate the inhibition of insulin secretion. Conclusion GA suppresses glucose-induced insulin secretion from rat pancreatic β-cells through impairment of intracellular glucose metabolism.

  6. Reduced glucose-induced insulin secretion in low-protein-fed rats is associated with altered pancreatic islets redox status.

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    Cappelli, Ana Paula G; Zoppi, Claudio C; Silveira, Leonardo R; Batista, Thiago M; Paula, Flávia M; da Silva, Priscilla M R; Rafacho, Alex; Barbosa-Sampaio, Helena C; Boschero, Antonio C; Carneiro, Everardo M

    2018-01-01

    In the present study, we investigated the relationship between early life protein malnutrition-induced redox imbalance, and reduced glucose-stimulated insulin secretion. After weaning, male Wistar rats were submitted to a normal-protein-diet (17%-protein, NP) or to a low-protein-diet (6%-protein, LP) for 60 days. Pancreatic islets were isolated and hydrogen peroxide (H 2 O 2 ), oxidized (GSSG) and reduced (GSH) glutathione content, CuZn-superoxide dismutase (SOD1), glutathione peroxidase (GPx1) and catalase (CAT) gene expression, as well as enzymatic antioxidant activities were quantified. Islets that were pre-incubated with H 2 O 2 and/or N-acetylcysteine, were subsequently incubated with glucose for insulin secretion measurement. Protein malnutrition increased CAT mRNA content by 100%. LP group SOD1 and CAT activities were 50% increased and reduced, respectively. H 2 O 2 production was more than 50% increased whereas GSH/GSSG ratio was near 60% lower in LP group. Insulin secretion was, in most conditions, approximately 50% lower in LP rat islets. When islets were pre-incubated with H 2 O 2 (100 μM), and incubated with glucose (33 mM), LP rats showed significant decrease of insulin secretion. This effect was attenuated when LP islets were exposed to N-acetylcysteine. © 2017 Wiley Periodicals, Inc.

  7. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non-glucose induced insulin secretion in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Aaboe, K; Knop, F K; Vilsbøll, T

    2010-01-01

    To examine the effects of 12 weeks of treatment with the DPP-4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non-glucose induced insulin secretion during a hyperglycaemic clamp, in patients...

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

    Science.gov (United States)

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

    2017-11-24

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

  9. Deletion of GPR40 Impairs Glucose-Induced Insulin Secretion In Vivo in Mice Without Affecting Intracellular Fuel Metabolism in Islets

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    Alquier, Thierry; Peyot, Marie-Line; Latour, M. G.; Kebede, Melkam; Sorensen, Christina M.; Gesta, Stephane; Kahn, C. R.; Smith, Richard D.; Jetton, Thomas L.; Metz, Thomas O.; Prentki, Marc; Poitout, Vincent J.

    2009-11-01

    The G protein-coupled receptor GPR40 mediates fatty-acid potentiation of glucose-stimulated insulin secretion, but its contribution to insulin secretion in vivo and mechanisms of action remain uncertain. This study was aimed to ascertain whether GPR40 controls insulin secretion in vivo and modulates intracellular fuel metabolism in islets. We observed that glucose- and arginine-stimulated insulin secretion, assessed by hyperglycemic clamps, was decreased by approximately 60% in GPR40 knock-out (KO) fasted and fed mice, without changes in insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps. Glucose and palmitate metabolism were not affected by GPR40 deletion. Lipid profiling revealed a similar increase in triglyceride and decrease in lysophosphatidylethanolamine species in WT and KO islets in response to palmitate. These results demonstrate that GPR40 regulates insulin secretion in vivo not only in response to fatty acids but also to glucose and arginine, without altering intracellular fuel metabolism.

  10. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose- and non-glucose-induced insulin secretion in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Aaboe, Kasper; Knop, Filip Krag; Vilsbøll, Tina

    2010-01-01

    with type 2 diabetes. METHOD: A double-blinded, placebo-controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add-on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90-min 20 m......AIM: To examine the effects of 12 weeks of treatment with the DPP-4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non-glucose induced insulin secretion during a hyperglycaemic clamp, in patients......M hyperglycaemic clamp with 5 g of l-arginine infusion. Main outcome measure was postprandial total glucagon-like peptide 1 (GLP-1) concentration. Additional measures were insulin and C-peptide, glycaemic control, intact and total peptide YY (PYY) and glucose-dependent insulinotropic polypeptide (GIP), and intact...

  11. GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion

    DEFF Research Database (Denmark)

    Cani, Patrice D; Holst, Jens Juul; Drucker, Daniel J

    2007-01-01

    to those described for beta-cells, brain and hepatoportal sensors. We determined the role of GLUT2, GLP-1 or GIP receptors in glucose-induced incretins secretion, in the corresponding knockout mice. GLP-1 secretion was reduced in all mutant mice, while GIP secretion did not require GLUT2. Intestinal GLP-1...... content was reduced only in GIP and GLUT2 receptors knockout mice suggesting that this impairment could contribute to the phenotype. Intestinal GIP content was similar in all mice studied. Furthermore, the impaired incretins secretion was associated with a reduced glucose-stimulated insulin secretion...

  12. Metformin Ameliorates Dysfunctional Traits of Glibenclamide- and Glucose-Induced Insulin Secretion by Suppression of Imposed Overactivity of the Islet Nitric Oxide Synthase-NO System.

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    Ingmar Lundquist

    Full Text Available Metformin lowers diabetic blood glucose primarily by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. However, possible effects by metformin on beta-cell function are incompletely understood. We speculated that metformin might positively influence insulin secretion through impacting the beta-cell nitric oxide synthase (NOS-NO system, a negative modulator of glucose-stimulated insulin release. In short-time incubations with isolated murine islets either glibenclamide or high glucose augmented insulin release associated with increased NO production from both neural and inducible NOS. Metformin addition suppressed the augmented NO generation coinciding with amplified insulin release. Islet culturing with glibenclamide or high glucose revealed pronounced fluorescence of inducible NOS in the beta-cells being abolished by metformin co-culturing. These findings were reflected in medium nitrite-nitrate levels. A glucose challenge following islet culturing with glibenclamide or high glucose revealed markedly impaired insulin response. Metformin co-culturing restored this response. Culturing murine islets and human islets from controls and type 2 diabetics with high glucose or high glucose + glibenclamide induced a pronounced decrease of cell viability being remarkably restored by metformin co-culturing. We show here, that imposed overactivity of the beta-cell NOS-NO system by glibenclamide or high glucose leads to insulin secretory dysfunction and reduced cell viability and also, importantly, that these effects are relieved by metformin inhibiting beta-cell NO overproduction from both neural and inducible NOS thus ameliorating a concealed negative influence by NO induced by sulfonylurea treatment and/or high glucose levels. This double-edged effect of glibenclamide on the beta-cellsuggests sulfonylurea monotherapy in type 2 diabetes being avoided.

  13. Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

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    Céline Cruciani-Guglielmacci

    2017-04-01

    Conclusion: Our results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress.

  14. Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease.

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    Christine Bernsmeier

    Full Text Available The incretins glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD. However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH patients and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001. In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.

  15. Effects of calcium buffering on glucose-induced insulin release in mouse pancreatic islets: an approximation to the calcium sensor.

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    Pertusa, J A; Sanchez-Andres, J V; Martín, F; Soria, B

    1999-10-15

    1. The properties of the calcium sensor for glucose-induced insulin secretion have been studied using cell-permeant Ca2+ buffers with distinct kinetics and affinities. In addition, submembrane cytosolic Ca2+ distribution has been modelled after trains of glucose-induced action potential-like depolarizations. 2. Slow Ca2+ buffers (around 1 mmol l-1 intracellular concentration) with different affinities (EGTA and Calcium Orange-5N) did not significantly affect glucose-induced insulin release. Modelling showed no effect on cytosolic Ca2+ concentrations at the outermost shell (0.05 microm), their effects being observed in the innermost shells dependent on Ca2+ affinity. 3. In contrast, fast Ca2+ buffers (around 1 mmol l-1 intracellular concentration) with different affinities (BAPTA and Calcium Green-5N) caused a 50 % inhibition of early insulin response and completely blocked the late phase of glucose-induced insulin response, their simulations showing a decrease of [Ca2+]i at both the inner and outermost shells. 4. These data are consistent with the existence in pancreatic beta-cells of a higher affinity Ca2+ sensor than that proposed for neurons. Moreover, these data are consistent with the proposed existence of two distinct pools of granules: (i) 'primed' vesicles, colocalized with Ca2+ channels and responsible of the first phase of insulin release; and (ii) 'reserved pool' vesicles, not colocalized and responsible for the second phase.

  16. Phorbol-ester-induced down-regulation of protein kinase C in mouse pancreatic islets. Potentiation of phase 1 and inhibition of phase 2 of glucose-induced insulin secretion

    DEFF Research Database (Denmark)

    Thams, P; Capito, K; Hedeskov, C J

    1990-01-01

    (45-55 min) was increased from 12.9 +/- 1.5 (4)% in controls to 35.8 +/- 3.9 (4)% in TPA-treated islets (P less than 0.01), and the percentage released during phase 2 (65-85 min) was decreased from 63.2 +/- 3.9 (4)% to 35.3 +/- 1.4 (4)% (P less than 0.005). In contrast, TPA exposure in TCM 199 medium...... (5.5 mM-glucose, 1.26 mM-Ca2+) caused a total abolition of both phases 1 and 2 of glucose-induced secretion. However, inclusion of the alpha 2-adrenergic agonists adrenaline (10 microM) or clonidine (10 microM), or lowering of the Ca2+ concentration in TCM 199 during down-regulation, preserved...

  17. Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor

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    Stamateris, Rachel E.; Sharma, Rohit B.; Kong, Yahui; Ebrahimpour, Pantea; Panday, Deepika; Ranganath, Pavana; Zou, Baobo; Levitt, Helena; Parambil, Nisha Abraham; O’Donnell, Christopher P.; García-Ocaña, Adolfo

    2016-01-01

    An important goal in diabetes research is to understand the processes that trigger endogenous β-cell proliferation. Hyperglycemia induces β-cell replication, but the mechanism remains debated. A prime candidate is insulin, which acts locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces β-cell proliferation through insulin signaling. By using mice lacking insulin signaling intermediate insulin receptor substrate 2 (IRS2), we confirmed that hyperglycemia-induced β-cell proliferation requires IRS2 both in vivo and ex vivo. Of note, insulin receptor activation was not required for glucose-induced proliferation, and insulin itself was not sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with mammalian target of rapamycin (MTOR) and extracellular signal–related kinase (ERK) activation by glucose and AKT activation by insulin. MTOR but not ERK activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced β-cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling was lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR, and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation. PMID:26740601

  18. [Effect of arotinolol on insulin secretion and insulin clearance rate in patients with Graves' disease].

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    Ohguni, S; Notsu, K; Tanaka, J; Sato, T; Kato, Y

    1993-08-20

    Glucose-induced insulin secretion, 24-h urinary C-peptide (CPR) and euglycemic clamp were examined in five patients with hyperthyroid Graves' disease before and 2 weeks after treatment with arotinolol (20 mg/day, p.o.). Plasma glucose and insulin responses to oral administration of 75 g glucose were not changed by arotinolol treatment. 24-h urinary CPR and basal posthepatic insulin delivery rate (BPIDR) as an indicator of insulin secretion were significantly suppressed by arotinolol. Glucose infusion rate (GIR) as an indicator of insulin sensitivity and glucose clearance rate (GCR) were not influenced by arotinolol therapy. Insulin clearance rate (ICR) was significantly suppressed by arotinolol. These findings suggest that arotinolol inhibits insulin secretion by decreasing ICR but does not attenuate insulin release induced by glucose in hyperthyroid patients, and that insulin sensitivity and GCR are not affected by arotinolol.

  19. Field trial on glucose-induced insulin and metabolite responses in Estonian Holstein and Estonian Red dairy cows in two herds

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    Kaart Tanel

    2010-01-01

    Full Text Available Abstract Background Insulin secretion and tissue sensitivity to insulin is considered to be one of the factors controlling lipid metabolism post partum. The objective of this study was to compare glucose-induced blood insulin and metabolite responses in Estonian Holstein (EH, n = 14 and Estonian Red (ER, n = 14 cows. Methods The study was carried out using the glucose tolerance test (GTT performed at 31 ± 1.9 days post partum during negative energy balance. Blood samples were obtained at -15, -5, 5, 10, 20, 30, 40, 50 and 60 min relative to infusion of 0.15 g/kg BW glucose and analysed for glucose, insulin, triglycerides (TG, non-esterified fatty acids (NEFA, cholesterol and β-hydroxybutyrate (BHB. Applying the MIXED Procedure with the SAS System the basal concentration of cholesterol, and basal concentration and concentrations at post-infusion time points for other metabolites, area under the curve (AUC for glucose and insulin, clearance rate (CR for glucose, and maximum increase from basal concentration for glucose and insulin were compared between breeds. Results There was a breed effect on blood NEFA (P P P P P P th min nadir (P th min postinfusion (P Conclusion Our results imply that glucose-induced changes in insulin concentration and metabolite responses to insulin differ between EH and ER dairy cows.

  20. Possible modulatory effect of endogenous islet catecholamines on insulin secretion

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    Gagliardino Juan J

    2001-10-01

    Full Text Available Abstract Background The possible participation of endogenous islet catecholamines (CAs in the control of insulin secretion was tested. Methods Glucose-induced insulin secretion was measured in the presence of 3-Iodo-L-Tyrosine (MIT, a specific inhibitor of tyrosine-hydroxylase activity, in fresh and precultured islets isolated from normal rats. Incubated islets were also used to measure CAs release in the presence of low and high glucose, and the effect of α2-(yohimbine [Y] and idazoxan [I] and α1-adrenergic antagonists (prazosin [P] and terazosin [T] upon insulin secretion elicited by high glucose. Results Fresh islets incubated with 16.7 mM glucose released significantly more insulin in the presence of 1 μM MIT (6.66 ± 0.39 vs 5.01 ± 0.43 ng/islet/h, p Conclusion Our results suggest that islet-originated CAs directly modulate insulin release in a paracrine manner.

  1. Pancreatic islet insulin secretion and metabolism in adult rats malnourished during neonatal life

    DEFF Research Database (Denmark)

    Barbosa, Francisco B; Capito, Kirsten; Kofod, Hans

    2002-01-01

    Pancreatic islets were isolated from rats that had been nursed by dams fed with a control or an 8.7% protein diet during the first 12 d of the lactation period. Glucose-induced insulin secretion from islets in the 8.7% protein group was reduced 50%. The islet insulin and DNA content were similar...

  2. Pancreatic islets of variable size - insulin secretion and glucose utilization

    International Nuclear Information System (INIS)

    Colella, R.M.; Bonner-Weir, S.; Braunstein, L.P.; Schwalke, M.; Weir, G.C.

    1985-01-01

    Glucose metabolism and insulin secretion were studied in isolated rat pacreatic islets of different sizes and the amount of tissue was quantitated by the measurement of DNA. It was found that larger islets (140-210 ng DNA/islet) utilized more glucose (based on the conversion of 3 H-5-glucose to 3 H 2 O) per ng of DNA than islets containing less DNA (60-120 ng/islet). However, the insulin secreted per ng of DNA in response to a given glucose concentration was the same in islets of all sizes. Also, the islet insulin and glucagon content when expressed in terms of DNA did not depend upon islet size. Thus, although glucose utilization rates expressed as a function of islet DNA content were greater in larger islets, no such relationship was found for glucose-induced insulin release or insulin and glucagon content. 17 reference, 1 figure, 3 tables

  3. Evaluation of insulin secretion and action in New World camelids.

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    Firshman, Anna M; Cebra, Christopher K; Schanbacher, Barbara J; Seaquist, Elizabeth R

    2013-01-01

    To measure and compare insulin secretion and sensitivity in healthy alpacas and llamas via glucose clamping techniques. 8 llamas and 8 alpacas. Hyperinsulinemic euglycemic clamping (HEC) and hyperglycemic clamping (HGC) were performed on each camelid in a crossover design with a minimum 48-hour washout period between clamping procedures. The HEC technique was performed to measure insulin sensitivity. Insulin was infused IV at 6 mU/min/kg for 4 hours, and an IV infusion of glucose was adjusted to maintain blood glucose concentration at 150 mg/dL. Concentrations of blood glucose and plasma insulin were determined throughout. The HGC technique was performed to assess insulin secretion in response to exogenous glucose infusion. An IV infusion of glucose was administered to maintain blood glucose concentration at 320 mg/dL for 3 hours, and concentrations of blood glucose and plasma insulin were determined throughout. Alpacas and llamas were not significantly different with respect to whole-body insulin sensitivity during HEC or in pancreatic β-cell response during HGC. Alpacas and llamas had markedly lower insulin sensitivity during HEC and markedly lower pancreatic β-cell response during HGC, in comparison with many other species. New World camelids had lower glucose-induced insulin secretion and marked insulin resistance in comparison with other species. This likely contributes to the disorders of fat and glucose metabolism that are common to camelids.

  4. TRPM5 regulates glucose-stimulated insulin secretion.

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    Brixel, Lili R; Monteilh-Zoller, Mahealani K; Ingenbrandt, Claudia S; Fleig, Andrea; Penner, Reinhold; Enklaar, Thorsten; Zabel, Bernhard U; Prawitt, Dirk

    2010-06-01

    Insulin secretion in beta-pancreatic cells due to glucose stimulation requires the coordinated alteration of cellular ion concentrations and a substantial membrane depolarization to enable insulin vesicle fusion with the cellular membrane. The cornerstones of this cascade are well characterized, yet current knowledge argues for the involvement of additional ion channels in this process. TRPM5 is a cation channel expressed in beta-cells and proposed to be involved in coupling intracellular Ca(2+) release to electrical activity and cellular responses. Here, we report that TRPM5 acts as an indispensable regulator of insulin secretion. In vivo glucose tolerance tests showed that Trpm5 (-/-) -mice maintain elevated blood glucose levels for over an hour compared to wild-type littermates, while insulin sensitivity is normal in Trpm5 (-/-) -mice. In pancreatic islets isolated from Trpm5 (-/-) -mice, hyperglycemia as well as arginine-induced insulin secretion was diminished. The presented results describe a major role for TRPM5 in glucose-induced insulin secretion beyond membrane depolarization. Dysfunction of the TRPM5 protein could therefore be an important factor in the etiology of some forms of type 2 diabetes, where disruption of the normal pattern of secretion is observed.

  5. Glucose-induced time-dependent potentiation of insulin release, but not islet blood perfusion, in anesthetized rats.

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    Jansson, Leif; Bodin, Birgitta; Källskog, Orjan

    2008-01-01

    Repeated administration of glucose in vivo leads to a time-dependent potentiation of insulin release. Glucose is also known to stimulate pancreatic islet blood flow, but whether this is associated with a time-dependent potentiation is unknown. We therefore repeatedly administered glucose to anesthetized rats and evaluated effects on insulin release and islet blood flow. Male Wistar-Furth rats, anesthetized with thiobutabarbital, were injected intravenously with 1 ml of saline or glucose at times 0, 30 and 60 min. The combinations used were saline + saline + saline (SSS), glucose + saline + saline (GSS), saline + saline + glucose (SSG) and glucose + glucose + glucose (GGG). Regional organ blood flow values were measured 3 min after the final injection with a microsphere technique, and at this time also serum insulin concentrations were determined with ELISA. Serum insulin concentrations as well as total pancreatic, pancreatic islet and duodenal blood flow were higher in SSG and GGG-treated rats when compared to those given SSS and GSS. However, only insulin concentrations, not blood flow values, were higher in GGG rats when compared to SSG animals. Glucose-induced time-dependent potentiation of insulin release occurs in vivo in thiobutabarbital-anesthetized rats, but is not associated with a further increase in islet blood flow.

  6. Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake

    DEFF Research Database (Denmark)

    Richter, Erik; Hansen, B F; Hansen, S A

    1988-01-01

    in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure......, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.......The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing...

  7. Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake

    DEFF Research Database (Denmark)

    Richter, Erik; Hansen, B F; Hansen, S A

    1988-01-01

    , impairment of insulin action on muscle glucose transport and uptake. Thus maximal insulin-stimulated glucose uptake at 12 mM-glucose decreased from 34.8 +/- 1.9 to 11.5 +/- 1.1 mumol/h per g (mean +/- S.E.M., n = 10) during 5 h perfusion. This decrease in glucose uptake was accompanied by a similar change...... in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure......, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation....

  8. Role of transient receptor potential melastatin-like subtype 5 channel in insulin secretion from rat β-cells.

    Science.gov (United States)

    Krishnan, Kalaiselvan; Ma, Zuheng; Björklund, Anneli; Islam, Md Shahidul

    2014-05-01

    Several studies have reported that the transient receptor potential melastatin-like subtype 5 (TRPM5) channel, a Ca(2+)-activated monovalent cation channel, is involved in the stimulus-secretion coupling in the mouse pancreatic β-cells. We have studied the role of the TRPM5 channel in regulating insulin secretion and cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) in the rat β-cells by using triphenylphosphine oxide, a selective inhibitor of the channel. Insulin secretion from islets from Sprague-Dawley rats was measured in batch incubations. Cytoplasmic free Ca(2+) concentration was measured from single β-cells by fura-2-based microfluorometry. Triphenylphosphine oxide did not alter insulin secretion and [Ca(2+)](i) response triggered by KCl or fructose. It inhibited insulin secretion in response to glucose, L-arginine, and glucagon-like peptide 1. It also inhibited glucose-induced insulin secretion by mechanisms that are independent of the adenosine triphosphate-sensitive potassium channels and [Ca(2+)](i) increase. Our results suggest that in the rat islets, TRPM5 is involved in mediating insulin secretion by glucose and l-arginine and in potentiating the glucose-induced insulin secretion by glucagon-like peptide 1.

  9. Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity.

    Science.gov (United States)

    Linder, Katarzyna; Schleger, Franziska; Ketterer, Caroline; Fritsche, Louise; Kiefer-Schmidt, Isabelle; Hennige, Anita; Häring, Hans-Ulrich; Preissl, Hubert; Fritsche, Andreas

    2014-06-01

    Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity. Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined. Maternal insulin increased from a fasting level of 67 ± 25 pmol/l (mean ± SD) to 918 ± 492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4 ± 0.3 to 7.4 ± 1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297 ± 99 to 235 ± 84 ms (p = 0.01) and then remained stable until 120 min (235 ± 84 vs 251 ± 91 ms, p = 0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r = 0.68, p = 0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283 ± 79 ms) than those of insulin-sensitive mothers (178 ± 46 ms, p = 0.03). Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.

  10. The effect of thyroidectomy and propylthiouracil-induced hypothyroidism on insulin secretion in male rats.

    Science.gov (United States)

    Godini, A; Ghasemi, A; Karbalaei, N; Zahediasl, S

    2014-09-01

    Data available on thyroid dysfunction and insulin secretion are inconsistent. The aim of this study was to assess the effect of hypothyroidism on insulin secretion, in vivo and in vitro, in rats. Adult Wistar male rats were divided into 4 groups, the control, the propylthiouracyl (PTU)-treated hypothyroid, the surgically thyroidectomized, and the sham-operated thyroidectomized. After 5 weeks, intravenous glucose tolerance test (IVGTT) was performed and 3 weeks later pancreatic islets were isolated to assess glucose induced insulin secretion and insulin content. Fasting serum glucose and insulin levels did not differ between the groups, but serum glucose concentration during IVGTT in the PTU-induced hypothyroid group was significantly higher as compared to controls, throughout 5-60 min. The serum glucose concentration during IVGTT in the thyroidectomized rats was also significantly higher than in the sham-operated ones, except at 10 and 60 min. The area under the curve of the serum insulin was significantly lower during IVGTT in the PTU-treated (10,010 ± 1,380 pmol/l/60 min) and thyroidectomized (13,930 ± 2,786) groups vs. their comparable groups (19,150 ± 2,110), phypothyroidism leads to impaired glucose tolerance due to reduced glucose stimulated insulin secretion. Islets insulin secretion is positively correlated with serum T3 and T4 concentrations. © Georg Thieme Verlag KG Stuttgart · New York.

  11. GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes

    DEFF Research Database (Denmark)

    Halden, Thea A S; Egeland, Erlend J; Åsberg, Anders

    2016-01-01

    OBJECTIVE: Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon...... h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp. RESULTS: Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups....... In PTDM patients, glucose-induced glucagon suppression was significantly less pronounced (maximal suppression from baseline: 43 ± 12 vs. 65 ± 12%, P insulin secretion were significantly lower. The PTDM group also exhibited a significantly lower insulin response...

  12. [Alteration of insulin secretion in the elderly].

    Science.gov (United States)

    Aizawa, Toru

    2006-01-01

    Aging per se is associated with reduced insulin secretion, which is an important contributing factor for pandemic of diabetes worldwide. Although underlying mechanism for it is not fully elucidated, a combination of reduced beta cell mass and impairment of insulin granule handing in the cell is most likely which may be due to age-related mitochondrial dysfunction and/or dysregulation of transcriptional factors. For effective prevention of diabetes in the elderly population, restoration of beta cell function is desired. Meanwhile, identification of insulin-deficient elderly patients with diabetes and an earlier institution of insulin therapy for them are recommended for improvement of treatment outcome.

  13. Impaired Sympathoadrenal Axis Function Contributes to Enhanced Insulin Secretion in Prediabetic Obese Rats

    Directory of Open Access Journals (Sweden)

    Ana Eliza Andreazzi

    2011-01-01

    Full Text Available The involvement of sympathoadrenal axis activity in obesity onset was investigated using the experimental model of treating neonatal rats with monosodium L-glutamate. To access general sympathetic nervous system activity, we recorded the firing rates of sympathetic superior cervical ganglion nerves in animals. Catecholamine content and secretion from isolated adrenal medulla were measured. Intravenous glucose tolerance test was performed, and isolated pancreatic islets were stimulated with glucose and adrenergic agonists. The nerve firing rate of obese rats was decreased compared to the rate for lean rats. Basal catecholamine secretion decreased whereas catecholamine secretion induced by carbachol, elevated extracellular potassium, and caffeine in the isolated adrenal medulla were all increased in obese rats compared to control. Both glucose intolerance and hyperinsulinaemia were observed in obese rats. Adrenaline strongly inhibited glucose-induced insulin secretion in obese animals. These findings suggest that low sympathoadrenal activity contributes to impaired glycaemic control in prediabetic obese rats.

  14. Factors influencing insulin secretion from encapsulated islets

    NARCIS (Netherlands)

    de Haan, BJ; Faas, MM; de Vos, P

    2003-01-01

    Adequate regulation of glucose levels by a microencapsulated pancreatic islet graft requires a minute-to-minute regulation of blood glucose. To design such a transplant, it is mandatory to have sufficient insight in factors influencing the kinetics of insulin secretion by encapsulated islets. The

  15. Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

    International Nuclear Information System (INIS)

    Naidoo, C.

    1986-01-01

    Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, 125 I-insulin binding to the solubilized erythrocyte membrane receptor and 125 I-insulin binding to fibroblasts in culture

  16. Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure.

    Science.gov (United States)

    Morton, Gregory J; Muta, Kenjiro; Kaiyala, Karl J; Rojas, Jennifer M; Scarlett, Jarrad M; Matsen, Miles E; Nelson, Jarrell T; Acharya, Nikhil K; Piccinini, Francesca; Stefanovski, Darko; Bergman, Richard N; Taborsky, Gerald J; Kahn, Steven E; Schwartz, Michael W

    2017-04-01

    Dynamic adjustment of insulin secretion to compensate for changes of insulin sensitivity that result from alteration of nutritional or metabolic status is a fundamental aspect of glucose homeostasis. To investigate the role of the brain in this coupling process, we used cold exposure as an experimental paradigm because the sympathetic nervous system (SNS) helps to coordinate the major shifts of tissue glucose utilization needed to ensure that increased thermogenic needs are met. We found that glucose-induced insulin secretion declined by 50% in rats housed at 5°C for 28 h, and yet, glucose tolerance did not change, owing to a doubling of insulin sensitivity. These potent effects on insulin secretion and sensitivity were fully reversed by returning animals to room temperature (22°C) for 4 h or by intravenous infusion of the α-adrenergic receptor antagonist phentolamine for only 30 min. By comparison, insulin clearance was not affected by cold exposure or phentolamine infusion. These findings offer direct evidence of a key role for the brain, acting via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure. © 2017 by the American Diabetes Association.

  17. Paliperidone Induced Hypoglycemia by Increasing Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Tsubasa Omi

    2016-01-01

    Full Text Available We report the case of a 41-year-old woman with schizophrenia who developed persistent hypoglycemia following paliperidone administration. After discontinuing paliperidone, the hypoglycemia resolved, but symptoms of diabetes emerged. Therefore, it appears that the hypoglycemia induced by paliperidone may mask symptoms of diabetes. Paliperidone may induce hypoglycemia by increasing insulin secretion. This report could help elucidate the relationship between atypical antipsychotics and glucose metabolism.

  18. Paliperidone Induced Hypoglycemia by Increasing Insulin Secretion

    OpenAIRE

    Omi, Tsubasa; Riku, Keisen; Fukumoto, Motoyuki; Kanai, Koji; Omura, Yumi; Takada, Hiromune; Matunaga, Hidenori

    2016-01-01

    We report the case of a 41-year-old woman with schizophrenia who developed persistent hypoglycemia following paliperidone administration. After discontinuing paliperidone, the hypoglycemia resolved, but symptoms of diabetes emerged. Therefore, it appears that the hypoglycemia induced by paliperidone may mask symptoms of diabetes. Paliperidone may induce hypoglycemia by increasing insulin secretion. This report could help elucidate the relationship between atypical antipsychotics and glucose m...

  19. Synaptotagmin-7 as a positive regulator of glucose-induced glucagon-like peptide-1 secretion in mice

    DEFF Research Database (Denmark)

    Gustavsson, N; Wang, Y; Kang, Y

    2011-01-01

    using synaptotagmin-7 knockout (KO) mice and GLUTag cells with lentiviral-mediated synaptotagmin-7 silencing. RESULTS: We found that synaptotagmin-7 was co-localised with GLP-1 in intestinal L-cells. GLP-1 secretion was impaired in synaptotagmin-7 KO mice when they were challenged by glucose ingestion...... that synaptotagmin-7 functions as a positive regulator of GLP-1 secretion in intestinal L-cells and GLUTag cells, consistent with its proposed role as a calcium sensor in GLP-1 secretion....

  20. The relationship between bone turnover and insulin sensitivity and secretion

    DEFF Research Database (Denmark)

    Frost, Morten; Balkau, Beverley; Hatunic, Mensud

    2018-01-01

    Bone metabolism appears to influence insulin secretion and sensitivity, and insulin promotes bone formation in animals, but similar evidence in humans is limited. The objectives of this study are to explore if bone turnover markers were associated with insulin secretion and sensitivity and to det...

  1. Branched-chain amino acid-enriched diet: effects on insulin secretion and cellular immune aggression.

    Science.gov (United States)

    Karabatas, L M; De Bruno, L F; Pastorale, C; Lombardo, Y B; Basabe, J C

    2000-07-01

    Several reports have demonstrated that high-protein diets may have beneficial effects on experimental models of diabetes and have raised the possibility that branched-chain amino acids could play a role in these protective effects. We investigated the effect of a normoproteic, branched-chain amino acid-enriched diet (experimental diet) on insulin secretion from C57BL/6N mice transferred with splenocytes from diabetic syngeneic donors. Mice previously fed with the experimental or control diet received three intraperitoneal injections, every other day, of 5 x 107 viable mononuclear splenocytes obtained from control or diabetic donors. Results showed that mice fed with the experimental diet and transferred with "diabetic" splenocytes presented: i) normoglycemia, and (ii) significantly higher levels in both phases of glucose-induced insulin secretion and normal values of arginine-glucose-induced insulin secretion. To evaluate the in vitro cellular immune aggression, dispersed mouse islet cells were co-cultured with splenocytes from syngeneic diabetic mice. First, dispersed islet cells from mice on the experimental or control diet were co-cultured with splenocytes from control or diabetic mice on a commercial diet. In the presence of "diabetic splenocytes, dispersed islet cells from mice on the experimental diet presented a significantly lower in vitro cellular immune aggression. On the other hand, "diabetic" splenocytes from mice fed with the experimental diet produced a significantly reduced cellular immune aggression on dispersed islet cells. Our results showed that feeding branched-chain amino acids increased the capacity of beta cells to withstand a functional assault and diminished the extent of in vitro cellular immune aggression.

  2. A Bayesian approach to estimating the prehepatic insulin secretion rate

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Højbjerre, Malene

    The prehepatic insulin secretion rate of the pancreatic $beta$-cells is not directly measurable, since part of the secreted insulin is absorbed by the liver prior to entering the blood stream. However, C-peptide is co-secreted equimolarly and is not absorbed by the liver, allowing...... for the estimation of the prehepatic insulin secretion rate. We consider a stochastic differential equation model that combines both insulin and C-peptide concentrations in plasma to estimate the prehepatic insulin secretion rate. Previously this model has been analysed in an iterative deterministic set-up, where...... the time courses of insulin and C-peptide subsequently are used as known forcing functions. In this work we adopt a Bayesian graphical model to describe the unied model simultaneously. We develop a model that also accounts for both measurement error and process variability. The parameters are estimated...

  3. Impaired glucose-induced glucagon suppression after partial pancreatectomy

    DEFF Research Database (Denmark)

    Schrader, Henning; Menge, Bjoern A; Breuer, Thomas G K

    2009-01-01

    INTRODUCTION: The glucose-induced decline in glucagon levels is often lost in patients with type 2 diabetes. It is unclear whether this is due to an independent defect in alpha-cell function or secondary to the impairment in insulin secretion. We examined whether a partial pancreatectomy in humans...... would also impair postchallenge glucagon concentrations and, if so, whether this could be attributed to the reduction in insulin levels. PATIENTS AND METHODS: Thirty-six patients with pancreatic tumours or chronic pancreatitis were studied before and after approximately 50% pancreatectomy with a 240-min...... oral glucose challenge, and the plasma concentrations of glucose, insulin, C-peptide, and glucagon were determined. RESULTS: Fasting and postchallenge insulin and C-peptide levels were significantly lower after partial pancreatectomy (P

  4. The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress.

    Science.gov (United States)

    Xie, Yun; Cui, Canqi; Nie, Aifang; Wang, Yan; Ni, Qicheng; Liu, Yun; Yin, Qinglei; Zhang, Hongli; Li, Yong; Wang, Qidi; Gu, Yanyun; Ning, Guang

    2017-08-01

    Compensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation. We challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4weeks and measured metabolic and pancreatic morphological parameters. We performed ex vivo experiments to analyse β cell insulin secretion and electrophysiology characteristics. Adenoviral-mediated overexpression and lentiviral-ShRNA-mediated knocking down proteins were applied in Min6 cells and cultured primary mouse islets. βRicKO mice showed a significant glucose intolerance and a reduced plasma insulin level and an unchanged level β cell mass versus the control mice under HFD. A HFD or palmitate treatment enhanced both glucose-induced insulin secretion (GIIS) and the PMA (phorbol 12-myristate 13-acetate)-induced insulin secretion in the control islets but not in the βRicKO islets. The KO β cells showed similar glucose-induced Ca 2+ influx but lower membrane capacitance increments versus the control cells. The enhanced mTORC2/PKC proteins levels in the control HFD group were ablated by Rictor deletion. Replenishing PKCα by overexpression of PKCα-T638D restored the defective GIIS in βRicKO islets. The mTORC2/Rictor pathway modulates β cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKCα. This study suggests that the mTORC2/PKC pathway in β cells is involved in the pathogenesis of T2D. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Influence of Flavonoids on Mechanism of Modulation of Insulin Secretion.

    Science.gov (United States)

    Soares, Juliana Mikaelly Dias; Pereira Leal, Ana Ediléia Barbosa; Silva, Juliane Cabral; Almeida, Jackson R G S; de Oliveira, Helinando Pequeno

    2017-01-01

    The development of alternatives for insulin secretion control in vivo or in vitro represents an important aspect to be investigated. In this direction, natural products have been progressively explored with this aim. In particular, flavonoids are potential candidates to act as insulin secretagogue. To study the influence of flavonoid on overall modulation mechanisms of insulin secretion. The research was conducted in the following databases and platforms: PubMed, Scopus, ISI Web of Knowledge, SciELO, LILACS, and ScienceDirect, and the MeSH terms used for the search were flavonoids, flavones, islets of Langerhans, and insulin-secreting cells. Twelve articles were included and represent the basis of discussion on mechanisms of insulin secretion of flavonoids. Papers in ISI Web of Knowledge were in number of 1, Scopus 44, PubMed 264, ScienceDirect 511, and no papers from LILACS and SciELO databases. According to the literature, the majority of flavonoid subclasses can modulate insulin secretion through several pathways, in an indication that corresponding molecule is a potential candidate for active materials to be applied in the treatment of diabetes. The action of natural products on insulin secretion represents an important investigation topic due to their importance in the diabetes controlIn addition to their typical antioxidant properties, flavonoids contribute to the insulin secretionThe modulation of insulin secretion is induced by flavonoids according to different mechanisms. Abbreviations used: K ATP channels: ATP-sensitive K + channels, GLUT4: Glucose transporter 4, ERK1/2: Extracellular signal-regulated protein kinases 1 and 2, L-VDCCs: L-type voltage-dependent Ca +2 channels, GLUT1: Glucose transporter 1, AMPK: Adenosine monophosphate-activated protein kinase, PTP1B: Protein tyrosine phosphatase 1B, GLUT2: Glucose transporter 2, cAMP: Cyclic adenosine monophosphate, PKA: Protein kinase A, PTK: Protein tyrosine kinase, CaMK II: Ca 2+ /calmodulin

  6. Insulin secretion and action in North Indian women during pregnancy

    DEFF Research Database (Denmark)

    Arora, G P; Almgren, P; Thaman, R G

    2017-01-01

    ) and adapted WHO 2013 (GDM2013) criteria, excluding the 1-h glucose value, in a high-risk Indian population from Punjab. METHODS: Insulin secretion (HOMA2-B) and insulin action (HOMA2-IR) were assessed in 4665 Indian women with or without gestational diabetes defined by the GDM1999 or adapted GDM2013 criteria...

  7. Assessment of benzene induced oxidative impairment in rat isolated pancreatic islets and effect on insulin secretion.

    Science.gov (United States)

    Bahadar, Haji; Maqbool, Faheem; Mostafalou, Sara; Baeeri, Maryam; Rahimifard, Mahban; Navaei-Nigjeh, Mona; Abdollahi, Mohammad

    2015-05-01

    Benzene (C6H6) is an organic compound used in petrochemicals and numerous other industries. It is abundantly released to our environment as a chemical pollutant causing widespread human exposure. This study mainly focused on benzene induced toxicity on rat pancreatic islets with respect to oxidative damage, insulin secretion and glucokinase (GK) activity. Benzene was dissolved in corn oil and administered orally at doses 200, 400 and 800mg/kg/day, for 4 weeks. In rats, benzene significantly raised the concentration of plasma insulin. Also the effect of benzene on the release of glucose-induced insulin was pronounced in isolated islets. Benzene caused oxidative DNA damage and lipid peroxidation, and also reduced the cell viability and total thiols groups, in the islets of exposed rats. In conclusion, the current study revealed that pancreatic glucose metabolism is susceptible to benzene toxicity and the resultant oxidative stress could lead to functional abnormalities in the pancreas. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Getting closer to physiologic insulin secretion.

    Science.gov (United States)

    Heise, Tim

    2007-01-01

    The goal of insulin replacement therapy in diabetes mellitus (DM) is to recreate a normal physiologic insulin supply throughout the day. This article reviewed the use of rapid acting insulin analogues in recreating physiologic postprandial insulin responses. This review article was based on a presentation at a satellite symposium entitled "Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues" that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa. In the context of mealtime insulin supply, recreating physiologic postprandial insulin responses requires rapid availability of insulin within a short time of eating and a duration of action that does not extend into the late postprandial period. Conventional human insulin is not ideally suited to SC injection, with its slow onset of action and dose-dependent duration of action. The rapid-acting insulin analogues have been designed to address these deficiencies, with more rapid onset of action, higher maximal effects, and consequently better postprandial glycemic control. These properties have been reported in patients with type 1 and type 2 DM, as well as in nondiabetic individuals in euglycemic clamp studies. Rapid-acting insulin analogues are also of particular interest in people with diabetic nephropathy, women with gestational DM, and elderly patients with DM. Compared with soluble human (regular) insulin, rapid-acting insulin analogues have a more rapid onset of action and a shorter duration of action. Their potential in special patient groups is now being established in clinical research and in everyday practice.

  9. Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes.

    Science.gov (United States)

    Satin, Leslie S; Butler, Peter C; Ha, Joon; Sherman, Arthur S

    2015-04-01

    Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and temporal pattern, has been understudied. Most of the insulin secreted from pancreatic beta cells of the pancreas is released in a pulsatile pattern, which is disrupted in T2DM. Here we review the evidence that changes in beta cell pulsatility occur during the progression from glucose intolerance to T2DM in humans, and contribute significantly to the etiology of the disease. We review the evidence that insulin pulsatility improves the efficacy of secreted insulin on its targets, particularly hepatic glucose production, but also examine evidence that pulsatility alters or is altered by changes in peripheral glucose uptake. Finally, we summarize our current understanding of the biophysical mechanisms responsible for oscillatory insulin secretion. Understanding how insulin pulsatility contributes to normal glucose homeostasis and is altered in metabolic disease states may help improve the treatment of T2DM. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

    Science.gov (United States)

    Satin, Leslie S.; Butler, Peter C.; Ha, Joon; Sherman, Arthur S.

    2015-01-01

    Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and temporal pattern has been understudied. Most of the insulin secreted from pancreatic beta cells of the pancreas is released in a pulsatile pattern, which is disrupted in T2DM. Here we review the evidence that changes in beta cell pulsatility occur during the progression from glucose intolerance to T2DM in humans, and contribute significantly to the etiology of the disease. We review the evidence that insulin pulsatility improves the efficacy of secreted insulin on its targets, particularly hepatic glucose production, but also examine evidence that pulsatility alters or is altered by changes in peripheral glucose uptake. Finally, we summarize our current understanding of the biophysical mechanisms responsible for oscillatory insulin secretion. Understanding how insulin pulsatility contributes to normal glucose homeostasis and is altered in metabolic disease states may help improve the treatment of T2DM. PMID:25637831

  11. Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models.

    Science.gov (United States)

    Mita, Yuichiro; Nakayama, Kaho; Inari, Shogo; Nishito, Yukina; Yoshioka, Yuya; Sakai, Naoko; Sotani, Kanade; Nagamura, Takahiro; Kuzuhara, Yuki; Inagaki, Kumi; Iwasaki, Miki; Misu, Hirofumi; Ikegawa, Masaya; Takamura, Toshinari; Noguchi, Noriko; Saito, Yoshiro

    2017-11-21

    Selenoprotein P (SeP) functions as a selenium (Se)-supply protein. SeP is identified as a hepatokine, promoting insulin resistance in type 2 diabetes. Thus, the suppression of Se-supply activity of SeP might improve glucose metabolism. Here, we develop an anti-human SeP monoclonal antibody AE2 as with neutralizing activity against SeP. Administration of AE2 to mice significantly improves glucose intolerance and insulin resistance that are induced by human SeP administration. Furthermore, excess SeP administration significantly decreases pancreas insulin levels and high glucose-induced insulin secretion, which are improved by AE2 administration. Epitope mapping reveals that AE2 recognizes a region of human SeP adjacent to the first histidine-rich region (FHR). A polyclonal antibody against the mouse SeP FHR improves glucose intolerance and insulin secretion in a mouse model of diabetes. This report describes a novel molecular strategy for the development of type 2 diabetes therapeutics targeting SeP.

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

    Science.gov (United States)

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

    2015-12-01

    α/β-Hydrolase domain-6 (ABHD6) is a newly identified monoacylglycerol (MAG) lipase. We recently reported that it negatively regulates glucose stimulated insulin secretion (GSIS) in the β cells by hydrolyzing lipolysis-derived MAG that acts as a metabolic coupling factor and signaling molecule via exocytotic regulator Munc13-1. Whether ABHD6 and MAG play a role in response to all classes of insulin secretagogues, in particular various fuel and non-fuel stimuli, is unknown. Insulin secretion in response to various classes of secretagogues, exogenous MAG and pharmacological agents was measured in islets of mice deficient in ABHD6 specifically in the β cell (BKO). Islet perifusion experiments and determinations of glucose and fatty acid metabolism, cytosolic Ca(2+) and MAG species levels were carried out. Deletion of ABHD6 potentiated insulin secretion in response to the fuels glutamine plus leucine and α-ketoisocaproate and to the non-fuel stimuli glucagon-like peptide 1, carbamylcholine and elevated KCl. Fatty acids amplified GSIS in control and BKO mice to the same extent. Exogenous 1-MAG amplified insulin secretion in response to fuel and non-fuel stimuli. MAG hydrolysis activity was greatly reduced in BKO islets without changes in total diacylglycerol and triacylglycerol lipase activity. ABHD6 deletion induced insulin secretion independently from KATP channels and did not alter the glucose induced rise in intracellular Ca(2+). Perifusion studies showed elevated insulin secretion during second phase of GSIS in BKO islets that was not due to altered cytosolic Ca(2+) signaling or because of changes in glucose and fatty acid metabolism. Glucose increased islet saturated long chain 1-MAG species and ABHD6 deletion caused accumulation of these 1-MAG species at both low and elevated glucose. ABHD6 regulates insulin secretion in response to fuel stimuli at large and some non-fuel stimuli by controlling long chain saturated 1-MAG levels that synergize with other

  13. Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells

    Energy Technology Data Exchange (ETDEWEB)

    Reinhardt, Florian; Schultz, Julia; Waterstradt, Rica; Baltrusch, Simone, E-mail: simone.baltrusch@med.uni-rostock.de

    2016-06-10

    Mitochondria form a tubular network in mammalian cells, and the mitochondrial life cycle is determined by fission, fusion and autophagy. Dynamin-related protein 1 (Drp1) has a pivotal role in these processes because it alone is able to constrict mitochondria. However, the regulation and function of Drp1 have been shown to vary between cell types. Mitochondrial morphology affects mitochondrial metabolism and function. In pancreatic beta cells mitochondrial metabolism is a key component of the glucose-induced cascade of insulin secretion. The goal of the present study was to investigate the action of Drp1 in pancreatic beta cells. For this purpose Drp1 was down-regulated by means of shDrp1 in insulin-secreting INS1 cells and mouse pancreatic islets. In INS1 cells reduced Drp1 expression resulted in diminished expression of proteins regulating mitochondrial fusion, namely mitofusin 1 and 2, and optic atrophy protein 1. Diminished mitochondrial dynamics can therefore be assumed. After down-regulation of Drp1 in INS1 cells and spread mouse islets the initially homogenous mitochondrial network characterised by a moderate level of interconnections shifted towards high heterogeneity with elongated, clustered and looped mitochondria. These morphological changes were found to correlate directly with functional alterations. Mitochondrial membrane potential and ATP generation were significantly reduced in INS1 cells after Drp1down-regulation. Finally, a significant loss of glucose-stimulated insulin secretion was demonstrated in INS1 cells and mouse pancreatic islets. In conclusion, Drp1 expression is important in pancreatic beta cells to maintain the regulation of insulin secretion. -- Highlights: •Down-regulation of Drp1 in INS1 cells reduces mitochondrial fusion protein expression. •Mitochondrial membrane potential in INS1 cells is diminished after Drp1 down-regulation. •Mitochondria become elongated after down-regulation of Drp1 in beta cells. •Down-regulation of

  14. Geniposide accelerates proteasome degradation of Txnip to inhibit insulin secretion in pancreatic β-cells.

    Science.gov (United States)

    Liu, C Y; Hao, Y N; Yin, F; Zhang, Y L; Liu, J H

    2017-05-01

    To analyze the role of geniposide in the protein degradation of Txnip and to determine the impact of Txnip on geniposide-regulated GSIS in pancreatic INS-1 cells. The content of Txnip protein was measured by western blot; insulin content and glucose uptake were determined by ELISA; and knockdown of Txnip was the method of RNA interference. Glucose induces a rapid increase in Txnip protein, and geniposide accelerates the degradation of Txnip via proteasome pathway in the presence of high glucose (25 mM) in INS-1 pancreatic β-cells. And MG132, a proteasomal inhibitor, potentiates glucose uptake, metabolism (ATP production) and glucose-stimulated insulin secretion (GSIS) in high-glucose (25 mM)-treated INS-1 cells, but geniposide significantly prevents these effects. Furthermore, the combination of geniposide and Txnip knockdown shows substantial synergistic effects to reduce glucose uptake, metabolism and GSIS in high-glucose (25 mM)-treated INS-1 cells. Txnip protein played an essential role in glucose uptake, metabolism and GSIS, and geniposide could accelerate the degradation via proteasome pathway in high-glucose-treated pancreatic INS-1 cells.

  15. Incretins, insulin secretion and Type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Holst, Jens Møller

    2004-01-01

    the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism......When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response...... to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where...

  16. TRPM5 regulates glucose-stimulated insulin secretion

    OpenAIRE

    Brixel, Lili R.; Monteilh-Zoller, Mahealani K.; Ingenbrandt, Claudia S.; Fleig, Andrea; Penner, Reinhold; Enklaar, Thorsten; Zabel, Bernhard U.; Prawitt, Dirk

    2010-01-01

    Insulin secretion in β-pancreatic cells due to glucose stimulation requires the coordinated alteration of cellular ion concentrations and a substantial membrane depolarization to enable insulin vesicle fusion with the cellular membrane. The cornerstones of this cascade are well characterized, yet current knowledge argues for the involvement of additional ion channels in this process. TRPM5 is a cation channel expressed in β-cells and proposed to be involved in coupling intracellular Ca2+ rele...

  17. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance

    International Nuclear Information System (INIS)

    Permana, Paska A.; Menge, Christopher; Reaven, Peter D.

    2006-01-01

    Macrophage infiltration into adipose tissue increases with obesity, a condition associated with low-grade inflammation and insulin resistance. We investigated the direct effects of macrophage-secreted factors on adipocyte inflammation and insulin resistance. 3T3-L1 adipocytes incubated with media conditioned by RAW264.7 macrophages (RAW-CM) showed dramatically increased transcription of several inflammation-related genes, greater nuclear factor kappa B (NF-κB) activity, and enhanced binding of U937 monocytes. All of these effects were prevented by co-incubation with pyrrolidinedithiocarbamate, an NF-κB inhibitor. Adipocytes incubated with RAW-CM also released more non-esterified fatty acids and this increased lipolysis was not suppressed by insulin. In addition, RAW-CM treatment decreased insulin-stimulated glucose uptake in adipocytes. Taken together, these results indicate that macrophage-secreted factors induce inflammatory responses and reduce insulin responsiveness in adipocytes. These effects of macrophage-secreted factors on adipocytes may contribute significantly to the systemic inflammation and insulin resistance associated with obesity

  18. Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.

    OpenAIRE

    Wang, S Y; Halban, P A; Rowe, J W

    1988-01-01

    Aging in men and rodents is associated with a marked decline in glucose stimulated insulin secretion by pancreatic beta cells (B cells). Secreted insulin is the end result of a series of steps along the biosynthetic protein-secretion pathway, including insulin gene transcription, processing of transcripts to preproinsulin mRNA, translation of mRNA, segregation and processing of newly made proinsulin in secretory vesicles, proinsulin to insulin conversion, transport of vesicles to the plasma m...

  19. Metabolic amplification of insulin secretion by glucose is independent of β-cell microtubules.

    Science.gov (United States)

    Mourad, Nizar I; Nenquin, Myriam; Henquin, Jean-Claude

    2011-03-01

    Glucose-induced insulin secretion (IS) by β-cells is controlled by two pathways. The triggering pathway involves ATP-sensitive potassium (K(ATP)) channel-dependent depolarization, Ca(2+) influx, and rise in the cytosolic Ca(2+) concentration ([Ca(2+)](c)), which triggers exocytosis of insulin granules. The metabolic amplifying pathway augments IS without further increasing [Ca(2+)](c). After exclusion of the contribution of actin microfilaments, we here tested whether amplification implicates microtubule-dependent granule mobilization. Mouse islets were treated with nocodazole or taxol, which completely depolymerized and polymerized tubulin. They were then perifused to measure [Ca(2+)](c) and IS. Metabolic amplification was studied during imposed steady elevation of [Ca(2+)](c) by tolbutamide or KCl or by comparing [Ca(2+)](c) and IS responses to glucose and tolbutamide. Nocodazole did not alter [Ca(2+)](c) or IS changes induced by the three secretagogues, whereas taxol caused a small inhibition of IS that is partly ascribed to a decrease in [Ca(2+)](c). When [Ca(2+)](c) was elevated and controlled by KCl or tolbutamide, the amplifying action of glucose was unaffected by microtubule disruption or stabilization. Both phases of IS were larger in response to glucose than tolbutamide, although triggering [Ca(2+)](c) was lower. This difference, due to amplification, persisted in nocodazole- or taxol-treated islets, even when IS was augmented fourfold by microfilament disruption with cytochalasin B or latrunculin B. In conclusion, metabolic amplification rapidly augments first and second phases of IS independently of insulin granule translocation along microtubules. We therefore extend our previous proposal that it does not implicate the cytoskeleton but corresponds to acceleration of the priming process conferring release competence to insulin granules.

  20. Insulin secretion and sensitivity in space flight: diabetogenic effects

    Science.gov (United States)

    Tobin, Brian W.; Uchakin, Peter N.; Leeper-Woodford, Sandra K.

    2002-01-01

    Nearly three decades of space flight research have suggested that there are subclinical diabetogenic changes that occur in microgravity. Alterations in insulin secretion, insulin sensitivity, glucose tolerance, and metabolism of protein and amino acids support the hypothesis that insulin plays an essential role in the maintenance of muscle mass in extended-duration space flight. Experiments in flight and after flight and ground-based bedrest studies have associated microgravity and its experimental paradigms with manifestations similar to those of diabetes, physical inactivity, and aging. We propose that these manifestations are characterized best by an etiology that falls into the clinical category of "other" causes of diabetes, including, but not restricted to, genetic beta-cell defects, insulin action defects, diseases of the endocrine pancreas, endocrinopathies, drug or chemically induced diabetes, infections, immune-mediated metabolic alteration, and a host of genetic related diseases. We present data showing alterations in tumor necrosis factor-alpha production, insulin secretion, and amino acid metabolism in pancreatic islets of Langerhans cultured in a ground-based cell culture bioreactor that mimics some of the effects of microgravity. Taken together, space flight research, ground-based studies, and bioreactor studies of pancreatic islets of Langerhans support the hypothesis that the pancreas is unable to overcome peripheral insulin resistance and amino acid dysregulation during space flight. We propose that measures of insulin secretion and insulin action will be necessary to design effective countermeasures against muscle loss, and we advance the "disposition index" as an essential model to be used in the clinical management of space flight-induced muscle loss.

  1. Targeting development of incretin-producing cells increases insulin secretion

    NARCIS (Netherlands)

    Petersen, Natalia; Reimann, Frank; van Es, Johan H; van den Berg, Bernard M; Kroone, Chantal; Pais, Ramona; Jansen, Erik; Clevers, Hans; Gribble, Fiona M; de Koning, Eelco J P

    Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the

  2. An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion

    Directory of Open Access Journals (Sweden)

    Kyle S. McCommis

    2016-08-01

    Conclusions: Altogether, these studies suggest that the MPC plays an important and ancestral role in insulin-secreting cells in mediating glucose sensing, regulating insulin secretion, and controlling systemic glycemia.

  3. Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells

    DEFF Research Database (Denmark)

    Wu, Bingbing; Wei, Shunhui; Petersen, Natalia

    2015-01-01

    Glucose stimulates insulin secretion from β-cells by increasing intracellular Ca(2+). Ca(2+) then binds to synaptotagmin-7 as a major Ca(2+) sensor for exocytosis, triggering secretory granule fusion and insulin secretion. In type-2 diabetes, insulin secretion is impaired; this impairment is amel...

  4. Importance of radioimmunoassay of insulin secretion disorder as atherogenic factor

    International Nuclear Information System (INIS)

    Knyazev, Yu.A.; Bespalova, V.A.; Vakhrusheva, L.L.; Kirbasova, N.P.; Severtseva, V.V.

    1984-01-01

    Using a radioimmunoassay a C-peptide levei was revealed in children, pregnant and lying-in women as well as in patients with insulin-dependent diabetes mellitus. After breakfast and insulin administration wich curative purposes the IRI concentration in children increased whereas the C-peptide level changed insignificantly. Changes of the insulin secretion were more noticeable in severe diabetes mejlitus with vascular complications and in disease decompensation. The atherogenic nature of the lipid metaboiism (an increase in the cholesterol, triglyceride and β-lipoprotein levels), changes in the liver and tendency to vascular involvement are results of insulin effect inadequacy. Such metabolic derangements in pregnant women create unfavorable conditions for the development of fetus and may lead to early atherogenic processes

  5. Glucose, other secretagogues, and nerve growth factor stimulate mitogen-activated protein kinase in the insulin-secreting beta-cell line, INS-1

    DEFF Research Database (Denmark)

    Frödin, M; Sekine, N; Roche, E

    1995-01-01

    The signaling pathways whereby glucose and hormonal secretagogues regulate insulin-secretory function, gene transcription, and proliferation of pancreatic beta-cells are not well defined. We show that in the glucose-responsive beta-cell line INS-1, major secretagogue-stimulated signaling pathways...... converge to activate 44-kDa mitogen-activated protein (MAP) kinase. Thus, glucose-induced insulin secretion was found to be associated with a small stimulatory effect on 44-kDa MAP kinase, which was synergistically enhanced by increased levels of intracellular cAMP and by the hormonal secretagogues......-1. Phorbol ester, an activator of protein kinase C, stimulated 44-kDa MAP kinase by both Ca(2+)-dependent and -independent pathways. Nerve growth factor, independently of changes in cytosolic Ca2+, efficiently stimulated 44-kDa MAP kinase without causing insulin release, indicating that activation...

  6. Targeting development of incretin-producing cells increases insulin secretion

    DEFF Research Database (Denmark)

    Petersen, Natalia; Reimann, Frank; van Es, Johan H

    2015-01-01

    Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing....... Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation...

  7. MiR-184 regulates insulin secretion through repression of Slc25a22

    Science.gov (United States)

    Morita, Sumiyo; Horii, Takuro; Kimura, Mika

    2013-01-01

    Insulin secretion from pancreatic β-cells plays an essential role in blood glucose homeostasis and type 2 diabetes. Many genes are involved in the secretion of insulin and most of these genes can be targeted by microRNAs (miRNAs). However, the role of miRNAs in insulin secretion and type 2 diabetes has not been exhaustively studied. The expression miR-184, a miRNA enriched in pancreatic islets, negatively correlates with insulin secretion, suggesting that it is a good candidate for miRNA-mediated regulation of insulin secretion. Here we report that miR-184 inhibits insulin secretion in the MIN6 pancreatic β-cell line through the repression of its target Slc25a22, a mitochondrial glutamate carrier. Our study provides new insight into the regulation of insulin secretion by glutamate transport in mitochondria. PMID:24109547

  8. Reconstruction of the insulin secretion rate by Bayesian deconvolution

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Højbjerre, Malene

    of the insulin secretion rate (ISR) can be done by solving a highly ill-posed deconvolution problem. We present a Bayesian methodology for the estimation of scaled densities of phase-type distributions via Markov chain Monte Carlo techniques, whereby closed form evaluation of ISR is possible. We demonstrate...... the methodology on simulated data concluding that the method seems as a promising alternative to existing methods where the ISR is considered as piecewise constant....

  9. Depressive symptoms, insulin sensitivity and insulin secretion in the RISC cohort study

    DEFF Research Database (Denmark)

    Bot, M; Pouwer, F; De Jonge, P

    2013-01-01

    . highest quartile of beta-cell rate sensitivity was 2.04; P=0.01). Also, significant depressive symptoms were associated with a statistically significant decrease in the potentiation factor ratio in unadjusted models, but not in the fully adjusted model. CONCLUSION: Depressive symptoms were not related......AIM: This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years. METHODS: The study population was derived from the 3-year follow-up of the Relationship between Insulin...... Sensitivity and Cardiovascular Disease Risk (RISC) study. Presence of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16. Standard oral glucose tolerance tests were performed. Insulin sensitivity was assessed with the oral glucose insulin...

  10. Incretins, insulin secretion and Type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, T; Holst, Jens Juul

    2004-01-01

    the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism...... of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas...... the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown...

  11. The Role of Taste in Cephalic Phase of Insulin Secretion

    Directory of Open Access Journals (Sweden)

    M. Dušková

    2013-01-01

    Full Text Available The effect of a short gustatory signal of a sweet solution was tested on 15 young male volunteers. The experiment consisted of mouth rinsing with either a sucrose or aspartate solution or pure water as a placebo. Blood was then taken in short intervals of 0, 5, 10, 15 and 20 min. Blood glucose, C-peptide, insulin and cortisol were determined. While C-peptide and glucose were unaffected, a short-term increase in insulin was observed after the sucrose, but not after the aspartate or placebo. The increase in insulin was significant, though it amounted to only 0.5 mIU/l and lasted approx. 15 min reaching then the starting value. The decline of cortisol level within 20 min of the experiment was approx. 40 nmol/l, although it was also observed after aspartate or placebo mouth rinsing and was probably caused by stress factors or anticipation. In conclusion, the contribution of taste to the cephalic phase of insulin secretion is small yet significant, and mouth rinsing with 5% sucrose causes an insulin increase of just under 1 IU/l, which returns to starting level within 15 min.

  12. DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet

    Directory of Open Access Journals (Sweden)

    Katherine Veras

    2014-01-01

    Full Text Available Dehydroepiandrosterone (DHEA and the dehydroepiandrosterone sulfate (DHEA-S are steroids produced mainly by the adrenal cortex. There is evidence from both human and animal models suggesting beneficial effects of these steroids for obesity, diabetes mellitus, hypertension, and osteoporosis, conditions associated with the post-menopausal period. Accordingly, we hypothesized that DHEA supplementation in ovariectomized (OVX female rats fed a high-fat diet would maintain glucose-induced insulin secretion (GSIS and pancreatic islet function. OVX resulted in a 30% enlargement of the pancreatic islets area compared to the control rats, which was accompanied by a 50% reduction in the phosphorylation of AKT protein in the pancreatic islets. However, a short-term high-fat diet induced insulin resistance, accompanied by impaired GSIS in isolated pancreatic islets. These effects were reversed by DHEA treatment, with improved insulin sensitivity to levels similar to the control group, and with increased serine phosphorylation of the AKT protein. These data confirm the protective effect of DHEA on the endocrine pancreas in a situation of diet-induced overweight and low estrogen concentrations, a phenotype similar to that of the post-menopausal period.

  13. Association of Nocturnal Melatonin Secretion With Insulin Resistance in Nondiabetic Young Women

    OpenAIRE

    McMullan, Ciaran J.; Curhan, Gary C.; Schernhammer, Eva S.; Forman, John P.

    2013-01-01

    Exogenous melatonin ameliorates insulin resistance in animals, while among humans, polymorphisms in the melatonin receptor gene are associated with insulin resistance. We aimed to investigate the association of endogenous nocturnal melatonin secretion with insulin resistance in humans. We analyzed the association between endogenous nocturnal melatonin secretion, estimated by measuring the main melatonin metabolite, 6-sulfatoxymelatonin, from the first morning urinary void, and the prevalence ...

  14. Tacrolimus reversibly reduces insulin secretion, induces insulin resistance, and causes islet cell damage in rats.

    Science.gov (United States)

    Xu, Chun; Niu, Yu-Jian; Liu, Xiao-Jun; Teng, Ya-Qin; Li, Chun-Feng; Wang, Hong-Yu; Yin, Jun-Ping; Wang, Le-Tian; Shen, Zhong-Yang

    2014-07-01

    To investigate the diabetogenic effects of the immunosuppressive agent tacrolimus, the reversibility of these effects upon treatment discontinuation, and the underlying mechanisms in a rat model. 60 healthy male rats were randomly divided into three groups for intragastric administration of tacrolimus either at 4 mg/kg/d or 2 mg/kg/d or an equal volume of normal saline (control). The treatment was administered for 5 months, followed by a 5-month period of no intervention. Fasting plasma glucose and insulin levels were used to calculate the homeostasis model assessment of ß-cell function (HOMA-ß) and insulin sensitivity index (ISI). Tacrolimus treatment significantly increased blood glucose concentrations (p insulin secretion pathway, local and/or systemic insulin resistance, and islet cell damage.

  15. Effect of Gymnema sylvestre Administration on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion.

    Science.gov (United States)

    Zuñiga, Laura Y; González-Ortiz, Manuel; Martínez-Abundis, Esperanza

    2017-08-01

    Gymnema sylvestre is a medicinal plant whose consumption has demonstrated benefits on lipid and glucose levels, blood pressure, and body weight (BWt). The aim of this study was to evaluate the effect of G. sylvestre administration on metabolic syndrome (MetS), insulin secretion, and insulin sensitivity. A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients (without pharmacological treatment), 30-60 years old, with diagnosis of MetS in accordance with the modified International Diabetes Federation criteria. Patients were randomly assigned to receive G. sylvestre or placebo twice daily before breakfast and dinner in 300 mg capsules for a total of 600 mg per day for 12 weeks. Before and after the intervention, the components of MetS were evaluated as well as BWt, body mass index (BMI), total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein (VLDL). Area under the curve of glucose and insulin, phases of insulin secretion, and insulin sensitivity were calculated. Statistical analysis was performed using Wilcoxon signed-rank, Mann-Whitney U, and chi-square tests; P ≤ .05 was considered statistically significant. After G. sylvestre administration, significant decreases in BWt (81.3 ± 10.6 kg vs. 77.9 ± 8.4 kg, P = .02), BMI (31.2 ± 2.5 kg/m 2 vs. 30.4 ± 2.2 kg/m 2 , P = .02), and VLDL levels (0.45 ± 0.15 mmol/dL vs. 0.35 ± 0.15 mmol/dL, P = .05) were observed, without modifying the components of MetS, insulin secretion, and insulin sensitivity. In conclusion, G. sylvestre administration decreased BWt, BMI, and VLDL levels in subjects with MetS, without changes in insulin secretion and insulin sensitivity.

  16. Dietary Sodium Restriction Decreases Insulin Secretion Without Affecting Insulin Sensitivity in Humans

    Science.gov (United States)

    Byrne, Loretta M.; Yu, Chang; Wang, Thomas J.; Brown, Nancy J.

    2014-01-01

    Context: Interruption of the renin-angiotensin-aldosterone system prevents incident diabetes in high-risk individuals, although the mechanism remains unclear. Objective: To test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system or exogenous aldosterone impairs insulin secretion in humans. Design: We conducted a randomized, blinded crossover study of aldosterone vs vehicle and compared the effects of a low-sodium versus a high-sodium diet. Setting: Academic clinical research center. Participants: Healthy, nondiabetic, normotensive volunteers. Interventions: Infusion of exogenous aldosterone (0.7 μg/kg/h for 12.5 h) or vehicle during low or high sodium intake. Low sodium (20 mmol/d; n = 12) vs high sodium (160 mmol/d; n = 17) intake for 5–7 days. Main Outcome Measures: Change in acute insulin secretory response assessed during hyperglycemic clamps while in sodium balance during a low-sodium vs high-sodium diet during aldosterone vs vehicle. Results: A low-sodium diet increased endogenous aldosterone and plasma renin activity, and acute glucose-stimulated insulin (−16.0 ± 5.6%; P = .007) and C-peptide responses (−21.8 ± 8.4%; P = .014) were decreased, whereas the insulin sensitivity index was unchanged (−1.0 ± 10.7%; P = .98). Aldosterone infusion did not affect the acute insulin response (+1.8 ± 4.8%; P = .72) or insulin sensitivity index (+2.0 ± 8.8%; P = .78). Systolic blood pressure and serum potassium were similar during low and high sodium intake and during aldosterone infusion. Conclusions: Low dietary sodium intake reduces insulin secretion in humans, independent of insulin sensitivity. PMID:25029426

  17. Possible links between glucose-induced changes in the energy state of pancreatic B cells and insulin release. Unmasking by decreasing a stable pool of adenine nucleotides in mouse islets.

    OpenAIRE

    Detimary, P; Jonas, J C; Henquin, J C

    1995-01-01

    Whether adenine nucleotides in pancreatic B cells serve as second messengers during glucose stimulation of insulin secretion remains disputed. Our hypothesis was that the actual changes in ATP and ADP are obscured by the large pool of adenine nucleotides (ATP/ADP ratio close to 1) in insulin granules. Therefore, mouse islets were degranulated acutely with a cocktail of glucose, KCl, forskolin, and phorbol ester or during overnight culture in RPMI-1640 medium containing 10 mM glucose. When the...

  18. Cocoa flavonoids attenuate high glucose-induced insulin signalling blockade and modulate glucose uptake and production in human HepG2 cells.

    Science.gov (United States)

    Cordero-Herrera, Isabel; Martín, María Ángeles; Goya, Luis; Ramos, Sonia

    2014-02-01

    Insulin resistance is the primary characteristic of type 2 diabetes. Cocoa and its main flavanol, (-)-epicatechin (EC), display some antidiabetic effects, but the mechanisms for their preventive activities related to glucose metabolism and insulin signalling in the liver remain largely unknown. In the present work, the preventive effect of EC and a cocoa polyphenolic extract (CPE) on insulin signalling and on both glucose production and uptake are studied in insulin-responsive human HepG2 cells treated with high glucose. Pre-treatment of cells with EC or CPE reverted decreased tyrosine-phosphorylated and total levels of IR, IRS-1 and -2 triggered by high glucose. EC and CPE pre-treatment also prevented the inactivation of the PI3K/AKT pathway and AMPK, as well as the diminution of GLUT-2 levels induced by high glucose. Furthermore, pre-treatment of cells with EC and CPE avoided the increase in PEPCK levels and the diminished glucose uptake provoked by high glucose, returning enhanced levels of glucose production and decreased glycogen content to control values. These findings suggest that EC and CPE improved insulin sensitivity of HepG2 treated with high glucose, preventing or delaying a potential hepatic dysfunction through the attenuation of the insulin signalling blockade and the modulation of glucose uptake and production. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Menge, Björn A; Grüber, Lena; Jørgensen, Signe M

    2011-01-01

    In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known.......In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known....

  20. Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers

    DEFF Research Database (Denmark)

    Øzbay, Aygen; Møller, Niels; Juhl, Claus

    2012-01-01

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: New onset diabetes after transplantation is related to treatment with immunosuppressive medications. Clinical studies have shown that risk of new onset diabetes is greater with tacrolimus compared with ciclosporin. The diabetogenicity of ciclosporin...... of NODAT remains unclear. We sought to compare the impact of CsA and Tac on glucose metabolism in human subjects. METHODS: Ten healthy men underwent 5 h infusions of CsA, Tac and saline in a randomized, double-blind, crossover study. During infusion glucose metabolism was investigated using following.......047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non-significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were...

  1. Insulin secretion and glucose uptake by isolated islets of the hamster

    International Nuclear Information System (INIS)

    Dunbar, J.C.; McLaughlin, W.J.; Walsh, M.F.J.; Foa, P.P.

    1976-01-01

    Isolated pancreatic islets of normal hamsters were perfused either in a closed or in a open system. When the buffer was recirculated and the endogenous insulin was allowed to accumulate, the islets secreted significantly less insulin than when the system was open and the endogenous insulin was washed away. The addition of monocomponent insulin or of proinsulin to the perfusion buffer significantly decreased insulin secretion. The inhibitory action of proinsulin was significantly greater than that of monocomponent insulin. C peptide had no effect. When pancreatic islets were incubated in a fixed volume of stationary buffer containing unlabeled glucose (1.0 mg or 3.0 mg/ml) and glucose-U- 14 C (1.0 μC/ml), the amount of insulin secreted and the 14 CO 2 produced by each islet decreased progressively as the number of islets in the sample increased. Under these conditions, the concentration of insulin required to inhibit insulin secretion increased with the concentration of glucose in the medium. Proinsulin did not alter the incorporation of leucine-4.5- 3 H into total extractable insulin (insulin + proinsulin). Thus, insulin and proinsulin appear to inhibit insulin release, but not insulin synthesis. (orig.) [de

  2. The possible mechanisms by which maternal hypothyroidism impairs insulin secretion in adult male offspring in rats.

    Science.gov (United States)

    Karbalaei, Narges; Ghasemi, Asghar; Hedayati, Mehdi; Godini, Aliashraf; Zahediasl, Saleh

    2014-04-01

    Previous studies have recently shown that maternal hypothyroidism leads to impaired glucose metabolism and reduced insulin secretion in adult offspring in rats. The aim of this study was to locate the defect in the insulin secretion pathway induced by maternal hypothyroidism. Pregnant Wistar rats were divided into two groups; the control group consumed water, while the hypothyroid (FH) group received water containing 0.025% 6-propyl-2-thiouracil during gestation. An intravenous glucose tolerance test was carried out on 5-month-old male offspring. In in vitro studies, the effects of various secretagogues and inhibitors acting at different levels of the insulin secretion cascade were investigated, and insulin content, insulin secretion and glucokinase activity of the islets were compared. Although insulin content of the FH islets did not differ from that of control islets, insulin secretion from FH islets was reduced when it was challenged by glucose or arginine. Compared with control islets, activities of both hexokinase and glucokinase were also significantly decreased in the FH islets. Although, in both groups, increasing glibenclamide and nifedipine concentrations in the presence of 16.7 mmol l(-1) glucose increased and decreased insulin secretion, respectively, the percentage of changes in secretion of FH islets was significantly lower compared with control islets. The response of FH islets to high extracellular potassium concentration and diazoxide was also significantly lower than that of the control islets. These findings demonstrate that impaired insulin secretion in the FH group is probably related to alterations in different steps of the insulin secretion pathway and not in the insulin pool of β-cells.

  3. Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men

    DEFF Research Database (Denmark)

    Jensen, Christine B; Storgaard, Heidi; Holst, Jens Juul

    2003-01-01

    We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp...... Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux......, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action.insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but...

  4. Environmental factors and dam characteristics associated with insulin sensitivity and insulin secretion in newborn Holstein calves

    International Nuclear Information System (INIS)

    Kamal, M.M.; Van Eetvelde, M.; Bogaert, H.; Hostens, M.; Vandaele, L.; Shamsuddin, M.; Opsomer, G.

    2016-01-01

    Full text: The objective of the present retrospective cohort study was to evaluate potential associations between environmental factors and dam characteristics, including level of milk production during gestation, and insulin traits in newborn Holstein calves. Birth weight and gestational age of the calves at delivery were determined. On the next day, heart girth, wither height and diagonal length of both the calves and their dams were measured. Parity, body condition score and age at calving were recorded for all dams. For the cows, days open before last gestation, lactation length (LL), lenght of dry period (DP) and calving interval were also calculated. The magnitude and shape of the lactation curve both quantified using the MilkBot model based on monthly milk weights, were used to calculate the amount of milk produced during gestation. Using the same procedure, cumulative milk production from conception to drying off (MGEST) was calculated. A blood sample was collected from all calves (n=481; 169 born to heifers and 312 born to cows) at least 5 h after a milk meal on day 3 of life to measure basal glucose and insulin levels. In addition, an intravenous glucose-stimulated insulin secretion test was performed in a subset of the calves (n=316). After descriptive analysis, generalized linear mixed models were used to identify factors that were significantly associated with the major insulin traits (Insb, basal insulin level; QUICKI, quantitative insulin sensitivity check index; AIR, acute insulin response; DI, disposition index) of the newborn calves. The overall average birth weight of the calves was 42.7 ± 5.92 kg. The insulin traits were significantly associated with MGEST (P=0.076) and longer DP (P=0.034). The QUICKI was estimated to be lower in calves born to the cows having passed a higher MGEST (P=0.030) and longer DP (P=0.058). Moreover, the AIR (P=0.009) and DI (P=0.049) were estimated to be lower in male compared with female calves. Furthermore, the AIR

  5. Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

    Energy Technology Data Exchange (ETDEWEB)

    Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan); Fujitani, Yoshio, E-mail: fujitani@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan)

    2009-12-18

    Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

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

    International Nuclear Information System (INIS)

    Bagge, Annika; Clausen, Trine R.; Larsen, Sylvester; Ladefoged, Mette; Rosenstierne, Maiken W.; Larsen, Louise; Vang, Ole; Nielsen, Jens H.; Dalgaard, Louise T.

    2012-01-01

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

  7. Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose-Tolerant Humans

    DEFF Research Database (Denmark)

    Simon, Marie-Christine; Strassburger, Klaus; Nowotny, Bettina

    2015-01-01

    OBJECTIVE: Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release...... cytokines. CONCLUSIONS: Enrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may serve as a novel therapeutic....... reuteri SD5865 or placebo over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess incretin effect and GLP-1 and GLP-2 secretion, and euglycemic-hyperinsulinemic clamps with [6,6-(2)H2]glucose were used to measure peripheral insulin sensitivity and endogenous glucose...

  8. Exercise Increases Insulin Content and Basal Secretion in Pancreatic Islets in Type 1 Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Han-Hung Huang

    2011-01-01

    Full Text Available Exercise appears to improve glycemic control for people with type 1 diabetes (T1D. However, the mechanism responsible for this improvement is unknown. We hypothesized that exercise has a direct effect on the insulin-producing islets. Eight-week-old mice were divided into four groups: sedentary diabetic, exercised diabetic, sedentary control, and exercised control. The exercised groups participated in voluntary wheel running for 6 weeks. When compared to the control groups, the islet density, islet diameter, and β-cell proportion per islet were significantly lower in both sedentary and exercised diabetic groups and these alterations were not improved with exercise. The total insulin content and insulin secretion were significantly lower in sedentary diabetics compared to controls. Exercise significantly improved insulin content and insulin secretion in islets in basal conditions. Thus, some improvements in exercise-induced glycemic control in T1D mice may be due to enhancement of insulin content and secretion in islets.

  9. Novel insulin from the bullfrog: its structure and function in protein secretion by hepatocytes

    International Nuclear Information System (INIS)

    Hulsebus, J.J.

    1987-01-01

    Bullfrog insulin was extracted and purified from the pancreas of Rana catesbeiana adults using gel filtration and reverse phase high performance liquid chromatography. Amino acid analysis of bullfrog insulin revealed 52 amino acids instead of the most common number of 51. The most unique features of bullfrog insulin is a two amino acid extension on the amino terminus (A1) of the A chain. This is the only insulin to date that has an extension at this position. Bullfrog and porcine insulin increase protein secretion from bullfrog adult and three developmental stages of tadpole hepatocytes in a totally defined, serum-free culture system. The hormone slightly stimulates protein secretion by premetamorphic and early prometamorphic tadpoles. Late prometamorphic tadpoles respond to bullfrog and porcine insulin with higher concentrations of secreted protein than either of the two previous developmental stages. Insulin treated adult hepatocytes secrete significantly higher concentrations of protein than any of the tadpole stages. 35 S-methionine and 35 S-cysteine were added to the culture medium for twelve hours. Proteins secreted into the medium were separated using SDS polyacrylamide linear gradient gels. Densitometer scans of autoradiograms did not show an increases in any specific proteins, but did show a generalized increase in all secreted proteins for both adults, and tadpoles

  10. Deletion of Protein Kinase D1 in Pancreatic β-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice.

    Science.gov (United States)

    Bergeron, Valérie; Ghislain, Julien; Vivot, Kevin; Tamarina, Natalia; Philipson, Louis H; Fielitz, Jens; Poitout, Vincent

    2018-01-01

    Ββ-Cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional β-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the β-cell and plays a critical role in the control of insulin secretion. However, the role of β-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using β-cell-specific, inducible PKD1 knockout mice (βPKD1KO), we examined the role of β-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO mice under a chow diet presented no significant difference in glucose tolerance or insulin secretion compared with mice expressing the Cre transgene alone; however, when compared with wild-type mice, both groups developed glucose intolerance. Under a high-fat diet, deletion of PKD1 in β-cells worsened hyperglycemia, hyperinsulinemia, and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat diet-fed βPKD1KO mice without changes in islet mass. This study demonstrates an essential role for PKD1 in the β-cell adaptive secretory response to high-fat feeding in mice. © 2017 by the American Diabetes Association.

  11. Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.

    Science.gov (United States)

    Scherer, Thomas; Lindtner, Claudia; O'Hare, James; Hackl, Martina; Zielinski, Elizabeth; Freudenthaler, Angelika; Baumgartner-Parzer, Sabina; Tödter, Klaus; Heeren, Joerg; Krššák, Martin; Scheja, Ludger; Fürnsinn, Clemens; Buettner, Christoph

    2016-06-01

    Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  12. Momordica charantia Administration Improves Insulin Secretion in Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Cortez-Navarrete, Marisol; Martínez-Abundis, Esperanza; Pérez-Rubio, Karina G; González-Ortiz, Manuel; Villar, Miriam Méndez-Del

    2018-02-12

    An improvement in parameters of glycemic control has been observed with Momordica charantia in patients with type 2 diabetes mellitus (T2DM). It is unknown whether this improvement is through a modification of insulin secretion, insulin sensitivity, or both. We hypothesized that M. charantia administration can improve insulin secretion and/or insulin sensitivity in patients with T2DM, without pharmacological treatment. The objective of the study was to evaluate the effect of M. charantia administration on insulin secretion and sensitivity. A randomized, double-blinded, placebo-controlled, clinical trial was carried out in 24 patients who received M. charantia (2000 mg/day) or placebo for 3 months. A 2-h oral glucose tolerance test (OGTT) was done before and after the intervention to calculate areas under the curve (AUC) of glucose and insulin, total insulin secretion (insulinogenic index), first phase of insulin secretion (Stumvoll index), and insulin sensitivity (Matsuda index). In the M. charantia group, there were significant decreases in weight, body mass index (BMI), fat percentage, waist circumference (WC), glycated hemoglobin A1c (A1C), 2-h glucose in OGTT, and AUC of glucose. A significant increase in insulin AUC (56,562 ± 36,078 vs. 65,256 ± 42,720 pmol/L/min, P = .043), in total insulin secretion (0.29 ± 0.18 vs. 0.41 ± 0.29, P = .028), and during the first phase of insulin secretion (557.8 ± 645.6 vs. 1135.7 ± 725.0, P = .043) was observed after M. charantia administration. Insulin sensitivity was not modified with any intervention. In conclusion, M. charantia administration reduced A1C, 2-h glucose, glucose AUC, weight, BMI, fat percentage, and WC, with an increment of insulin AUC, first phase and total insulin secretion.

  13. Effect of Human Myotubes-Derived Media on Glucose-Stimulated Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Maria L. Mizgier

    2017-01-01

    Full Text Available Fasting to postprandial transition requires a tight adjustment of insulin secretion to its demand, so tissue (e.g., skeletal muscle glucose supply is assured while hypo-/hyperglycemia are prevented. High muscle glucose disposal after meals is pivotal for adapting to increased glycemia and might drive insulin secretion through muscle-released factors (e.g., myokines. We hypothesized that insulin influences myokine secretion and then increases glucose-stimulated insulin secretion (GSIS. In conditioned media from human myotubes incubated with/without insulin (100 nmol/L for 24 h, myokines were qualitatively and quantitatively characterized using an antibody-based array and ELISA-based technology, respectively. C57BL6/J mice islets and Wistar rat beta cells were incubated for 24 h with control and conditioned media from noninsulin- and insulin-treated myotubes prior to GSIS determination. Conditioned media from insulin-treated versus nontreated myotubes had higher RANTES but lower IL6, IL8, and MCP1 concentration. Qualitative analyses revealed that conditioned media from noninsulin- and insulin-treated myotubes expressed 32 and 23 out of 80 myokines, respectively. Islets incubated with conditioned media from noninsulin-treated myotubes had higher GSIS versus control islets (p<0.05. Meanwhile, conditioned media from insulin-treated myotubes did not influence GSIS. In beta cells, GSIS was similar across conditions. In conclusion, factors being present in noninsulin-stimulated muscle cell-derived media appear to influence GSIS in mice islets.

  14. Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion

    DEFF Research Database (Denmark)

    Müssig, Karsten; Staiger, Harald; Machicao, Fausto

    2009-01-01

    OBJECTIVE: KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered beta-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different...... C-peptide levels during OGTT, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P insulin secretion indexes (all P ... and basal or stimulated incretin levels (all P > or = 0.05). CONCLUSIONS: Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems...

  15. Aminophylline stimulates insulin secretion in patients with type 2 diabetes mellitus

    NARCIS (Netherlands)

    Arias, A. M.; Bisschop, P. H.; Ackermans, M. T.; Nijpels, G.; Endert, E.; Romijn, J. A.; Sauerwein, H. P.

    2001-01-01

    In healthy subjects, paracrine factors partly regulate insulin secretion and basal endogenous glucose production. Administration of pentoxifylline, an adenosine receptor antagonist, inhibits transiently endogenous glucose production in healthy humans without any changes in glucoregulatory hormone

  16. Pancreatic β-Cell Electrical Activity and Insulin Secretion: of Mice and Men

    Science.gov (United States)

    Rorsman, Patrik; Ashcroft, Frances M

    2018-01-01

    The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration. Impaired insulin secretion results in the chronic hyperglycaemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca2+ concentration and initiation of Ca2+-dependent exocytosis of insulin-containing secretory granules. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity and insulin exocytosis. We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM. PMID:29212789

  17. Intra- and Inter-islet Synchronization of Metabolically Driven Insulin Secretion

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram; Bertram, Richard; Sherman, Arthur

    2005-01-01

    Insulin secretion from pancreatic beta-cells is pulsatile with a period of 5-10 min and is believed to be responsible for plasma insulin oscillations with similar frequency. To observe an overall oscillatory insulin pro. le it is necessary that the insulin secretion from individual beta......-cells is synchronized within islets, and that the population of islets is also synchronized. We have recently developed a model in which pulsatile insulin secretion is produced as a result of calcium-driven electrical oscillations in combination with oscillations in glycolysis. We use this model to investigate possible...... mechanisms for intra-islet and inter-islet synchronization. We show that electrical coupling is sufficient to synchronize both electrical bursting activity and metabolic oscillations. We also demonstrate that islets can synchronize by mutually entraining each other by their effects on a simple model "liver...

  18. Glucose-induced effects and joker function of glucose: endocrine or genotoxic prevalence?

    Science.gov (United States)

    Berstein, L M; Vasilyev, D A; Poroshina, T E; Kovalenko, I G

    2006-10-01

    The steady increase in chronic "glycemic load" is characteristic for modern times. Among myriad of glucose functions, two principals can be emphasized: first, endocrine (in particular, ability to induce insulin secretion) and second, DNA-damaging related to formation of reactive oxygen species (ROS). It was suggested by us earlier that a shift in the ratio of mentioned functions reflects a possible "joker" role of glucose as an important modifier of human pathology. Therefore, we embarked on a study to investigate an individual effect of peroral glucose challenge on serum insulin level and ROS generation by mononuclears (luminol-dependent/latex-induced chemiluminescence) in 20 healthy people aged between 28-75. Concentrations of glucose, blood lipids, carbonylated proteins, malondialdehyde, leptin and TNF-alpha were determined as well. On the basis of received data two separate groups could be distinguished: one (n=8), in which glucose stimulation of ROS generation by mononuclears was increased and relatively prevailed over induction of insulin secretion (state of the so called glucose-induced genotoxicity, GIGT), and another (n=12), in which signs of GIGT were not revealed. People who belonged to the first group were characterized with a tendency to lower body mass index, blood leptin and cholesterol and to higher TNF-alpha concentration. Thus, if joker function of glucose is realized in "genotoxic mode", the phenotype (and probably genotype) of subjects may be rather distinctive to the one discovered in glucose-induced "endocrine prevalence". Whether such changes may serve as a pro-mutagenic or pro-endocrine basis for the rise of different chronic diseases or, rather, different features/aggressiveness of the same disease warrants further study.

  19. Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men

    DEFF Research Database (Denmark)

    Jensen, Christine B; Storgaard, Heidi; Holst, Jens Juul

    2003-01-01

    not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes.......We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp...

  20. Enhanced insulin secretion and insulin sensitivity in young lambs with placental insufficiency-induced intrauterine growth restriction.

    Science.gov (United States)

    Camacho, Leticia E; Chen, Xiaochuan; Hay, William W; Limesand, Sean W

    2017-08-01

    Intrauterine growth restriction (IUGR) is associated with persistent metabolic complications, but information is limited for IUGR infants. We determined glucose-stimulated insulin secretion (GSIS) and insulin sensitivity in young lambs with placental insufficiency-induced IUGR. Lambs with hyperthermia-induced IUGR ( n = 7) were compared with control lambs ( n = 8). GSIS was measured at 8 ± 1 days of age, and at 15 ± 1 days, body weight-specific glucose utilization rates were measured with radiolabeled d-glucose during a hyperinsulinemic-euglycemic clamp (HEC). IUGR lambs weighed 23% less ( P insulin concentrations were not different between IUGR and controls for either study. First-phase insulin secretion was enhanced 2.3-fold in IUGR lambs compared with controls. However, second-phase insulin concentrations, glucose-potentiated arginine-stimulated insulin secretion, and β-cell mass were not different, indicating that IUGR β-cells have an intrinsic enhancement in acute GSIS. Compared with controls, IUGR lambs had higher body weight-specific glucose utilization rates and greater insulin sensitivity at fasting (1.6-fold) and hyperinsulinemic periods (2.4-fold). Improved insulin sensitivity for glucose utilization was not due to differences in skeletal muscle insulin receptor and glucose transporters 1 and 4 concentrations. Plasma lactate concentrations during HEC were elevated in IUGR lambs compared with controls, but no differences were found for glycogen content or citrate synthase activity in liver and muscle. Greater insulin sensitivity for glucose utilization and enhanced acute GSIS in young lambs are predicted from fetal studies but may promote conditions that exaggerate glucose disposal and lead to episodes of hypoglycemia in IUGR infants. Copyright © 2017 the American Physiological Society.

  1. Intracellular and extracellular adenosine triphosphate in regulation of insulin secretion from pancreatic β cells (β).

    Science.gov (United States)

    Wang, Chunjiong; Geng, Bin; Cui, Qinghua; Guan, Youfei; Yang, Jichun

    2014-03-01

    Adenosine triphosphate (ATP) synthesis and release in mitochondria play critical roles in regulating insulin secretion in pancreatic β cells. Mitochondrial dysfunction is mainly characterized by a decrease in ATP production, which is a central event in the progression of pancreatic β cell dysfunction and diabetes. ATP has been demonstrated to regulate insulin secretion via several pathways: (i) Intracellular ATP directly closes ATP-sensitive potassium channel to open L-type calcium channel, leading to an increase in free cytosolic calcium levels and exocytosis of insulin granules; (ii) A decrease in ATP production is always associated with an increase in production of reactive oxygen species, which exerts deleterious effects on pancreatic β cell survival and insulin secretion; and (iii) ATP can be co-secreted with insulin from pancreatic β cells, and the released ATP functions as an autocrine signal to modulate insulin secretory process via P2 receptors on the cell membrane. In this review, the recent findings regarding the role and mechanism of ATP synthesis and release in regulation of insulin secretion from pancreatic β cells will be summarized and discussed. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  2. Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males.

    Science.gov (United States)

    Merovci, Aurora; Abdul-Ghani, Muhammad; Mari, Andrea; Solis-Herrera, Carolina; Xiong, Juan; Daniele, Giuseppe; Tripathy, Devjit; DeFronzo, Ralph A

    2016-03-01

    To investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals. Fourteen male T2DM patients received an oral glucose tolerance test and euglycemic hyperinsulinemic clamp at baseline and were treated for 3 weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The oral glucose tolerance test and insulin clamp were repeated at the end of weeks 2 and 3. Dapagliflozin caused glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dL; P insulin-mediated glucose disposal increased significantly at week 2 (from 4.48 ± 0.50 to 5.30 ± 0.50 mg/kg · min; P insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline, and it increased further and significantly at week 3 compared to week 2. Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and β-cell function, whereas lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves β-cell function without significantly affecting insulin sensitivity.

  3. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion : A DIRECT study

    NARCIS (Netherlands)

    Gudmundsdottir, Valborg; Pedersen, Helle Krogh; Allebrandt, Karla Viviani; Brorsson, Caroline; van Leeuwen, Nienke; Banasik, Karina; Mahajan, Anubha; Groves, Christopher J; van de Bunt, Martijn; Dawed, Adem Y; Fritsche, Andreas; Staiger, Harald; Simonis-Bik, Annemarie M C; Deelen, Joris; Kramer, Mark H H; Dietrich, Axel; Hübschle, Thomas; Willemsen, Gonneke; Häring, Hans-Ulrich; de Geus, Eco J C; Boomsma, Dorret I; Eekhoff, Elisabeth M W; Ferrer, Jorge; McCarthy, Mark I; Pearson, Ewan R; Gupta, Ramneek; Brunak, Søren; 't Hart, Leen M

    2018-01-01

    Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin

  4. Parasympathetic involvement in rapid meal-associated conditioned insulin secretion in the rat

    NARCIS (Netherlands)

    Strubbe, J.H.

    Blood glucose and plasma insulin concentrations were measured in blood sampled via a cardiac catheter in freely moving rats. To obtain a rapid conditioned cephalic phase of insulin secretion, rats were habituated to one of two feeding schedules. Clock-activated opening of doors in front of the food

  5. Circadian control of insulin secretion is independent of the temporal distribution of feeding

    NARCIS (Netherlands)

    Kalsbeek, Andries; Strubbe, JH

    1998-01-01

    To investigate whether there is a circadian regulation of insulin secretion, rats were adapted to a feeding regimen of six meals equally distributed over 24 h. Under these conditions basal glucose and insulin levels increased during the light phase and decreased during the dark phase. Maximal blood

  6. Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

    DEFF Research Database (Denmark)

    Wewer Albrechtsen, Nicolai J.; Kuhre, Rune E.; Hornburg, Daniel

    2017-01-01

    that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in...

  7. SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion

    DEFF Research Database (Denmark)

    Anderson, Kristin A; Huynh, Frank K; Fisher-Wellman, Kelsey

    2017-01-01

    in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance...

  8. LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol.

    Science.gov (United States)

    Nøhr, Mark K; Dudele, Anete; Poulsen, Morten M; Ebbesen, Lene H; Radko, Yulia; Christensen, Lars P; Jessen, Niels; Richelsen, Bjørn; Lund, Sten; Pedersen, Steen B

    2016-01-01

    Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P insulin and glucose homeostasis was normalized by resveratrol. Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

  9. LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol.

    Directory of Open Access Journals (Sweden)

    Mark K Nøhr

    Full Text Available Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose from 13.73 to 22.40 pmol/mmol (P < 0.001. This aberration in insulin and glucose homeostasis was normalized by resveratrol.Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

  10. The influence of GLP-1 on glucose-stimulated insulin secretion

    DEFF Research Database (Denmark)

    Kjems, Lise L; Holst, Jens Juul; Vølund, Aage

    2003-01-01

    The intestinally derived hormone glucagon-like peptide 1 (GLP-1) (7-36 amide) has potent effects on glucose-mediated insulin secretion, insulin gene expression, and beta-cell growth and differentiation. It is, therefore, considered a potential therapeutic agent for the treatment of type 2 diabetes....... However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2...... that of the control subjects without GLP-1. Our results show that GLP-1 increases insulin secretion in patients with type 2 diabetes and control subjects in a dose-dependent manner and that the beta-cell responsiveness to glucose may be increased to normal levels with a low dose of GLP-1 infusion. Nevertheless...

  11. Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency.

    Science.gov (United States)

    Limesand, Sean W; Rozance, Paul J

    2017-08-01

    Placental insufficiency and intrauterine growth restriction (IUGR) of the fetus affects approximately 8% of all pregnancies and is associated with short- and long-term disturbances in metabolism. In pregnant sheep, experimental models with a small, defective placenta that restricts delivery of nutrients and oxygen to the fetus result in IUGR. Low blood oxygen concentrations increase fetal plasma catecholamine concentrations, which lower fetal insulin concentrations. All of these observations in sheep models with placental insufficiency are consistent with cases of human IUGR. We propose that sustained high catecholamine concentrations observed in the IUGR fetus produce developmental adaptations in pancreatic β-cells that impair fetal insulin secretion. Experimental evidence supporting this hypothesis shows that chronic elevation in circulating catecholamines in IUGR fetuses persistently inhibits insulin concentrations and secretion. Elevated catecholamines also allow for maintenance of a normal fetal basal metabolic rate despite low fetal insulin and glucose concentrations while suppressing fetal growth. Importantly, a compensatory augmentation in insulin secretion occurs following inhibition or cessation of catecholamine signalling in IUGR fetuses. This finding has been replicated in normally grown sheep fetuses following a 7-day noradrenaline (norepinephrine) infusion. Together, these programmed effects will potentially create an imbalance between insulin secretion and insulin-stimulated glucose utilization in the neonate which probably explains the transient hyperinsulinism and hypoglycaemia in some IUGR infants. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

  12. The Relationship between 25-hydroxyvitamin D Levels, Insulin Sensitivity and Insulin Secretion in Women 3 Years after Delivery.

    Science.gov (United States)

    Tänczer, Tímea; Magenheim, Rita; Fürst, Ágnes; Domján, Beatrix; Janicsek, Zsófia; Szabó, Eszter; Ferencz, Viktória; Tabák, Ádám G

    2017-12-01

    There is a direct correlation between 25-hydroxyvitamin D (25[OH]D) levels and insulin sensitivity. Furthermore, women with gestational diabetes (GDM) may have lower levels of 25(OH)D compared to controls. The present study intended to investigate 25(OH)D levels and their association with insulin sensitivity and insulin secretion in women with prior GDM and in controls 3.2 years after delivery. A total of 87 patients with prior GDM and 45 randomly selected controls (age range, 22 to 44 years) with normal glucose tolerance during pregnancy nested within a cohort of all deliveries at Saint Margit Hospital, Budapest, between January 1 2005, and December 31 2006, were examined. Their 25(OH) D levels were measured by radioimmunoassay. Insulin sensitivity and fasting insulin secretion were estimated using the homeostasis model asssessment (HOMA) calculator and early insulin secretion by the insulinogenic index based on a 75 g oral glucose tolerance test. There was no significant difference in 25(OH)D levels between cases and controls (27.2±13.1 [±SD] vs. 26.9±9.8 ng/L). There was a positive association between HOMA insulin sensitivity and 25(OH)D levels (beta = 0.017; 95% CI 0.001 to 0.034/1 ng/mL) that was robust to adjustment for age and body mass index. There was a nonsignificant association between HOMA insulin secretion and 25(OH)D (p=0.099), while no association was found with the insulinogenic index. Prior GDM status was not associated with 25(OH)D levels; however, 25(OH) D levels were associated with HOMA insulin sensitivity. It is hypothesized that the association between HOMA insulin secretion and 25(OH)D levels is related to the autoregulation of fasting glucose levels because no association between 25(OH)D and insulinogenic index was found. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2015-04-01

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

  14. Sodium arsenite impairs insulin secretion and transcription in pancreatic β-cells

    International Nuclear Information System (INIS)

    Diaz-Villasenor, Andrea; Sanchez-Soto, M. Carmen; Cebrian, Mariano E.; Ostrosky-Wegman, Patricia; Hiriart, Marcia

    2006-01-01

    Human studies have shown that chronic inorganic arsenic (iAs) exposure is associated with a high prevalence and incidence of type 2 diabetes. However, the mechanism(s) underlying this effect are not well understood, and practically, there is no information available on the effects of arsenic on pancreatic β-cells functions. Thus, since insulin secreted by the pancreas plays a crucial role in maintaining glucose homeostasis, our aim was to determine if sodium arsenite impairs insulin secretion and mRNA expression in single adult rat pancreatic β-cells. Cells were treated with 0.5, 1, 2, 5 and 10 μM sodium arsenite and incubated for 72 and 144 h. The highest dose tested (10 μM) decreased β-cell viability, by 33% and 83%, respectively. Insulin secretion and mRNA expression were evaluated in the presence of 1 and 5 μM sodium arsenite. Basal insulin secretion, in 5.6 mM glucose, was not significantly affected by 1 or 5 μM treatment for 72 h, but basal secretion was reduced when cells were exposed to 5 μM sodium arsenite for 144 h. On the other hand, insulin secretion in response to 15.6 mM glucose decreased with sodium arsenite in a dose-dependent manner in such a way that cells were no longer able to distinguish between different glucose concentrations. We also showed a significant decrease in insulin mRNA expression of cells exposed to 5 μM sodium arsenite during 72 h. Our data suggest that arsenic may contribute to the development of diabetes mellitus by impairing pancreatic β-cell functions, particularly insulin synthesis and secretion

  15. Early differential defects of insulin secretion and action in 19-year-old caucasian men who had low birth weight

    DEFF Research Database (Denmark)

    Jensen, Christine B; Storgaard, Heidi; Dela, Flemming

    2002-01-01

    were significantly lower in the LBW group. Insulin-stimulated glycolytic flux was significantly reduced, and suppression of endogenous glucose production was enhanced in the LBW group. Nevertheless, basal and insulin-stimulated rates of whole-body peripheral glucose disposal, glucose oxidation, lipid...... oxidation, exogenous glucose storage, and nonoxidative glucose metabolism were similar in the two groups. Insulin secretion was reduced by 30% in the LBW group, when expressed relative to insulin sensitivity (disposition index = insulin secretion x insulin action). We propose that reduced insulin-stimulated...

  16. Evaluation of insulin expression and secretion in genetically engineered gut K and L-cells

    Directory of Open Access Journals (Sweden)

    Ahmad Zalinah

    2012-09-01

    Full Text Available Abstract Background Gene therapy could provide an effective treatment of diabetes. Previous studies have investigated the potential for several cell and tissue types to produce mature and active insulin. Gut K and L-cells could be potential candidate hosts for gene therapy because of their special features. Results In this study, we isolated gut K and L-cells to compare the potential of both cell types to produce insulin when exposed to similar conditions. The isolated pure K and L-cells were transfected with recombinant plasmids encoding insulin and with specific promoters for K or L-cells. Insulin expression was studied in response to glucose or meat hydrolysate. We found that glucose and meat hydrolysate efficiently induced insulin secretion from K and L-cells. However, the effects of meat hydrolysate on insulin secretion were more potent in both cells compared with glucose. Results of enzyme-linked immunosorbent assays showed that L-cells secreted more insulin compared with K-cells regardless of the stimulator, although this difference was not statistically significant. Conclusion The responses of K and L-cells to stimulation with glucose or meat hydrolysate were generally comparable. Therefore, both K and L-cells show similar potential to be used as surrogate cells for insulin gene expression in vitro. The potential use of these cells for diabetic gene therapy warrants further investigation.

  17. Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

    Science.gov (United States)

    Tudurí, Eva; Beiroa, Daniel; Stegbauer, Johannes; Fernø, Johan; López, Miguel; Diéguez, Carlos; Nogueiras, Rubén

    2016-11-01

    Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Effect of Magnesium Supplements on Insulin Secretion After Kidney Transplantation: A Randomized Controlled Trial.

    Science.gov (United States)

    Van Laecke, Steven; Caluwe, Rogier; Huybrechts, Inge; Nagler, Evi V; Vanholder, Raymond; Peeters, Patrick; Van Vlem, Bruno; Van Biesen, Wim

    2017-08-29

    BACKGROUND Hypomagnesemia is associated with a disturbed glucose metabolism. Insulin hypo-secretion predicts diabetes in the general population and in transplant recipients. We aimed to assess whether magnesium improves insulin secretion and glycemic control after transplantation in prevalent hypomagnesemic kidney transplant recipients. MATERIAL AND METHODS We conducted an open-label, randomized, parallel-group study. Eligible participants were adults more than 4 months after kidney transplantation on tacrolimus with persisting serum magnesium concentrations food-frequency questionnaire. All analyses were done on an intention-to-treat basis. RESULTS Magnesium with a mean daily dose of 688±237mg in the treatment group failed to lead to significant differences between the 2 groups in FPIR, fasting glucose, HbA1c, or HOMA-IR. Persisting hypomagnesemia was very common and associated with more insulin hypo-secretion, glucose intolerance, and lower dietary magnesium intake (142±56 versus 202±90 mg; p=0.015) as compared to patients with a rise in serum magnesium over 6 months. CONCLUSIONS Magnesium supplementation does not improve insulin secretion in stable hypomagnesemic kidney transplant recipients on tacrolimus. Persisting hypomagnesemia is associated with impaired glucose tolerance, insulin hypo-secretion, and dietary factors.

  19. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

    Science.gov (United States)

    Shigeto, Makoto; Ramracheya, Reshma; Tarasov, Andrei I; Cha, Chae Young; Chibalina, Margarita V; Hastoy, Benoit; Philippaert, Koenraad; Reinbothe, Thomas; Rorsman, Nils; Salehi, Albert; Sones, William R; Vergari, Elisa; Weston, Cathryn; Gorelik, Julia; Katsura, Masashi; Nikolaev, Viacheslav O; Vennekens, Rudi; Zaccolo, Manuela; Galione, Antony; Johnson, Paul R V; Kaku, Kohei; Ladds, Graham; Rorsman, Patrik

    2015-12-01

    Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.

  20. Similar weight-adjusted insulin secretion and insulin sensitivity in short-duration late autoimmune diabetes of adulthood (LADA) and Type 2 diabetes

    DEFF Research Database (Denmark)

    Juhl, C B; Bradley, U; Holst, Jens Juul

    2014-01-01

    AIMS: To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with Type 2 diabetes. METHODS: A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year...... of insulin independency (group A) were age-matched pairwise to people with Type 2 diabetes (group B) and to six people with Type 2 diabetes of similar age and BMI (group C). β-cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic......-euglycemic clamp) and metabolic response during a mixed meal were studied. RESULTS: Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in Type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C...

  1. Insulin Sensitivity and Secretion in Obese Type 2 Diabetic Women after Various Bariatric Operations

    Directory of Open Access Journals (Sweden)

    Jana Vrbikova

    2016-12-01

    Full Text Available Objective: To compare the effects of biliopancreatic diversion (BPD and laparoscopic gastric banding (LAGB on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P. Methods: A total of 52 obese women (age 30-66 years suffering from type 2 diabetes mellitus (T2DM were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. Results: Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. Conclusion: We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion, but without increasing the beta cell glucose sensitivity.

  2. Insulin Sensitivity and Secretion in Obese Type 2 Diabetic Women after Various Bariatric Operations.

    Science.gov (United States)

    Vrbikova, Jana; Kunesova, Marie; Kyrou, Ioannis; Tura, Andrea; Hill, Martin; Grimmichova, Tereza; Dvorakova, Katerina; Sramkova, Petra; Dolezalova, Karin; Lischkova, Olga; Vcelak, Josef; Hainer, Vojtech; Bendlova, Bela; Kumar, Sudhesh; Fried, Martin

    2016-01-01

    To compare the effects of biliopancreatic diversion (BPD) and laparoscopic gastric banding (LAGB) on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P). A total of 52 obese women (age 30-66 years) suffering from type 2 diabetes mellitus (T2DM) were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity) increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion), but without increasing the beta cell glucose sensitivity. © 2016 The Author(s) Published by S. Karger GmbH, Freiburg.

  3. Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance

    DEFF Research Database (Denmark)

    Rask, E; Olsson, T; Söderberg, S

    2004-01-01

    Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects...... with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements...... of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean...

  4. Insulin Stimulates S100B Secretion and These Proteins Antagonistically Modulate Brain Glucose Metabolism.

    Science.gov (United States)

    Wartchow, Krista Minéia; Tramontina, Ana Carolina; de Souza, Daniela F; Biasibetti, Regina; Bobermin, Larissa D; Gonçalves, Carlos-Alberto

    2016-06-01

    Brain metabolism is highly dependent on glucose, which is derived from the blood circulation and metabolized by the astrocytes and other neural cells via several pathways. Glucose uptake in the brain does not involve insulin-dependent glucose transporters; however, this hormone affects the glucose influx to the brain. Changes in cerebrospinal fluid levels of S100B (an astrocyte-derived protein) have been associated with alterations in glucose metabolism; however, there is no evidence whether insulin modulates glucose metabolism and S100B secretion. Herein, we investigated the effect of S100B on glucose metabolism, measuring D-(3)H-glucose incorporation in two preparations, C6 glioma cells and acute hippocampal slices, and we also investigated the effect of insulin on S100B secretion. Our results showed that: (a) S100B at physiological levels decreases glucose uptake, through the multiligand receptor RAGE and mitogen-activated protein kinase/ERK signaling, and (b) insulin stimulated S100B secretion via PI3K signaling. Our findings indicate the existence of insulin-S100B modulation of glucose utilization in the brain tissue, and may improve our understanding of glucose metabolism in several conditions such as ketosis, streptozotocin-induced dementia and pharmacological exposure to antipsychotics, situations that lead to changes in insulin signaling and extracellular levels of S100B.

  5. DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity

    DEFF Research Database (Denmark)

    Böhm, Anja; Wagner, Robert; Machicao, Fausto

    2017-01-01

    , inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). RESEARCH DESIGN...... determined. RESULTS: We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype......-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. CONCLUSIONS: A common variant, i...

  6. Glucotoxicity induces abnormal glucagon secretion through impaired insulin signaling in InR1G cells.

    Directory of Open Access Journals (Sweden)

    Takashi Katsura

    Full Text Available The significance of glucagon in the pathophysiology of diabetes mellitus is widely recognized, but the mechanisms underlying dysregulated glucagon secretion are still unclear. Here, we explored the molecular mechanisms of glucagon dysregulation, using an in vitro model. Hamster-derived glucagon-secreting InR1G cells were exposed to high glucose (25 mM levels for 12 h before analyzing glucagon secretion and the activity of components involved in insulin signaling. High-glucose treatment induced increased glucagon secretion in InR1G cells, which represents a hallmark of diabetes mellitus. This treatment reduced the phosphorylation of Akt, indicating the deterioration of insulin signaling. Simultaneously, oxidative stress and JNK activity were shown to be increased. The inhibition of JNK signaling resulted in the amelioration of high-glucose level-induced glucagon secretion. Abnormally elevated glucagon secretion in diabetes can be reproduced by high-glucose treatment of InR1G cells, and the involvement of high glucose-oxidative stress-JNK-insulin signaling pathway axis has been demonstrated. These data elucidate, at least partly, the previously unclear mechanism of abnormal glucagon secretion, providing insights into a potential novel approach to diabetes treatment, targeting glucagon.

  7. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Douillet, Christelle [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Currier, Jenna [Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Saunders, Jesse [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Bodnar, Wanda M. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431 (United States); Matoušek, Tomáš [Institute of Analytical Chemistry of the ASCR, v.v.i., Veveří 97, 602 00 Brno (Czech Republic); Stýblo, Miroslav, E-mail: styblo@med.unc.edu [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States)

    2013-02-15

    Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs{sup III}) or its methylated trivalent metabolites, methylarsonite (MAs{sup III}) and dimethylarsinite (DMAs{sup III}), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs{sup III}, MAs{sup III} or DMAs{sup III} inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs{sup III} and DMAs{sup III} were more potent than iAs{sup III} as GSIS inhibitors with estimated IC{sub 50} ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs{sup III}, MAs{sup III} or DMAs{sup III} could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs{sup III} and DMAs{sup III} are more potent inhibitors than arsenite with IC{sub 50} ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of

  8. Zip4 mediated zinc influx stimulates insulin secretion in pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Alexandre B Hardy

    Full Text Available Zinc has an important role in normal pancreatic beta cell physiology as it regulates gene transcription, insulin crystallization and secretion, and cell survival. Nevertheless, little is known about how zinc is transported through the plasma membrane of beta cells and which of the class of zinc influx transporters (Zip is involved. Zip4 was previously shown to be expressed in human and mouse beta cells; however, its function there is still unknown. Therefore, the aim of this study was to define the zinc transport role of Zip4 in beta cells. To investigate this, Zip4 was over-expressed in MIN6 beta cells using a pCMV6-Zip4GFP plasmid. Organelle staining combined with confocal microscopy showed that Zip4 exhibits a widespread localization in MIN6 cells. Time-lapse zinc imaging experiments showed that Zip4 increases cytoplasmic zinc levels. This resulted in increased granular zinc content and glucose-stimulated insulin secretion. Interestingly, it is unlikely that the increased glucose stimulated insulin secretion was triggered by a modulation of mitochondrial function, as mitochondrial membrane potential remained unchanged. To define the role of Zip4 in-vivo, we generated a beta cell-specific knockout mouse model (Zip4BKO. Deletion of the Zip4 gene was confirmed in Zip4BKO islets by PCR, RT-PCR, and immuno-histochemistry. Zip4BKO mice showed slightly improved glucose homeostasis but no change in insulin secretion during an oral glucose tolerance test. While Zip4 was not found to be essential for proper glucose homeostasis and insulin secretion in vivo in mice, this study also found that Zip4 mediates increases in cytoplasmic and granular zinc pools and stimulates glucose dependant insulin secretion in-vitro.

  9. Effect of alcohol on insulin secretion and viability of human pancreatic islets

    Directory of Open Access Journals (Sweden)

    Nikolić Dragan

    2017-01-01

    Full Text Available Introduction/Objective. There are controversial data in the literature on the topic of effects of alcohol on insulin secretion, apoptosis, and necrosis of the endocrine and exocrine pancreas. The goal of this research was to determine how alcohol affects the insulin secretion and viability of human adult pancreatic islets in vitro during a seven-day incubation. Methods. Human pancreatic tissue was digested with Collagenase XI, using a non-automated method. Cultures were incubated in Roswell Park Memorial Institute (RPMI medium containing alcohol (10 μl of alcohol in 100 ml of medium. Insulin stimulation index (SI and viability of the islets were determined on the first, third, and seventh day of cultivation. Results. Analysis of the viability of the islets showed that there wasn’t significant difference between the control and the test group. In the test group, viability of the cultures declined with the time of incubation. SI of the test group was higher compared to the control group, by 50% and 25% on the first and third day of cultivation, respectively. On the seventh day, insulin secretion was reduced by 25%. The difference was not statistically significant (p > 0.05. In the test group, significant decline in insulin secretion was found on the third and seventh day of incubation (p ≤ 0.05. Conclusion. Alcohol can increase or decrease insulin secretion of islets cultures, which may result in an inadequate response of pancreatic β-cells to blood glucose, leading to insulin resistance, and increased risk of developing type 2 diabetes. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 41002

  10. Conditioned insulin secretion and meal feeding in rats.

    Science.gov (United States)

    Woods, S C; Vasselli, J R; Kaestner, E; Szakmary, G A; Milburn, P; Vitiello, M V

    1977-02-01

    Previous researchers have reported that rats placed upon a feeding regimen such that they receive only 2 hr of food per day (meal-fed rats) develop hyperinsulinemia at the time of the day associated with feeding, even in the absence of food. Controls fed ad lib had no such response. In a series of several experiments, meal-fed rats had elevated insulin levels at only the specific time of the day associated with feeding, and the increment of insulin at that time could be eliminated with atropine. Free-feeding controls, on the other hand, always had higher insulin levels than the meal-fed rats, did not have an elevation of insulin at the time of the day that the meal-fed rats normally ate, and had insulin values that were unaffected by atropine. Further experimentation showed that hyperinsulinemia could become associated with arbitrary stimuli always associated with eating for meal-fed rats. It is concluded that the hyperinsulinemia of meal-fed rats associated with their feeding time is a learned response.

  11. Perilipin 5 regulates islet lipid metabolism and insulin secretion in a cAMP-dependent manner: implication of its role in the postprandial insulin secretion.

    Science.gov (United States)

    Trevino, Michelle B; Machida, Yui; Hallinger, Daniel R; Garcia, Eden; Christensen, Aaron; Dutta, Sucharita; Peake, David A; Ikeda, Yasuhiro; Imai, Yumi

    2015-04-01

    Elevation of circulating fatty acids (FA) during fasting supports postprandial (PP) insulin secretion that is critical for glucose homeostasis and is impaired in diabetes. We tested our hypothesis that lipid droplet (LD) protein perilipin 5 (PLIN5) in β-cells aids PP insulin secretion by regulating intracellular lipid metabolism. We demonstrated that PLIN5 serves as an LD protein in human islets. In vivo, Plin5 and triglycerides were increased by fasting in mouse islets. MIN6 cells expressing PLIN5 (adenovirus [Ad]-PLIN5) and those expressing perilipin 2 (PLIN2) (Ad-PLIN2) had higher [(3)H]FA incorporation into triglycerides than Ad-GFP control, which support their roles as LD proteins. However, Ad-PLIN5 cells had higher lipolysis than Ad-PLIN2 cells, which increased further by 8-Br-cAMP, indicating that PLIN5 facilitates FA mobilization upon cAMP stimulation as seen postprandially. Ad-PLIN5 in islets enhanced the augmentation of glucose-stimulated insulin secretion by FA and 8-Br-cAMP in G-protein-coupled receptor 40 (GPR40)- and cAMP-activated protein kinase-dependent manners, respectively. When PLIN5 was increased in mouse β-cells in vivo, glucose tolerance after an acute exenatide challenge was improved. Therefore, the elevation of islet PLIN5 during fasting allows partitioning of FA into LD that is released upon refeeding to support PP insulin secretion in cAMP- and GPR40-dependent manners. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  12. Saponins from the traditional medicinal plant Momordica charantia stimulate insulin secretion in vitro

    Science.gov (United States)

    Keller, Amy C.; Ma, Jun; Kavalier, Adam; He, Kan; Brillantes, Anne-Marie B.; Kennelly, Edward J.

    2012-01-01

    The antidiabetic activity of Momordica charantia (L.), Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 β-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (1), momordicine I (2), momordicine II (3), 3-hydroxycucurbita-5,24-dien-19-al-7,23-di-O-β-glucopyranoside (4), and kuguaglycoside G (5). Treatments were compared to incubation with high glucose (27 mM) and the insulin secretagogue, glipizide (50 μM). At 125 μg/ml, an LC-ToF-MS characterized saponin-rich fraction stimulated insulin secretion significantly more than the DMSO vehicle, p=0.02. At concentrations 10 and 25 μg/ml, compounds 3 and 5 also significantly stimulated insulin secretion as compared to the vehicle, p≤0.007, and p= 0.002, respectively. This is the first report of a saponin-rich fraction, and isolated compounds from M. charantia, stimulating insulin secretion in an in vitro, static incubation assay. PMID:22133295

  13. Saponins from the traditional medicinal plant Momordica charantia stimulate insulin secretion in vitro.

    Science.gov (United States)

    Keller, Amy C; Ma, Jun; Kavalier, Adam; He, Kan; Brillantes, Anne-Marie B; Kennelly, Edward J

    2011-12-15

    The antidiabetic activity of Momordica charantia (L.), Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 β-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (1), momordicine I (2), momordicine II (3), 3-hydroxycucurbita-5,24-dien-19-al-7,23-di-O-β-glucopyranoside (4), and kuguaglycoside G (5). Treatments were compared to incubation with high glucose (27 mM) and the insulin secretagogue, glipizide (50 μM). At 125 μg/ml, an LC-ToF-MS characterized saponin-rich fraction stimulated insulin secretion significantly more than the DMSO vehicle, p=0.02. At concentrations 10 and 25 μg/ml, compounds 3 and 5 also significantly stimulated insulin secretion as compared to the vehicle, p≤0.007, and p=0.002, respectively. This is the first report of a saponin-rich fraction, and isolated compounds from M. charantia, stimulating insulin secretion in an in vitro, static incubation assay. Copyright © 2011 Elsevier GmbH. All rights reserved.

  14. Moderate alcohol consumption is associated with improved insulin sensitivity, reduced basal insulin secretion rate and lower fasting glucagon concentration in healthy women

    DEFF Research Database (Denmark)

    Bonnet, F; Disse, E; Laville, M

    2012-01-01

    Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes with a stronger effect in women. As the underlying mechanisms remain poorly characterised, we investigated its relationship with insulin resistance, insulin secretion, clearance of insulin and glucagon concentration....

  15. Potent humanin analog increases glucose-stimulated insulin secretion through enhanced metabolism in the β cell.

    Science.gov (United States)

    Kuliawat, Regina; Klein, Laura; Gong, Zhenwei; Nicoletta-Gentile, Marianna; Nemkal, Anjana; Cui, Lingguang; Bastie, Claire; Su, Kai; Huffman, Derek; Surana, Manju; Barzilai, Nir; Fleischer, Norman; Muzumdar, Radhika

    2013-12-01

    Humanin (HN) is a 24-aa polypeptide that offers protection from Alzheimer's disease and myocardial infarction, increases insulin sensitivity, improves survival of β cells, and delays onset of diabetes. Here we examined the acute effects of HN on insulin secretion and potential mechanisms through which they are mediated. Effects of a potent HN analog, HNGF6A, on glucose-stimulated insulin secretion (GSIS) were assessed in vivo and in isolated pancreatic islets and cultured murine β cell line (βTC3) in vitro. Sprague-Dawley rats (3 mo old) that received HNGF6A required a significantly higher glucose infusion rate and demonstrated higher insulin levels during hyperglycemic clamps compared to saline controls. In vitro, compared to scrambled peptide controls, HNGF6A increased GSIS in isolated islets from both normal and diabetic mice as well as in βTC3 cells. Effects of HNGF6A on GSIS were dose dependent, K-ATP channel independent, and associated with enhanced glucose metabolism. These findings demonstrate that HNGF6A increases GSIS in whole animals, from isolated islets and from cells in culture, which suggests a direct effect on the β cell. The glucose-dependent effects on insulin secretion along with the established effects on insulin action suggest potential for HN and its analogs in the treatment of diabetes.

  16. Mitochondrial malic enzyme 3 is important for insulin secretion in pancreatic β-cells.

    Science.gov (United States)

    Hasan, Noaman M; Longacre, Melissa J; Stoker, Scott W; Kendrick, Mindy A; MacDonald, Michael J

    2015-03-01

    Pancreatic β-cells with severely knocked down cytosolic malic enzyme (ME1) and mitochondrial NAD(P) malic enzyme (ME2) show normal insulin secretion. The mitochondrial NADP malic enzyme (ME3) is very low in pancreatic β-cells, and ME3 was previously thought unimportant for insulin secretion. Using short hairpin RNAs that targeted one or more malic enzyme mRNAs in the same cell, we generated more than 25 stable INS-1 832/13-derived insulin cell lines expressing extremely low levels of ME1, ME2, and ME3 alone or low levels of two of these enzymes in the same cell line. We also used double targeting of the same Me gene to achieve even more severe reduction in Me1 and Me2 mRNAs and enzyme activities than we reported previously. Knockdown of ME3, but not ME1 or ME2 alone or together, inhibited insulin release stimulated by glucose, pyruvate or 2-aminobicyclo [2,2,1]heptane-2-carboxylic acid-plus-glutamine. The data suggest that ME3, far more than ME1 or ME2, is necessary for insulin release. Because ME3 enzyme activity is low in β-cells, its role in insulin secretion may involve a function other than its ME catalytic activity.

  17. Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yunli, E-mail: chrisyu1255@yahoo.com.cn [Department of Pharmaceutics, The Second Affiliated Hospital of Soochow University, Suzhou 215004 (China); Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Wang, Xinting, E-mail: wxinting1986@yahoo.com.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Can, E-mail: ltsan@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Yao, Dan, E-mail: erinyao@126.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Shanghai Institute of Materia Medica, Shanghai 201203 (China); Hu, Mengyue, E-mail: juliahmy@126.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Li, Jia, E-mail: ljbzd@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Hu, Nan, E-mail: hn_324@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Li, E-mail: liulee@cpu.edu.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Xiaodong, E-mail: xdliu@cpu.edu.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China)

    2013-02-01

    Accumulating evidences have showed that gatifloxacin causes dysglycemia in both diabetic and non-diabetic patients. Our preliminary study demonstrated that gatifloxacin stimulated glucagon-like peptide 1 (GLP-1) secretion from intestinal cells. The aim of the study was to investigate the association between gatifloxacin-stimulated GLP-1 release and dysglycemia in both normal and streptozotocin-induced diabetic rats and explore the possible mechanisms. Oral administration of gatifloxacin (100 mg/kg/day and 200 mg/kg/day) for 3 and 12 days led to marked elevation of GLP-1 levels, accompanied by significant decrease in insulin levels and increase in plasma glucose. Similar results were found in normal rats treated with 3-day gatifloxacin. Gatifloxacin-stimulated GLP-1 release was further confirmed in NCI-H716 cells, which was abolished by diazoxide, a K{sub ATP} channel opener. QT-PCR analysis showed that gatifloxacin also upregulated expression of proglucagon and prohormone convertase 3 mRNA. To clarify the contradiction on elevated GLP-1 without insulinotropic effect, effects of GLP-1 and gatifloxacin on insulin release were investigated using INS-1 cells. We found that short exposure (2 h) to GLP-1 stimulated insulin secretion and biosynthesis, whereas long exposure (24 h and 48 h) to high level of GLP-1 inhibited insulin secretion and biosynthesis. Moreover, we also confirmed gatifloxacin acutely stimulated insulin secretion while chronically inhibited insulin biosynthesis. All the results gave an inference that gatifloxacin stimulated over-secretion of GLP-1, in turn, high levels of GLP-1 and gatifloxacin synergistically impaired insulin release, worsening hyperglycemia. -- Highlights: ► Gatifloxacin induced hyperglycemia both in diabetic rats and normal rats. ► Gatifloxacin enhanced GLP-1 secretion but inhibited insulin secretion in rats. ► Long-term exposure to high GLP-1 inhibited insulin secretion and biosynthesis. ► GLP-1 over-secretion may be

  18. Insulin Secretion in Bantu with Siderosis or Hepatoma*

    African Journals Online (AJOL)

    1971-08-14

    Aug 14, 1971 ... Similar glucose and insulin studies were carried out on a group of 11 Bantu males from H. F. Verwoerd Hospital,. "Date received: 8 April 1971. in whom a diagnosis of hepatoma was made after liver biopsy. Tbeir ages ranged from 37 to 65 years. Control Group. A group of 25 Bantu males served as controls.

  19. Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients

    DEFF Research Database (Denmark)

    Yabe, Daisuke; Kuroe, Akira; Watanabe, Koin

    2015-01-01

    AIMS: Hypersecretion of glucagon and reduced insulin secretion both contribute to hyperglycemia in type 2 diabetes (T2DM). However, the relative contributions of impaired glucagon and insulin secretions in glucose excursions at the various stages of T2DM development remain to be determined. METHO...

  20. Insulin secretion in lipodystrophic HIV-infected patients is associated with high levels of nonglucose secretagogues and insulin resistance of beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Storgaard, Heidi

    2004-01-01

    We examined whether plasma concentrations of nonglucose insulin secretagogues are associated with prehepatic insulin secretion rates (ISR) in nondiabetic, insulin-resistant, human immunodeficiency virus (HIV)-infected, lipodystrophic patients (LIPO). Additionally, the negative feedback of insulin...... on ISR was evaluated. ISR were estimated by deconvolution of plasma C-peptide concentrations during fasting (basal) and during the last 30 min of a 120-min euglycemic insulin clamp (40 mU.m(-2).min(-1)). Eighteen normoglycemic LIPO were compared with 25 normoglycemic HIV-infected patients without...... lipodystrophy (controls). Thirty minutes before start of the clamp, a bolus of glucose was injected intravenously to stimulate endogenous insulin secretion. Insulin sensitivity index (SiRd) was estimated from glucose tracer analysis. LIPO displayed increased basal ISR (69%), clamp ISR (114%), basal insulin (130...

  1. Plasma kisspeptin levels are associated with insulin secretion in nondiabetic individuals.

    Directory of Open Access Journals (Sweden)

    Francesco Andreozzi

    Full Text Available To evaluate if plasma kisspeptin concentrations are associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders. 261 nondiabetic subjects were stratified into tertiles according to kisspeptin values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT. After adjusting for age, gender, and BMI, subjects in the highest (tertile 3 kisspeptin group exhibited significantly lower values of insulinogenic index, corrected insulin response (CIR30, and Stumvoll indexes for first-phase and second-phase insulin release as compared with low (tertile 1 or intermediate (tertile 2 kisspeptin groups. Univariate correlations between kisspeptin concentration and metabolic variables showed that kisspeptin concentration was significantly and positively correlated with age, blood pressure, and 2-h post-load glucose, and inversely correlated with BMI, and waist circumference. There was an inverse relationship between kisspeptin levels and OGTT-derived indexes of glucose-stimulated insulin secretion. A multivariable regression analysis in a model including all the variables significantly correlated with kisspeptin concentration showed thar age (β = -0.338, P<0.0001, BMI (β = 0.272, P<0.0001, 2-h post-load glucose (β = -0.229, P<0.0001, and kisspeptin (β = -0.105, P = 0.03 remained associated with insulinogenic index. These factors explained 34.6% of the variance of the insulinogenic index. In conclusion, kisspeptin concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, 2-h post-load glucose, and insulin sensitivity.

  2. Insulin-degrading enzyme is exported via an unconventional protein secretion pathway

    Directory of Open Access Journals (Sweden)

    Leissring Malcolm A

    2009-01-01

    Full Text Available Abstract Insulin-degrading enzyme (IDE is a ubiquitously expressed zinc-metalloprotease that degrades several pathophysiologically significant extracellular substrates, including insulin and the amyloid β-protein (Aβ, and accumulating evidence suggests that IDE dysfunction may be operative in both type 2 diabetes mellitus and Alzheimer disease (AD. Although IDE is well known to be secreted by a variety of cell types, the underlying trafficking pathway(s remain poorly understood. To address this topic, we investigated the effects of known inhibitors or stimulators of protein secretion on the secretion of IDE from murine hepatocytes and HeLa cells. IDE secretion was found to be unaffected by the classical secretion inhibitors brefeldin A (BFA, monensin, or nocodazole, treatments that readily inhibited the secretion of α1-antitrypsin (AAT overexpressed in the same cells. Using a novel cell-based Aβ-degradation assay, we show further that IDE secretion was similarly unaffected by multiple stimulators of protein secretion, including glyburide and 3'-O-(4-benzoylbenzoyl-ATP (Bz-ATP. The calcium ionophore, A23187, increased extracellular IDE activity, but only under conditions that also elicited cytotoxicity. Our results provide the first biochemical evidence that IDE export is not dependent upon the classical secretion pathway, thereby identifying IDE as a novel member of the select class of unconventionally secreted proteins. Further elucidation of the mechanisms underlying IDE secretion, which would be facilitated by the assays described herein, promises to uncover processes that might be defective in disease or manipulated for therapeutic benefit.

  3. Altered pancreatic growth and insulin secretion in WSB/EiJ mice.

    Directory of Open Access Journals (Sweden)

    Maggie M Ho

    Full Text Available These data suggest that insulin secretion in WSB mice is blunted specifically in vivo, either due to a reduced insulin requirement and/or due to factors that are absent or destroyed in vitro. These studies also highlight the role of post-natal growth in determining adult β-cell mass. Mice are important animal models for the study of metabolic physiology and the genetics of complex traits. Wild-derived inbred mouse strains, such as WSB/EiJ (WSB, are unrelated to the commonly studied mouse strains and are valuable tools to identify novel genes that modify disease risk. We have previously shown that in contrast to C57BL/6J (B6 mice, WSB mice fed a high fat diet do not develop hyperinsulinemia or insulin resistance, and had nearly undetectable insulin secretion in response to an intraperitoneal glucose challenge. As hyperinsulinemia may drive obesity and insulin resistance, we examined whether defects in β-cell mass or function could contribute to the low insulin levels in WSB mice. In young WSB mice, β-cell mass was similar to B6 mice. However, we found that adult WSB mice had reduced β-cell mass due to reduced pancreatic weights. Pancreatic sizes were similar between the strains when normalized to body weight, suggesting their pancreatic size is appropriate to their body size in adults, but overall post-natal pancreatic growth was reduced in WSB mice compared to B6 mice. Islet architecture was normal in WSB mice. WSB mice had markedly increased insulin secretion from isolated islets in vitro. These data suggest that insulin secretion in WSB mice is blunted specifically in vivo, either due to a reduced insulin requirement and/or due to factors that are absent or destroyed in vitro. These studies suggest that WSB mice may provide novel insight into mechanisms regulating insulin secretion and also highlight the role of post-natal growth in determining adult β-cell mass.

  4. Insulin Secretion in Bantu with Siderosis or Hepatoma | De Bruin ...

    African Journals Online (AJOL)

    The IR and concomitant GTC was evaluated in 10 siderotic Bantu patients and in 11 Bantu patients suffering from hepatoma. A normal IR was found in the siderotic Bantu, occurring, however, at much higher blood glucose levels than those of the control Bantu group. This relatively low IR is ascribed to impaired secretion of ...

  5. Role of vitamin D in the development of insulin resistance and type 2 diabetes.

    NARCIS (Netherlands)

    Pilz, S.; Kienreich, K.; Rutters, F.; de Jongh, R.T.; van Ballegooijen, A.J.; Grübler, M.; Tomaschitz, A.; Dekker, J.M.

    2013-01-01

    Vitamin D deficiency is mainly a consequence of insufficient sunlight induced vitamin D production in the skin and has been associated with various chronic diseases including type 2 diabetes. Experimental data have shown that vitamin D is important for glucose induced insulin secretion, improves

  6. Direct Substrate Delivery Into Mitochondrial Fission-Deficient Pancreatic Islets Rescues Insulin Secretion.

    Science.gov (United States)

    Kabra, Uma D; Pfuhlmann, Katrin; Migliorini, Adriana; Keipert, Susanne; Lamp, Daniel; Korsgren, Olle; Gegg, Moritz; Woods, Stephen C; Pfluger, Paul T; Lickert, Heiko; Affourtit, Charles; Tschöp, Matthias H; Jastroch, Martin

    2017-05-01

    In pancreatic β-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1 , we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient β-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic β-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria. © 2017 by the American Diabetes Association.

  7. Involvement of nitric oxide in neuroglycopenia-induced insulin and glucagon secretion in the mouse

    NARCIS (Netherlands)

    Ahrén, Bo; Karlsson, Sven; Scheurink, Anton J.W.; Steffens, Anton B.

    1995-01-01

    Neuroglycopenia induced by administration of 2-deoxy-D-glucose is known to stimulate the secretion of both insulin and glucagon in mice by a mechanism that is dependent on neural activity. In the present study, we examined whether the neurotransmitter nitric oxide (NO) is involved in this process.

  8. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study

    DEFF Research Database (Denmark)

    Gudmundsdottir, Valborg; Pedersen, Helle Krogh; Allebrandt, Karla Viviani

    2018-01-01

    cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one...

  9. [Effect of mazindol on insulin and glucagon secretion in ventromedial hypothalamic obese rats].

    Science.gov (United States)

    Usami, M; Seino, Y; Nishi, S; Nakahara, H; Ikeda, M; Matsukura, S; Imura, H

    1985-04-01

    The effect of mazindol on insulin and glucagon secretion was studied in ventromedial hypothalamic lesioned (VMH) obese rats with hyperinsulinemia and VMH sham rats. Three weeks after the VMH or sham operation, VMH and sham rats were divided into two groups: one was fed diet containing mazindol (50 mg/kg) and the other was fed diet without mazindol. They were housed three more weeks before the experiment. Mazindol reduced significantly body weight increase and calorie intake in VMH rats, but not in sham rats. In addition, the fasting plasma insulin level and the arginine-induced insulin secretion in VMH rats treated with mazindol were significantly lower than those in the VMH rats without treatment of mazindol. On the other hand, in both in vivo and in vitro experiments, mazindol produced no significant change in the insulin secretion of sham-operated rats. These results suggest that mazindol suppresses hypersecretion of insulin in VMH rats probably through an anorectic effect and/or suppression of vagal hyperactivity.

  10. The Possible Mechanisms of the Impaired Insulin Secretion in Hypothyroid Rats

    Science.gov (United States)

    Godini, Aliashraf; Ghasemi, Asghar

    2015-01-01

    Although the insulin secretion deficit in hypothyroid male rats has been documented, the underling mechanisms of the effect of hypothyroidism on insulin secretion are not clear. Isolated islets of the PTU-induced hypothyroid and control rats were exposed to glibenclamide, acetylcholine, and nifedipine in the presence of glucose concentrations of 2.8 or 8.3 and 16.7 mmol/L. Glucokinase and hexokinase specific activity, glucokinase content, and glucose transporter 2 protein expression were also determined in the isolated islets. Isolated islets from the hypothyroid rats showed a defect in insulin secretion in response to high glucose. In the presence of glibenclamide or acetylcholine, the isolated islets from the hypothyroid and control rats stimulated by glucose concentration of 16.7 mmol/L secreted similar amounts of insulin. In the presence of glucose concentrations of 8.3 mmol/L and 16.7 mmol/L, nifedipine was able to diminish insulin secretion from isolated islets of both groups, indicating that probably the defect may not arise from L type calcium channels or the steps beyond depolarization or the elements involved in the acetylcoline signaling pathway. Glucokinase content and hexokinase specific activity were also the same in the control and hypothyroid groups. On the other hand, glucokinase specific activity and glucose transporter 2 protein expression were significantly (phypothyroid rats (6.50 ± 0.46 mU/min/mg protein and 0.55 ± 0.09 arbitrary unit) compared to the controls (10.93 ± 0.83 mU/min/mg protein and 0.98 ± 0.07 arbitrary unit) respectively. In conclusion, the results of this study indicated that hypothyroidism reduced insulin secretion from isolated pancreatic islets, which confirms the finding of the previous studies; in addition, the insulin secretion deficit observed in hypothyroid rats may arise from the abnormalities in some parts of the glucose sensor apparatus of the pancreatic islets including glucokinase activity and glucose

  11. The Possible Mechanisms of the Impaired Insulin Secretion in Hypothyroid Rats.

    Directory of Open Access Journals (Sweden)

    Aliashraf Godini

    Full Text Available Although the insulin secretion deficit in hypothyroid male rats has been documented, the underling mechanisms of the effect of hypothyroidism on insulin secretion are not clear. Isolated islets of the PTU-induced hypothyroid and control rats were exposed to glibenclamide, acetylcholine, and nifedipine in the presence of glucose concentrations of 2.8 or 8.3 and 16.7 mmol/L. Glucokinase and hexokinase specific activity, glucokinase content, and glucose transporter 2 protein expression were also determined in the isolated islets. Isolated islets from the hypothyroid rats showed a defect in insulin secretion in response to high glucose. In the presence of glibenclamide or acetylcholine, the isolated islets from the hypothyroid and control rats stimulated by glucose concentration of 16.7 mmol/L secreted similar amounts of insulin. In the presence of glucose concentrations of 8.3 mmol/L and 16.7 mmol/L, nifedipine was able to diminish insulin secretion from isolated islets of both groups, indicating that probably the defect may not arise from L type calcium channels or the steps beyond depolarization or the elements involved in the acetylcoline signaling pathway. Glucokinase content and hexokinase specific activity were also the same in the control and hypothyroid groups. On the other hand, glucokinase specific activity and glucose transporter 2 protein expression were significantly (p<0.001 and p<0.01 respectively lower in the islets isolated from the hypothyroid rats (6.50 ± 0.46 mU/min/mg protein and 0.55 ± 0.09 arbitrary unit compared to the controls (10.93 ± 0.83 mU/min/mg protein and 0.98 ± 0.07 arbitrary unit respectively. In conclusion, the results of this study indicated that hypothyroidism reduced insulin secretion from isolated pancreatic islets, which confirms the finding of the previous studies; in addition, the insulin secretion deficit observed in hypothyroid rats may arise from the abnormalities in some parts of the glucose sensor

  12. Factors influencing insulin and glucagon secretion in lean and genetically obese mice

    International Nuclear Information System (INIS)

    Beloff-Chain, A.; Newman, M.E.; Mansford, K.R.L.

    1977-01-01

    The control of 125 I-labelled insulin and glucagon secretion from isolated pancreatic islets of lean and genetically obese mice has been compared. The enlarged islets of obese mouse pancreas and islets of obese mice maintained on a restricted diet manifested a greater response to glucose stimulation of insulin secretion than the lean mice islets. The glucagon content of the islets, the secretion of glucagon in a medium containing 150 mg% glucose and the stimulation of glucagon secretion by arginine did not differ significantly in the two groups. Adrenaline stimulated glucagon secretion in vitro from obese mice but not from lean mice. Antiinsulin serum injections into obese mice increased the plasma glucagon levels about twofold and had no effect on glucagon levels in lean mice, although the level of hyperglycaemia was the same in both groups. It is suggested that the suppression of glucagon release by glucose requires a higher concentration of insulin in the obese mouse pancreas than in lean mice. (orig./AJ) [de

  13. Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue

    International Nuclear Information System (INIS)

    Lechner, Andreas; Nolan, Anna L.; Blacken, Robyn A.; Habener, Joel F.

    2005-01-01

    Cellular replacement therapy holds promise for the treatment of diabetes mellitus but donor tissue is severely limited. Therefore, we investigated whether insulin-secreting cells could be differentiated in vitro from a monolayer of cells expanded from human donor pancreatic islets. We describe a three-step culture protocol that allows for the efficient generation of insulin-producing cell clusters from in vitro expanded, hormone-negative cells. These clusters express insulin at levels of up to 34% that of average freshly isolated human islets and secrete C-peptide upon membrane depolarization. They also contain cells expressing the other major islet hormones (glucagon, somatostatin, and pancreatic polypeptide). The source of the newly differentiated endocrine cells could either be indigenous stem/progenitor cells or the proliferation-associated dedifferentiation and subsequent redifferentiation of mature endocrine cells. The in vitro generated cell clusters may be efficacious in providing islet-like tissue for transplantation into diabetic recipients

  14. Effects of olive leaf polyphenols against H₂O₂ toxicity in insulin secreting β-cells.

    Science.gov (United States)

    Cumaoğlu, Ahmet; Rackova, Lucia; Stefek, Milan; Kartal, Murat; Maechler, Pierre; Karasu, Cimen

    2011-01-01

    In pancreatic β-cells, although H₂O₂ is a metabolic signal for glucose stimulated insulin secretion, it may induce injury in the presence of increased oxidative stress (OS) as in the case of diabetic chronic hyperglycemia. Olea europea L. (olive) leaves contain polyphenolic compounds that may protect insulin-secreting cells against OS. The major polyphenolic compound in ethanolic olive leaf extract (OLE) is oleuropein (about 20%), thus we compared the effects of OLE with the effects of standard oleuropein on INS-1 cells. The cells were incubated with increasing concentrations of OLE or oleuropein for 24 h followed by exposure to H₂O₂ (0.035 mM) for 45 min. H₂O₂ alone resulted in a significantly decreased viability (MTT assay), depressed glucose-stimulated insulin secretion, increased apoptotic and necrotic cell death (AO/EB staining), inhibited glutathione peroxidase activity (GPx) and stimulated catalase activity that were associated with increased intracellular generation of reactive oxygen species (ROS) (fluorescence DCF). OLE and oleuropein partly improved the viability, attenuated necrotic and apoptotic death, inhibited the ROS generation and improved insulin secretion in H₂O₂-exposed cells. The effects of oleuropein on insulin secretion were more pronounced than those of OLE, while OLE exerted a stronger anti-cytotoxic effect than oleuropein. Unlike OLE, oleuropein had no significant preserving effect on GPx; however, both compounds stimulated the activity of catalase in H₂O₂-exposed cells. These findings indicate different modulatory roles of polyphenolic constituents of olive leaves on redox homeostasis that may have a role in the maintenance of β-cell physiology against OS.

  15. A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells.

    Directory of Open Access Journals (Sweden)

    Claudiane Guay

    Full Text Available Cytosolic NADPH may act as one of the signals that couple glucose metabolism to insulin secretion in the pancreatic ß-cell. NADPH levels in the cytoplasm are largely controlled by the cytosolic isoforms of malic enzyme and isocitrate dehydrogenase (IDHc. Some studies have provided evidence for a role of malic enzyme in glucose-induced insulin secretion (GIIS via pyruvate cycling, but the role of IDHc in ß-cell signaling is unsettled. IDHc is an established component of the isocitrate/α-ketoglutarate shuttle that transfers reducing equivalents (NADPH from the mitochondrion to the cytosol. This shuttle is energy consuming since it is coupled to nicotinamide nucleotide transhydrogenase that uses the mitochondrial proton gradient to produce mitochondrial NADPH and NAD(+ from NADP(+ and NADH. To determine whether flux through IDHc is positively or negatively linked to GIIS, we performed RNAi knockdown experiments in ß-cells. Reduced IDHc expression in INS 832/13 cells and isolated rat islet ß-cells resulted in enhanced GIIS. This effect was mediated at least in part via the KATP-independent amplification arm of GIIS. IDHc knockdown in INS 832/13 cells did not alter glucose oxidation but it reduced fatty acid oxidation and increased lipogenesis from glucose. Metabolome profiling in INS 832/13 cells showed that IDHc knockdown increased isocitrate and NADP(+ levels. It also increased the cellular contents of several metabolites linked to GIIS, in particular some Krebs cycle intermediates, acetyl-CoA, glutamate, cAMP and ATP. The results identify IDHc as a component of the emerging pathways that negatively regulate GIIS.

  16. Natural history of insulin sensitivity and insulin secretion in the progression from normal glucose tolerance to impaired fasting glycemia and impaired glucose tolerance: the Inter99 study

    DEFF Research Database (Denmark)

    Faerch, Kristine; Vaag, Allan; Holst, Jens J

    2008-01-01

    of insulin sensitivity (HOMA-IS), early-phase insulin release (EPIR), and insulin secretion relative to insulin action (disposition index) were estimated. RESULTS: Five years before the pre-diabetes diagnoses (i-IFG, i-IGT, and IFG/IGT), ISI, HOMA-IS, EPIR, and disposition index were lower than...... in individuals who maintained NGT. During the 5-year follow-up, individuals developing i-IFG experienced a significant decline only in HOMA-IS, whereas individuals developing i-IGT experienced significant declines in ISI, EPIR, and disposition index. Individuals with IFG/IGT exhibited pronounced declines in ISI......, HOMA-IS, EPIR, and disposition index during the 5-year follow-up. CONCLUSIONS: A stationary reduced insulin secretion followed by a decline in primarily hepatic insulin sensitivity characterizes the transition from NGT to i-IFG. In contrast, low whole-body insulin sensitivity with a secondary lack...

  17. Altered insulin and glucagon secretion in treated genetic hyperlipemia: a mechanism of theraphy?

    Science.gov (United States)

    Eaton, R P; Oase, R; Schade, D S

    1976-03-01

    The influence of Halofenate therapy on insulin and glucagon secretion was examined in the Zucker rat with genetic endogenous hyperlipemia. Coincident with the lipid lowering effects of Halofenate, the net change in the basal bihormonal axis favored glucagon, with the I/G molar ratio (Insulin/Glucagon) decreasing from 2.72 +/- 0.53 to 0.96 +/- 0.20 during treatment with this drug. Following arginine stimulation the I/G ratio remained reduced at 0.87 +/- 0.13 in Halofenate treated animals, contrasting with the statistically greater ratio of 2.5 +/- 0.55 in control animals. The Halofenate induced state of reduced insulin:glucagon was associated with hypolipemia, postarginine hyperglycemia, and hyperketonemia,-three metabolic parameters characteristic of glucagon excess relative to insulin. It is suggested that the lipid-lowering action of Halofenate in genetic hyperlipemia may reflect the altered bihormonal axis induced by the drug.

  18. Effect of Chlorogenic Acid Administration on Glycemic Control, Insulin Secretion, and Insulin Sensitivity in Patients with Impaired Glucose Tolerance.

    Science.gov (United States)

    Zuñiga, Laura Y; Aceves-de la Mora, Martha C Aceves-de; González-Ortiz, Manuel; Ramos-Núñez, Julia L; Martínez-Abundis, Esperanza

    2017-12-20

    Chlorogenic acid has been described as a novel polyphenol with metabolic effects on glucose homeostasis. The aim of this study was to evaluate the effect of chlorogenic acid administration on glycemic control, insulin secretion, and insulin sensitivity in patients with impaired glucose tolerance (IGT). A randomized, double-blind, placebo-controlled clinical trial was performed in 30 patients with IGT; 15 patients randomly assigned to oral chlorogenic acid received 400 mg three times per day for 12 weeks, and the other 15 patients received placebo in the same way. Before and after the intervention, anthropometric and metabolic measurements, including fasting plasma glucose (FPG), glycated hemoglobin A1c, and a lipid profile, were performed. Area under the curve of glucose and insulin as well as the insulinogenic, Stumvoll, and Matsuda indices were calculated. Wilcoxon, Mann-Whitney U, and chi-square tests were performed, and P ≤ .05 was considered statistically significant. There were significant decreases in FPG (5.7 ± 0.4 vs. 5.5 ± 0.4 mmol/L, P = .002), insulinogenic index (0.71 ± 0.25 vs. 0.63 ± 0.25, P = .028), body weight, body mass index, waist circumference, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein levels in the chlorogenic acid group, with an increment in the Matsuda index (1.98 ± 0.88 vs. 2.30 ± 1.23, P = .002). There were no significant differences in the placebo group. In conclusion, chlorogenic acid administration in patients with IGT decreased FPG and insulin secretion, while increasing insulin sensitivity and improving both anthropometric evaluations and the lipid profile.

  19. Effect of almonds on insulin secretion and insulin resistance in nondiabetic hyperlipidemic subjects: a randomized controlled crossover trial.

    Science.gov (United States)

    Jenkins, David J A; Kendall, Cyril W C; Marchie, Augustine; Josse, Andrea R; Nguyen, Tri H; Faulkner, Dorothea A; Lapsley, Karen G; Singer, William

    2008-07-01

    Nuts appear to have a marked effect in cohort studies in reducing the risk of coronary heart disease (CHD), but their demonstrated ability to lower cholesterol can only explain a proportion of the reduction in risk. Our aim was to assess whether improvement in carbohydrate metabolism provides a further explanation for the effect of nuts in reducing CHD. The effects of whole almonds, taken as snacks, were compared with the effects of low saturated fat (<5% energy) whole-wheat muffins (control) in the therapeutic diets of hyperlipidemic subjects. In a randomized crossover study, 27 hyperlipidemic men and women consumed 3 isoenergetic (mean, 423 kcal/d) supplements each for 1 month. Supplements provided 22.2% of energy and consisted of full-dose almonds (73 +/- 3 g/d), half-dose almonds plus half-dose muffins, and full-dose muffins. Subjects were assessed at weeks 0, 2, and 4 and fasting blood samples were obtained. Twenty-four-hour urinary output was collected at the end of week 4 on each treatment. Mean body weights differed by less than 300 g between treatments. No differences were seen in baseline or treatment values for fasting glucose, insulin, C-peptide, or insulin resistance as measured by homeostasis model assessment of insulin resistance. However, 24-hour urinary C-peptide output as a marker of 24-hour insulin secretion was significantly reduced on the half-and full-dose almonds by comparison to the control after adjustment for urinary creatinine output (P = .002 and P = .004, respectively). We conclude that reductions in 24-hour insulin secretion appear to be a further metabolic advantage of nuts that in the longer term may help to explain the association of nut consumption with reduced CHD risk.

  20. Estimation of second-phase insulin secretion in the Zucker fatty rat.

    Science.gov (United States)

    Morettini, Micaela; Di Nardo, Francesco; Cogo, Carla E; Faelli, Emanuela; Fioretti, Sandro; Burattini, Laura; Ruggeri, Piero

    2016-08-01

    The purpose of the present study was to test the efficacy of the empiric index SPIR (Second-phase Insulin Release) in the quantification of second-phase insulin secretion in the Zucker Fatty Rat. SPIR index is defined as the area under the curve of insulin between 8 and 90 min after an Intravenous Glucose Tolerance Test (IVGTT). The validation of such index was performed against the second-phase β-cell responsiveness index (Φ 2 ) provided by C-peptide minimal model. To this aim, Φ 2 and SPIR were simultaneously computed from IVGTT data, measured in six Zucker fatty rats (ZFR), 7-to-9week-old, and seven age-matched Zucker lean rats (ZLR). SPIR index showed a significant linear correlation with Φ 2 (Pearson's correlation coefficient, r = 0.91, R-square = 0.82, Pinsulin secretion and of its alteration in Zucker Fatty Rats. Thus, the study proposes the SPIR, as a suitable index for a simple, reliable and low-cost quantification of the second-phase insulin secretion in ZFR.

  1. Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion.

    Directory of Open Access Journals (Sweden)

    M Mar González-Barroso

    Full Text Available Although the most common mechanism underlying congenital hyperinsulinism is dysfunction of the pancreatic ATP-sensitive potassium channel, the pathogenesis and genetic origins of this disease remains largely unexplained in more than half of all patients. UCP2 knockout mice exhibit an hyperinsulinemic hypoglycemia, suggesting an involvement of UCP2 in insulin secretion. However, a possible pathogenic role for UCP2 protein in the development of human congenital hyperinsulinism or of any human disease has not yet been investigated. We studied ten children exhibiting congenital hyperinsulinism, without detectable mutations in the known congenital hyperinsulinism-causing genes. Parental-inherited heterozygous UCP2 variants encoding amino-acid changes were found in two unrelated children with congenital hyperinsulinism. Functional assays in yeast and in insulin-secreting cells revealed an impaired activity of UCP2 mutants. Therefore, we report the finding of UCP2 coding variants in human congenital hyperinsulinism, which reveals a role for this gene in the regulation of insulin secretion and glucose metabolism in humans. Our results show for the first time a direct association between UCP2 amino acid alteration and human disease and highlight a role for mitochondria in hormone secretion.

  2. Sox17 regulates insulin secretion in the normal and pathologic mouse β cell.

    Directory of Open Access Journals (Sweden)

    Diva Jonatan

    Full Text Available SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1β and FOXA2, which are known to regulate postnatal β cell function. Given this, we investigated the role of SOX17 in the developing and postnatal pancreas and found a novel role for SOX17 in regulating insulin secretion. Deletion of the Sox17 gene in the pancreas (Sox17-paLOF had no observable impact on pancreas development. However, Sox17-paLOF mice had higher islet proinsulin protein content, abnormal trafficking of proinsulin, and dilated secretory organelles suggesting that Sox17-paLOF adult mice are prediabetic. Consistant with this, Sox17-paLOF mice were more susceptible to aged-related and high fat diet-induced hyperglycemia and diabetes. Overexpression of Sox17 in mature β cells using Ins2-rtTA driver mice resulted in precocious secretion of proinsulin. Transcriptionally, SOX17 appears to broadly regulate secretory networks since a 24-hour pulse of SOX17 expression resulted in global transcriptional changes in factors that regulate hormone transport and secretion. Lastly, transient SOX17 overexpression was able to reverse the insulin secretory defects observed in MODY4 animals and restored euglycemia. Together, these data demonstrate a critical new role for SOX17 in regulating insulin trafficking and secretion and that modulation of Sox17-regulated pathways might be used therapeutically to improve cell function in the context of diabetes.

  3. Environmental factors and dam characteristics associated with insulin sensitivity and insulin secretion in newborn Holstein calves

    International Nuclear Information System (INIS)

    Kamal, M.M.; Van Eetvelde, M.; Bogaert, H.; Hostens, M.; Vandaele, L.; Shamsuddin, M.; Opsomer, G.

    2015-01-01

    The objective of the present retrospective cohort study was to evaluate potential associations between environmental factors and dam characteristics, including level of milk production during gestation, and insulin traits in newborn Holstein calves

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

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Wang, Xiaorui; Wang, Yue

    2010-01-01

    neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium...... tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice. CONCLUSIONS: Thus, synaptotagmin-9, although a major calcium sensor in the brain......BACKGROUND: Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define...

  5. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion

    DEFF Research Database (Denmark)

    Vozarova, B; Weyer, C; Hanson, K

    2001-01-01

    Plasma concentrations of interleukin-6 (IL-6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined w...... whether circulating plasma IL-6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes....

  6. Complete loss of insulin secretion capacity in type 1A diabetes patients during long-term follow up.

    Science.gov (United States)

    Uno, Sae; Imagawa, Akihisa; Kozawa, Junji; Fukui, Kenji; Iwahashi, Hiromi; Shimomura, Iichiro

    2017-10-16

    Patients with type 1 diabetes are classified into three subtypes in Japan: acute onset, fulminant and slowly progressive. Acute-onset type 1 diabetes would be equivalent to type 1A diabetes, the typical type 1 diabetes in Western countries. The insulin secretion capacity in Japanese patients with long-standing type 1A diabetes is unclear. The aim of the present study was to clarify the course of endogenous insulin secretion during long-term follow up and the factors associated with residual insulin secretion in patients with acute-onset type 1 diabetes (autoimmune). We retrospectively investigated endogenous insulin secretion capacity in 71 patients who fulfilled the diagnostic criteria for acute-onset type 1 diabetes (autoimmune) in Japan. To assess the residual insulin secretion capacity, we evaluated randomly measured C-peptide levels and the results of glucagon stimulation test in 71 patients. In the first year of disease, the child- and adolescent-onset patients had significantly more in residual insulin secretion than the adult-onset patients (34 patients in total). C-peptide levels declined more rapidly in patients whose age of onset was ≤18 years than in patients whose age of onset was ≥19 years. Endogenous insulin secretion capacity stimulated by glucagon was completely lost in almost all patients at >15 years after onset (61 patients in total). Most patients with acute-onset type 1 diabetes (autoimmune) completely lose their endogenous insulin secretion capacity during the disease duration in Japan. Age of onset might affect the course of insulin secretion. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  7. CFTR Influences Beta Cell Function and Insulin Secretion Through Non-Cell Autonomous Exocrine-Derived Factors.

    Science.gov (United States)

    Sun, Xingshen; Yi, Yaling; Xie, Weiliang; Liang, Bo; Winter, Michael C; He, Nan; Liu, Xiaoming; Luo, Meihui; Yang, Yu; Ode, Katie Larson; Uc, Aliye; Norris, Andrew W; Engelhardt, John F

    2017-10-01

    Although β-cell dysfunction in cystic fibrosis (CF) leads to diabetes, the mechanism by which the cystic fibrosis transmembrane conductance regulator (CFTR) channel influences islet insulin secretion remains debated. We investigated the CFTR-dependent islet-autonomous mechanisms affecting insulin secretion by using islets isolated from CFTR knockout ferrets. Total insulin content was lower in CF as compared with wild-type (WT) islets. Furthermore, glucose-stimulated insulin secretion (GSIS) was impaired in perifused neonatal CF islets, with reduced first, second, and amplifying phase secretion. Interestingly, CF islets compensated for reduced insulin content under static low-glucose conditions by secreting a larger fraction of islet insulin than WT islets, probably because of elevated SLC2A1 transcripts, increased basal inhibition of adenosine triphosphate-sensitive potassium channels (K-ATP), and elevated basal intracellular Ca2+. Interleukin (IL)-6 secretion by CF islets was higher relative to WT, and IL-6 treatment of WT ferret islets produced a CF-like phenotype with reduced islet insulin content and elevated percentage insulin secretion in low glucose. CF islets exhibited altered expression of INS, CELA3B, and several β-cell maturation and proliferation genes. Pharmacologic inhibition of CFTR reduced GSIS by WT ferret and human islets but similarly reduced insulin secretion and intracellular Ca2+ in CFTR knockout ferret islets, indicating that the mechanism of action is not through CFTR. Single-molecule fluorescent in situ hybridization, on isolated ferret and human islets and ferret pancreas, demonstrated that CFTR RNA colocalized within KRT7+ ductal cells but not endocrine cells. These results suggest that CFTR affects β-cell function via a paracrine mechanism involving proinflammatory factors secreted from islet-associated exocrine-derived cell types. Copyright © 2017 Endocrine Society.

  8. Soy Germed Protein Plus Zn as an Inducer Insulin Secretion on Type-2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    HERY WINARSI

    2010-09-01

    Full Text Available Hyperglicemic induces pancreatic cells to produce inadequate insulin. However, previous studies revealed that soy protein induce pancreatic cells to secrete insulin. Hence, this study was aimed to investigate effect of soy germed protein on the insulin and blood glucose level of type-2 diabetes mellitus with Zn enrichment. The research involved twenty four women that characterized with having more blood glucose level than normal, body mass index more than twenty three kg/m2, and age more than fourty years old. They were divided into three groups randomly, eight woman for each group. The first, second and third group were treated respectively with milk containing soy germed protein plus Zn, this product without Zn, and placebo, all for two months. Blood samples were taken at baseline, one and two months after observation. Results showed that two months after observation the insulin level increased from 194.79 to 519.82 pmol/ml (P = 0.033 in group consuming milk containing soy germed protein with or without Zn, supported by significantly reduced blood glucose level. This result might be correlated with the potency of isoflavones in soy germ protein to protect pancreatic beta cellsmembrane from free radicals attack. Therefore, this maintain the cells integrity and to secrete optimal insulin.

  9. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.

    Directory of Open Access Journals (Sweden)

    Valborg Gudmundsdottir

    Full Text Available Glucagon-like peptide 1 (GLP-1 stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126. This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100. Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05 with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated

  10. The effect of a very low calorie diet on insulin sensitivity, beta cell function, insulin clearance, incretin hormone secretion, androgen levels and body composition in obese young women

    DEFF Research Database (Denmark)

    Svendsen, Pernille F; Jensen, Frank K; Holst, Jens Juul

    2012-01-01

    Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500-600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women.......Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500-600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women....

  11. Exposure to static magnetic fields increases insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins.

    Science.gov (United States)

    Mao, Libin; Wang, Huiqin; Ma, Fenghui; Guo, Zhixia; He, Hongpeng; Zhou, Hao; Wang, Nan

    2017-08-01

    To evaluate the effect of static magnetic fields (SMFs) on insulin secretion and explore the mechanisms underlying exposure to SMF-induced insulin secretion in rat insulinoma INS-1 cells. INS-1 cells were exposed to a 400 mT SMF for 72 h, and the proliferation of INS-1 cells was detected by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The secretion of insulin was measured with an enzyme linked immunosorbent assays (ELISA), the expression of genes was detected by real-time PCR, and the expression of proteins was measured by Western blotting. Exposure to an SMF increased the expression and secretion of insulin by INS-1 cells but did not affect cell proliferation. Moreover, SMF exposure up-regulated the expression of several pancreas-specific transcriptional factors. Specifically, the activity of the rat insulin promoter was enhanced in INS-1 cells exposed to an SMF, and the expression levels of synaptosomal-associated protein 25 (SNAP-25) and syntaxin-1A were up-regulated after exposure to an SMF. SMF exposure can promote insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins.

  12. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats

    DEFF Research Database (Denmark)

    Lundh, Morten; Galbo, Thomas; Poulsen, Steen Seier

    2015-01-01

    Failure of pancreatic β cells to compensate for insulin resistance is a prerequisite for the development of type 2 diabetes. Sustained elevated circulating levels of free fatty acids and glucose contribute to β-cell failure. Selective inhibition of Histone deacetylase (HDAC)-3 protects pancreatic β...... cells against inflammatory and metabolic insults in vitro. Here we tested the ability of a selective HDAC3 inhibitor, BRD3308, to reduce hyperglycemia and increase insulin secretion in an animal model of type 2 diabetes. At diabetes onset, an ambulatory hyperglycemic clamp was performed. HDAC3......3 as a key therapeutic target for β-cell protection in type 2 diabetes....

  13. A TRP channel contributes to insulin secretion by pancreatic β-cells.

    Science.gov (United States)

    Liman, Emily R

    2010-01-01

    The release of insulin by pancreatic beta cells involves a complex interplay of conductances that generate oscillations and drive secretion. A recent report identifies a new player in this process, the ion channel TRPM5. TRPM5 was originally identified in taste cells, where it forms a Ca(2+)-activated cation channel that is required for sensory responses to bitter and sweet tastes. New research now shows that TRPM5 is expressed within the pancreatic islets of Langerhans, where it regulates the frequency of Ca(2+) oscillations and contributes to insulin release by β-cells.

  14. Trajectories of glycaemia, insulin sensitivity and insulin secretion in South Asian and white individuals before diagnosis of type 2 diabetes

    DEFF Research Database (Denmark)

    Hulman, Adam; Simmons, Rebecca K; Brunner, Eric J

    2017-01-01

    (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI0,120) among 120 South Asian and 867 white participants who developed diabetes during.......03) and a higher FPG level at diagnosis (0.27 mmol/l; 95% CI 0.06, 0.48; p = 0.01). They also had higher FSI and 2hSI levels before and at diabetes diagnosis. South Asians had a faster decline and lower HOMA2-S (log e -transformed) at diagnosis compared with white individuals (0.33; 95% CI 0.21, 0.46; p ....001). HOMA2-B increased in both ethnic groups until 7 years before diagnosis and then declined; the initial increase was faster in white individuals. ISI0,120 declined steeply in both groups before diagnosis; levels were lower among South Asians before and at diagnosis. There were no ethnic differences in 2h...

  15. Insulin Secretion and Risk for Future Diabetes in Subjects with a Nonpositive Insulinogenic Index

    Directory of Open Access Journals (Sweden)

    Daisuke Aono

    2018-01-01

    Full Text Available Aim. To characterize subjects with a nonpositive insulinogenic index and longitudinally observe changes in their glucose tolerance. Subjects and Methods. A historical cohort study was conducted using data from the medical checkups of public school workers. Indices of insulin secretion and insulin sensitivity derived from oral glucose tolerance test (OGTT and the incidences of diabetes and impaired glucose tolerance (IGT were compared among subgroups of subjects with different insulinogenic index (change in insulin/change in glucose over the first 30 min on the OGTT. Results. Of the 1464 nondiabetic subjects at baseline, 72 (4.9% subjects had a nonpositive insulinogenic index: 42 of those subjects had a nonpositive glucose response (ΔGlu0–30 ≤ 0 and 30 had a nonpositive insulin response (ΔIns0–30 ≤ 0. Compared with subjects who had normal glucose tolerance (NGT with insulinogenic index ≥ 0.4, subjects with a nonpositive glucose response had a higher first-phase Stumvoll and lower incidences of diabetes and IGT based on a log-rank test (p<0.05, whereas subjects with a nonpositive insulin response had lower indices of insulin secretion and a higher incidence of diabetes (p<0.05. Conclusions. These results demonstrate that in the first 30 min on the OGTT, subjects with a nonpositive insulinogenic index due to a nonpositive glucose response (ΔGlu0–30 ≤ 0 had a lower risk for future diabetes and that subjects with nonpositive insulin response (ΔIns0–30 ≤ 0 had a higher risk for future one.

  16. Long-term antidiabetic activity of vanadyl after treatment withdrawal: restoration of insulin secretion?

    Science.gov (United States)

    Cros, G H; Cam, M C; Serrano, J J; Ribes, G; McNeill, J H

    In its vanadate (V5+) or vanadyl (V4+) forms, vanadium has been demonstrated to possess antidiabetic activity. Oral treatment of streptozotocin (STZ)-diabetic animals with either form is associated with correction of hyperglycemia, and prevention of diabetes-induced complications, although weight gain is unaffected. Vanadium treatment of non-diabetic animals lowers plasma insulin levels by reducing insulin demand, as these animals remain normoglycemic. These results suggest that vanadium has in vivo insulin-mimetic or insulin-enhancing effects, in agreement with several in vitro observations. Chronic treatment with vanadium has also been shown to result in sustained antidiabetic effects in STZ-diabetic animals long after treatment has ceased. Thus, at 13 weeks after withdrawal from treatment, corrected animals had normalized glucose and weight gain, and improved basal insulin levels. In addition, near-normal glucose tolerance was found despite an insignificant insulin response. Since vanadium accumulates in several tissue sites (e.g. bone, kidney) when pharmacological doses are administered, it is possible that stored vanadium may be important in maintaining near-normal glucose tolerance at least in the short-term following withdrawal from treatment. Recently, following withdrawal of vanadyl treatment up to 30 weeks, diabetic animals which had remained normoglycemic and had normalized glucose tolerance showed improvements in plasma insulin levels both in the basal state and in response to oral glucose, as compared to those which had reverted to hyperglycemia. The observed significant improvements in insulin capacity over the long-term ( > 3 months) suggests that a restored and/or preserved insulin secretion may be essential for maintained reversal of the diabetic state over a prolonged period after treatment is withdrawn.

  17. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance.

    Science.gov (United States)

    Pereira, Renata Oliveira; Tadinada, Satya M; Zasadny, Frederick M; Oliveira, Karen Jesus; Pires, Karla Maria Pereira; Olvera, Angela; Jeffers, Jennifer; Souvenir, Rhonda; Mcglauflin, Rose; Seei, Alec; Funari, Trevor; Sesaki, Hiromi; Potthoff, Matthew J; Adams, Christopher M; Anderson, Ethan J; Abel, E Dale

    2017-07-14

    Mitochondrial dynamics is a conserved process by which mitochondria undergo repeated cycles of fusion and fission, leading to exchange of mitochondrial genetic content, ions, metabolites, and proteins. Here, we examine the role of the mitochondrial fusion protein optic atrophy 1 (OPA1) in differentiated skeletal muscle by reducing OPA1 gene expression in an inducible manner. OPA1 deficiency in young mice results in non-lethal progressive mitochondrial dysfunction and loss of muscle mass. Mutant mice are resistant to age- and diet-induced weight gain and insulin resistance, by mechanisms that involve activation of ER stress and secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle, resulting in increased metabolic rates and improved whole-body insulin sensitivity. OPA1-elicited mitochondrial dysfunction activates an integrated stress response that locally induces muscle atrophy, but via secretion of FGF21 acts distally to modulate whole-body metabolism. © 2017 The Authors.

  18. Superoxide generation is diminished during glucose-stimulated insulin secretion in INS-1E cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Petr; Hlavatá, Lydie; Špaček, Tomáš

    2008-01-01

    Roč. 275, Suppl.1 (2008), s. 310-310 ISSN 1742-464X. [FEBS Congress /33./ and IUBMB Conference /11./. 28.06.2008-03.07.2008, Athens] R&D Projects: GA MZd(CZ) NR7917; GA AV ČR(CZ) IAA500110701 Institutional research plan: CEZ:AV0Z50110509 Keywords : cpo1 * superoxide production * glucose-stimulated insulin secretion * INS-1E cells Subject RIV: ED - Physiology

  19. Dual role of proapoptotic BAD in insulin secretion and beta cell survival

    OpenAIRE

    Danial, Nika N.; Walensky, Loren D.; Zhang, Chen-Yu; Choi, Cheol Soo; Fisher, Jill K.; Molina, Anthony J. A.; Datta, Sandeep Robert; Pitter, Kenneth L.; Bird, Gregory H.; Wikstrom, Jakob D.; Deeney, Jude T.; Robertson, Kirsten; Morash, Joel; Kulkarni, Ameya; Neschen, Susanne

    2008-01-01

    The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeab...

  20. L-leucine methyl ester stimulates insulin secretion and islet glutamate dehydrogenase

    DEFF Research Database (Denmark)

    Knudsen, P; Kofod, Hans; Lernmark, A

    1983-01-01

    , a cloned rat islet tumor cell line. A twofold increase in islet glutamate dehydrogenase activity was induced by 5 mmol/liter L-leucine OMe, a larger effect than that of L-leucine (P less than 0.02), whereas L-arginine OMe had a small inhibitory effect. We conclude that L-leucine OMe is a potent stimulus...... of insulin secretion and that its effect on the beta-cells may be exerted by activating islet glutamate dehydrogenase....

  1. Saponins from the traditional medicinal plant Momordica charantia stimulate insulin secretion in vitro

    OpenAIRE

    Keller, Amy C.; Ma, Jun; Kavalier, Adam; He, Kan; Brillantes, Anne-Marie B.; Kennelly, Edward J.

    2011-01-01

    The antidiabetic activity of Momordica charantia (L.), Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 β-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(...

  2. Effects of glucose and insulin on secretion of amyloid?? by human adipose tissue cells

    OpenAIRE

    Tharp, William G.; Gupta, Dhananjay; Smith, Joshua; Jones, Karen P.; Jones, Amanda M.; Pratley, Richard E.

    2016-01-01

    Objective Obesity and type 2 diabetes mellitus are risk factors for developing Alzheimer disease. Overlapping patterns of metabolic dysfunction may be common molecular links between these complex diseases. Amyloid?? (A?) precursor protein and associated ?? and ??secretases are expressed in adipose tissue. A? precursor protein is up?regulated with obesity and correlated to insulin resistance. A? may be secreted by adipose tissue, its production may be regulated through metabolic pathways, and ...

  3. Differential pattern for regulating insulin secretion, insulin resistance, and lipid metabolism by osteocalcin in male and female T2DM patients.

    Science.gov (United States)

    Rui, Xuefei; Xu, Bei; Su, Junlei; Pan, Chunping; Zhan, Chenyu; Su, Bin; Li, Hong; Wang, Jiying; Sheng, Hui; Qu, Shen

    2014-05-01

    Osteocalcin has been reported to be relevant to glucose and lipid metabolism, indicating it may stimulate insulin secretion and improve insulin resistance. Yet the difference between male and female patients is still not clear. We aimed to investigate the difference in serum osteocalcin, and its association with glucose, lipid metabolism, pancreatic function, insulin sensitivity, and resistance in male and female middle-aged and elderly type 2 diabetic (T2DM) patients. 739 T2DM patients were included. After measurement of body mass index (BMI), the levels of fasting plasma glucose (FPG), insulin (FINS), C peptide (FC-P), 2-h post-OGTT plasma glucose (2h-PG), HbA1C, and osteocalcin were determined. Homeostasis model assessment of β-cell function (HOMA-%B), homeostasis model assessment of insulin sensitivity (HOMA-%S), and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Females had higher osteocalcin concentration than males (Pinsulin (2h-INS), and HOMA-%B (Pmetabolism through enhancing insulin secretion in males, and through increasing insulin secretion and improving insulin resistance in females with T2DM. Osteocalcin probably also plays an important role in lipid metabolism.

  4. The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion.

    Science.gov (United States)

    Nakatsu, Yusuke; Mori, Keiichi; Matsunaga, Yasuka; Yamamotoya, Takeshi; Ueda, Koji; Inoue, Yuki; Mitsuzaki-Miyoshi, Keiko; Sakoda, Hideyuki; Fujishiro, Midori; Yamaguchi, Suguru; Kushiyama, Akifumi; Ono, Hiraku; Ishihara, Hisamitsu; Asano, Tomoichiro

    2017-07-14

    The prolyl isomerase Pin1 binds to the phosphorylated Ser/Thr-Pro motif of target proteins and enhances their cis-trans conversion. This report is the first to show that Pin1 expression in pancreatic β cells is markedly elevated by high-fat diet feeding and in ob/ob mice. To elucidate the role of Pin1 in pancreatic β cells, we generated β-cell-specific Pin1 KO (βPin1 KO) mice. These mutant mice showed exacerbation of glucose intolerance but had normal insulin sensitivity. We identified two independent factors underlying impaired insulin secretion in the βPin1 KO mice. Pin1 enhanced pancreatic β-cell proliferation, as indicated by a reduced β-cell mass in βPin1 KO mice compared with control mice. Moreover, a diet high in fat and sucrose failed to increase pancreatic β-cell growth in the βPin1 KO mice, an observation to which up-regulation of the cell cycle protein cyclin D appeared to contribute. The other role of Pin1 was to activate the insulin-secretory step: Pin1 KO β cells showed impairments in glucose- and KCl-induced elevation of the intracellular Ca 2+ concentration and insulin secretion. We also identified salt-inducible kinase 2 (SIK2) as a Pin1-binding protein that affected the regulation of Ca 2+ influx and found Pin1 to enhance SIK2 kinase activity, resulting in a decrease in p35 protein, a negative regulator of Ca 2+ influx. Taken together, our observations demonstrate critical roles of Pin1 in pancreatic β cells and that Pin1 both promotes β-cell proliferation and activates insulin secretion. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Differential Insulin Secretion of High-Fat Diet-Fed C57BL/6NN and C57BL/6NJ Mice: Implications of Mixed Genetic Background in Metabolic Studies.

    Directory of Open Access Journals (Sweden)

    Camille Attané

    Full Text Available Many metabolic studies employ tissue-specific gene knockout mice, which requires breeding of floxed gene mice, available mostly on C57BL/6N (NN genetic background, with cre or Flp recombinase-expressing mice, available on C57BL/6J (JJ background, resulting in the generation of mixed C57BL/6NJ (NJ genetic background mice. Recent awareness of many genetic differences between NN and JJ strains including the deletion of nicotinamide nucleotide transhydrogenase (nnt, necessitates examination of the consequence of mixed NJ background on glucose tolerance, beta cell function and other metabolic parameters. Male mice with NN and NJ genetic background were fed with normal or high fat diets (HFD for 12 weeks and glucose and insulin homeostasis were studied. Genotype had no effect on body weight and food intake in mice fed normal or high fat diets. Insulinemia in the fed and fasted states and after a glucose challenge was lower in HFD-fed NJ mice, even though their glycemia and insulin sensitivity were similar to NN mice. NJ mice showed mild glucose intolerance. Moreover, glucose- but not KCl-stimulated insulin secretion in isolated islets was decreased in HFD-fed NJ vs NN mice without changes in insulin content and beta cell mass. Under normal diet, besides reduced fed insulinemia, NN and NJ mice presented similar metabolic parameters. However, HFD-fed NJ mice displayed lower fed and fasted insulinemia and glucose-induced insulin secretion in vivo and ex vivo, as compared to NN mice. These results strongly caution against using unmatched mixed genetic background C57BL/6 mice for comparisons, particularly under HFD conditions.

  6. Geniposide regulates glucose-stimulated insulin secretion possibly through controlling glucose metabolism in INS-1 cells.

    Directory of Open Access Journals (Sweden)

    Jianhui Liu

    Full Text Available Glucose-stimulated insulin secretion (GSIS is essential to the control of metabolic fuel homeostasis. The impairment of GSIS is a key element of β-cell failure and one of causes of type 2 diabetes mellitus (T2DM. Although the KATP channel-dependent mechanism of GSIS has been broadly accepted for several decades, it does not fully describe the effects of glucose on insulin secretion. Emerging evidence has suggested that other mechanisms are involved. The present study demonstrated that geniposide enhanced GSIS in response to the stimulation of low or moderately high concentrations of glucose, and promoted glucose uptake and intracellular ATP levels in INS-1 cells. However, in the presence of a high concentration of glucose, geniposide exerted a contrary role on both GSIS and glucose uptake and metabolism. Furthermore, geniposide improved the impairment of GSIS in INS-1 cells challenged with a high concentration of glucose. Further experiments showed that geniposide modulated pyruvate carboxylase expression and the production of intermediates of glucose metabolism. The data collectively suggest that geniposide has potential to prevent or improve the impairment of insulin secretion in β-cells challenged with high concentrations of glucose, likely through pyruvate carboxylase mediated glucose metabolism in β-cells.

  7. Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Henry, R R; Smith, Susanne; Schwartz, Saul

    2011-01-01

    Aim: To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on ß-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Methods: Patients in this randomized, parallel-group, double-blind, placebo......-oral hyperglycaemic clamp (180–480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. Results......: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose...

  8. Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Fabienne Billiard

    2018-01-01

    Full Text Available Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation. Furthermore, we showed that Notch inhibition could drive proliferation of β-islet cells and confer protection from the development of STZ-induced diabetes. Importantly, inhibition of the Dll4 pathway in WT mice increased insulin secretion by inducing the differentiation of pancreatic β-islet cell progenitors, as well as the proliferation of insulin-secreting cells. These findings reveal a direct effect of Dll4-blockade on pancreatic islets that, in conjunction with its immunomodulatory effects, could be used for unmet medical needs hallmarked by inefficient insulin action.

  9. Improvement of insulin secretion in rat models of diabetes after ACEI/ARB therapy

    International Nuclear Information System (INIS)

    Tian Jingyan; Li Fengying; Liu Yun; Long Hongmei; Li Weiyi; Wang Xiao; Zhang Hongli; Li Guo; Luo Min

    2009-01-01

    Objective To study the effect of ACEI/ARB therapy on the secretion of insulin and glucagon as well as serum lipid peroxidation marker 8-iso PGF-2α levels in streptozoticin (STZ) induced diabetic rat models.Methods Twenty-four rat models of STZ induced diabetes were prepared (random blood sugar>16.7 mmol/L). Of which, 8 models were fed enalaprial 5mg/kg/d, 8 models were fed losartan 10μg/kg/d and 8 models left unterated. Fasting serum insulin,glucagon (with RIA) and 8-iso PGF-2α (with ELISA) levels were measured in these models and 8 control rats three weeks later. Intravenous glucose tolerance test (IVGTT) were performed in 12 rats (3 animals in each group) six weeks later. Results: Serum levels of insulin in the treated models were higher than those in the non-treated models but without significance (P>0.05). Serum levels of glucagon and 8-iso PGF-2α levels in the treated models were significantly lower than those in the non-treated models (P 6 x ) in the treated models. Conclusion: ACEI/ARB treatment could improve the secretion of insulin in rat models of diabetes, which might be beneficial for controlling the progression of the disease. This phenomenon is consistent with the result of clinical study. (authors)

  10. Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

    Science.gov (United States)

    Dayeh, Tasnim; Ling, Charlotte

    2015-10-01

    β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.

  11. Restructuring of pancreatic islets and insulin secretion in a postnatal critical window.

    Directory of Open Access Journals (Sweden)

    Cristina Aguayo-Mazzucato

    Full Text Available Function and structure of adult pancreatic islets are determined by early postnatal development, which in rats corresponds to the first month of life. We analyzed changes in blood glucose and hormones during this stage and their association with morphological and functional changes of alpha and beta cell populations during this period. At day 20 (d20, insulin and glucose plasma levels were two- and six-fold higher, respectively, as compared to d6. Interestingly, this period is characterized by physiological hyperglycemia and hyperinsulinemia, where peripheral insulin resistance and a high plasmatic concentration of glucagon are also observed. These functional changes were paralleled by reorganization of islet structure, cell mass and aggregate size of alpha and beta cells. Cultured beta cells from d20 secreted the same amount of insulin in 15.6 mM than in 5.6 mM glucose (basal conditions, and were characterized by a high basal insulin secretion. However, beta cells from d28 were already glucose sensitive. Understanding and establishing morphophysiological relationships in the developing endocrine pancreas may explain how events in early life are important in determining adult islet physiology and metabolism.

  12. Investigating the Roles of Mitochondrial and Cytosolic Malic Enzyme in Insulin Secretion

    Science.gov (United States)

    Pongratz, Rebecca L.; Kibbey, Richard G.; Cline, Gary W.

    2015-01-01

    Glucose homeostasis depends upon the appropriate release of insulin from pancreatic islet β-cells. Postpandrial changes in circulating nutrient concentrations are coupled with graded release of stored insulin pools by the proportional changes in mitochondrial metabolism. The corresponding increased synthesis rates of both ATP and of anaplerotic metabolites have been shown to be mediators for nutrient-stimulated insulin secretion. Anaplerosis leads to the export of malate or citrate from the mitochondria, both of which can be recycled through metabolic pathways to reenter the Kreb's cycle. These metabolic cycles have the net effect of either transferring mitochondrial reducing equivalents to the cytosol, or of efficiently providing pyruvate to facilitate responsive changes in the Kreb's cycle flux in proportion to increased availability of glutamate and anaplerotic flux through glutamate dehydrogenase. Here, we describe siRNA knock-down and isotopic labeling strategies to evaluate the role of cytosolic and mitochondrial isoforms of malic enzyme in facilitating malate–pyruvate cycling in the context of fuel-stimulated insulin secretion. PMID:19426882

  13. [Evaluation of preserved insulin secretion in children and adolescents with type 1 diabetes].

    Science.gov (United States)

    Wegner, Olga; Wyka, Krystyna; Fendler, Wojciech; Zmysłowska, Agnieszka; Młynarski, Wojciech

    2010-01-01

    The pathogenesis of type 1 diabetes is connected with immune-mediated beta-cell destruction leading to insulin deficiency. The majority of patients will become completely incapable of insulin secretion within a few years, however, some individuals will have persistent beta-cell function years after the diagnosis of diabetes. Despite clinical symptoms of insulin deficiency, residual beta-cell secretion can modify the clinical course and can be an independent factor influencing the delay of development of chronic diabetic complications. The aim of the study was to compare a 10-year clinical course in children with type 1 diabetes with and without preserved beta-cell secretion. 72 children and adolescents with diabetes lasting for minimum 10 years and available biological material to c-peptide evaluation (3-4 years and 10 years from the onset of diabetes) were chosen from 768 children with type 1 diabetes. We assessed fasting c-peptide and recruited 23 out of 72 patients whose concentration of c-peptide was below or over 0.23 ng/ml at all time points (this cut point derives from the definition of preserved beta-cell function according to DCCT). Afterwards we divided children into two subgroups: A (n=13) - without insulin secretion and B (n=10) - with preserved beta-cell function during 10 years of observation. We assessed markers of beta-cell autoimmunity (ICA, GADA, IA2, IAA) in the examined groups. Insulin requirement and concentration of glycated hemoglobin (assessed as the year mean from four measurements in each year) were compared between group A and B. The age at onset of diabetes in children from both examined groups was similar. All children from group B and 12/13 from group A were positive for at least one type of the screened autoantibodies. There was no difference in insulin requirement between the groups (p=0.6). The level of glycated hemoglobin was significantly lower in group B during a 10-year observational period (p=0.04). Repeated measures of c

  14. Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents

    DEFF Research Database (Denmark)

    Perry, Rachel J; Cardone, Rebecca L; Petersen, Max C

    2016-01-01

    directly activates β-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the β-cell mechanism that explains the acute, antidiabetic activity of imeglimin....

  15. The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing

    DEFF Research Database (Denmark)

    Luu, L; Dai, F F; Prentice, K J

    2013-01-01

    Sirtuin 1 (SIRT1) has emerged as a key metabolic regulator of glucose homeostasis and insulin secretion. Enhanced SIRT1 activity has been shown to be protective against diabetes, although the mechanisms remain largely unknown. The aim of this study was to determine how SIRT1 regulates insulin sec...

  16. High saturated fatty acid intake induces insulin secretion by elevating gastric inhibitory polypeptide levels in healthy individuals

    DEFF Research Database (Denmark)

    Itoh, Kazue; Moriguchi, Ririko; Yamada, Yuichiro

    2014-01-01

    insulin and gastric inhibitory polypeptide (GIP) secretion. To clarify the effect of ingested fatty acid composition on glucose levels, we conducted an intervention study to investigate the insulin and plasma GIP responses in 11 healthy women, including a dietary control. Subjects were provided daily...... and FB-30 or F-30. However, insulin levels were higher after the FB-30 than after the F-20 (P incremental GIP between FB-30 and F-30 correlated significantly and positively...

  17. Insulin Secretion and Incretin Hormone Concentration in Women with Previous Gestational Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Sung Hoon Yu

    2011-02-01

    Full Text Available BackgroundWe examined the change in the levels of incretin hormone and effects of glucose-dependent insulinotropic polypeptide (GIP and glucagon-like peptide 1 (GLP-1 on insulin secretion in women with previous gestational diabetes (pGDM.MethodsA 75-g oral glucose tolerance test (OGTT was conducted on 34 women with pGDM. In addition, 11 women with normal glucose tolerance, matched for age, height and weight, were also tested. The insulin, GIP, GLP-1, and glucagon concentrations were measured, and their anthropometric and biochemical markers were also measured.ResultsAmong 34 women with pGDM, 18 had normal glucose tolerance, 13 had impaired glucose tolerance (IGT and 1 had diabetes. No significant differences were found in GLP-1 concentration between the pGDM and control group. However, a significantly high level of glucagon was present in the pGDM group at 30 minutes into the OGTT. The GIP concentration was elevated at 30 minutes and 60 minutes in the pGDM group. With the exception of the 30-minute timepoint, women with IGT had significantly high blood glucose from 0 to 120 minutes. However, there was no significant difference in insulin or GLP-1 concentration. The GIP level was significantly high from 0 to 90 minutes in patients diagnosed with IGT.ConclusionGLP-1 secretion does not differ between pGDM patients and normal women. GIP was elevated, but that does not seem to induce in increase in insulin secretion. Therefore, we conclude that other factors such as heredity and environment play important roles in the development of type 2 diabetes.

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

    Directory of Open Access Journals (Sweden)

    Natalia Gustavsson

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

  19. Chronic intermittent hypoxia disturbs insulin secretion and causes pancreatic injury via the MAPK signaling pathway.

    Science.gov (United States)

    Wang, Yeying; Hai, Bing; Niu, Xiaoqun; Ai, Li; Cao, Yu; Li, Ran; Li, Yongxia

    2017-06-01

    Obstructive sleep apnea (OSA) is a breathing disorder during sleep, with a most prominent character of chronic intermittent hypoxia (CIH), which induces the generation of reactive oxygen species (ROS) that damages multiple tissues and causes metabolic disorders. In this study, we established a rat model of varying OSA with different grades of CIH (12.5% O 2 , 10% O 2 , 7.5% O 2 , and 5% O 2 ) for 12 weeks, and found that CIH stimulated insulin secretion, reduced the insulin:proinsulin ratio in pancreatic tissue, and caused pancreatic tissue lesions and cell apoptosis in a dose-dependent manner. Moreover, CIH promoted the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and activated mitogen-activated protein kinase (MAPK) family members, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and P38, depending on the O 2 concentration. In summary, CIH disturbed insulin secretion, and caused inflammation, lesions, and cell apoptosis in pancreatic tissue via the MAPK signaling pathway, which may be of great significance for clinical treatment of OSA and type 2 diabetes mellitus (T2DM).

  20. Dual role of proapoptotic BAD in insulin secretion and beta cell survival.

    Science.gov (United States)

    Danial, Nika N; Walensky, Loren D; Zhang, Chen-Yu; Choi, Cheol Soo; Fisher, Jill K; Molina, Anthony J A; Datta, Sandeep Robert; Pitter, Kenneth L; Bird, Gregory H; Wikstrom, Jakob D; Deeney, Jude T; Robertson, Kirsten; Morash, Joel; Kulkarni, Ameya; Neschen, Susanne; Kim, Sheene; Greenberg, Michael E; Corkey, Barbara E; Shirihai, Orian S; Shulman, Gerald I; Lowell, Bradford B; Korsmeyer, Stanley J

    2008-02-01

    The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.

  1. OXIDATIVE STRESS: ITS ROLE IN INSULIN SECRETION, HORMONE RECEPTION BY ADIPOCYTES AND LIPOLYSIS IN ADIPOSE TISSUE

    Directory of Open Access Journals (Sweden)

    V. V. Ivanov

    2014-01-01

    Full Text Available Oxidative stress is one of the pathogenetic components of many diseases during which generation of reactive oxigen species increases and the capacity of the antioxidant protection system diminishes. In the research of the last decades special attention has been given to adipose tissue, production of adipokines by it and their role in development of immunoresistance associated with formation of the metabolic syndrome and diabetes.Search for methods of therapeutic correction of adipokine secretion disorders, their influence on metabolism of separate cells and the organism on the whole as well as development of new approaches to correction of disorders in cell sensitivity to insulin are extremely topical nowadays. Systematization and consolidation of accumulated data allow to determine the strategies of further research more accurately; as a result, we have attempted to summarize and analyze the accumulated data on the role of adipose tissue in oxidative stress development.On the basis of literature data and the results of the personal investigations, the role of adipose tissue in forming oxidative stress in diabetes has been analyzed in the article. Brief description of adipose tissue was given as a secretory organ regulating metabolic processes in adipocytes and influencing functions of various organs and systems of the body. Mechanisms of disorder in insulin secretion as well as development of insulin sesistance in type I diabetes were described along with the contribution of lipolysis in adipose tissue to these processes.

  2. Block of Kv1.7 potassium currents increases glucose-stimulated insulin secretion.

    Science.gov (United States)

    Finol-Urdaneta, Rocio K; Remedi, Maria S; Raasch, Walter; Becker, Stefan; Clark, Robert B; Strüver, Nina; Pavlov, Evgeny; Nichols, Colin G; French, Robert J; Terlau, Heinrich

    2012-05-01

    Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking activity of the beta cell membrane. Cyclic activation of voltage-gated potassium channels (K(v) ) generates an outward, 'delayed rectifier' potassium current, which drives the repolarizing phase of each spike and modulates insulin release. Although several K(v) channels are expressed in pancreatic islets, their individual contributions to GSIS remain incompletely understood. We take advantage of a naturally occurring cone-snail peptide toxin, Conkunitzin-S1 (Conk-S1), which selectively blocks K(v) 1.7 channels to provide an intrinsically limited, finely graded control of total beta cell delayed rectifier current and hence of GSIS. Conk-S1 increases GSIS in isolated rat islets, likely by reducing K(v) 1.7-mediated delayed rectifier currents in beta cells, which yields increases in action potential firing and cytoplasmic free calcium. In rats, Conk-S1 increases glucose-dependent insulin secretion without decreasing basal glucose. Thus, we conclude that K(v) 1.7 contributes to the membrane-repolarizing current of beta cells during GSIS and that block of this specific component of beta cell K(v) current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes. Copyright © 2012 EMBO Molecular Medicine.

  3. Protein malnutrition after weaning disrupts peripheral clock and daily insulin secretion in mice.

    Science.gov (United States)

    Borck, Patricia Cristine; Batista, Thiago Martins; Vettorazzi, Jean Franciesco; Camargo, Rafael Ludemann; Boschero, Antonio Carlos; Vieira, Elaine; Carneiro, Everardo Magalhães

    2017-12-01

    Changes in nutritional state may alter circadian rhythms through alterations in expression of clock genes. Protein deficiency has a profound effect on body metabolism, but the effect of this nutrient restriction after weaning on biological clock has not been explored. Thus, this study aims to investigate whether the protein restriction affects the daily oscillation in the behavior and metabolic rhythms, as well as expression of clock genes in peripheral tissues. Male C57BL/6 J mice, after weaning, were fed a normal-protein (NP) diet or a low-protein (LP) diet for 8 weeks. Mice fed an LP diet did not show difference in locomotor activity and energy expenditure, but the food intake was increased, with parallel increased expression of the orexigenic neuropeptide Npy and disruption of the anorexigenic Pomc oscillatory pattern in the hypothalamus. LP mice showed disruption in the daily rhythmic patterns of plasma glucose, triglycerides and insulin. Also, the rhythmic expression of clock genes in peripheral tissues and pancreatic islets was altered in LP mice. In pancreatic islets, the disruption of clock genes was followed by impairment of daily glucose-stimulated insulin secretion and the expression of genes involved in exocytosis. Pharmacological activation of REV-ERBα could not restore the insulin secretion in LP mice. The present study demonstrates that protein restriction, leading to development of malnutrition, alters the peripheral clock and metabolic outputs, suggesting that this nutrient provides important entraining cues to regulate the daily fluctuation of biological clock. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. The GLP-1 mimetic exenatide potentiates insulin secretion in healthy cats.

    Science.gov (United States)

    Gilor, C; Graves, T K; Gilor, S; Ridge, T K; Rick, M

    2011-07-01

    The glucagon-like peptide-1 mimetic exenatide has a glucose-dependent insulinotropic effect, and it is effective in controlling blood glucose (BG) with minimal side effects in people with type 2 diabetes. Exenatide also delays gastric emptying, increases satiety, and improves β-cell function. We studied the effect of exenatide on insulin secretion during euglycemia and hyperglycemia in cats. Nine young, healthy, neutered, purpose-bred cats were used in a randomized, cross-over design. BG concentrations during an oral glucose tolerance test were determined in these cats previously. Two isoglycemic glucose clamps (mimicking the BG concentration during the oral glucose tolerance test) were performed in each cat on separate days, one without prior treatment (IGC) and the second with exenatide (1 μg/kg) injected subcutaneously 2 h before (ExIGC). BG, insulin, and exenatide concentrations were measured, and glucose infusion rates were recorded and compared in paired tests between the two experiments. After exenatide injection, insulin serum concentrations increased significantly (2.4-fold; range 1.0- to 9.2-fold; P = 0.004) within 15 min. This was followed by a mild decrease in BG concentration and a return of insulin concentration to baseline despite a continuous increase in serum exenatide concentrations. Insulin area under the curve (AUC) during ExIGC was significantly higher than insulin AUC during IGC (AUC ratio, 2.0 ± 0.4; P = 0.03). Total glucose infused was not significantly different between IGC and ExIGC. Exenatide was detectable in plasma at 15 min after injection. The mean exenatide concentration peaked at 45 min and then returned to baseline by 75 min. Exenatide was still detectable in the serum of three of five cats 8 h after injection. No adverse reactions to exenatide were observed. In conclusion, exenatide affects insulin secretion in cats in a glucose-dependent manner, similar to its effect in other species. Although this effect was not accompanied

  5. Insulin Modulates Cytokine Release, Collagen and Mucus Secretion in Lung Remodeling of Allergic Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Sabrina S. Ferreira

    2017-06-01

    cytokines, and collagen deposition and mucus secretion into the lungs.ConclusionThe results suggest that insulin modulates the production/release of cytokines, cell migration, deposition of collagen, and mucus secretion in lung remodeling of a mouse model of asthma.

  6. [Primary study on characteristics of insulin secretion rate, metabolic clearance rate and sensitivity in non-insulin-dependent diabetic subjects from multiplex diabetic pedigrees].

    Science.gov (United States)

    Ran, J; Cheng, H; Li, F

    2000-01-01

    To investigate the characteristics of insulin secretion rate (ISR), metabolic clearance rate (MCR-I) and sensitivity and to explore their relationship with obesity in non-insulin-dependent diabetic subjects from multiplex diabetic pedigrees (MDP). Fifteen subjects with normal glucose tolerance and 11 non-insulin-dependent diabetic patients from MDP were included in the study. Frequently sampled intravenous glucose tolerance test (FSIVGTT) was performed. Glucose, insulin (INS) and connecting-peptide (C-P) concentrations were measured. A computer procedure devised by our laboratory was used to calculate the value of ISR at each time point, then MCR-I was acquired. Insulin sensitivity index (SI) was calculated according to minimal model technique about glucose in FSIVGTT. The ISR curve in control group was biphasic, while in non-insulin. In non-insulin-dependent diabetic group, areas under the curves of C-P (AUCC) and ISR level (AUCS) measured during 0 approximately 16 min were 7.9 nmol.min(-1).L(-1) +/- 2.8 nmol.min(-1).L(-1), and 6.1 nmol +/- 2.2 nmol, respectively, which were significantly lower than those in control group 17.7 nmol.min(-1).L(-1) +/- 4.92 nmol.min(-1).L(-1) and 12.3 nmol +/- 3.9 nmol (P < 0.01). The two parameters were slightly higher than those in control group 155 nmol.min(-1).L(-1) +/- 44 nmol.min(-1).L(-1) vs 101 nmol.min(-1).L(-1) +/- 30 nmol.min(-1).L(-1) and 76 nmol +/- 26 nmol vs 54 nmol +/- 20.0 nmol (P < 0.05)measured during 16 approximately 180 min. There was no significant difference, between the two groups about the amount of insulin secretion during 3 hours (82 nmol +/- 28nmol vs 68 nmol +/- 21 nmol, P = 0.2). In control group, there were significant positive correlation, between AUCS, waist-hip ratio (WHR), and body surface area, (BSA) and significant negative correlation between MCR-I, SI and WHR, BSA (P < 0.01), and also between MCR-I and SI. In non-insulin-dependent diabetic group, AUCS were significantly correlated with body mass

  7. Imeglimin increases glucose-dependent insulin secretion and improves β-cell function in patients with type 2 diabetes.

    Science.gov (United States)

    Pacini, G; Mari, A; Fouqueray, P; Bolze, S; Roden, M

    2015-06-01

    To assess the glucose-stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes. We conducted a double-blind, randomized, placebo-controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 ± 0.1% (51 mmol/mol)], who were drug-naïve or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose-stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0-45 min ] and insulin secretion rate (ISR) calculated from C-peptide deconvolution. β-cell glucose sensitivity at steady state (second phase: 25-45 min), hepatic insulin extraction and insulin clearance were also calculated. Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0-45 , p = 0.035), first-phase ISR by +110% (p = 0.034) and second-phase ISR by +29% (p = 0.031). Imeglimin improved β-cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (-13%; p = 0.056). Imeglimin did not affect glucagon secretion. In patients with type 2 diabetes, imeglimin improves β-cell function, which may contribute to the glucose-lowering effect observed with imeglimin in clinical trials. © 2015 John Wiley & Sons Ltd.

  8. Standardized Mori ramulus extract improves insulin secretion and insulin sensitivity in C57BLKS/J db/db mice and INS-1 cells.

    Science.gov (United States)

    Park, Soo-Yeon; Jin, Bora; Shin, Jae-Ho; Adisakwattana, Sirichai; Kwon, Oran

    2017-08-01

    Abnormalities in the hyperbolic relationship between insulin sensitivity and insulin secretion may cause oxidative stress and non-enzymatic glycation, resulting in an increased risk of type 2 diabetes. Here, we performed a 14-week study to investigate the effects of ethanolic extract of Mori ramulus (MRE; 0, 800, and 1600mg/kg body weight) and its signature component oxyresveratrol (OXY; 800mg/kg body weight) on β-cell dysfunction and insulin resistance in C57BLKS/J db/db mice fed with a high-fat diet. Compared with the diabetic control group, the high-dose MRE group showed a significant decrease in fasting blood glucose (p=0.0024); a significant increase in insulin secretion as measured by insulin (p=0.0012) and C-peptide (p=0.0103) levels in plasma and insulin content (p=0.0440) and homeobox factor-1 protein expression (p=0.0148) in the pancreas; and a significant increase in insulin sensitivity as measured by insulin receptor mRNA expression in the liver (p=0.0179) and adipose tissue (p=0.0491). In addition, improvements in the reactive oxygen species level and inflammatory pancreatic and hepatic tissue damage were also observed in the MRE group as assessed by histological findings. A similar but weaker effect was found in the OXY group. Furthermore, we observed a potentiating effect of MRE and OXY on insulin secretion in INS-1 cells in the presence of 27mM glucose, together with an anti-glycation effect as indicated by methylglyoxal-trapping capacity and inhibition of advanced glycation end-product formation. Taken together, these data suggest that MRE could ameliorate β-cell dysfunction and insulin resistance by reducing oxidative damage and advanced glycation end-product (Wagenknecht et al., 2003) formation and that these effects are due, at least in part, to OXY. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Activation of PPARd and RXRa stimulates fatty acid oxidatin and insulin secretion inpancreatic beta-cells

    DEFF Research Database (Denmark)

    Børgesen, Michael; Ravnskjær, Kim; Frigerio, Francesca

    , in animal models of obesity PPARd agonists display a modest insulin sensitizing action and a marked improvement of the plasma lipid profile by reducing circulating free fatty acids and triglycerides and raising HDL-cholesterol. The lipid-lowering effect of PPARd-activation correlates with increased......ACTIVATION OF PPARd AND RXRa STIMULATES FATTY ACID OXIDATION AND INSULIN SECRETION IN PANCREATIC b-CELLS Michael Boergesen1, Kim Ravnskjaer2, Francesca Frigerio3, Allan E. Karlsen4, Pierre Maechler3 and Susanne Mandrup1 1 Department of Biochemistry and Molecular Biology, University of Southern...... Denmark, DK-5230 Odense M, Denmark; 2 Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; 3 Department of Cell Physiology and Metabolism, University Medical Centre, CH-1211 Geneva 4, Switzerland; 4 Novo Nordisk, Denmark Synthetic agonists of the peroxisome...

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

    Directory of Open Access Journals (Sweden)

    Ellen B. Fung

    2015-06-01

    Full Text Available 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.

  11. Observations on the insulin-secretion function in the offsprings of patients with type II diabetes

    International Nuclear Information System (INIS)

    Xu Shujie; Tian Xiaoping; Wu Yan

    2004-01-01

    Objective: To investigate the disturbance of insulin-secretion function in the offsprings of patients with type II diabetes. Methods: Blood sugar (with oxidase method) and insulin (with RIA) levels were measured after overnight fasting and repeatedly measured 2h after 75g glucose per oral in the following subjects: 1) Group A, 23 non-obese offsprings of type II diabetics 2) group B, 18 obese offsprings (BMI ≥25kg/m 2 ) and 3) 27 controls. Homeostatic model assessment-insulin resistance (HOMA-IR) and β-cell function index (HCI) were calculated from the data (glucose and insulin levels) obtained. Results: For Group A subjects, the fasting blood sugar (FPG) levels were significantly higher and HBCI significantly lower than those in te controls (both P<0.05). For Group B obese subjects, in addition to the above two parameters (with HBCI P<0.01), 2h PG levels as well as HOMA-IR were also significantly higher (both P<0.05). Conclusion: Present study showed that in the offsprings of diabetics, HBCI was already lowered before definite impaired glucose tolerance (IGT) could be demonstrated, especially in the obese ones. (authors)

  12. Genetic Markers of Insulin Sensitivity and Insulin Secretion Are Associated With Spontaneous Postnatal Growth and Response to Growth Hormone Treatment in Short SGA Children

    DEFF Research Database (Denmark)

    Jensen, Rikke Beck; Thankamony, Ajay; Day, Felix

    2015-01-01

    PURPOSE: The wide heterogeneity in the early growth and metabolism of children born small for gestational age (SGA), both before and during GH therapy, may reflect common genetic variations related to insulin secretion or sensitivity. METHOD: Combined multiallele single nucleotide polymorphism...... scores with known associations with insulin sensitivity or insulin secretion were analyzed for their relationships with spontaneous postnatal growth and first-year responses to GH therapy in 96 short SGA children. RESULTS: The insulin sensitivity allele score (GS-InSens) was positively associated...... with spontaneous postnatal weight gain (regression coefficient [B]: 0.12 SD scores per allele; 95% confidence interval [CI], 0.01-0.23; P = .03) and also in response to GH therapy with first-year height velocity (B: 0.18 cm/y per allele; 95% CI, 0.02-0.35; P = .03) and change in IGF-1 (B: 0.17 SD scores per allele...

  13. Evaluation of immunoisolated insulin-secreting beta TC6-F7 cells as a bioartificial pancreas.

    Science.gov (United States)

    Mamujee, S N; Zhou, D; Wheeler, M B; Vacek, I; Sun, A M

    1997-01-01

    To evaluate the growth and insulin secretion from microencapsulated beta TC6-F7 cells in vitro and to assess the in vivo function of microencapsulated cells transplanted in rats with steptozotocin (STZ)-induced diabetes. Alginate-poly-L-lysine encapsulated beta TC6-F7 cells were exposed to glucose, isobutylmethylxanthine (IBMX) and glucagon-like peptide I (7-36 amide) in a static in vitro challenge. In vivo, 2.5-3.5 x 10(7) encapsulated cells were implanted into diabetic rats. Graft function was evaluated by monitoring blood glucose concentrations and by an intraperitoneal glucose tolerance test. The cell density (number of cells per capsule) of cultured microencapsulated beta TC6-F7 cells increased almost 35-fold over a 55 day observation period to reach a plateau of approximately 3500 cells/capsule. While insulin secretion per capsule remained unchanged over the first 21 days of culture, a 7-fold increase was observed during the last 14 days of the 55 day observation period. Intraperitoneal transplantation of 3.5 x 10(7) encapsulated cells into diabetic rats resulted, within 24 hours, in reversal of hyperglycemia for up to 60 days. Post-transplantation blood glucose concentrations varied between 2 and 4 mM. Glucose clearance rates evaluated by an intraperitoneal glucose tolerance test at 30 days post-transplantation resulted in a markedly flat glucose clearance curve with blood glucose never rising above 4 mM. The glucose challenge of microencapsulated cells recovered 30 days post-transplantation resulted in a 2-fold increase in insulin response at glucose concentrations greater than 5.5 mM as compared to glucose-free media. In addition, immunostaining of recovered grafted tissue for insulin, reveals a strong presence of the peptide within the cell population. These data demonstrate the potential use of an immunoisolated beta-cell line for the treatment of diabetes.

  14. Reconstructing the insulin secretion rate by Bayesian deconvolution of phase-type densities

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Højbjerre, Malene

    2005-01-01

    of the insulin secretion rate (ISR) can be done by solving a highly ill-posed deconvolution problem. We represent the ISR, the C-peptide concentration and the convolution kernel as scaled phase-type densities and develop a Bayesian methodology for estimating such densities via Markov chain Monte Carlo techniques....... Hereby closed form evaluation of ISR is possible. We demonstrate the methodology on experimental data from healthy subjects and obtain results which are more realistic than recently reported conclusions based upon methods where the ISR is considered as piecewise constant....

  15. Mathematical Beta Cell Model for Insulin Secretion following IVGTT and OGTT

    DEFF Research Database (Denmark)

    Madsen, Henrik; Henriksen, Jan Erik; Karlsson, Mats

    2006-01-01

    Evaluation of beta cell function is conducted by a variety of glucose tolerance tests and evaluated by a number of different models with less than perfect consistency among results obtained from different tests. We formulated a new approximation of the distributed threshold model for insulin...... secretion in order to approach a model for quantifying beta cell function, not only for one, but for several different experiments. Data was obtained from 40 subjects that had both an oral glucose tolerance test (OGTT) and an intravenous tolerance test (IVGTT) performed. Parameter estimates from the two...

  16. Insulin elevates leptin secretion and mRNA levels via cyclic AMP in 3T3-L1 adipocytes deprived of glucose

    Directory of Open Access Journals (Sweden)

    Tomomi Tsubai

    2016-11-01

    Conclusion: Insulin alone stimulates leptin secretion and elevates leptin mRNA levels via cAMP under the lack of glucose metabolism, while glucose is a significant and ambivalent effector on the insulin effects of leptin.

  17. Phenolic Substances from Ocimum Species Enhance Glucose- Stimulated Insulin Secretion and Modulate the Expression of Key Insulin Regulatory Genes in Mice Pancreatic Islets

    DEFF Research Database (Denmark)

    Casanova, Livia Marques; Gu, Wenqian; Costa, Sônia Soares

    2017-01-01

    cinnamic acid derivatives (caftaric, caffeic, chicoric, and rosmarinic acids) or a C-glucosylated flavonoid (vicenin-2). All substances acutely enhanced glucose-stimulated insulin secretion (GSIS) from islets at concentrations from 10−10 to 10−6 M. They also increased GSIS after chronic incubation (10−8 M...... islets. Thus, they may play an important role in diabetes treatment. This is the first report on the insulin-secretory activity of caftaric acid, rosmarinic acid, and vicenin-2....

  18. Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1.

    Directory of Open Access Journals (Sweden)

    Maki Koyanagi

    Full Text Available AIM: We previously found that chronic tuberous sclerosis protein 2 (TSC2 deletion induces activation of mammalian target of rapamycin Complex 1 (mTORC1 and leads to hypertrophy of pancreatic beta cells from pancreatic beta cell-specific TSC2 knockout (βTSC2(-/- mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells. METHODS: Isolated islets from βTSC2(-/- mice and TSC2 knockdown insulin 1 (INS-1 insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes. RESULTS: Activation of mTORC1 increased mitochondrial DNA expression, mitochondrial density and ATP production in pancreatic beta cells of βTSC2(-/- mice. In TSC2 knockdown INS-1 cells, mitochondrial DNA expression, mitochondrial density and ATP production were increased compared with those in control INS-1 cells, consistent with the phenotype of βTSC2(-/- mice. TSC2 knockdown INS-1 cells also exhibited augmented insulin secretory response to glucose. Rapamycin inhibited mitochondrial DNA expression and ATP production as well as insulin secretion in response to glucose. Thus, βTSC2(-/- mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1. CONCLUSION: Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells.

  19. Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion.

    Science.gov (United States)

    Wollam, Joshua; Mahata, Sumana; Riopel, Matthew; Hernandez-Carretero, Angelina; Biswas, Angshuman; Bandyopadhyay, Gautam K; Chi, Nai-Wen; Eiden, Lee E; Mahapatra, Nitish R; Corti, Angelo; Webster, Nicholas J G; Mahata, Sushil K

    2017-06-01

    Chromogranin A (CgA) is a prohormone and a granulogenic factor that regulates secretory pathways in neuroendocrine tissues. In β-cells of the endocrine pancreas, CgA is a major cargo in insulin secretory vesicles. The impact of CgA deficiency on the formation and exocytosis of insulin vesicles is yet to be investigated. In addition, no literature exists on the impact of CgA on mitochondrial function in β-cells. Using three different antibodies, we demonstrate that CgA is processed to vasostatin- and catestatin-containing fragments in pancreatic islet cells. CgA deficiency in Chga-KO islets leads to compensatory overexpression of chromogranin B, secretogranin II, SNARE proteins and insulin genes, as well as increased insulin protein content. Ultrastructural studies of pancreatic islets revealed that Chga-KO β-cells contain fewer immature secretory granules than wild-type (WT) control but increased numbers of mature secretory granules and plasma membrane-docked vesicles. Compared to WT control, CgA-deficient β-cells exhibited increases in mitochondrial volume, numerical densities and fusion, as well as increased expression of nuclear encoded genes (Ndufa9, Ndufs8, Cyc1 and Atp5o). These changes in secretory vesicles and the mitochondria likely contribute to the increased glucose-stimulated insulin secretion observed in Chga-KO mice. We conclude that CgA is an important regulator for coordination of mitochondrial dynamics, secretory vesicular quanta and GSIS for optimal secretory functioning of β-cells, suggesting a strong, CgA-dependent positive link between mitochondrial fusion and GSIS.

  20. Effects of the pesticide amitraz and its metabolite BTS 27271 on insulin and glucagon secretion from the perfused rat pancreas: involvement of alpha2D-adrenergic receptors.

    Science.gov (United States)

    Abu-Basha, E A; Yibchok-Anun, S; Hopper, D L; Hsu, W H

    1999-11-01

    The study purpose was to investigate the direct effect of amitraz, a formamidine insecticide/acaricide, and its active metabolite BTS 27271 on insulin and glucagon secretion from the perfused rat pancreas. Amitraz and BTS 27271 (0.01, 0.1, 1, and 10 micromol/L) inhibited insulin secretion in a concentration-dependent manner. Amitraz increased glucagon secretion at 10 micromol/L, whereas BTS 27271 increased glucagon secretion at 1 and 10 micromol/L. Amitraz- and BTS 27271-induced decreases in insulin secretion and increases in glucagon secretion were not abolished during the 10-minute washout period. During the arginine treatment, both amitraz and BTS 27271 groups (0.1, 1, and 10 micromol/L) had lower insulin secretion and higher glucagon secretion than the control group. Idazoxan, an alpha2A/2D-adrenergic receptor (AR) antagonist, prevented the inhibitory effect of amitraz on insulin secretion in a concentration-dependent manner, but prazosin, an alpha1- and alpha2B/2C-AR antagonist, failed to antagonize the effect of amitraz. These results demonstrate that (1) amitraz and BTS 27271 inhibit insulin and stimulate glucagon secretion from the perfused rat pancreas, (2) amitraz inhibits insulin secretion by activation of alpha2D-ARs, since rats have alpha2D- but not alpha2A-ARs, and (3) amitraz and BTS 27271 may have a high binding affinity to the alpha2D-ARs of pancreatic islets.

  1. A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion.

    Science.gov (United States)

    Shigeto, Makoto; Cha, Chae Young; Rorsman, Patrik; Kaku, Kohei

    2017-04-01

    Glucagon-like peptide-1 (GLP-1) is an endogenous glucose-lowering hormone and GLP-1 receptor agonists are currently being used as antidiabetic drugs clinically. The canonical signalling pathway (including cAMP, Epac2, protein kinase A (PKA) and K ATP channels) is almost universally accepted as the main mechanism of GLP-1-stimulated insulin secretion. This belief is based on in vitro studies that used nanomolar (1-100 nM) concentrations of GLP-1. Recently, it was found that the physiological concentrations (1-10 pM) of GLP-1 also stimulate insulin secretion from isolated islets, induce membrane depolarization and increase of intracellular [Ca 2+ ] in isolated β cells/pancreatic islets. These responses were unaffected by PKA inhibitors and occurred without detectable increases in intracellular cAMP and PKA activity. These PKA-independent actions of GLP-1 depend on protein kinase C (PKC), involve activation of the standard GLP-1 receptor (GLP1R) and culminate in activation of phospholipase C (PLC), leading to an elevation of diacylglycerol (DAG), increased L-type Ca 2+ and TRPM4/TRPM5 channel activities. Here, we review these recent data and contrast them against the effects of nanomolar concentrations of GLP-1. The differential intracellular signalling activated by low and high concentrations of GLP-1 could provide a clue to explain how GLP-1 exerts different function in the central nervous system and peripheral organs.

  2. Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes

    Directory of Open Access Journals (Sweden)

    Julia H. Kreznar

    2017-02-01

    Full Text Available Genetic variation drives phenotypic diversity and influences the predisposition to metabolic disease. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a high-fat/high-sucrose diet. We found significant variation in diabetes-related phenotypes and gut microbiota composition among the different mouse strains in response to the dietary challenge and identified taxa associated with these traits. Follow-up microbiota transplant experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease. Animals harboring microbial communities with enhanced capacity for processing dietary sugars and for generating hydrophobic bile acids showed increased susceptibility to metabolic disease. Notably, differences in glucose-stimulated insulin secretion between different mouse strains were partially recapitulated via gut microbiota transfer. Our results suggest that the gut microbiome contributes to the genetic and phenotypic diversity observed among mouse strains and provide a link between the gut microbiome and insulin secretion.

  3. Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes.

    Science.gov (United States)

    Kreznar, Julia H; Keller, Mark P; Traeger, Lindsay L; Rabaglia, Mary E; Schueler, Kathryn L; Stapleton, Donald S; Zhao, Wen; Vivas, Eugenio I; Yandell, Brian S; Broman, Aimee Teo; Hagenbuch, Bruno; Attie, Alan D; Rey, Federico E

    2017-02-14

    Genetic variation drives phenotypic diversity and influences the predisposition to metabolic disease. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a high-fat/high-sucrose diet. We found significant variation in diabetes-related phenotypes and gut microbiota composition among the different mouse strains in response to the dietary challenge and identified taxa associated with these traits. Follow-up microbiota transplant experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease. Animals harboring microbial communities with enhanced capacity for processing dietary sugars and for generating hydrophobic bile acids showed increased susceptibility to metabolic disease. Notably, differences in glucose-stimulated insulin secretion between different mouse strains were partially recapitulated via gut microbiota transfer. Our results suggest that the gut microbiome contributes to the genetic and phenotypic diversity observed among mouse strains and provide a link between the gut microbiome and insulin secretion. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  4. The Effect of a Diet Moderately High in Protein and Fiber on Insulin Sensitivity Measured Using the Dynamic Insulin Sensitivity and Secretion Test (DISST

    Directory of Open Access Journals (Sweden)

    Lisa Te Morenga

    2017-11-01

    Full Text Available Evidence shows that weight loss improves insulin sensitivity but few studies have examined the effect of macronutrient composition independently of weight loss on direct measures of insulin sensitivity. We randomised 89 overweight or obese women to either a standard diet (StdD, that was intended to be low in fat and relatively high in carbohydrate (n = 42 or to a relatively high protein (up to 30% of energy, relatively high fibre (>30 g/day diet (HPHFib (n = 47 for 10 weeks. Advice regarding strict adherence to energy intake goals was not given. Insulin sensitivity and secretion was assessed by a novel method—the Dynamic Insulin Sensitivity and Secretion Test (DISST. Although there were significant improvements in body composition and most cardiometabolic risk factors on HPHFib, insulin sensitivity was reduced by 19.3% (95% CI: 31.8%, 4.5%; p = 0.013 in comparison with StdD. We conclude that the reduction in insulin sensitivity after a diet relatively high in both protein and fibre, despite cardiometabolic improvements, suggests insulin sensitivity may reflect metabolic adaptations to dietary composition for maintenance of glucose homeostasis, rather than impaired metabolism.

  5. Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K+ATP channel-dependent pathway

    DEFF Research Database (Denmark)

    Thams, Peter; Anwar, Mohammad R; Capito, Kirsten

    2005-01-01

    OBJECTIVE: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K(+) (K(+)(ATP)) channel-dependent insulin secretion and in glucose amplification of K(+)(ATP) channel-independent insulin secretion. METHODS: Insulin release from cultured perifused mouse...... pancreatic islets was determined by radioimmunoassay. RESULTS: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs-Ringer medium, the PKA inhibitors, H89 (10 micromol/l) and PKI 6-22 amide (30 micromol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion...... glucose amplification of K(+)(ATP) channel-independent insulin secretion. In the presence of 1 mmol/l ouabain and 250 micromol/l diazoxide, which cause modest Ca(2+) influx, glucose amplification of K(+)(ATP) channel-independent insulin secretion was observed without concomitant Ca(2+) stimulation of PKA...

  6. Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5−/− mice

    OpenAIRE

    Colsoul, Barbara; Schraenen, Anica; Lemaire, Katleen; Quintens, Roel; Van Lommel, Leentje; Segal, Andrei; Owsianik, Grzegorz; Talavera, Karel; Voets, Thomas; Margolskee, Robert F.; Kokrashvili, Zaza; Gilon, Patrick; Nilius, Bernd; Schuit, Frans C.; Vennekens, Rudi

    2010-01-01

    Glucose homeostasis is critically dependent on insulin release from pancreatic beta-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (V(m)) and the cytosolic calcium level ([Ca(2+)](cyt)). We propose that TRPM5, a Ca(2+)-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca(2+)-activated nonselective cation current with TRPM5-like proper...

  7. Opiate-prostaglandin interactions in the regulation of insulin secretion from rat islets of Langerhans in vitro

    International Nuclear Information System (INIS)

    Green, I.C.; Tadayyon, M.

    1988-01-01

    The inadequate insulin secretory response to glucose stimulation in non-insulin dependent diabetes has been attributed to many factors including high PGE 2 levels blunting the secretory response, and to the existence of inhibitory opiate activity in vivo. The purpose of the present work was to see if there was a connection between these two independent theories. Radioimmunoassayable PGE 2 in islets of Langerhans was found to be proportional to islet number and protein content and was typically 4 to 5pg/μg islet protein. Indomethacin sodium salicylate and chlorpropamide all lowered islet PGE 2 levels and stimulated insulin release in vitro. Dynorphin stimulated insulin release at a concentration of 6 x 10 -9 M, while lowering islet PGE 2 . Conversely, at a higher concentration, dynorphin had no stimulatory effect on insulin secretion and did not lower PGE 2 levels in islets or in the incubation media. The stimulatory effects of dynorphin and sodium salicylate on insulin secretion were blocked by exogenous PGE 2 . PGE 2 at a lower concentration did not exert any inhibitory effect on dynorphin- or sodium salicylate-induced insulin release. This concentration of exogenous PGE 2 stimulated insulin release in the presence of 6mM glucose

  8. Possible involvement of transient receptor potential channels in electrophile-induced insulin secretion from RINm5F cells.

    Science.gov (United States)

    Numazawa, Satoshi; Takase, Makiko; Ahiko, Tomomi; Ishii, Masakazu; Shimizu, Shun-ichi; Yoshida, Takemi

    2012-01-01

    Endogenously produced reactive oxygen species reportedly stimulate insulin secretion from islet β-cells. However, the molecular machinery that governs the oxidant-induced insulin secretion has yet to be determined. The present study demonstrates, using rat islet β-cell-derived RINm5F cells, the involvement of the transient receptor potential (TRP) cation channels in the insulin secretion induced by the lipid peroxidation product 4-hydroxy-2-nonenal. Short-term (1 h) exposure of 4-hydroxy-2-nonenal induced a transient increase in intracellular Ca(2+) concentration and subsequent insulin secretion in a concentration-dependent manner. The increase in intracellular Ca(2+) concentration seemed to be due to an influx through the L-type voltage-dependent Ca(2+) channel, since it was not observed when extracellular Ca(2+) was absent and was inhibited almost completely by diltiazem or nifedipine. Ruthenium red, a non-specific inhibitor of TRP channels, inhibited the Ca(2+) influx and insulin secretion evoked by 4-hydroxy-2-nonenal. Among the TRP channels, TRPA1 was found to be predominantly expressed, not only in RINm5F cells, but also rat islets. TRPA1 agonists, allylisothiocyanate and 15-deoxy-Δ(12,14)-prostaglandin J(2), significantly induced Ca(2+) influx, and a specific inhibitor TRPA1, HC-030031, blocked the effects elicited by 4-hydroxy-2-nonenal. These results suggest that 4-hydroxy-2-nonenal induces Ca(2+) influx via the activation of TRP channels, including TRPA1, which appears to be coupled with the L-type voltage-dependent Ca(2+) channel, and ultimately insulin secretion in RINm5F cells.

  9. 1-Hour OGTT Plasma Glucose as a Marker of Progressive Deterioration of Insulin Secretion and Action in Pregnant Women

    Directory of Open Access Journals (Sweden)

    Alessandra Ghio

    2012-01-01

    Full Text Available Considering old GDM diagnostic criteria, alterations in insulin secretion and action are present in women with GDM as well as in women with one abnormal value (OAV during OGTT. Our aim is to assess if changes in insulin action and secretion during pregnancy are related to 1-hour plasma glucose concentration during OGTT. We evaluated 3 h/100 g OGTT in 4,053 pregnant women, dividing our population on the basis of 20 mg/dL increment of plasma glucose concentration at 1 h OGTT generating 5 groups (<120 mg/dL, =661; 120–139 mg/dL, =710; 140–159 mg/dL, =912; 160–179 mg/dL, =885; and ≥180 mg/dL, =996. We calculated incremental area under glucose (AUCgluc and insulin curves (AUCins, indexes of insulin secretion (HOMA-B, and insulin sensitivity (HOMA-R, AUCins/AUCgluc. AUCgluc and AUCins progressively increased according to 1-hour plasma glucose concentrations (both <0.0001 for trend. HOMA-B progressively declined (<0.001, and HOMA-R progressively increased across the five groups. AUCins/AUCgluc decreased in a linear manner across the 5 groups (<0.001. Analysing the groups with 1-hour value <180 mg/dL, defects in insulin secretion (HOMA-B: −29.7% and sensitivity (HOMA-R: +15% indexes were still apparent (all <0.001. Progressive increase in 1-hour OGTT is associated with deterioration of glucose tolerance and alterations in indexes of insulin action and secretion.

  10. The effect of a very low calorie diet on insulin sensitivity, beta cell function, insulin clearance, incretin hormone secretion, androgen levels and body composition in obese young women.

    Science.gov (United States)

    Svendsen, Pernille F; Jensen, Frank K; Holst, Jens J; Haugaard, Steen B; Nilas, Lisbeth; Madsbad, Sten

    2012-09-01

    Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500-600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women. Seventeen overweight women (BMI > 28) were recruited to the study. Glucose, insulin and lipid metabolism were evaluated by euglycemic clamp technique, indirect calorimetry and an oral glucose tolerance test (OGTT). Insulin sensitivity was calculated as glucose disposal rate (GDR) and insulin sensitivity index (ISI), and also by HOMA-IR. Insulin secretion rate (ISR) was calculated from plasma C-peptide measurements. Secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) was measured during an oral glucose tolerance test. Abdominal fat distribution was assessed by dual x-ray absorptiometry scan and computed tomography. Ten women completed the intervention. The subjects lost an average 11% of their baseline weight. There was a significant loss of subcutaneous abdominal fatty tissue (p testosterone. A VLCD is an effective weight loss treatment, which results in an immediate improvement in several metabolic parameters.

  11. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes

    DEFF Research Database (Denmark)

    Fehse, Frauke; Trautmann, Michael; Holst, Jens Juul

    2005-01-01

    CONTEXT: First-phase insulin secretion (within 10 min after a sudden rise in plasma glucose) is reduced in type 2 diabetes mellitus (DM2). The incretin mimetic exenatide has glucoregulatory activities in DM2, including glucose-dependent enhancement of insulin secretion. OBJECTIVE: The objective...... by iv glucose challenge. PATIENTS: Thirteen evaluable DM2 subjects were included in the study: 11 males, two females; age, 56 +/- 7 yr; body mass index, 31.7 +/- 2.4 kg/m2; hemoglobin A1c, 6.6 +/- 0.7% (mean +/- sd) treated with diet/exercise (n = 1), metformin (n = 10), or acarbose (n = 2). Controls...

  12. Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility

    DEFF Research Database (Denmark)

    Miki, Takashi; Minami, Kohtaro; Shinozaki, Hidehiro

    2005-01-01

    lacking K(ATP) channels (Kir6.2(-/-) mice), we found that pretreatment with GIP in vivo failed to blunt the rise in blood glucose levels after oral glucose load. In Kir6.2(-/-) mice, potentiation of insulin secretion by GIP in vivo was markedly attenuated, indicating that K(ATP) channels are essential...... in the insulinotropic effect of GIP. In contrast, pretreatment with glucagon-like peptide-1 (GLP-1) in Kir6.2(-/-) mice potentiated insulin secretion and blunted the rise in blood glucose levels. We also found that GLP-1 inhibited gut motility whereas GIP did not. Perfusion experiments of Kir6.2(-/-) mice revealed...

  13. Impact of TCF7L2 rs7903146 on insulin secretion and action in young and elderly Danish twins

    DEFF Research Database (Denmark)

    Wegner, Lise; Hussain, Meena S; Pilgaard, Kasper

    2008-01-01

    OBJECTIVE: We investigated the regulation and metabolic effects of TCF7L2 gene expression in human sc fat and skeletal muscle and the impact of the TCF7L2, rs7903146, T-allele on gene expression and measures of glucose metabolism including insulin secretion and peripheral and hepatic insulin action...... tests, and population 2 was additionally examined with iv glucose tolerance tests and hyperinsulinemic, euglycemic clamps. RESULTS: Elderly T-allele carriers had decreased plasma insulin responses and lower disposition index, whereas insulinogenic index was similar between genotype groups. Elderly...

  14. Exendin-4 Alleviates High Glucose-Induced Rat Mesangial Cell Dysfunction through the AMPK Pathway

    Directory of Open Access Journals (Sweden)

    Wen-Wei Xu

    2014-02-01

    Full Text Available Background/Aims: Glucagon-like peptide-1 (GLP-1, which counteracts insulin resistance in humans with type 2 diabetes, has been shown to ameliorate diabetic nephropathy in experimental models. However, the mechanisms through which GLP-1 modulates renal function remained illdefined. The present study investigated the putative mechanisms underlying effects of exendin-4, a GLP-1 analog, on mesangial cell proliferation and fibronectin. Methods: Rat mesangial cells (MCs were treated with exendin-4 under high glucose conditions. AMP-activated protein kinase (AMPK inhibitors (compound C and agonists (AICAR were used to analyze the role of this kinase. Cell proliferation was measured using a MTT assay. Fibronectin expression and AMPK-signaling pathway activity were assessed using ELISA and Western blotting, respectively. The production of matrix metalloproteinase (MMP-2 and tissue inhibitors of metalloproteinases (TIMP-2 was evaluated using quantitative real-time RT-PCR. Results: Exendin-4 inhibited cell proliferation and fibronectin secretion in high glucose-induced MCs. It also caused phosphorylation of AMPK and subsequently increased the ratio of MMP-2 to TIMP-2, which resulted in the degradation of fibronectin. Exendin-4 reversed extracellular signal-regulated kinase (ERK phosphorylation and enhanced expression of mammalian target of rapamycin (mTOR in MCs. Moreover, the activation of the AMPK pathway by exendin-4 was induced by AICAR, which was inhibited by compound C. Conclusion: Exendin-4 exerts an inhibitory effect on cell proliferation and fibronectin secretion in rat MCs, partly through AMPK activation. These results may explain some of the beneficial effects of exendin-4 on the kidney.

  15. A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants

    DEFF Research Database (Denmark)

    Wood, Andrew R; Jonsson, Anna; Jackson, Anne U

    2017-01-01

    Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intrav...

  16. Effects of 12 weeks' treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Hove, K D; Brøns, Cecilie; Færch, Kai Erik Vinther

    2013-01-01

    Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA(1c...

  17. Common variants related to serum uric acid concentrations are associated with glucose metabolism and insulin secretion in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Xue Sun

    Full Text Available Elevated serum uric acid concentration is an independent risk factor and predictor of type 2 diabetes (T2D. Whether the uric acid-associated genes have an impact on T2D remains unclear. We aimed to investigate the effects of the uric acid-associated genes on the risk of T2D as well as glucose metabolism and insulin secretion.We recruited 2,199 normal glucose tolerance subjects from the Shanghai Diabetes Study I and II and 2,999 T2D patients from the inpatient database of Shanghai Diabetes Institute. Fifteen single nucleotide polymorphisms (SNPs mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1 were genotyped and serum biochemical parameters related to uric acid and T2D were determined.SF1 rs606458 showed strong association to T2D in both males and females (p = 0.034 and 0.0008. In the males, LRRC16A was associated with 2-h insulin and insulin secretion (p = 0.009 and 0.009. SLC22A11 was correlated with HOMA-B and insulin secretion (p = 0.048 and 0.029. SLC2A9 rs3775948 was associated with 2-h glucose (p = 0.043. In the females, LRP2 rs2544390 and rs1333049 showed correlations with fasting insulin, HOMA-IR and insulin secretion (p = 0.028, 0.033 and 0.052 and p = 0.034, 0.047 and 0.038, respectively. SLC2A9 rs11722228 was correlated with 2-h glucose, 2-h insulin and insulin secretion (p = 0.024, 0.049 and 0.049, respectively.Our results indicated that the uric acid-associated genes have an impact on the risk of T2D, glucose metabolism and insulin secretion in a Chinese population.

  18. Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5-/- mice.

    Science.gov (United States)

    Colsoul, Barbara; Schraenen, Anica; Lemaire, Katleen; Quintens, Roel; Van Lommel, Leentje; Segal, Andrei; Owsianik, Grzegorz; Talavera, Karel; Voets, Thomas; Margolskee, Robert F; Kokrashvili, Zaza; Gilon, Patrick; Nilius, Bernd; Schuit, Frans C; Vennekens, Rudi

    2010-03-16

    Glucose homeostasis is critically dependent on insulin release from pancreatic beta-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (V(m)) and the cytosolic calcium level ([Ca(2+)](cyt)). We propose that TRPM5, a Ca(2+)-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca(2+)-activated nonselective cation current with TRPM5-like properties is significantly reduced in Trpm5(-/-) cells. Ca(2+)-imaging and electrophysiological analysis show that glucose-induced oscillations of V(m) and [Ca(2+)](cyt) have on average a reduced frequency in Trpm5(-/-) islets, specifically due to a lack of fast oscillations. As a consequence, glucose-induced insulin release from Trpm5(-/-) pancreatic islets is significantly reduced, resulting in an impaired glucose tolerance in Trpm5(-/-) mice.

  19. Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5−/− mice

    Science.gov (United States)

    Colsoul, Barbara; Schraenen, Anica; Lemaire, Katleen; Quintens, Roel; Van Lommel, Leentje; Segal, Andrei; Owsianik, Grzegorz; Talavera, Karel; Voets, Thomas; Margolskee, Robert F.; Kokrashvili, Zaza; Gilon, Patrick; Nilius, Bernd; Schuit, Frans C.; Vennekens, Rudi

    2010-01-01

    Glucose homeostasis is critically dependent on insulin release from pancreatic β-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (Vm) and the cytosolic calcium level ([Ca2+]cyt). We propose that TRPM5, a Ca2+-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca2+-activated nonselective cation current with TRPM5-like properties is significantly reduced in Trpm5−/− cells. Ca2+-imaging and electrophysiological analysis show that glucose-induced oscillations of Vm and [Ca2+]cyt have on average a reduced frequency in Trpm5−/− islets, specifically due to a lack of fast oscillations. As a consequence, glucose-induced insulin release from Trpm5−/− pancreatic islets is significantly reduced, resulting in an impaired glucose tolerance in Trpm5−/− mice. PMID:20194741

  20. The stimulatory activities of polysaccharide compounds derived from algae extracts on insulin secretion in vitro.

    Science.gov (United States)

    Zhang, Dandan; Fujii, Isao; Lin, Changzheng; Ito, Kaori; Guan, Huashi; Zhao, Ji'en; Shinohara, Makoto; Matsukura, Makoto

    2008-05-01

    We prepared two series of polysaccharide compounds derived from algae extracts and investigated their stimulatory activity on insulin secretion in vitro using the rat pancreatic cell line, RIN-5F. Several of the compounds exhibited significant stimulatory activity in a dose-dependent manner without apparent cytotoxicity at concentrations above 10 microM. Glybenclamide, a commonly prescribed sulfonylurea (SU) against diabetes mellitus type II, was used as a positive control and showed moderate cytotoxicity in the cell culture assay system. Amylin (IAPP; islet amyloid polypeptide), an inhibitor for glybenclamide, did not inhibit the activity of the isolated compounds, suggesting that they act through a mechanism(s) different from glybenclamide. Algae-derived extracts could be candidates for a new class of anti-diabetic drugs.

  1. Insulin-Like Growth Factor-Phosphatidylinositol 3 Kinase Signaling in Canine Cortisol-Secreting Adrenocortical Tumors

    NARCIS (Netherlands)

    Kool, M M J; Galac, S; van der Helm, N; Corradini, S; Kooistra, H S; Mol, J A

    BACKGROUND: Hypercortisolism is a common endocrine disorder in dogs, caused by a cortisol-secreting adrenocortical tumor (AT) in approximately 15% of cases. In adrenocortical carcinomas of humans, activation of the phosphatidylinositol 3 kinase (PI3K) signaling pathway by insulin-like growth factor

  2. A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion

    DEFF Research Database (Denmark)

    Jonsson, Anna Elisabet; Isomaa, Bo; Tuomi, Tiinamaija

    2009-01-01

    Two independent genome-wide association studies for type 2 diabetes in Japanese subjects have recently identified common variants in the KCNQ1 gene that are strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI as well as insulin secretion...... and action and predict future type 2 diabetes in subjects from Sweden and Finland....

  3. Glucose-induced repression of PPARalpha gene expression in pancreatic beta-cells involves PP2A activation and AMPK inactivation

    DEFF Research Database (Denmark)

    Ravnskjaer, Kim; Boergesen, Michael; Dalgaard, Louise T

    2006-01-01

    , the mechanism underlying this transcriptional repression by glucose remains unclear. Here we report that glucose-induced repression of PPARalpha gene expression in INS-1E cells is independent of beta-cell excitation and insulin secretion but requires activation of protein phosphatase 2A in a process involving...... but not AMPKalpha1 using RNAi suppressed PPARalpha expression, thereby mimicking the effect of glucose. These results indicate that activation of protein phosphatase 2A and subsequent inactivation of AMPK is necessary for glucose repression of PPARalpha expression in pancreatic beta-cells....... inactivation of the AMP-activated protein kinase (AMPK). Pharmacological activation of AMPK at high glucose concentrations interferes with glucose repression of PPARalpha and PPARalpha target genes in INS-1E cells as well as in rat islets. Specific knock-down of the catalytic AMPK-subunit AMPKalpha2...

  4. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

    DEFF Research Database (Denmark)

    Schäfer, S A; Tschritter, O; Machicao, F

    2007-01-01

    AIMS/HYPOTHESIS: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes and reduced insulin secretion. The transcription factor TCF7L2 is an essential factor for glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells. We studied whether...... a defect in the enteroinsular axis contributes to impaired insulin secretion in carriers of TCF7L2 polymorphisms. METHODS: We genotyped 1,110 non-diabetic German participants for five single nucleotide polymorphisms in TCF7L2. All participants underwent an OGTT; GLP-1 secretion was measured in 155...... and an arginine bolus. RESULTS: The OGTT data confirmed that variants in TCF7L2 are associated with reduced insulin secretion. In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 concentrations during the OGTT...

  5. Region-Specific Suppression of Hypothalamic Responses to Insulin To Adapt to Elevated Maternal Insulin Secretion During Pregnancy.

    Science.gov (United States)

    Ladyman, Sharon R; Grattan, David R

    2017-12-01

    As part of the adaptation of maternal glucose regulation during pregnancy to ensure glucose provision to the fetus, maternal insulin concentrations become elevated. However, increased central actions of insulin, such as suppression of appetite, would be maladaptive during pregnancy. We hypothesized that central nervous system targets of insulin become less responsive during pregnancy to prevent overstimulation by the increased circulating insulin concentrations. To test this hypothesis, we have measured insulin-induced phosphorylation of Akt (pAkt) in specific hypothalamic nuclei as an index of hypothalamic insulin responsiveness. Despite higher endogenous insulin concentrations following feeding, arcuate nucleus pAkt levels were significantly lower in the pregnant group compared with the nonpregnant group. In response to an intracerebroventricular injection of insulin, insulin-induced pAkt was significantly reduced in the arcuate nucleus and ventromedial nucleus of pregnant rats compared with nonpregnant rats. Similar levels of insulin receptor β and PTEN, a negative regulator of the phosphoinositide 3-kinase/Akt pathway, were detected in hypothalamic areas of nonpregnant and pregnant rats. In the ventromedial nucleus, however, levels of phosphorylated PTEN were significantly lower in pregnancy, suggesting that reduced inactivation of PTEN may contribute to the attenuated insulin signaling in this area during pregnancy. In conclusion, these results demonstrate region-specific changes in responsiveness to insulin in the hypothalamus during pregnancy that may represent an adaptive response to minimize the impact of elevated circulating insulin on the maternal brain. Copyright © 2017 Endocrine Society.

  6. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways.

    Directory of Open Access Journals (Sweden)

    Manoj K Bhasin

    Full Text Available The relaxation response (RR is the counterpart of the stress response. Millennia-old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS as top upregulated critical molecules (focus hubs and NF-κB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-κB-associated upstream and downstream targets that mitigates stress.

  7. The voltage-gated proton channel Hv1 is expressed in pancreatic islet β-cells and regulates insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Qing [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Che, Yongzhe [School of Medicine, Nankai University, Tianjin 300071 (China); Li, Qiang; Zhang, Shangrong [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Gao, Ying-Tang [Key Laboratory of Artificial Cell, Third Central Clinical College of Tianjin Medical University, Tianjin 300170 (China); Wang, Yifan; Wang, Xudong; Xi, Wang; Zuo, Weiyan [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Li, Shu Jie, E-mail: shujieli@nankai.edu.cn [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China)

    2015-12-25

    The voltage-gated proton channel Hv1 is a potent acid extruder that participates in the extrusion of the intracellular acid. Here, we showed for the first time, Hv1 is highly expressed in mouse and human pancreatic islet β-cells, as well as β-cell lines. Imaging studies demonstrated that Hv1 resides in insulin-containing granules in β-cells. Knockdown of Hv1 with RNA interference significantly reduces glucose- and K{sup +}-induced insulin secretion in isolated islets and INS-1 (832/13) β-cells and has an impairment on glucose- and K{sup +}-induced intracellular Ca{sup 2+} homeostasis. Our data demonstrated that the expression of Hv1 in pancreatic islet β-cells regulates insulin secretion through regulating Ca{sup 2+} homeostasis.

  8. Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents.

    Science.gov (United States)

    Perry, Rachel J; Cardone, Rebecca L; Petersen, Max C; Zhang, Dongyan; Fouqueray, Pascale; Hallakou-Bozec, Sophie; Bolze, Sébastien; Shulman, Gerald I; Petersen, Kitt Falk; Kibbey, Richard G

    2016-08-01

    Imeglimin is a promising new oral antihyperglycemic agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose and improve hemoglobin A1c (1-3, 9). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-wk of treatment in type 2 diabetic patients. However, whether the β-cell stimulatory effect of imeglimin is solely or partially responsible for its effects on glycemia remains to be fully confirmed. Here, we show that imeglimin directly activates β-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the β-cell mechanism that explains the acute, antidiabetic activity of imeglimin. Copyright © 2016 the American Physiological Society.

  9. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Mirshahi, Faridoddin [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Grider, John R. [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Murthy, Karnam S., E-mail: skarnam@vcu.edu [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Sanyal, Arun J., E-mail: asanyal@mcvh-vcu.edu [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer G protein coupled receptor TGR5 is expressed in mouse and human islets. Black-Right-Pointing-Pointer TGR5 is coupled to activation of Gs and Ca{sup 2+} release via cAMP/Epac/PLC-{epsilon} pathway. Black-Right-Pointing-Pointer Activation of TGR5 by bile salts and selective ligands causes insulin secretion. Black-Right-Pointing-Pointer TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic {beta} cells. In the present study, we have identified the expression of TGR5 in pancreatic {beta} cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated G{alpha}{sub s} and caused an increase in intracellular cAMP and Ca{sup 2+}. OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective G{alpha}{sub s} inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G{sub s}/cAMP/Ca{sup 2+} pathway. 8-pCPT-2 Prime -O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic {beta} cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

  10. Effect of early life stress on pancreatic isolated islets' insulin secretion in young adult male rats subjected to chronic stress.

    Science.gov (United States)

    Sadeghimahalli, Forouzan; Karbaschi, Roxana; Zardooz, Homeira; Khodagholi, Fariba; Rostamkhani, Fatemeh

    2015-03-01

    Early stressful experiences may predispose organisms to certain disorders, including those of metabolic defects. This study aimed to explore the effects of early life stress on pancreatic insulin secretion and glucose transporter 2 (GLUT2) protein levels in stressed young adult male rats. Foot shock stress was induced in early life (at 2 weeks of age) and/or in young adulthood (at 8-10 weeks of age) for five consecutive days. Blood samples were taken before and after stress exposure in young adult rats. At the end of the experiment, glucose tolerance, isolated islets' insulin secretion, and pancreatic amounts of GLUT2 protein were measured. Our results show that early life stress has no effect on basal plasma corticosterone levels and adrenal weight, either alone or combined with young adulthood stress, but that early life + young adulthood stress could prevent weight gain, and cause an increase in basal plasma glucose and insulin. The homeostasis model assessment of insulin resistance index did not increase, when the rats were subjected to early life stress alone, but increased when combined with young adulthood stress. Moreover, glucose tolerance was impaired by the combination of early life + young adult stress. There was a decrease in islet's insulin secretion in rats subjected to early life stress in response to 5.6 mM glucose concentration, but an increase with a concentration of 16.7 mM glucose. However, in rats subjected to early life + young adulthood stress, islet's insulin secretion increased in response to both the levels of glucose concentrations. GLUT2 protein levels decreased in response to early life stress and early life + young adulthood stress, but there was a greater decrease in the early life stress group. In conclusion, perhaps early life stress sensitizes the body to stressors later in life, making it more susceptible to metabolic syndrome only when the two are in combination.

  11. Extracts from Leonurus sibiricus L. increase insulin secretion and proliferation of rat INS-1E insulinoma cells.

    Science.gov (United States)

    Schmidt, S; Jakab, M; Jav, S; Streif, D; Pitschmann, A; Zehl, M; Purevsuren, S; Glasl, S; Ritter, M

    2013-10-28

    Traditional Mongolian medicine (TMM) uses preparations from herbs as one form of medication for the treatment of a diversity of diseases including diabetes mellitus (DM). We evaluated the effect of extracts from the plant Leonurus sibiricus L. (LS), used in TMM to treat typical symptoms of type 2 DM, on insulin secretion, electrophysiological properties, intracellular calcium concentration and cell proliferation of INS-1E insulinoma cells under standard cell culture conditions (SCC; 11.1mM glucose). Insulin secretion was measured by ELISA, electrical properties were assessed by whole cell patch clamping, intracellular calcium concentration (Cai) by Fluo-4 time lapse imaging, insulin receptor expression was verified by RT-PCR and cell proliferation assessed by CellTiter-Glo® cell viability assay. Insulin released from INS-1E cells into the culture medium over 24h was significantly increased in presence of 500 mg/L aqueous LS extract (LS OWE) as well as methanolic LS extract (LS MeOH/H2O) but not in the presence of the butanol-soluble extract (LS MeOH/BuOH). Acute application of LS OWE resulted in a depolarization of the cell membrane potential paralleled by an initial increase and subsequent decline and silencing of action potential frequency, by KATP channel inhibition, persisting depolarization and an increase in Cai. The electrophysiological effects were comparable to those of 100 μM tolbutamide, which, however failed to elevate insulin secretion under SCC. Furthermore all LS extracts stimulated INS-1E cell proliferation. The finding that extracts from Leonurus sibiricus L. enhance insulin secretion and/or foster cell proliferation may provide possible explanations for the underlying therapeutic principles in the empirical use of LS-containing formulations in DM and DM-related disorders as applied in TMM. © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Estimation of insulin secretion, glucose uptake by tissues, and liver handling of glucose using a mathematical model of glucose-insulin homeostasis in lean and obese mice.

    Science.gov (United States)

    Brenner, Michael; Abadi, Sakineh Esmaeili Mohsen; Balouchzadeh, Ramin; Lee, H Felix; Ko, Hoo Sang; Johns, Michael; Malik, Nehal; Lee, Joshua J; Kwon, Guim

    2017-06-01

    Destruction of the insulin-producing β-cells is the key determinant of diabetes mellitus regardless of their types. Due to their anatomical location within the islets of Langerhans scattered throughout the pancreas, it is difficult to monitor β-cell function and mass clinically. To this end, we propose to use a mathematical model of glucose-insulin homeostasis to estimate insulin secretion, glucose uptake by tissues, and hepatic handling of glucose. We applied the mathematical model by Lombarte et al. (2013) to compare various rate constants representing glucose-insulin homeostasis between lean (11% fat)- and high fat diet (HFD; 45% fat)-fed mice. Mice fed HFD (n = 12) for 3 months showed significantly higher body weights (49.97 ± 0.52 g vs. 29.86 ± 0.46 g), fasting blood glucose levels (213.08 ± 10.35 mg/dl vs. 121.91 ± 2.26 mg/dl), and glucose intolerance compared to mice fed lean diet (n = 12). Mice were injected with 1 g/kg glucose intraperitoneally and blood glucose levels were measured at various intervals for 120 min. We performed simulation using Arena™ software based on the mathematical model and estimated the rate constants (9 parameters) for various terms in the differential equations using OptQuest™. The simulated data fit accurately to the observed data for both lean and obese mice, validating the use of the mathematical model in mice at different stages of diabetes progression. Among 9 parameters, 5 parameters including basal insulin, k 2 (rate constant for insulin-dependent glucose uptake to tissues), k 3 (rate constant for insulin-independent glucose uptake to tissues), k 4 (rate constant for liver glucose transfer), and I pi (rate constant for insulin concentration where liver switches from glucose release to uptake) were significantly different between lean- and HFD-fed mice. Basal blood insulin levels, k 3 , and I pi were significantly elevated but k 2 and k 4 were reduced in mice fed a HFD compared to those fed a lean diet. Non

  13. Cotransplantation of Adipose Tissue-Derived Insulin-Secreting Mesenchymal Stem Cells and Hematopoietic Stem Cells: A Novel Therapy for Insulin-Dependent Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    A. V. Vanikar

    2010-01-01

    Full Text Available Aims. Insulin dependent diabetes mellitus (IDDM is believed to be an autoimmune disorder with disturbed glucose/insulin metabolism, requiring life-long insulin replacement therapy (IRT, 30% of patients develop end-organ failure. We present our experience of cotransplantation of adipose tissue derived insulin-secreting mesenchymal stem cells (IS-AD-MSC and cultured bone marrow (CBM as IRT for these patients. Methods. This was a prospective open-labeled clinical trial to test efficacy and safety of IS-AD-MSC+CBM co-transplantation to treat IDDM, approved by the institutional review board after informed consent in 11 (males : females: 7 : 4 patients with 1–24-year disease duration, in age group: 13–43 years, on mean values of exogenous insulin requirement of 1.14 units/kg BW/day, glycosylated hemoglobin (Hb1Ac: 8.47%, and c-peptide levels: 0.1 ng/mL. Intraportal infusion of xenogeneic-free IS-AD-MSC from living donors, subjected to defined culture conditions and phenotypically differentiated to insulin-secreting cells, with mean quantum: 1.5 mL, expressing Pax-6, Isl-1, and pdx-1, cell counts: 2.1×103/μL, CD45−/90+/73+:40/30.1%, C-Peptide level:1.8 ng/mL, and insulin level: 339.3  IU/mL with CBM mean quantum: 96.3 mL and cell counts: 28.1×103/μL, CD45−/34+:0.62%, was carried out. Results. All were successfully transplanted without any untoward effect. Over mean followup of 23 months, they had a decreased mean exogenous insulin requirement to 0.63 units/kgBW/day, Hb1Ac to 7.39%, raised serum c-peptide levels to 0.38 ng/mL, and became free of diabetic ketoacidosis events with mean 2.5 Kg weight gain on normal vegetarian diet and physical activities. Conclusion. This is the first report of treating IDDM with insulin-secreting-AD-MSC+CBM safely and effectively with relatively simple techniques.

  14. Transfer plate radioassay using adsorbed anti-insulin antibody to detect insulin secreted by islet cell cultures

    International Nuclear Information System (INIS)

    Scearce, R.M.; Oie, H.K.; Gazdar, A.F.; Chick, W.L.; Eisenbarth, G.S.

    1981-01-01

    A solid-phase radioimmunoassay for detection of insulin synthesized by islet cell clones is described. This assay employs anti-insulin antibody adsorbed onto fenestrated polyvinyl chloride 96-well plates ('transfer plates'). The calibrated aperture in the bottom of each transfer plate well permits fluid to enter the wells when transfer plates are lowered into microculture wells containing insulin. With this assay it is possible to rapidly screen hundreds of islet cell cultures for insulin production. The authors have used this assay to facilitate cloning of the RIN rat insulinoma cell line. The assay readily detects insulin synthesis by RIN cells and [ 125 I]insulin is not displaced by culture medium from cells which do not produce insulin. The transfer plate format should be applicable to semiautomate other radioimmunoassays. (Auth.)

  15. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion

    DEFF Research Database (Denmark)

    Lyssenko, Valeriya; Nagorny, Cecilia L F; Erdos, Michael R

    2009-01-01

    Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype...... was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets....... Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which...

  16. Insulin secretion after short- and long-term low-grade free fatty acid infusion in men with increased risk of developing type 2 diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Jensen, Christine B; Vaag, Allan A

    2003-01-01

    We studied the effect of a low-grade short- and long-term 20% Intralipid infusion (0.4 mL(-1) x kg(-1) x h(-1)) on insulin secretion and insulin action in 15 elderly obese men; 7 glucose intolerant first-degree relatives of type 2 diabetic patients (impaired glucose tolerance [IGT] relatives) and 8...... secretion rates (ISR). ISR were calculated by deconvolution of plasma C-peptide concentrations. Insulin action was determined by performing a 120-minute hyperinsulinemic euglycemic clamp. All tests were performed 3 times, preceded by 0, 2, or 24 hours Intralipid infusion. Disposition indices (DI) were......- and long-term Intralipid infusion is not balanced by an adequate compensatory increase in insulin secretion in IGT relatives or in matched controls. IGT relatives appear to be more sensitive to the deleterious effects of low-grade fat infusion on insulin secretion than normal glucose tolerant control...

  17. Ethanolic Extract of Butea monosperma Leaves Elevate Blood Insulin Level in Type 2 Diabetic Rats, Stimulate Insulin Secretion in Isolated Rat Islets, and Enhance Hepatic Glycogen Formation

    Directory of Open Access Journals (Sweden)

    Mehdi Bin Samad

    2014-01-01

    Full Text Available We measured a vast range of parameters, in an attempt to further elucidate previously claimed antihyperglycemic activity of Butea monosperma. Our study clearly negates the possibility of antidiabetic activity by inhibited gastrointestinal enzyme action or by reduced glucose absorption. Reduction of fasting and postprandial glucose level was reconfirmed (P<0.05. Improved serum lipid profile via reduced low density lipoprotein (LDL, cholesterol, triglycerides (TG, and increased high density lipoprotein (HDL was also reestablished (P<0.05. Significant insulin secretagogue activity of B. monosperma was found in serum insulin assay of B. monosperma treated type 2 diabetic rats (P<0.01. This was further ascertained by our study on insulin secretion on isolated rat islets (P<0.05. Improved sensitivity of glucose was shown by the significant increase in hepatic glycogen deposition (P<0.05. Hence, we concluded that antihyperglycemic activity of B. monosperma was mediated by enhanced insulin secretion and enhanced glycogen formation in the liver.

  18. Mitochondrial Dysfunction Contributes to Impaired Insulin Secretion in INS-1 Cells with Dominant-negative Mutations of HNF-1α and in HNF-1α-deficient Islets*

    OpenAIRE

    Pongratz, Rebecca L.; Kibbey, Richard G.; Kirkpatrick, Clare L.; Zhao, Xiaojian; Pontoglio, Marco; Yaniv, Moshe; Wollheim, Claes B.; Shulman, Gerald I.; Cline, Gary W.

    2009-01-01

    Maturity Onset Diabetes of the Young-type 3 (MODY-3) has been linked to mutations in the transcription factor hepatic nuclear factor (HNF)-1α, resulting in deficiency in glucose-stimulated insulin secretion. In INS-1 cells overexpressing doxycycline-inducible HNF-1α dominant-negative (DN-) gene mutations, and islets from Hnf-1α knock-out mice, insulin secretion was impaired in response to glucose (15 mm) and other nutrient secretagogues. Decreased rates of insulin secretion in response to glu...

  19. Enhancement of glucose uptake in skeletal muscle L6 cells and insulin secretion in pancreatic hamster-insulinoma-transfected cells by application of non-thermal plasma jet

    Science.gov (United States)

    Kumar, Naresh; Kaushik, Nagendra K.; Park, Gyungsoon; Choi, Eun H.; Uhm, Han S.

    2013-11-01

    Type-II diabetes Mellitus is characterized by defects in insulin action on peripheral tissues, such as skeletal muscle, adipose tissue, and liver and pancreatic beta cells. Since the skeletal muscle accounts for approximately 75% of insulin-stimulated glucose-uptake in our body, impaired insulin secretion from defected beta cell plays a major role in the afflicted glucose homoeostasis. It was shown that the intracellular reactive oxygen species and nitric oxide level was increased by non-thermal-plasma treatment in ambient air. These increased intracellular reactive species may enhance glucose uptake and insulin secretion through the activation of intracellular calcium (Ca+) and cAMP production.

  20. The T-allele of TCF7L2 rs7903146 associates with a reduced compensation of insulin secretion for insulin resistance induced by 9 days of bed rest

    DEFF Research Database (Denmark)

    Alibegovic, Amra C; Sonne, Mette P; Højbjerre, Lise

    2010-01-01

    , the TCF7L2 rs7903146 did not influence peripheral insulin action or the rate of lipolysis before or after bed rest. CONCLUSIONS: Healthy carriers of the T-allele of TCF7L2 rs7903146 exhibit a diminished increase of insulin secretion in response to intravenous glucose to compensate for insulin resistance......OBJECTIVE: The aim of this study was to determine whether the type 2 diabetes-associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest. RESEARCH DESIGN AND METHODS: A total of 38....... The genetic analyses were done assuming a dominant model of inheritance. RESULTS: The first-phase insulin response (FPIR) was significantly lower in carriers of the T-allele compared with carriers of the CC genotype before bed rest, with and without correction for insulin resistance. The incremental rise...

  1. The influence of GLP-1 on glucose-stimulated insulin secretion

    DEFF Research Database (Denmark)

    Kjems, Lise L; Holst, Jens Juul; Vølund, Aage

    2003-01-01

    . However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2......, 4, 6, 8, and 12 mg x kg(-1) x min(-1) over 150 min on four occasions with infusion of saline or GLP-1 at 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1). GLP-1 enhanced ISR in a dose-dependent manner during the graded glucose infusion from 332 +/- 51 to 975 +/- 198 pmol/kg in the patients with type 2...... diabetes and from 711 +/- 123 to 2,415 +/- 243 pmol/kg in the control subjects. The beta-cell responsiveness to glucose, expressed as the slope of the linear relation between ISR and the glucose concentration, increased in proportion to the GLP-1 dose to 6 times relative to saline at the highest GLP-1 dose...

  2. Effect of butanol fraction from Cassia tora L. seeds on glycemic control and insulin secretion in diabetic rats.

    Science.gov (United States)

    Nam, Jeongsu; Choi, Hyunju

    2008-01-01

    Cassia tora L. seeds have previously been reported to reduce blood glucose level in human and animals with diabetes. In the present study, the effects of Cassia tora L. seed butanol fraction (CATO) were studied on postprandial glucose control and insulin secretion from the pancreas of the normal and diabetic rats. Diabetes was induced by an i.p. injection of Streptozotocin (55 mg/kg BW) into the male Sprague-Dawley rats. The postprandial glucose control was monitored during a 240 min-period using a maltose loading test. In normal rats, rats fed CATO (20 mg/100 g BW/d) showed lower postprandial glucose levels in all the levels from 30 min up to 180 min than those in the control rats without CATO (pCassia tora L. seeds have beneficial effect on postprandial blood glucose control which may be partially mediated by stimulated insulin secretion from the pancreas of the diabetic rats.

  3. Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes

    DEFF Research Database (Denmark)

    Bacos, Karl; Gillberg, Linn; Volkov, Petr

    2016-01-01

    Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA...... methylation genome-wide in islets from 87 non-diabetic donors, aged 26-74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for example, KLF14. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes...... identified in human islets (for example, KLF14, FHL2, ZNF518B and FAM123C) and some associate with insulin secretion and T2D. DNA methylation correlates with islet expression of multiple genes, including FHL2, ZNF518B, GNPNAT1 and HLTF. Silencing these genes in β-cells alter insulin secretion. Together, we...

  4. Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats.

    Science.gov (United States)

    Garcia-Diaz, Diego F; Arellano, Arianna V; Milagro, Fermin I; Moreno-Aliaga, Maria Jesus; Portillo, Maria Puy; Martinez, J Alfredo; Campion, Javier

    2011-09-01

    Thrombospondin 1 (TSP-1), an antiangiogenic factor and transforming growth factor (TGF)-β activity regulator, has been recently recognized as an adipokine that correlates with obesity, inflammation and insulin resistance processes. In the present study, epididymal adipocytes of rats that were fed a chow or a high-fat diet (HFD) for 50 days were isolated and incubated (24-72 h) in low (5.6 mM) or high (HG; 25 mM) glucose, in the presence or absence of 1.6 nM insulin. Rats fed the HF diet showed an established obesity state. Serum TSP-1 levels and TSP-1 mRNA basal expression of adipocytes from HFD rats were higher than those from controls. Adipocytes from HFD animals presented an insulin resistance state, as suggested by the lower insulin-stimulated glucose uptake as compared to controls. TSP-1 expression in culture was higher in adipocytes from obese animals at 24 h, but when the adipocytes were treated with HG, these expression levels dropped dramatically. Later at 72 h, TSP-1 expression was lower in adipocytes from HFD rats, and no effects of the other treatments were observed. Surprisingly, the secretion levels of this protein at 72 h were increased significantly by the HG treatment in both types of adipocytes, although they were even higher in adipocytes from obese animals. Finally, cell viability was significantly reduced by HG treatment in both types of adipocytes. In summary, TSP-1 expression/secretion was modulated in an in vitro model of insulin-resistant adipocytes. The difference between expression and secretion patterns suggests a posttranscriptional regulation. The present study confirms that TPS-1 is closely associated with obesity-related mechanisms.

  5. Downregulation of lncRNA TUG1 Affects Apoptosis and Insulin Secretion in Mouse Pancreatic β Cells

    Directory of Open Access Journals (Sweden)

    Dan-dan Yin

    2015-03-01

    Full Text Available Background: Increasing evidence indicates that long noncoding RNAs (IncRNAs perform specific biological functions in diverse processes. Recent studies have reported that IncRNAs may be involved in β cell function. The aim of this study was to characterize the role of IncRNA TUG1 in mouse pancreatic β cell functioning both in vitro and in vivo. Methods: qRT-PCR analyses were performed to detect the expression of lncRNA TUG1 in different tissues. RNAi, MTT, TUNEL and Annexin V-FITC assays and western blot, GSIS, ELISA and immunochemistry analyses were performed to detect the effect of lncRNA TUG1 on cell apoptosis and insulin secretion in vitro and in vivo. Results: lncRNA TUG1 was highly expressed in pancreatic tissue compared with other organ tissues, and expression was dynamically regulated by glucose in Nit-1 cells. Knockdown of lncRNA TUG1 expression resulted in an increased apoptosis ratio and decreased insulin secretion in β cells both in vitro and in vivo . Immunochemistry analyses suggested decreased relative islet area after treatment with lncRNA TUG1 siRNA. Conclusion: Downregulation of lncRNA TUG1 expression affected apoptosis and insulin secretion in pancreatic β cells in vitro and in vivo. lncRNA TUG1 may represent a factor that regulates the function of pancreatic β cells.

  6. Downregulation of lncRNA TUG1 affects apoptosis and insulin secretion in mouse pancreatic β cells.

    Science.gov (United States)

    Yin, Dan-dan; Zhang, Er-bao; You, Liang-hui; Wang, Ning; Wang, Lin-tao; Jin, Fei-yan; Zhu, Ya-nan; Cao, Li-hua; Yuan, Qing-xin; De, Wei; Tang, Wei

    2015-01-01

    Increasing evidence indicates that long noncoding RNAs (IncRNAs) perform specific biological functions in diverse processes. Recent studies have reported that IncRNAs may be involved in β cell function. The aim of this study was to characterize the role of IncRNA TUG1 in mouse pancreatic β cell functioning both in vitro and in vivo. qRT-PCR analyses were performed to detect the expression of lncRNA TUG1 in different tissues. RNAi, MTT, TUNEL and Annexin V-FITC assays and western blot, GSIS, ELISA and immunochemistry analyses were performed to detect the effect of lncRNA TUG1 on cell apoptosis and insulin secretion in vitro and in vivo. lncRNA TUG1 was highly expressed in pancreatic tissue compared with other organ tissues, and expression was dynamically regulated by glucose in Nit-1 cells. Knockdown of lncRNA TUG1 expression resulted in an increased apoptosis ratio and decreased insulin secretion in β cells both in vitro and in vivo . Immunochemistry analyses suggested decreased relative islet area after treatment with lncRNA TUG1 siRNA. Downregulation of lncRNA TUG1 expression affected apoptosis and insulin secretion in pancreatic β cells in vitro and in vivo. lncRNA TUG1 may represent a factor that regulates the function of pancreatic β cells. © 2015 S. Karger AG, Basel.

  7. Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: Protection by casein kinase 2 inhibitor

    Directory of Open Access Journals (Sweden)

    Nicolai M. Doliba

    2017-10-01

    Conclusions: These results show that chronic FA treatment decreases acetylcholine potentiation of insulin secretion and that this effect is strictly glucose dependent and might involve CK2 phosphorylation of β-cell M3 muscarinic receptors.

  8. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

    Energy Technology Data Exchange (ETDEWEB)

    Sekiya, Motohiro [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yahagi, Naoya, E-mail: nyahagi-tky@umin.ac.jp [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Tamura, Yoshiaki; Okazaki, Hiroaki; Igarashi, Masaki; Ohta, Keisuke; Takanashi, Mikio; Kumagai, Masayoshi; Takase, Satoru; Nishi, Makiko; Takeuchi, Yoshinori; Izumida, Yoshihiko; Kubota, Midori; Ohashi, Ken; Iizuka, Yoko [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yagyu, Hiroaki [Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498 (Japan); Gotoda, Takanari [Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Nagai, Ryozo [Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Shimano, Hitoshi; Yamada, Nobuhiro [Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaragi 305-8575 (Japan); and others

    2009-09-25

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  9. Suppression of the Nuclear Factor Eny2 Increases Insulin Secretion in Poorly Functioning INS-1E Insulinoma Cells

    Directory of Open Access Journals (Sweden)

    P. Dames

    2012-01-01

    Full Text Available Eny2, the mammalian ortholog of yeast Sus1 and drosophila E(y2, is a nuclear factor that participates in several steps of gene transcription and in mRNA export. We had previously found that Eny2 expression changes in mouse pancreatic islets during the metabolic adaptation to pregnancy. We therefore hypothesized that the protein contributes to the regulation of islet endocrine cell function and tested this hypothesis in rat INS-1E insulinoma cells. Overexpression of Eny2 had no effect but siRNA-mediated knockdown of Eny2 resulted in markedly increased glucose and exendin-4-induced insulin secretion from otherwise poorly glucose-responsive INS-1E cells. Insulin content, cellular viability, and the expression levels of several key components of glucose sensing remained unchanged; however glucose-dependent cellular metabolism was higher after Eny2 knockdown. Suppression of Eny2 enhanced the intracellular incretin signal downstream of cAMP. The use of specific cAMP analogues and pathway inhibitors primarily implicated the PKA and to a lesser extent the EPAC pathway. In summary, we identified a potential link between the nuclear protein Eny2 and insulin secretion. Suppression of Eny2 resulted in increased glucose and incretin-induced insulin release from a poorly glucose-responsive INS-1E subline. Whether these findings extend to other experimental conditions or to in vivo physiology needs to be determined in further studies.

  10. Exogenous glucose administration impairs glucose tolerance and pancreatic insulin secretion during acute sepsis in non-diabetic mice.

    Directory of Open Access Journals (Sweden)

    Yoshio Watanabe

    Full Text Available OBJECTIVES: The development of hyperglycemia and the use of early parenteral feeding are associated with poor outcomes in critically ill patients. We therefore examined the impact of exogenous glucose administration on the integrated metabolic function of endotoxemic mice using our recently developed frequently sampled intravenous glucose tolerance test (FSIVGTT. We next extended our findings using a cecal ligation and puncture (CLP sepsis model administered early parenteral glucose support. METHODS: Male C57BL/6J mice, 8-12 weeks, were instrumented with chronic indwelling arterial and venous catheters. Endotoxemia was initiated with intra-arterial lipopolysaccharide (LPS; 1 mg/kg in the presence of saline or glucose infusion (100 µL/hr, and an FSIVGTT was performed after five hours. In a second experiment, catheterized mice underwent CLP and the impact of early parenteral glucose administration on glucose homeostasis and mortality was assessed over 24 hrs. MEASUREMENTS: AND MAIN RESULTS: Administration of LPS alone did not impair metabolic function, whereas glucose administration alone induced an insulin sensitive state. In contrast, LPS and glucose combined caused marked glucose intolerance and insulin resistance and significantly impaired pancreatic insulin secretion. Similarly, CLP mice receiving parenteral glucose developed fulminant hyperglycemia within 18 hrs (all > 600 mg/dl associated with increased systemic cytokine release and 40% mortality, whereas CLP alone (85 ± 2 mg/dL or sham mice receiving parenteral glucose (113 ± 3 mg/dL all survived and were not hyperglycemic. Despite profound hyperglycemia, plasma insulin in the CLP glucose-infused mice (3.7 ± 1.2 ng/ml was not higher than sham glucose infused mice (2.1 ± 0.3 ng/ml. CONCLUSIONS: The combination of parenteral glucose support and the systemic inflammatory response in the acute phase of sepsis induces profound insulin resistance and impairs compensatory pancreatic insulin

  11. Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice.

    Science.gov (United States)

    Liu, Lijie; Wang, Fanfan; Lu, Haiying; Ren, Xiaomei; Zou, Jihong

    2014-01-01

    Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic β-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive β-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.

  12. Human pituitary and placental hormones control human insulin-like growth factor II secretion in human granulosa cells

    International Nuclear Information System (INIS)

    Ramasharma, K.; Li, C.H.

    1987-01-01

    Human granulosa cells cultured with calf serum actively proliferated for 18-20 generations and secreted progesterone into the medium; progesterone levels appeared to decline with increase in generation number. Cells cultured under serum-free conditions secreted significant amounts of progesterone and insulin-like growth factor II (IGF-II). The progesterone secretion was enhanced by the addition of human follitropin, lutropin, and chorionic gonadotropin but not by growth hormone. These cells, when challenged to varying concentrations of human growth hormone, human chorionic somatomammotropin, human prolactin, chorionic gonadotropin, follitropin, and lutropin, secreted IGF-II into the medium as measured by specific IGF-II RIA. Among these human hormones, chorionic gonadotropin, follitropin, and lutropin were most effective in inducing IGF-II secretion from these cells. When synthetic lutropin-releasing hormone and α-inhibin-92 were tested, only lutropin-releasing hormone was effective in releasing IGF-II. The results described suggest that cultured human granulosa cells can proliferate and actively secrete progesterone and IGF-II into the medium. IGF-II production in human granulosa cells was influenced by a multi-hormonal complex including human growth hormone, human chorionic somatomammotropin, and prolactin

  13. Regulation of adiponectin secretion by insulin and amino acids in 3T3-L1 adipocytes

    NARCIS (Netherlands)

    Blümer, Regje M. E.; van Roomen, Cindy P.; Meijer, Alfred J.; Houben-Weerts, Judith H. P. M.; Sauerwein, Hans P.; Dubbelhuis, Peter F.

    2008-01-01

    Adiponectin is a fat cell-derived hormone with insulin-sensitizing properties. Low plasma adiponectin levels are associated with insulin resistance as found in obesity. One of the mechanisms for this finding is hampered insulin signaling via phosphatidylinositol 3-kinase (PI3K) with concomitant

  14. Quantification of beta-cell function during IVGTT in Type II and non-diabetic subjects: assessment of insulin secretion by mathematical methods

    DEFF Research Database (Denmark)

    Kjems, L L; Vølund, A; Madsbad, Sten

    2001-01-01

    AIMS/HYPOTHESIS: We compared four methods to assess their accuracy in measuring insulin secretion during an intravenous glucose tolerance test in patients with Type II (non-insulin-dependent) diabetes mellitus and with varying beta-cell function and matched control subjects. METHODS: Eight control...

  15. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study

    DEFF Research Database (Denmark)

    Tabák, A.G.; Jokela, M.; Akbaraly, T.N.

    2009-01-01

    assessed retrospective trajectories of fasting and 2-h postload glucose, homoeostasis model assessment (HOMA) insulin sensitivity, and HOMA beta-cell function from up to 13 years before diabetes diagnosis (diabetic group) or at the end of follow-up (non-diabetics). FINDINGS: Multilevel models adjusted...... by a steep quadratic increase (from 5.79 mmol/L to 7.40 mmol/L) starting 3 years before diagnosis of diabetes. 2-h postload glucose showed a rapid increase starting 3 years before diagnosis (from 7.60 mmol/L to 11.90 mmol/L), and HOMA insulin sensitivity decreased steeply during the 5 years before diagnosis...... (to 86.7%). HOMA beta-cell function increased between years 4 and 3 before diagnosis (from 85.0% to 92.6%) and then decreased until diagnosis (to 62.4%). INTERPRETATION: In this study, we show changes in glucose concentrations, insulin sensitivity, and insulin secretion as much as 3-6 years before...

  16. Baseline IGF-I Levels Determine Insulin Secretion and Insulin Sensitivity during the First Year on Growth Hormone Therapy in Children Born Small for Gestational Age. Results from a North European Multicentre Study (NESGAS)

    DEFF Research Database (Denmark)

    Jensen, Rikke Beck; Thankamony, Ajay; O'Connell, Susan M

    2013-01-01

    Objective: Developmental programming alters growth and metabolic outcome in children born small for gestational age (SGA). We explored insulin and glucose metabolism in SGA children treated with a fixed GH dose over 1 year. Methods: In the North European Small for Gestational Age Study (NESGAS......), 110 short SGA children received GH at 67 µg/kg/day for 1 year. Insulin secretion was assessed by acute insulin response (AIR), insulin sensitivity (IS) by HOMA and disposition index (DI) by insulin secretion adjusted for IS. Results: First-year GH therapy led to increases in height and IGF-I standard...... deviation score (SDS), and reductions in IS (p insulin sensitive at baseline (p = 0.024) and 1 year (p = 0.006). IGF-I responses...

  17. High Glucose Predisposes Gene Expression and ERK Phosphorylation to Apoptosis and Impaired Glucose-Stimulated Insulin Secretion via the Cytoskeleton

    Science.gov (United States)

    Yeo, Ronne Wee Yeh; Yang, Kaiyuan; Li, GuoDong; Lim, Sai Kiang

    2012-01-01

    Chronic high glucose (HG) inflicts glucotoxicity on vulnerable cell types such as pancreatic β cells and contributes to insulin resistance and impaired insulin secretion in diabetic patients. To identify HG-induced cellular aberrations that are candidate mediators of glucotoxicity in pancreatic β cells, we analyzed gene expression in ERoSHK6, a mouse insulin-secreting cell line after chronic HG exposure (six-day exposure to 33.3 mM glucose). Chronic HG exposure which reduced glucose-stimulated insulin secretion (GSIS) increased transcript levels of 185 genes that clustered primarily in 5 processes namely cellular growth and proliferation; cell death; cellular assembly and organization; cell morphology; and cell-to-cell signaling and interaction. The former two were validated by increased apoptosis of ERoSHK6 cells after chronic HG exposure and reaffirmed the vulnerability of β cells to glucotoxicity. The three remaining processes were partially substantiated by changes in cellular morphology and structure, and instigated an investigation of the cytoskeleton and cell-cell adhesion. These studies revealed a depolymerized actin cytoskeleton that lacked actin stress fibers anchored at vinculin-containing focal adhesion sites as well as loss of E-cadherin-mediated cell-cell adherence after exposure to chronic HG, and were concomitant with constitutive ERK1/2 phosphorylation that was refractory to serum and glucose deprivation. Although inhibition of ERK phosphorylation by PD98059 promoted actin polymerization, it increased apoptosis and GSIS impairment. These findings suggest that ERK phosphorylation is a proximate regulator of cellular processes targeted by chronic HG-induced gene expression and that dynamic actin polymerization and depolymerization is important in β cell survival and function. Therefore, chronic HG alters gene expression and signal transduction to predispose the cytoskeleton towards apoptosis and GSIS impairment. PMID:23024780

  18. Adverse effects on insulin secretion of replacing saturated fat with refined carbohydrate but not with monounsaturated fat: A randomized controlled trial in centrally obese subjects.

    Science.gov (United States)

    Chang, Lin F; Vethakkan, Shireene R; Nesaretnam, Kalanithi; Sanders, Thomas A B; Teng, Kim-Tiu

    Current dietary guidelines recommend the replacement of saturated fatty acids (SAFAs) with carbohydrates or monounsaturated fatty acids (MUFAs) based on evidence on lipid profile alone, the chronic effects of the mentioned replacements on insulin secretion and insulin sensitivity are however unclear. To assess the chronic effects of the substitution of refined carbohydrate or MUFA for SAFA on insulin secretion and insulin sensitivity in centrally obese subjects. Using a crossover design, randomized controlled trial in abdominally overweight men and women, we compared the effects of substitution of 7% energy as carbohydrate or MUFA for SAFA for a period of 6 weeks each. Fasting and postprandial blood samples in response to corresponding SAFA, carbohydrate, or MUFA-enriched meal-challenges were collected after 6 weeks on each diet treatment for the assessment of outcomes. As expected, postprandial nonesterified fatty acid suppression and elevation of C-peptide, insulin and glucose secretion were the greatest with high-carbohydrate (CARB) meal. Interestingly, CARB meal attenuated postprandial insulin secretion corrected for glucose response; however, the insulin sensitivity and disposition index were not affected. SAFA and MUFA had similar effects on all markers except for fasting glucose-dependent insulinotropic peptide concentrations, which increased after MUFA but not SAFA when compared with CARB. In conclusion, a 6-week lower-fat/higher-carbohydrate (increased by 7% refined carbohydrate) diet may have greater adverse effect on insulin secretion corrected for glucose compared with isocaloric higher-fat diets. In contrast, exchanging MUFA for SAFA at 7% energy had no appreciable adverse impact on insulin secretion. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  19. Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion

    DEFF Research Database (Denmark)

    Hagemann, Dirk; Holst, Jens Juul; Gethmann, Arnica

    2007-01-01

    INTRODUCTION: Ghrelin is an orexigenic peptide predominantly secreted by the stomach. Ghrelin plasma levels rise before meal ingestion and sharply decline afterwards, but the mechanisms controlling ghrelin secretion are largely unknown. Since meal ingestion also elicits the secretion of the incre...... postprandial period at supraphysiological plasma levels. Most likely, these effects are indirectly mediated through its insulinotropic action. The GLP-1-induced suppression of ghrelin secretion might be involved in its anorexic effects....

  20. An extract from date seeds stimulates endogenous insulin secretion in streptozotocin-induced type I diabetic rats

    Directory of Open Access Journals (Sweden)

    Ahmed F. El Fouhil

    2013-11-01

    Full Text Available Background: The efficacy of an extract from date seeds has been tested successfully on the glycemic control of type I diabetes mellitus in rats. A suggestion that date seed extract could stimulate certain cells to differentiate into insulin-secreting cells has been proposed. In order to investigate such a possibility, this study was conducted to measure C-peptide levels in the serum of type 1 diabetic rats treated with date seed extract. Methods: Two hundred rats were divided into 4 groups. Group I served as the control. Group II was given daily ingestions of 10 ml of date seed extract. Groups III and IV were made diabetic by streptozotocin injection and were given daily subcutaneous injections of 3 IU/day of insulin for 8 weeks. Group IV received, in addition, daily ingestions of 10 ml of seed extract. At the end of experiment, blood samples were collected from each rat, and blood glucose and serum Cpeptide levels were measured. Results: No significant differences in the means of blood glucose and serum C-peptide levels were observed between groups I (control group and II (date seed extract-treated control group. Group IV (date seed extract-insulin-treated diabetic group showed a statistically significant reduction in the mean blood glucose level compared to Group III (insulin-treated diabetic group. The mean serum C-peptide level was significantly higher in group IV compared to group III. Conclusion: Biochemical results suggested an increase in endogenous insulin secretion in the case of type 1 diabetic rats treated with date seed extract, which might be the cause of its hypoglycemic effect.

  1. Chronic effects of neuroendocrine regulatory peptide (NERP-1 and -2) on insulin secretion and gene expression in pancreatic β-cells.

    Science.gov (United States)

    Kim, Ji-Won; Rhee, Marie; Park, Jae-Hyung; Yamaguchi, Hideki; Sasaki, Kazuki; Minamino, Naoto; Nakazato, Masamitsu; Song, Dae-Kyu; Yoon, Kun-Ho

    2015-02-06

    Neuroendocrine regulatory peptides (NERP-1 and -2) are novel amidated peptides derived from VGF, a polypeptide secreted from neurons and endocrine cells through a regulated pathway. Dr. Nakazato Masamitsu reported that NERP-1 and -2 may have a local modulator function on the human endocrine system, and clearly showed expression of NERP-1 and -2 in human pancreas islets. Based on these data, we investigated the alteration of insulin secretion, insulin granule-related protein, and pancreas-specific transcription factors in response to NERPs expression. We confirmed the expression of NERP-1 and -2 in the pancreas of a human diabetes patient, in addition to diabetic animal models. When INS1 cells and primary rat islets were incubated with 10nM NERPs for 3 days, glucose-stimulated insulin secretion levels were blunted by NERP-1 and -2. The number of insulin granules released from the readily releasable pool, which is associated with the first phase of glucose-stimulated insulin release, was decreased by NERP-1 and -2. Insulin granule-related proteins and mRNAs were down-regulated by NERP-2 treatment. NERP-2 decreased the expression of BETA2/NeuroD and insulin and controlled the nucleo-cytoplasmic translocation of FOXO1 and Pdx-1. We observed that NERP-2 levels were dramatically increased in diabetic pancreas. In conclusion, NERP-2 may play an important role in insulin secretion through the regulation of insulin secretory granules and β-cell transcription factors. In addition, NERP-2 expression is increased in diabetic conditions. Therefore, we suggest that NERPs may be potent endogenous suppressors of glucose-dependent insulin secretion. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. The inhibitor of connexin Cx36 channels, mefloquine, inhibits voltage-dependent Ca2+channels and insulin secretion.

    Science.gov (United States)

    Seemann, Nele; Welling, Andrea; Rustenbeck, Ingo

    2017-12-05

    The antimalarial agent, mefloquine, inhibits the function of connexin Cx36 gap junctions and hemichannels and has thus become a tool to investigate their physiological relevance in pancreatic islets. In view of earlier reports on a K ATP channel-block by mefloquine, the specificity of mefloquine as a pharmacological tool was investigated. Mouse pancreatic islets and single beta cells were used to measure membrane potential, whole cell currents, Ca 2+ channel activity, cytosolic Ca 2+ concentration ([Ca 2+ ] i ) and insulin secretion. Mefloquine was tested in the concentration range of 5-50 μM 25 μM mefloquine was as effective as 500 μM tolbutamide to depolarize the plasma membrane of beta cells, but did not induce action potentials. Rather, it abolished tolbutamide-induced action potentials and the associated increase of [Ca 2+ ] i . In the range of 5-50 μM mefloquine inhibited voltage-dependent Ca 2+ currents in primary beta cells as effectively as 1 μM nisoldipine, a specific blocker of L-type Ca 2+ channels. The Ca 2+ channel opening effect of Bay K8644 was completely antagonized by mefloquine. Likewise, the increase of [Ca 2+ ] i and of insulin secretion stimulated by 40 mM KCl, but not that by 30 mM glucose was antagonized by 50 μM mefloquine. Neither at 5 μM nor at 50 μM did mefloquin stimulate insulin secretion at basal glucose. In conclusion, mefloquine blocks K ATP channels and L-type Ca 2+ channels in pancreatic beta cells in the range from 5 to 50 μM. Thus it inhibits depolarization-induced insulin secretion, but in the presence of a stimulatory glucose concentration additional effects of mefloquine, possibly on intracellular Ca 2+ mobilization, and the metabolic amplification by glucose permit a sustained rate of secretion. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Fuel-Stimulated Insulin Secretion Depends upon Mitochondria Activation and the Integration of Mitochondrial and Cytosolic Substrate Cycles

    Directory of Open Access Journals (Sweden)

    Gary W. Cline

    2011-10-01

    Full Text Available The pancreatic islet β-cell is uniquely specialized to couple its metabolism and rates of insulin secretion with the levels of circulating nutrient fuels, with the mitochondrial playing a central regulatory role in this process. In the β-cell, mitochondrial activation generates an integrated signal reflecting rates of oxidativephosphorylation, Kreb's cycle flux, and anaplerosis that ultimately determines the rate of insulin exocytosis. Mitochondrial activation can be regulated by proton leak and mediated by UCP2, and by alkalinization to utilize the pH gradient to drive substrate and ion transport. Converging lines of evidence support the hypothesis that substrate cycles driven by rates of Kreb's cycle flux and by anaplerosis play an integral role in coupling responsive changes in mitochondrial metabolism with insulin secretion. The components and mechanisms that account for the integrated signal of ATP production, substrate cycling, the regulation of cellular redox state, and the production of other secondary signaling intermediates are operative in both rodent and human islet β-cells.

  4. Impact of Moderate Alcohol Discontinuation on Insulin Action and Secretion in Latinos With and Without Hepatitis C.

    Science.gov (United States)

    Uribe, Lindsay A; Bacchetti, Peter; Gelman, Nicholas; Burchard, Esteban; Fitch, Mark; Hellerstein, Marc; Khalili, Mandana

    2018-03-01

    Insulin resistance (IR) is associated with hepatitis C virus (HCV), and Latinos are both at risk of IR and are disproportionately affected by HCV. Moderate alcohol consumption improves insulin sensitivity and may modify HCV-associated IR. We investigated the impact of moderate alcohol discontinuation on insulin sensitivity and secretion in Latinos using direct measurements. Twenty-five nondiabetic, noncirrhotic Latino adults without (n = 17) or with (n = 8) HCV underwent 3-day metabolic assessment before and after prescription of 6 weeks of moderate alcohol discontinuation. Peripheral IR was measured via steady-state plasma glucose (SSPG) and hepatic IR using endogenous glucose production during a 2-step 240-minute insulin suppression test. Insulin secretion was measured using graded glucose infusion test. Baseline mean age was 46 ± 11 years, 63% male, 29% had HCV, and mean body mass index was 27 ± 4 kg/m 2 . Compared to non-HCV, HCV patients had a higher median SSPG (132 vs. 98.8 mg/dl, p = 1.0), hepatic IR (13.5 vs. 11.3, p = 0.24), and insulin secretion rate (ISR-AUC, 1,290 vs. 1,250 pmol/min, p = 0.98). After confirmed alcohol discontinuation, hepatic IR was the only parameter that changed significantly (increased, mean change 2.6 ± 4.8, p = 0.02). Higher baseline alanine aminotransferase (ALT) was also associated with a greater change in hepatic IR (average 4.0 points/ALT doubling, p = 0.004), and HCV was associated with a lesser change (average -7.3 points, p = 0.002), independent of ALT. Short-term moderate alcohol discontinuation adversely impacted hepatic IR in Latinos which was influenced by level of ALT at baseline independent of etiology. Although reduction in ALT through weight loss and HCV eradication remains a priority in improving IR, the observed nonharmful effect of moderate alcohol use represents a potentially confounding variable that warrants further study. Copyright © 2017 by the Research Society on Alcoholism.

  5. The amino acid transporters of the glutamate/GABA-glutamine cycle and their impact on insulin and glucagon secretion

    Directory of Open Access Journals (Sweden)

    Monica eJenstad

    2013-12-01

    Full Text Available Intercellular communication is pivotal in optimising and synchronising cellular responses to keep internal homeostasis and to respond adequately to external stimuli. In the central nervous system (CNS, glutamatergic and GABAergic signals are postulated to be dependent on the glutamate/GABA-glutamine (GGG cycle for vesicular loading of neurotransmitters, for inactivating the signal and for the replenishment of the neurotransmitters. Islets of Langerhans release the hormones insulin and glucagon, but share similarities with CNS cells in for example transcriptional control of development and differentiation, and chromatin methylation. Interestingly, proteins involved in the CNS in secretion of the neurotransmitters and emitting their responses as well as the regulation of these processes, are also found in islet cells. Moreover, high levels of glutamate, GABA and glutamine and their respective vesicular and plasma membrane transporters have been shown in the islet cells and there is emerging support for these amino acids and their transporters playing important roles in the maturation and secretion of insulin and glucagon. In this review, we will discuss the feasibility of recent data in the field in relation to the biophysical properties of the transporters (Slc1, Slc17, Slc32 and Slc38 and physiology of hormone secretion in islets of Langerhans.

  6. Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance.

    Directory of Open Access Journals (Sweden)

    Serenella Salinari

    Full Text Available Two recent studies demonstrated that bariatric surgery induced remission of type 2 diabetes very soon after surgery and far too early to be attributed to weight loss. In this study, we sought to explore the mechanism/s of this phenomenon by testing the effects of proteins from the duodenum-jejunum conditioned-medium (CM of db/db or Swiss mice on glucose uptake in vivo in Swiss mice and in vitro in both Swiss mice soleus and L6 cells. We studied the effect of sera and CM proteins from insulin resistant (IR and insulin-sensitive subjects on insulin signaling in human myoblasts.db/db proteins induced massive IR either in vivo or in vitro, while Swiss proteins did not. In L6 cells, only db/db proteins produced a noticeable increase in basal (473Ser-Akt phosphorylation, lack of GSK3β inhibition and a reduced basal (389Thr-p70-S6K1 phosphorylation. Human IR serum markedly increased basal (473Ser-Akt phosphorylation in a dose-dependent manner. Human CM IR proteins increased by about twofold both basal and insulin-stimulated (473Ser-Akt. Basal (9Ser-GSK3β phosphorylation was increased by IR subjects serum with a smaller potentiating effect of insulin.These findings show that jejunal proteins either from db/db mice or from insulin resistant subjects impair muscle insulin signaling, thus inducing insulin resistance.

  7. Phenolic Compounds from Fermented Berry Beverages Modulated Gene and Protein Expression To Increase Insulin Secretion from Pancreatic β-Cells in Vitro.

    Science.gov (United States)

    Johnson, Michelle H; de Mejia, Elvira Gonzalez

    2016-03-30

    Berries are a rich source of bioactive phenolic compounds that are able to bind and inhibit the enzyme dipeptidyl peptidase-IV (DPP-IV), a current target for type-2 diabetes therapy. The objectives were to determine the role of berry phenolic compounds to modulate incretin-cleaving DPP-IV and its substrate glucagon-like peptide-1 (GLP-1), insulin secretion from pancreatic β-cells, and genes and proteins involved in the insulin secretion pathway using cell culture. Anthocyanins (ANC) from 50% blueberry-50% blackberry (Blu-Bla) and 100% blackberry (Bla) fermented beverages at 50 μM cyanidin-3-glucoside equivalents increased (p together, anthocyanins, predominantly delphinidin-3-arabinoside, from fermented berry beverages have the potential to modulate DPP-IV and its substrate GLP-1, to increase insulin secretion, and to upregulate expression of mRNA of insulin-receptor associated genes and proteins in pancreatic β-cells.

  8. Insulin

    Science.gov (United States)

    ... Information by Audience For Women Women's Health Topics Insulin Share Tweet Linkedin Pin it More sharing options ... medicines. You can do it. Back to Top Insulin Safety Tips Never drink insulin. Do not share ...

  9. Increased secretion of insulin and proliferation of islet {beta}-cells in rats with mesenteric lymph duct ligation

    Energy Technology Data Exchange (ETDEWEB)

    Nagino, Ko; Yokozawa, Junji; Sasaki, Yu; Matsuda, Akiko; Takeda, Hiroaki [Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585 (Japan); Kawata, Sumio, E-mail: Sumio_Kawata@pref.hyogo.lg.jp [Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585 (Japan); Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanji-cho, Nishinomiya 662-0918 (Japan)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Insulin secretion was increased during the OGTT or IVGTT in mesenteric lymph duct-ligated rats. Black-Right-Pointing-Pointer Proliferation of islet {beta}-cells was upregulated in lymph duct-ligated rats. Black-Right-Pointing-Pointer Mesenteric lymph duct flow has a role in glucose metabolism. -- Abstract: Background and aims: It has been suggested that intestinal lymph flow plays an important role in insulin secretion and glucose metabolism after meals. In this study, we investigated the influence of ligation of the mesenteric lymph duct on glucose metabolism and islet {beta}-cells in rats. Methods: Male Sprague-Dawley rats (10 weeks old) were divided into two groups: one underwent ligation of the mesenteric lymph duct above the cistern (ligation group), and the other underwent a sham operation (sham group). After 1 and 2 weeks, fasting plasma concentrations of glucose, insulin, triglyceride, glucose-dependent insulinotropic polypeptide (GIP), and the active form of glucagon-like peptide-1 (GLP-1) were measured. At 2 weeks after the operation, the oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT) were performed. After the rats had been sacrificed, the insulin content of the pancreas was measured and the proliferation of {beta}-cells was assessed immunohistochemically using antibodies against insulin and Ki-67. Results: During the OGTT, the ligation group showed a significant decrease in the plasma glucose concentration at 120 min (p < 0.05) and a significant increase in the plasma insulin concentration by more than 2-fold at 15 min (p < 0.01). On the other hand, the plasma GIP concentration was significantly decreased at 60 min (p < 0.01) in the ligated group, while the active form of GLP-1 showed a significantly higher level at 90 min (1.7-fold; p < 0.05) and 120 min (2.5-fold; p < 0.01). During the IVGTT, the plasma insulin concentration in the ligation group was significantly higher at 2

  10. Mechanisms of estradiol-induced insulin secretion by the G protein-coupled estrogen receptor GPR30/GPER in pancreatic beta-cells.

    Science.gov (United States)

    Sharma, Geetanjali; Prossnitz, Eric R

    2011-08-01

    Sexual dimorphism and supplementation studies suggest an important role for estrogens in the amelioration of glucose intolerance and diabetes. Because little is known regarding the signaling mechanisms involved in estradiol-mediated insulin secretion, we investigated the role of the G protein-coupled receptor 30, now designated G protein-coupled estrogen receptor (GPER), in activating signal transduction cascades in β-cells, leading to secretion of insulin. GPER function in estradiol-induced signaling in the pancreatic β-cell line MIN6 was assessed using small interfering RNA and GPER-selective ligands (G-1 and G15) and in islets isolated from wild-type and GPER knockout mice. GPER is expressed in MIN6 cells, where estradiol and the GPER-selective agonist G-1 mediate calcium mobilization and activation of ERK and phosphatidylinositol 3-kinase. Both estradiol and G-1 induced insulin secretion under low- and high-glucose conditions, which was inhibited by pretreatment with GPER antagonist G15 as well as depletion of GPER by small interfering RNA. Insulin secretion in response to estradiol and G-1 was dependent on epidermal growth factor receptor and ERK activation and further modulated by phosphatidylinositol 3-kinase activity. In islets isolated from wild-type mice, the GPER antagonist G15 inhibited insulin secretion induced by estradiol and G-1, both of which failed to induce insulin secretion in islets obtained from GPER knockout mice. Our results indicate that GPER activation of the epidermal growth factor receptor and ERK in response to estradiol treatment plays a critical role in the secretion of insulin from β-cells. The results of this study suggest that the activation of downstream signaling pathways by the GPER-selective ligand G-1 could represent a novel therapeutic strategy in the treatment of diabetes.

  11. Mechanisms of Estradiol-Induced Insulin Secretion by the G Protein-Coupled Estrogen Receptor GPR30/GPER in Pancreatic β-Cells

    Science.gov (United States)

    Sharma, Geetanjali

    2011-01-01

    Sexual dimorphism and supplementation studies suggest an important role for estrogens in the amelioration of glucose intolerance and diabetes. Because little is known regarding the signaling mechanisms involved in estradiol-mediated insulin secretion, we investigated the role of the G protein-coupled receptor 30, now designated G protein-coupled estrogen receptor (GPER), in activating signal transduction cascades in β-cells, leading to secretion of insulin. GPER function in estradiol-induced signaling in the pancreatic β-cell line MIN6 was assessed using small interfering RNA and GPER-selective ligands (G-1 and G15) and in islets isolated from wild-type and GPER knockout mice. GPER is expressed in MIN6 cells, where estradiol and the GPER-selective agonist G-1 mediate calcium mobilization and activation of ERK and phosphatidylinositol 3-kinase. Both estradiol and G-1 induced insulin secretion under low- and high-glucose conditions, which was inhibited by pretreatment with GPER antagonist G15 as well as depletion of GPER by small interfering RNA. Insulin secretion in response to estradiol and G-1 was dependent on epidermal growth factor receptor and ERK activation and further modulated by phosphatidylinositol 3-kinase activity. In islets isolated from wild-type mice, the GPER antagonist G15 inhibited insulin secretion induced by estradiol and G-1, both of which failed to induce insulin secretion in islets obtained from GPER knockout mice. Our results indicate that GPER activation of the epidermal growth factor receptor and ERK in response to estradiol treatment plays a critical role in the secretion of insulin from β-cells. The results of this study suggest that the activation of downstream signaling pathways by the GPER-selective ligand G-1 could represent a novel therapeutic strategy in the treatment of diabetes. PMID:21673097

  12. Effect of physical training on insulin secretion and action in skeletal muscle and adipose tissue of first-degree relatives of type 2 diabetic patients

    DEFF Research Database (Denmark)

    Dela, Flemming; Stallknecht, Bente Merete

    2010-01-01

    in CON but not in FDR, whereas glucose-mediated GU increased (P groups. Adipose tissue GU was not affected by training, but it was higher (abdominal, P Training increased skeletal muscle lipolysis (P ...- to sevenfold. We conclude that insulin-secretory capacity is lower in FDR than in CON and that there is dissociation between training-induced changes in insulin secretion and insulin-mediated GU. Maximal GU rates are similar between groups and increases with physical training.......Physical training affects insulin secretion and action, but there is a paucity of data on the direct effects in skeletal muscle and adipose tissue and on the effect of training in first-degree relatives (FDR) of patients with type 2 diabetes. We studied insulin action at the whole body level...

  13. Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact

    DEFF Research Database (Denmark)

    Mulder, Hindrik; Sörhede-Winzell, Maria; Contreras, Juan Antonio

    2003-01-01

    of the HSL gene for glucose homeostasis were examined. HSL null mice were slightly hyperglycemic in the fasted, but not fed state, which was accompanied by moderate hyperinsulinemia. During glucose challenges, however, disposal of the sugar was not affected in HSL null mice, presumably because of release......-stimulated glucose uptake into soleus muscle, and lipogenesis in adipocytes were moderately reduced, suggesting additional sites of insulin resistance. Morphometric analysis of pancreatic islets revealed a doubling of beta-cell mass in HSL null mice, which is consistent with an adaptation to insulin resistance......Lipid metabolism plays an important role in glucose homeostasis under normal and pathological conditions. In adipocytes, skeletal muscle, and pancreatic beta-cells, lipids are mobilized from acylglycerides by the hormone-sensitive lipase (HSL). Here, the consequences of a targeted disruption...

  14. Effect of mufa enriched extra virgin olive oil on glycemic status and insulin secretion in diabetic rats

    International Nuclear Information System (INIS)

    Naveed, A.K.; Yousaf, M.J.; Khan, S.; Ahmed, T.; Azeem, Z.

    2013-01-01

    Objective: To evaluate the effect of monounsaturated fatty acid enriched extra virgin olive oil on glycemic status and insulin secretion in diabetic rats. Study Design: Randomized Control Trial. Place and Duration of Study: Department of Biochemistry, Army Medical College, Rawalpindi in collaboration with Centre for Research in Experimental and Applied Medicine, Army Medical College, Rawalpindi and National Institute of Health, Islamabad from March 2010 to June 2011. Material and Methods: Eighty albino rats of Sprague-dawley strain weighing 200-250 g were randomly divided into two groups of 40 rats each. Rats were made diabetic by injecting streptozotocin. Group 1 and Group II were given normal rodent diet and extra virgin olive oil supplemented diet respectively for 06 weeks. At the end of experimentation, fasting blood glucose, glycosylated hemoglobin and insulin were measured. Results: There was significant decrease of fasting blood glucose and glycosylated hemoglobin and significant increase of serum insulin of group II rats when it was compared with group I (control). Conclusion: Monounsaturated fatty acids enriched extra virgin olive oil can significantly improve glycemic status and serum insulin in diabetic rats. (author)

  15. Impact of 9 days of bed rest on hepatic and peripheral insulin action, insulin secretion, and whole-body lipolysis in healthy young male offspring of patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Alibegovic, Amra C; Højbjerre, Lise; Sonne, Mette P

    2009-01-01

    OBJECTIVE: The aim of this study was to investigate the impact of 9 days of bed rest on insulin secretion, insulin action, and whole-body glucose and fat metabolism in first-degree relative (FDR) and matched control (CON) subjects. RESEARCH DESIGN AND METHODS: A total of 13 FDR and 20 CON subjects...... deteriorates with 9 days of bed rest, converging toward similar degrees of whole-body insulin resistance. FDR subjects exhibit hepatic insulin resistance (HIR), which, in contrast to CON subjects, deteriorates in response to physical inactivity. FDR subjects exhibit reduced insulin secretion when seen...... participated in the study. All were studied before and after 9 days of bed rest using the clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. Glucose and glycerol turnover rates were studied using stable isotope kinetics. RESULTS: Bed rest caused a significant...

  16. Physical activity, sedentary behaviors, and estimated insulin sensitivity and secretion in pregnant and non-pregnant women

    Directory of Open Access Journals (Sweden)

    Wright Antony

    2011-06-01

    Full Text Available Abstract Background Overweight and obesity during pregnancy raise the risk of gestational diabetes and birth complications. Lifestyle factors like physical activity may decrease these risks through beneficial effects on glucose homeostasis. Here we examined physical activity patterns and their relationships with measures of glucose homeostasis in late pregnancy compared to non-pregnant women. Methods Normal weight and overweight women without diabetes (N = 108; aged 25-35 years were studied; 35 were pregnant (in gestational weeks 28-32 and 73 were non-pregnant. Insulin sensitivity and β-cell response were estimated from an oral glucose tolerance test. Physical activity was measured during 10-days of free-living using a combined heart rate sensor and accelerometer. Total (TEE, resting (REE, and physical activity (PAEE energy expenditure were measured using doubly-labeled water and expired gas indirect calorimetry. Results Total activity was associated with reduced first-phase insulin response in both pregnant (Regression r2 = 0.11; Spearman r = -0.47; p = 0.007 and non-pregnant women (Regression r2 = 0.11 Spearman; r = -0.36; p = 0.002. Relative to non-pregnant women, pregnant women were estimated to have secreted 67% more insulin and had 10% lower fasting glucose than non-pregnant women. Pregnant women spent 13% more time sedentary, 71% less time in moderate-to-vigorous intensity activity, had 44% lower objectively measured total activity, and 12% lower PAEE than non-pregnant women. Correlations did not differ significantly for any comparison between physical activity subcomponents and measures of insulin sensitivity or secretion. Conclusions Our findings suggest that physical activity conveys similar benefits on glucose homeostasis in pregnant and non-pregnant women, despite differences in subcomponents of physical activity.

  17. Effect of neonatal hypothyroidism on carbohydrate metabolism, insulin secretion, and pancreatic islets morphology of adult male offspring in rats.

    Science.gov (United States)

    Farahani, H; Ghasemi, A; Roghani, M; Zahediasl, S

    2013-01-01

    Neonatal hypothyroidism has serious effects on growth, development, and metabolism. This study aims to investigate the effects of the neonatal hypothyroidism on carbohydrate metabolism, islet insulin secretion and morphology of the pancreatic islets in adult male offspring. Lactating mothers of Wistar rats consumed 0.02% solution of 6-propyl-2-thiouracil during the weaning period (neonatal hypothyroid group), while mothers of the control group drank merely tap water. Body weight and survival of pups were followed up. Intravenous glucose tolerance test was performed in adult male offspring and 5-6 weeks later, glucose-stimulated insulin secretion (GSIS) was evaluated. During the glucose tolerance test, plasma glucose level of the neonatal hypothyroid group (13.18 ± 0.59 mmol/l) was significantly higher at 5 min compared to the control group (11.54 ± 0.47 mmol/l), whereas plasma insulin concentrations and GSIS of the groups was not significantly different. Homeostasis model assessment of insulin resistance of adult male offspring of the hypothyroid group (9.1 ± 1.0) was significantly higher as compared to the control group (4.5 ± 0.6). Area (14,613.0 ± 2646.3 μm2) and the diameter of the islets (147 ± 3.0 μm) of the neonatal hypothyroid group were significantly lower, as compared to the control group (32,886.3 ± 4690.3 and 206.6 ± 5.9 μm2 and μm, respectively). Neonatal hypothyroidism can alter carbohydrate metabolism in euthyroid adult offspring, which may increase susceptibility to the development of glucose intolerance and occurrence of Type 2 diabetes later in life.

  18. The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice

    DEFF Research Database (Denmark)

    Ørgaard, Anne; Holst, Jens J

    2017-01-01

    AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion...... effect of GLP-1 was preserved at hypoglycaemic levels, leaving unanswered the question of how this is avoided in vivo in individuals treated with GLP-1 receptor agonists........ The latter has been demonstrated to account for about half of their blood glucose-lowering activity. Whereas the effect of GLP-1 on insulin secretion is clearly dependent on ambient glucose concentrations and has been described in detail, the mechanism responsible for the inhibitory effect of GLP-1...

  19. Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents

    OpenAIRE

    Perry, Rachel J.; Cardone, Rebecca L.; Petersen, Max C.; Zhang, Dongyan; Fouqueray, Pascale; Hallakou-Bozec, Sophie; Bolze, Sébastien; Shulman, Gerald I.; Petersen, Kitt Falk; Kibbey, Richard G.

    2016-01-01

    Imeglimin is a promising new oral antihyperglycemic agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose and improve hemoglobin A1c (1–3, 9). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-wk of treatment in type 2 diabetic patients. However, whether the β-cell stimulatory effect of imeglimin is solely or par...

  20. Effect of taurine on the insuline secretion isolated by the pancreatic tissue of intact and irradiated rats

    International Nuclear Information System (INIS)

    Dokshina, G.A.; Silaeva, T.Yu.

    1976-01-01

    The whole-body irradiation of rats (700 rads) inhibits the secretory activity of insular pancreatic tissue. Administration of taurine (200 mg/kg), on the fifth day after irradiation, five times every second day normalizes the secretory function of pancreatic islands. In the experiments in vitro, taurine (1.5 and 3.0 mg/ml) stimulated hormone secretion. The stimulating action of the amino acid manifests itself when β-receptors are blocked by obsidane (0.5 μg/ml). It is suggested that insuline secretion by β-cells of pancreas is restored and enhanced by taurine not merely through the adenylatecyclase system; other ways are also possible

  1. Amaranthus caudatus Stimulates Insulin Secretion in Goto-Kakizaki Rats, a Model of Diabetes Mellitus Type 2

    Science.gov (United States)

    Zambrana, Silvia; Lundqvist, Lena C. E.; Veliz, Virginia; Catrina, Sergiu-Bogdan; Gonzales, Eduardo; Östenson, Claes-Göran

    2018-01-01

    Diabetes Mellitus Type 2 prevalence is increasing worldwide; thus efforts to develop novel therapeutic strategies are required. Amaranthus caudatus (AC) is a pseudo-cereal with reported anti-diabetic effects that is usually consumed in food preparations in Bolivia. This study evaluated the anti-diabetic nutraceutical property of an AC hydroethanolic extract that contains mainly sugars and traces of polyphenols and amino acids (as shown by nalysis with liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR)), in type 2 diabetic Goto-Kakizaki (GK) rats and healthy Wistar (W) rats. A single oral administration of AC extract (2000 mg/kg body weight) improved glucose tolerance during Oral Glucose Tolerance Tests (OGTT) in both GK rats and in W rats. Long-term treatment (21 days) with AC (1000 mg/kg b.w.) improved the glucose tolerance evaluated by the area under the curve (AUC) of glucose levels during the OGTT, in both GK and W rats. The HbA1c levels were reduced in both GK (19.83%) and W rats (10.7%). This effect was secondary to an increase in serum insulin levels in both GK and W rats and confirmed in pancreatic islets, isolated from treated animals, where the chronic AC exposure increased the insulin production 4.1-fold in GK and 3.7-fold in W rat islets. Furthermore, the effect of AC on in vitro glucose-dependent insulin secretion (16.7 mM glucose) was concentration-dependent up to 50 mg/mL, with 8.5-fold increase in GK and 5.7-fold in W rat islets, and the insulin secretion in perifused GK and W rat islets increased 31 and nine times, respectively. The mechanism of action of AC on insulin secretion was shown to involve calcium, PKA and PKC activation, and G-protein coupled-exocytosis since the AC effect was reduced 38% by nifedipine (L-type channel inhibitor), 77% by H89 (PKA inhibitor), 79% by Calphostine-C (PKC inhibitor) and 20% by pertussis toxin (G-protein suppressor). PMID:29342984

  2. Androgen receptor-deficient islet β-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse.

    Science.gov (United States)

    Xu, Weiwei; Niu, Tianhua; Xu, Beibei; Navarro, Guadalupe; Schipma, Matthew J; Mauvais-Jarvis, Franck

    2017-05-01

    Testosterone action is mediated via the androgen receptor (AR). We have reported that male mice lacking AR selectively in β-cells (βARKO -/y ) develop decreased glucose-stimulated insulin secretion (GSIS), producing glucose intolerance. We showed that testosterone action on AR in β-cells amplifies the insulinotropic action of GLP-1 on its receptor via a cAMP-dependent protein kinase-A pathway. To investigate AR-dependent gene networks in β-cells, we performed a high throughput whole transcriptome sequencing (RNA-Seq) in islets from male βARKO -/y and control mice. We identified 214 differentially expressed genes (DEGs) (158 up- and 56 down-regulated) with a false discovery rate (FDR) 2. Our analysis of individual transcripts revealed alterations in β-cell genes involved in cellular inflammation/stress and insulin secretion. Based on 312 DEGs with an FDR insulin signaling, MAPK signaling, type 2 diabetes (T2D) and pancreatic secretion. The gene ontology analysis confirmed the results of the individual DEGs and the pathway analysis in showing enriched biological processes encompassing inflammation, ion transport, exocytosis and insulin secretion. AR-deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion demonstrating the importance of androgen action in β-cell health in the male with implications for T2D development in men. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Insulin secretion and signaling in response to dietary restriction and subsequent re-alimentation in cattle.

    Science.gov (United States)

    Keogh, Kate; Kenny, David A; Kelly, Alan K; Waters, Sinéad M

    2015-08-01

    The objectives of this study were to examine systemic insulin response to a glucose tolerance test (GTT) and transcript abundance of genes of the insulin signaling pathway in skeletal muscle, during both dietary restriction and re-alimentation-induced compensatory growth. Holstein Friesian bulls were blocked to one of two groups: 1) restricted feed allowance for 125 days (period 1) (RES, n = 15) followed by ad libitum feeding for 55 days (period 2) or 2) ad libitum access to feed throughout (periods 1 and 2) (ADLIB, n = 15). On days 90 and 36 of periods 1 and 2, respectively, a GTT was performed. M. longissimus dorsi biopsies were harvested from all bulls on days 120 and 15 of periods 1 and 2, respectively, and RNA-Seq analysis was performed. RES displayed a lower growth rate during period 1 (RES: 0.6 kg/day, ADLIB: 1.9 kg/day; P alimentation (RES: 2.5 kg/day, ADLIB: 1.4 kg/day; P alimentation (P > 0.05). Genes differentially expressed in the insulin signaling pathway suggested a greater sensitivity to insulin in skeletal muscle, with pleiotropic effects of insulin signaling interrupted during dietary restriction. Collectively, these results indicate increased sensitivity to glucose clearance and skeletal muscle insulin signaling during dietary restriction; however, no overall role for insulin was apparent in expressing compensatory growth. Copyright © 2015 the American Physiological Society.

  4. Intracellular alkalinization by phosphate uptake via type III sodium-phosphate cotransporter participates in high-phosphate-induced mitochondrial oxidative stress and defective insulin secretion.

    Science.gov (United States)

    Nguyen, Tuyet Thi; Quan, Xianglan; Xu, Shanhua; Das, Ranjan; Cha, Seung-Kuy; Kong, In Deok; Shong, Minho; Wollheim, Claes B; Park, Kyu-Sang

    2016-12-01

    Elevated plasma levels of inorganic phosphate (P i ) are harmful, causing, among other complications, vascular calcification and defective insulin secretion. The underlying molecular mechanisms of these complications remain poorly understood. We demonstrated the role of P i transport across the plasmalemma on P i toxicity in INS-1E rat clonal β cells and rat pancreatic islet cells. Type III sodium-phosphate cotransporters (NaP i s) are the predominant P i transporters expressed in insulin-secreting cells. Transcript and protein levels of sodium-dependent phosphate transporter 1 and 2 (PiT-1 and -2), isotypes of type III NaP i , were up-regulated by high-P i incubation. In patch-clamp experiments, extracellular P i elicited a Na + -dependent, inwardly rectifying current, which was markedly reduced under acidic extracellular conditions. Cellular uptake of P i elicited cytosolic alkalinization; intriguingly, this pH change facilitated P i transport into the mitochondrial matrix. Increased mitochondrial P i uptake accelerated superoxide generation, mitochondrial permeability transition (mPT), and endoplasmic reticulum stress-mediated translational attenuation, leading to reduced insulin content and impaired glucose-stimulated insulin secretion. Silencing of PiT-1/2 prevented P i -induced superoxide generation and mPT, and restored insulin secretion. We propose that P i transport across the plasma membrane and consequent cytosolic alkalinization could be a therapeutic target for protection from P i toxicity in insulin-secreting cells, as well as in other cell types.-Nguyen, T. T., Quan, X., Xu, S., Das, R., Cha, S.-K., Kong, I. D., Shong, M., Wollheim, C. B., Park, K.-S. Intracellular alkalinization by phosphate uptake via type III sodium-phosphate cotransporter participates in high-phosphate-induced mitochondrial oxidative stress and defective insulin secretion. © FASEB.

  5. [Spontaneous changes in carbohydrate tolerance and insulin secretion in persons with indications of disturbed carbohydrate tolerance. Preliminary results and follow-up observations for 7 years].

    Science.gov (United States)

    Ratzmann, K P; Schulz, B; Witt, S; Heinke, P; Michaelis, D

    1980-03-15

    115 patients with normal weight and 15 adipose persons with suspicion of a disturbance of the carbohydrate metabolism were characterized by means of a glucose infusion test lasting two hours concerning the carbohydrate tolerance and insulin secretion. Longitudinal analyses of the spontaneous behaviour of the carbohydrate tolerance and insulin secretion depending on the degree of the carbohydrate tolerance up to duration of the observation of 7 years. A deterioration of the carbohydrate tolerance was to be proved in 21% of 87 persons with normal carbohydrate tolerance within two years. With normal carbohydrate tolerance within two years. With an increase of the duration of the observation up to 7 years the frequency of disturbances of the carbohydrate tolerance increases to 30%. This development cannot be coordinated to a certain type of insulin secretion. In the individual case a deterioration of the carbohydrate tolerance may be associated with an increase or reduction of the glucose stimulated insuline secretion. An improvement of the carbohydrate tolerance was observed in 15 (54%) of 28 patients with disturbed carbohydrate tolerance within 2 years. In a group with pathological carbohydrate tolerance this development was associated with a significant reduction of the basic and glucose stimulated insulin secretion. In all patients with improved carbohydrate tolerance on the side of the insulin secretion primarily the type of "normal response" was present. The lacking relation between changes of the B-cell function and the carbohydrate tolerance emphasizes the importance of other factors, such as a peripheral insulin resistance, for the development of disturbances in the carbohydrate metabolism.

  6. Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men

    DEFF Research Database (Denmark)

    Jensen, Christine B; Storgaard, Heidi; Holst, Jens J

    2003-01-01

    (HI), 40 mU/m(2) x min], 3-(3)H-glucose, indirect calorimetry, and iv glucose tolerance test. Free fatty acid concentrations were similar during basal steady state but 3.7- to 13-fold higher during clamps. P-glucagon increased and the insulin/glucagon ratio decreased at both LI and HI during...... not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes....

  7. Collagen and Stretch Modulate Autocrine Secretion of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Proteins from Differentiated Skeletal Muscle Cells

    Science.gov (United States)

    Perrone, Carmen E.; Fenwick-Smith, Daniela; Vandenburgh, Herman H.

    1995-01-01

    Stretch-induced skeletal muscle growth may involve increased autocrine secretion of insulin-like growth factor-1 (IGF-1) since IGF-1 is a potent growth factor for skeletal muscle hypertrophy, and stretch elevates IGF-1 mRNA levels in vivo. In tissue cultures of differentiated avian pectoralis skeletal muscle cells, nanomolar concentrations of exogenous IGF-1 stimulated growth in mechanically stretched but not static cultures. These cultures released up to 100 pg of endogenously produced IGF-1/micro-g of protein/day, as well as three major IGF binding proteins of 31, 36, and 43 kilodaltons (kDa). IGF-1 was secreted from both myofibers and fibroblasts coexisting in the muscle cultures. Repetitive stretch/relaxation of the differentiated skeletal muscle cells stimulated the acute release of IGF-1 during the first 4 h after initiating mechanical activity, but caused no increase in the long-term secretion over 24-72 h of IGF-1, or its binding proteins. Varying the intensity and frequency of stretch had no effect on the long-term efflux of IGF-1. In contrast to stretch, embedding the differentiated muscle cells in a three-dimensional collagen (Type I) matrix resulted in a 2-5-fold increase in long-term IGF-1 efflux over 24-72 h. Collagen also caused a 2-5-fold increase in the release of the IGF binding proteins. Thus, both the extracellular matrix protein type I collagen and stretch stimulate the autocrine secretion of IGF-1, but with different time kinetics. This endogenously produced growth factor may be important for the growth response of skeletal myofibers to both types of external stimuli.

  8. High heritability and genetic correlation of intravenous glucose- and tolbutamide-induced insulin secretion among non-diabetic family members of type 2 diabetic patients

    DEFF Research Database (Denmark)

    Gjesing, Anette Marianne Prior; Hornbak, Malene; Allin, Kristine H.

    2014-01-01

    -induced beta cell response. In addition, single nucleotide polymorphisms (SNPs) having an exclusive effect on either glucose- or tolbutamide-stimulated insulin release were identified. Methods: Two hundred and eighty-four non-diabetic family members of patients with type 2 diabetes underwent a t......-FSIGT with intravenous injection of glucose at t∈=∈0 min and tolbutamide at t∈=∈20 min. Measurements of plasma glucose, serum insulin and serum C-peptide were taken at 33 time points from fasting to 180 min. Insulin secretion rate, acute insulin response (AIR), disposition index (DI) after glucose and disposition index...... after tolbutamide (DIT), insulin sensitivity (SI), glucose effectiveness (SG) and beta cell responsiveness to glucose were calculated. A polygenic variance component model was used to estimate heritability, genetic correlations and associations. Results: We found high heritabilities for acute insulin...

  9. Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance

    DEFF Research Database (Denmark)

    Rask, E; Olsson, T; Söderberg, S

    2004-01-01

    +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P =.018) and lower OGIS (397 +/- 21 v 463 +/- 12 mL/min/m(2......); P =.005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 +/- 51 v 774 +/- 91 nmol/min/m(2), P =.001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P ...). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT (P =.036). We conclude that also in non-obese subjects...

  10. M19 modulates skeletal muscle differentiation and insulin secretion in pancreatic β-cells through modulation of respiratory chain activity.

    Directory of Open Access Journals (Sweden)

    Linda Cambier

    Full Text Available Mitochondrial dysfunction due to nuclear or mitochondrial DNA alterations contributes to multiple diseases such as metabolic myopathies, neurodegenerative disorders, diabetes and cancer. Nevertheless, to date, only half of the estimated 1,500 mitochondrial proteins has been identified, and the function of most of these proteins remains to be determined. Here, we characterize the function of M19, a novel mitochondrial nucleoid protein, in muscle and pancreatic β-cells. We have identified a 13-long amino acid sequence located at the N-terminus of M19 that targets the protein to mitochondria. Furthermore, using RNA interference and over-expression strategies, we demonstrate that M19 modulates mitochondrial oxygen consumption and ATP production, and could therefore regulate the respiratory chain activity. In an effort to determine whether M19 could play a role in the regulation of various cell activities, we show that this nucleoid protein, probably through its modulation of mitochondrial ATP production, acts on late muscle differentiation in myogenic C2C12 cells, and plays a permissive role on insulin secretion under basal glucose conditions in INS-1 pancreatic β-cells. Our results are therefore establishing a functional link between a mitochondrial nucleoid protein and the modulation of respiratory chain activities leading to the regulation of major cellular processes such as myogenesis and insulin secretion.

  11. Alkali pH directly activates ATP-sensitive K+ channels and inhibits insulin secretion in beta-cells.

    Science.gov (United States)

    Manning Fox, Jocelyn E; Karaman, Gunce; Wheeler, Michael B

    2006-11-17

    Glucose stimulation of pancreatic beta-cells is reported to lead to sustained alkalization, while extracellular application of weak bases is reported to inhibit electrical activity and decrease insulin secretion. We hypothesize that beta-cell K(ATP) channel activity is modulated by alkaline pH. Using the excised patch-clamp technique, we demonstrate a direct stimulatory action of alkali pH on recombinant SUR1/Kir6.2 channels due to increased open probability. Bath application of alkali pH similarly activates native islet beta-cell K(ATP) channels, leading to an inhibition of action potentials, and hyperpolarization of membrane potential. In situ pancreatic perfusion confirms that these cellular effects of alkali pH are observable at a functional level, resulting in decreases in both phase 1 and phase 2 glucose-stimulated insulin secretion. Our data are the first to report a stimulatory effect of a range of alkali pH on K(ATP) channel activity and link this to downstream effects on islet beta-cell function.

  12. Shared Genetic Control of Brain Activity During Sleep and Insulin Secretion: A Laboratory-Based Family Study.

    Science.gov (United States)

    Morselli, Lisa L; Gamazon, Eric R; Tasali, Esra; Cox, Nancy J; Van Cauter, Eve; Davis, Lea K

    2018-01-01

    Over the past 20 years, a large body of experimental and epidemiologic evidence has linked sleep duration and quality to glucose homeostasis, although the mechanistic pathways remain unclear. The aim of the current study was to determine whether genetic variation influencing both sleep and glucose regulation could underlie their functional relationship. We hypothesized that the genetic regulation of electroencephalographic (EEG) activity during non-rapid eye movement sleep, a highly heritable trait with fingerprint reproducibility, is correlated with the genetic control of metabolic traits including insulin sensitivity and β-cell function. We tested our hypotheses through univariate and bivariate heritability analyses in a three-generation pedigree with in-depth phenotyping of both sleep EEG and metabolic traits in 48 family members. Our analyses accounted for age, sex, adiposity, and the use of psychoactive medications. In univariate analyses, we found significant heritability for measures of fasting insulin sensitivity and β-cell function, for time spent in slow-wave sleep, and for EEG spectral power in the delta, theta, and sigma ranges. Bivariate heritability analyses provided the first evidence for a shared genetic control of brain activity during deep sleep and fasting insulin secretion rate. © 2017 by the American Diabetes Association.

  13. Effects of acarbose on proinsulin and insulin secretion and their potential significance for the intermediary metabolism and cardiovascular system.

    Science.gov (United States)

    Rosak, Christoph; Mertes, Gabriele

    2009-08-01

    The alpha-glucosidase inhibitor acarbose is administered to control blood glucose levels in type 2 diabetic patients and, in several countries, in those with impaired glucose tolerance. The efficacy and safety of the drug has been well established in these patient populations. Acarbose shows no weakening of efficacy in long-term diabetes treatment, reduces the development of type 2 diabetes in those with impaired glucose tolerance, and also appears to reduce the risk of cardiovascular disease. The underlying mechanisms of its effect on the risk of developing macrovascular complications have still to be elucidated. The mode of action of acarbose, which precedes all other metabolic processes involved in blood glucose regulation, inhibits high increases in postprandial blood glucose. Due to this early mode of action, acarbose also modifies insulin and proinsulin secretion which are both involved in ss-cell dysfunction and insulin resistance and may be independent risk factors for cardiovascular mortality. Based on the literature available the present state of knowledge on insulin and proinsulin as risk factors for cardiovascular mortality is reviewed as well as the effect of acarbose on the regulation of the ss-cells as monotherapy and in combination regimens. Possible associated interactions with the cardiovascular system are identified.

  14. Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass

    DEFF Research Database (Denmark)

    Martinussen, Christoffer; Bojsen-Moller, Kirstine N; Dirksen, Carsten

    2015-01-01

    effectiveness with Bergman's minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and β-cell function by HOMA-β. Moreover, mixed meal tests and OGTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response...... to iv glucose increased two-fold and HOMA-β improved already 1 week postoperatively, with further enhancements at 3 months. Insulin sensitivity increased in the liver (HOMA-S) at 1 week and at 3 months in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral...... first-phase insulin secretion to iv glucose and increased HOMA-β. A major role for improved glucose effectiveness after RYGB was not supported by this study....

  15. Glucose-Dependent Insulin Secretion in Pancreatic β-Cell Islets from Male Rats Requires Ca2+ Release via ROS-Stimulated Ryanodine Receptors.

    Directory of Open Access Journals (Sweden)

    Paola Llanos

    Full Text Available Glucose-stimulated insulin secretion (GSIS from pancreatic β-cells requires an increase in intracellular free Ca2+ concentration ([Ca2+]. Glucose uptake into β-cells promotes Ca2+ influx and reactive oxygen species (ROS generation. In other cell types, Ca2+ and ROS jointly induce Ca2+ release mediated by ryanodine receptor (RyR channels. Therefore, we explored here if RyR-mediated Ca2+ release contributes to GSIS in β-cell islets isolated from male rats. Stimulatory glucose increased islet insulin secretion, and promoted ROS generation in islets and dissociated β-cells. Conventional PCR assays and immunostaining confirmed that β-cells express RyR2, the cardiac RyR isoform. Extended incubation of β-cell islets with inhibitory ryanodine suppressed GSIS; so did the antioxidant N-acetyl cysteine (NAC, which also decreased insulin secretion induced by glucose plus caffeine. Inhibitory ryanodine or NAC did not affect insulin secretion induced by glucose plus carbachol, which engages inositol 1,4,5-trisphosphate receptors. Incubation of islets with H2O2 in basal glucose increased insulin secretion 2-fold. Inhibitory ryanodine significantly decreased H2O2-stimulated insulin secretion and prevented the 4.5-fold increase of cytoplasmic [Ca2+] produced by incubation of dissociated β-cells with H2O2. Addition of stimulatory glucose or H2O2 (in basal glucose to β-cells disaggregated from islets increased RyR2 S-glutathionylation to similar levels, measured by a proximity ligation assay; in contrast, NAC significantly reduced the RyR2 S-glutathionylation increase produced by stimulatory glucose. We propose that RyR2-mediated Ca2+ release, induced by the concomitant increases in [Ca2+] and ROS produced by stimulatory glucose, is an essential step in GSIS.

  16. Mitochondrial Dysfunction Contributes to Impaired Insulin Secretion in INS-1 Cells with Dominant-negative Mutations of HNF-1α and in HNF-1α-deficient Islets*

    Science.gov (United States)

    Pongratz, Rebecca L.; Kibbey, Richard G.; Kirkpatrick, Clare L.; Zhao, Xiaojian; Pontoglio, Marco; Yaniv, Moshe; Wollheim, Claes B.; Shulman, Gerald I.; Cline, Gary W.

    2009-01-01

    Maturity Onset Diabetes of the Young-type 3 (MODY-3) has been linked to mutations in the transcription factor hepatic nuclear factor (HNF)-1α, resulting in deficiency in glucose-stimulated insulin secretion. In INS-1 cells overexpressing doxycycline-inducible HNF-1α dominant-negative (DN-) gene mutations, and islets from Hnf-1α knock-out mice, insulin secretion was impaired in response to glucose (15 mm) and other nutrient secretagogues. Decreased rates of insulin secretion in response to glutamine plus leucine and to methyl pyruvate, but not potassium depolarization, indicate defects specific to mitochondrial metabolism. To identify the biochemical mechanisms responsible for impaired insulin secretion, we used 31P NMR measured mitochondrial ATP synthesis (distinct from glycolytic ATP synthesis) together with oxygen consumption measurements to determine the efficiency of mitochondrial oxidative phosphorylation. Mitochondrial uncoupling was significantly higher in DN-HNF-1α cells, such that rates of ATP synthesis were decreased by approximately one-half in response to the secretagogues glucose, glutamine plus leucine, or pyruvate. In addition to closure of the ATP-sensitive K+ channels with mitochondrial ATP synthesis, mitochondrial production of second messengers through increased anaplerotic flux has been shown to be critical for coupling metabolism to insulin secretion. 13C-Isotopomer analysis and tandem mass spectrometry measurement of Krebs cycle intermediates revealed a negative impact of DN-HNF-1α and Hnf-1α knock-out on mitochondrial second messenger production with glucose but not amino acids. Taken together, these results indicate that, in addition to reduced glycolytic flux, uncoupling of mitochondrial oxidative phosphorylation contributes to impaired nutrient-stimulated insulin secretion with either mutations or loss of HNF-1α. PMID:19376774

  17. Plasma Asprosin Concentrations Are Increased in Individuals with Glucose Dysregulation and Correlated with Insulin Resistance and First-Phase Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Yuren Wang

    2018-01-01

    Full Text Available Background. Adipokines are reported to participate in many common pathologic processes of glucose dysregulation, such as insulin resistance, β-cell dysfunction, and chronic inflammation. Objective. To detect the concentrations of plasma asprosin in subjects with impaired glucose regulation (IGR and newly diagnosed type 2 diabetes (nT2DM and its relationship to parameters of glucose and lipid metabolism, insulin resistance, and pancreatic β-cell function. Methods. 143 eligible participants were included and were divided into three groups including normal glucose regulation (NGR, n=52, IGR (n=40, and nT2DM group (n=51. The intravenous glucose tolerance test (IVGTT and clinical and biochemical parameters were measured in all participants. Results. Plasma asprosin levels were higher in IGR (82.40 ± 91.06 ng/mL, P<0.001 and nT2DM (73.25 ± 91.69 ng/mL, P<0.001 groups compared with those in the NGR (16.22 ± 9.27 ng/mL group, especially in IGR subjects. Correlation analysis showed that plasma asprosin levels were positively correlated with waist circumference (Wc, fasting plasma glucose (FPG, postchallenge plasma glucose (2hPG, HbA1c, triglyceride (TG, and homeostasis model assessment for insulin resistance (HOMA-IR and negatively correlated with homeostasis model assessment for β-cell function (HOMA-β, area under the curve of the first-phase (0–10 min insulin secretion (AUC, acute insulin response (AIR, and glucose disposition index (GDI (all P<0.05. Multiple logistical regression analyses revealed that plasma asprosin concentrations were significantly correlated with IGR and nT2DM after controlling for age, sex, BMI, and WHR. Conclusions. Circulating asprosin might be a predictor of early diagnosis in DM and might be a potential therapeutic target for prediabetes and T2DM.

  18. L-leucine methyl ester stimulates insulin secretion and islet glutamate dehydrogenase

    DEFF Research Database (Denmark)

    Knudsen, P; Kofod, Hans; Lernmark, A

    1983-01-01

    Column perifusion of collagenase-isolated mouse pancreatic islets was used to study the dynamics of insulin release in experiments lasting for several hours. The methyl esters of L-leucine and L-arginine were synthesized. Whereas L-arginine methyl ester (L-arginine OMe) had no effect, L-leucine OMe...... stimulated the release of insulin. The effect of L-leucine OMe was maximal at 5 mmol/liter. Whereas the Km for glucose-stimulated insulin release was unaffected by 1 mmol/liter L-leucine OMe, the maximal release of D-glucose was increased by the amino acid derivative that appeared more effective than L-leucine....... L-Leucine OMe was also a potent stimulus of insulin release from the perfused mouse pancreas. In the presence of 10 mmol/liter L-glutamine, 1 mmol/liter L-leucine OMe induced a 50- to 75-fold increase in insulin release. A similar stimulatory effect was also observed in column-perifused RIN 5F cells...

  19. Pigment epithelium-derived factor (PEDF) regulates metabolism and insulin secretion from a clonal rat pancreatic beta cell line BRIN-BD11 and mouse islets.

    Science.gov (United States)

    Chen, Younan; Carlessi, Rodrigo; Walz, Nikita; Cruzat, Vinicius Fernandes; Keane, Kevin; John, Abraham N; Jiang, Fang-Xu; Carnagarin, Revathy; Dass, Crispin R; Newsholme, Philip

    2016-05-05

    Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein, associated with lipid catabolism and insulin resistance. In the present study, PEDF increased chronic and acute insulin secretion in a clonal rat β-cell line BRIN-BD11, without alteration of glucose consumption. PEDF also stimulated insulin secretion from primary mouse islets. Seahorse flux analysis demonstrated that PEDF did not change mitochondrial respiration and glycolytic function. The cytosolic presence of the putative PEDF receptor - adipose triglyceride lipase (ATGL) - was identified, and ATGL associated stimulation of glycerol release was robustly enhanced by PEDF, while intracellular ATP levels increased. Addition of palmitate or ex vivo stimulation with inflammatory mediators induced β-cell dysfunction, effects not altered by the addition of PEDF. In conclusion, PEDF increased insulin secretion in BRIN-BD11 and islet cells, but had no impact on glucose metabolism. Thus elevated lipolysis and enhanced fatty acid availability may impact insulin secretion following PEDF receptor (ATGL) stimulation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism.

    Directory of Open Access Journals (Sweden)

    Hua V Lin

    Full Text Available GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 null mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.

  1. Maternal Moderate Physical Training during Pregnancy Attenuates the Effects of a Low-Protein Diet on the Impaired Secretion of Insulin in Rats: Potential Role for Compensation of Insulin Resistance and Preventing Gestational Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Carol Góis Leandro

    2012-01-01

    Full Text Available The effects of pregestational and gestational low-to-moderate physical training on insulin secretion in undernourished mothers were evaluated. Virgin female Wistar rats were divided into four groups as follows: control (C, n=5; trained (T, n=5; low-protein diet (LP, n=5; trained with a low-protein diet (T + LP, n=5. Trained rats ran on a treadmill over a period of 4 weeks before mate (5 days week−1 and 60 min day−1, at 65% of VO2max. At pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8% casein diet, and controls were provided with a 17% casein diet. At third day after delivery, mothers and pups were killed and islets were isolated by collagenase digestion of pancreas and incubated for a further 1 h with medium containing 5.6 or 16.7 mM glucose. T mothers showed increased insulin secretion by isolated islets incubated with 16.7 mM glucose, whereas LP group showed reduced secretion of insulin by isolated islets when compared with both C and LP + T groups. Physical training before and during pregnancy attenuated the effects of a low-protein diet on the secretion of insulin, suggesting a potential role for compensation of insulin resistance and preventing gestational diabetes mellitus.

  2. The effect of hyaluronic acid on insulin secretion in HIT-T15 cells through the enhancement of gap-junctional intercellular communications.

    Science.gov (United States)

    Li, Yuping; Nagira, Tsutomu; Tsuchiya, Toshie

    2006-03-01

    The transplantation of bioartificial pancreas has the potential to restore endogenous insulin secretion in type I diabetes. The bioartificial pancreas is constructed in vitro from cells and a support matrix. Hyaluronic acid (HA) is an extremely ubiquitous polysaccharide of extracellular matrix in the body and plays various biological roles. It has been suggested that high molecular weight (HMW) HA increases in the function of gap-junctional intercellular communications (GJIC) and the expression of connexin-43 (Cx43). To determine whether the function of pancreatic beta-cells is affected by gap junctions after HMW HA-treatment, we exposed HIT-T15, a clonal pancreatic beta-cell line, in various concentrations of HA for 24h, and then detected the insulin secretion and content, using an insulin assay kit by ELISA technique. The cellular functions of GJIC were assayed by dye-transfer method using the dye solution of Lucifer yellow. HA-treatment resulted in the enhancement of GJIC function, the increase of insulin release and insulin content. The results obtained in this study suggest that HA-coating increases the insulin secretion of HIT-T15 cells by the enhancement of Cx43-mediated GJIC. The results give useful information on design biocompatibility of HA when is used as a biomaterial for bioartificial pancreas.

  3. Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Zhidong Tu

    Full Text Available Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6 and diabetes-susceptible (BTBR mouse strains made genetically obese by the Leptin(ob/ob mutation (Lep(ob. High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.

  4. No evidence for genetically determined alteration in insulin secretion or sensitivity predisposing to type 1 diabetes: a study of identical twins.

    Science.gov (United States)

    Hawa, Mohammed I; Bonfanti, Riccardo; Valeri, Christina; Delli Castelli, Michela; Beyan, Huriya; Leslie, R David G

    2005-06-01

    To determine whether inherited changes in insulin secretion or sensitivity could predispose to type 1 diabetes, we studied identical twins of type 1 diabetic patients. We studied prospectively a consecutive series of 27 identical twins of patients with type 1 diabetes who were initially nondiabetic, as well as 14 control subjects, over a period of 18 years. Of these 27 twins, 15 remain nondiabetic (now estimated at low disease risk) and 12 developed diabetes (pre-diabetic twins). Subjects were tested when not diabetic on at least two occasions with an intravenous glucose tolerance test (IVGTT), and we estimated insulin secretion as first-phase insulin response (FPIR), glucose clearance (K(g)), and insulin sensitivity both by homeostasis model assessment of insulin resistance (HOMA-IR) and relative to insulin response by the basal HOMA-IR-to-FPIR ratio. Twins now at low risk and control subjects had similar fasting blood glucose and insulin levels, FPIR, K(g), HOMA-IR, and HOMA-IR-to-FPIR ratio. In contrast, pre-diabetic twins compared with control twins had higher fasting insulin levels (10.3 +/- 6.0 vs. 4.6 +/- 4.0 mIU/ml), lower FPIR (245 +/- 129 vs. 796 +/- 622 mIU . ml(-1) . 10 min(-1)), lower K(g) (1.5 +/- 0.6 vs. 2.6 +/- 0.8% per min), and higher HOMA-IR-to-FPIR ratio (0.007 +/- 0.005 vs. 0.001 +/- 0.0009) (all P alteration in either insulin secretion or sensitivity predisposing to type 1 diabetes.

  5. Insulin sensitizers improve the GLP-1 secretion and the amount of intestinal L cells on high-fat-diet-induced catch-up growth.

    Science.gov (United States)

    Zheng, Juan; Xiao, Kang-Li; Chen, Lulu; Wu, Chaodong; Hu, Xiang; Zeng, Tianshu; Chen, Xiao-Qian; Li, Wen-Juan; Deng, Xiuling; Li, Huiqing; Li, Yu-Ming

    The aim of this study was to investigate whether insulin resistance can result in impaired glucagon-like peptide (GLP)-1 secretion and to determine whether insulin-sensitizing drugs could improve the secretion of GLP-1 in catch-up growth rats. Male Sprague Dawley rats were used to establish a catch-up growth model. At the end of weeks 6 and 14, these rats were euthanized to measure energy intake, body weight, plasma triacylglycerol, and nonesterified fatty acid. Fat mass percentage was analyzed by dual-energy x-ray absorptiometry scan. The GLP-1 concentrations were measured by enzyme-linked immunosorbent assay, the glucose infusion rates were measured by hyperinsulinemic-glucose clamp experiment. Quantification of the GLP-1 positive cells in distal ileum was done by immunohistochemical staining method. The L cell line NCI-H716 cells were treated in vitro with palmitate acid, the cells' viability, the carnitine palmitoyl transferase-1, and the insulin signaling pathway were detected. Rats fed a high-fat diet rats had rapidly developed insulin resistance, impaired incretin effect, and a reduction in the number of intestinal L cells. The insulin sensitizers, metformin and pioglitazone, improved insulin resistance and the concentration of circulating GLP-1, increased the relative number of intestinal L cells to a certain degree. In vitro, the NCI-H716 cell viability was decreased and impaired insulin signaling pathway with palmitate acid treatment, metformin treatment could reverse these effects, whereas pioglitazone could not. Insulin resistance caused by a high-fat diet could result in reduced GLP-1 secretion; the insulin sensitizing drugs were able to improve the incretin effect in catch-up growth rats. Copyright © 2017. Published by Elsevier Inc.

  6. Possible contribution of taurine to distorted glucagon secretion in intra-islet insulin deficiency: a metabolome analysis using a novel α-cell model of insulin-deficient diabetes.

    Directory of Open Access Journals (Sweden)

    Megumi Bessho

    Full Text Available Glycemic instability is a serious problem in patients with insulin-deficient diabetes, and it may be due in part to abnormal endogenous glucagon secretion. However, the intracellular metabolic mechanism(s involved in the aberrant glucagon response under the condition of insulin deficiency has not yet been elucidated. To investigate the metabolic traits that underlie the distortion of glucagon secretion under insulin deficient conditions, we generated an αTC1-6 cell line with stable knockdown of the insulin receptor (IRKD, i.e., an in vitro α-cell model for insulin-deficient diabetes, which exhibits an abnormal glucagon response to glucose. A comprehensive metabolomic analysis of the IRKD αTC1-6 cells (IRKD cells revealed some candidate metabolites whose levels differed markedly compared to those in control αTC1-6 cells, but also which could affect the glucagon release in IRKD cells. Of these candidates, taurine was remarkably increased in the IRKD cells and was identified as a stimulator of glucagon in αTC1-6 cells. Taurine also paradoxically exaggerated the glucagon secretion at a high glucose concentration in IRKD cells and islets with IRKD. These results indicate that the metabolic alterations induced by IRKD in α-cells, especially the increase of taurine, may lead to the distorted glucagon response in IRKD cells, suggesting the importance of taurine in the paradoxical glucagon response and the resultant glucose instability in insulin-deficient diabetes.

  7. Interactions of obesity and glucose-stimulated insulin secretion in familial hypertriglyceridemia.

    Science.gov (United States)

    Maruhama, Y; Abe, R; Okuguchi, F; Oikawa, S; Ohneda, A; Goto, Y

    1978-06-01

    Plasma lipids and lipoproteins, glucose tolerance, plasma insulin response to glucose load, and liver function were examined in 81 relatives of 12 index cases with primary endogenous hypertriglyceridemia, hyperinsulinemia, and hepatic steatosis, as well as in 90 nonrelatives, including the spouses, as controls. Insulin hypersecretion (with or without glucose intolerance), endogenous hypertriglyceridemia, and abnormal liver function suggesting hepatic steatosis were shown to exist in the relatives mostly in combined fashion. Correlation analysis and stepwise multiple regression analysis revealed that the combined disorder developed on the basis of obesity. The incidence of diabetes mellitus was significantly high in the relatives (14.8 per cent) as compared with the normal Japanese population (3.5 per cent). Although the vertical transmission of the combined disorder was noted in almost all pedigrees, the frequency distribution analysis of insulin response, glucose tolerance, and plasma triglyceride showed the histograms of these variables similarly skewed to the right as compared with those of the controls, with no apparent bimodality. In view of the hitherto suggested role of insulin in triglyceride metabolism, it is concluded that hyperinsulinemia coupled with obesity seems to be the basic trait of this form of familial hypertriglyceridemia and hepatic steatosis, though the mode of transmission remains to be elucidated.

  8. LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol

    DEFF Research Database (Denmark)

    Nøhr, Mark K; Dudele, Anete; Poulsen, Morten M

    2016-01-01

    UNLABELLED: Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. He...

  9. DEFECTS IN INSULIN-SECRETION IN NIDDM - B-CELL GLUCOSE INSENSITIVITY OR GLUCOSE TOXICITY

    NARCIS (Netherlands)

    VANHAEFTEN, TW

    In NIDDM, first-phase insulin release to glucose is (almost) absent. However, in contrast to older studies which suggested that in NIDDM the B-cell is ''blind'' for glucose, recent evidence indicates that the B-cell is not insensitive for glucose as far as second phase release is concerned. This

  10. Meal composition affects insulin secretion in women with type 2 diabetes: a comparison with healthy controls. The Hoorn prandial study.

    Science.gov (United States)

    Alssema, M; Schindhelm, R K; Rijkelijkhuizen, J M; Kostense, P J; Teerlink, T; Nijpels, G; Heine, R J; Dekker, J M

    2009-03-01

    Early insulin secretion following a meal is representative for normal physiology and may depend on meal composition. To compare the effects of a fat-rich and a carbohydrate-rich mixed meal on insulinogenic index as a measure of early insulin secretion in normoglycemic women (NGM) and in women with type 2 diabetes mellitus (DM2), and to assess the relationship of anthropometric and metabolic factors with insulinogenic index. Postmenopausal women, 76 with NGM and 64 with DM2, received a fat-rich meal and a carbohydrate-rich meal on separate occasions. Early insulin response was estimated as insulinogenic index ( big up tri, Deltainsulin(0-30 min)/ big up tri, Deltaglucose(0-30 min)) for each meal. Associations of fasting and postprandial triglycerides, body mass index, waist and hip circumference and alanine aminotransferase with insulinogenic indices were determined. Women with NGM present with higher insulinogenic index than women with DM2. The insulinogenic index following the fat-rich meal ( big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat)) was higher than the index following the carbohydrate-rich meal (big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH)) (Pwomen with DM2, and not significant in women with NGM). In women with DM2, homeostasis model assessment for insulin resistance was positively associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH). In women with NGM, waist circumference was independently and inversely associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat) and with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH); hip circumference was positively associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat). The insulinogenic index following the fat-rich meal was higher than following the isocaloric carbohydrate-rich meal, which might favorably affect postprandial glucose excursions, especially in women with DM2. The association between a larger waist circumference and a lower meal-induced insulinogenic

  11. Stimulatory effect of serum from diabetic patients on insulin release from mouse pancreatic islets maintained in tissue culture

    DEFF Research Database (Denmark)

    Eff, C; Deckert, T; Andersson, A

    1981-01-01

    Islets of Langerhans from NMRI-mice were kept for one week in tissue culture in medium supplemented with human serum obtained from either normal healthy subjects or newly diagnosed juvenile diabetic patients before insulin treatment. Islets cultured in diabetic serum released more insulin than...... islets cultured in normal serum, whether tissue culture medium 199 with 5.5-8.3 mmol/l glucose and 10% serum, or culture medium RPMI 1640 with 11 mmol/l glucose and 0.5% serum were used. Islets kept for one week in culture with diabetic serum did not show any decrease in DNA content or glucose induced...... insulin secretion and biosynthesis. It is concluded that serum from newly diagnosed insulin-dependent diabetic patients stimulates insulin release from isolated mouse islets kept in tissue culture. The underlying mechanism is unknown....

  12. High Serum Advanced Glycation End Products Are Associated with Decreased Insulin Secretion in Patients with Type 2 Diabetes: A Brief Report

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Okura

    2017-01-01

    Full Text Available Objective. Advanced glycation end products (AGEs are important in the pathophysiology of type 2 diabetes mellitus (T2DM. They directly cause insulin secretory defects in animal and cell culture models and may promote insulin resistance in nondiabetic subjects. We have developed a highly sensitive liquid chromatography-tandem mass spectrometry method for measuring AGEs in human serum. Here, we use this method to investigate the relationship between AGEs and insulin secretion and resistance in patients with T2DM. Methods. Our study involved 15 participants with T2DM not on medication and 20 nondiabetic healthy participants. We measured the AGE carboxyethyllysine (CEL, carboxymethyllysine (CML, and methyl-glyoxal-hydro-imidazolone (MG-H1. Plasma glucose and insulin were measured in these participants during a meal tolerance test, and the glucose disposal rate was measured during a euglycemic-hyperinsulinemic clamp. Results. CML and CEL levels were significantly higher in T2DM than non-DM participants. CML showed a significant negative correlation with insulin secretion, HOMA-%B, and a significant positive correlation with the insulin sensitivity index in T2DM participants. There was no correlation between any of the AGEs measured and glucose disposal rate. Conclusions. These results suggest that AGE might play a role in the development or prediction of insulin secretory defects in type 2 diabetes.

  13. Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults: a randomized placebo-controlled trial.

    Science.gov (United States)

    Mousa, Aya; Naderpoor, Negar; de Courten, Maximilian Pj; Teede, Helena; Kellow, Nicole; Walker, Karen; Scragg, Robert; de Courten, Barbora

    2017-06-01

    Background: Vitamin D supplementation has been proposed as a potential strategy to prevent type 2 diabetes. Existing clinical trials have been limited by short duration, low doses of vitamin D, variability in participants' vitamin D-deficiency status, and the use of surrogate measures of body composition, insulin sensitivity, and insulin secretion. Objective: To address existing knowledge gaps, we conducted a double-blind, randomized, placebo-controlled trial to investigate whether vitamin D supplementation that is provided in a sufficient dose and duration to vitamin D-deficient individuals would improve insulin sensitivity or secretion as measured with the use of gold-standard methods. We hypothesized that vitamin D supplementation would improve insulin sensitivity and secretion compared with placebo. Design: Sixty-five overweight or obese, vitamin D-deficient (25-hydroxyvitamin D [25(OH)D] concentration ≤50 nmol/L) adults were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 wk. Before and after the intervention, participants received gold-standard assessments of body composition (via dual X-ray absorptiometry), insulin sensitivity (via hyperinsulinemic-euglycemic clamps), and insulin secretion [via intravenous-glucose-tolerance tests (IVGTTs)]. Results: Fifty-four participants completed the study [35 men and 19 women; mean ± SD age: 31.9 ± 8.5 y; body mass index (in kg/m 2 ): 30.9 ± 4.4]. 25(OH)D increased with vitamin D supplementation compared with placebo (57.0 ± 21.3 compared with 1.9 ± 15.1 nmol/L, respectively; P = 0.02). Vitamin D and placebo groups did not differ in change in insulin sensitivity (0.02 ± 2.0 compared with -0.03 ± 2.8 mg · kg -1 · min -1 , respectively; P = 0.9) or first-phase insulin secretion (-21 ± 212 compared with 24 ± 184 mU/L, respectively; P = 0.9). Results remained nonsignificant after adjustment for age, sex

  14. The protective effects and genetic pathways of thorn grape seeds oil against high glucose-induced apoptosis in pancreatic β-cells.

    Science.gov (United States)

    Lai, Xihu; Kang, Xincong; Zeng, Luman; Li, Jian; Yang, Yan; Liu, Dongbo

    2014-01-09

    Excessive apoptosis of β-cell is closely related to diabetes mellitus. Chronic exposure to high glucose causes β-cell dysfunction and apoptosis in diabetes. Thorn grape (Vitis davidii Foex.) has been used to treat diabetes in Traditional Chinese medicine for many years. In our previous research, thorn grape seeds oil (TGSO) showed promising anti-diabetic effects in animal models. However, it is unknown whether TGSO played an anti-apoptotic role in the anti-diabetic effects and the mechanism regarding signal transduction pathway is unclear either. The rattus pancreatic β-cell line RIN-m5F was treated with/without TGSO which was extracted by supercritical carbon dioxide (CO2) fluid extraction and analyzed by Gas Chromatography/Mass Spectrometry (GC/MS). Cell apoptosis was detected by fluorescence activated cell sorting (FACS), insulin secretion was assayed by Enzyme-Linked Immunosorbent Assay (ELISA), and the apoptosis-related genes expressions were evaluated by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). TGSO, containing 87.02% unsaturated fatty acids (UFAs), significantly reduced pancreatic β-cell apoptosis and protected the insulin secretion impaired by high glucose. The expressions of pro-apoptotic genes such as iNOS, Caspase-3, ATF-3, JNK, p38 and Fas were down-regulated while the anti-apoptotic genes Akt and Bcl-2/Bax were up-regulated. The results indicated that TGSO protected β-cells from high glucose-induced apoptosis and its protective activity may be linked to mitochondrial pathway, endoplasmic reticulum (ER) stress pathway and Fas signal pathway, which implied that TGSO might be an effective complementary or alternative medicine to reduce β-cell apoptosis and dysfunction.

  15. Validation of methods for measurement of insulin secretion in humans in vivo

    DEFF Research Database (Denmark)

    Kjems, L L; Christiansen, E; Vølund, A

    2000-01-01

    ). These results indicate that both approaches provide accurate assessment of prehepatic ISRs in type 2 diabetic patients and control subjects. A simplified version of the deconvolution method based on standard kinetic parameters for C-peptide (Van Cauter et al.) was compared with the 2-day deconvolution method......)-considered the "gold standard"-and the combined model (by Vølund et al.). The deconvolution method is a 2-day method, which generally requires separate assessment of C-peptide kinetics, whereas the combined model is a single-day method that uses insulin and C-peptide data from a single test of interest. The validity...... similar whether measured during constant peripheral somatostatin infusion or without somatostatin infusion. Assessment of C-peptide kinetics can be performed without infusion of somatostatin, because the endogenous insulin concentration remains constant. Assessment of C-peptide kinetics with and without...

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

    Directory of Open Access Journals (Sweden)

    Anna Wendt

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

  17. Reevaluation of Fatty acid receptor 1 (FFAR1/GPR40) as drug target for the stimulation of insulin secretion in humans

    DEFF Research Database (Denmark)

    Wagner, Robert; Kaiser, Gabriele; Gerst, Felicia

    2013-01-01

    The role of free fatty acid receptor 1 (FFAR1/GPR40) in glucose homeostasis is still incompletely understood. Small receptor agonists stimulating insulin secretion are under investigation for the treatment of type 2 diabetes. Surprisingly, genome-wide association studies did not discover diabetes...

  18. Calcium has a permissive role in interleukin-1beta-induced c-jun N-terminal kinase activation in insulin-secreting cells

    DEFF Research Database (Denmark)

    Størling, Joachim; Zaitsev, Sergei V; Kapelioukh, Iouri L

    2005-01-01

    The c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1beta-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic beta-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1beta activation of JNK in beta-cells are la...

  19. Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion.

    Science.gov (United States)

    Ramaswamy, S; Grace, C; Mattei, A A; Siemienowicz, K; Brownlee, W; MacCallum, J; McNeilly, A S; Duncan, W C; Rae, M T

    2016-06-06

    Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells.

  20. Impact of taurine depletion on glucose control and insulin secretion in mice.

    Science.gov (United States)

    Ito, Takashi; Yoshikawa, Natsumi; Ito, Hiromi; Schaffer, Stephen W

    2015-09-01

    Taurine, an endogenous sulfur-containing amino acid, is found in millimolar concentrations in mammalian tissue, and its tissue content is altered by diet, disease and aging. The effectiveness of taurine administration against obesity and its related diseases, including type 2 diabetes, has been well documented. However, the impact of taurine depletion on glucose metabolism and fat deposition has not been elucidated. In this study, we investigated the effect of taurine depletion (in the taurine transporter (TauT) knockout mouse model) on blood glucose control and high fat diet-induced obesity. TauT-knockout (TauTKO) mice exhibited lower body weight and abdominal fat mass when maintained on normal chow than wild-type (WT) mice. Blood glucose disposal after an intraperitoneal glucose injection was faster in TauTKO mice than in WT mice despite lower serum insulin levels. Islet beta-cells (insulin positive area) were also decreased in TauTKO mice compared to WT mice. Meanwhile, overnutrition by high fat (60% fat)-diet could lead to obesity in TauTKO mice despite lower body weight under normal chow diet condition, indicating nutrition in normal diet is not enough for TauTKO mice to maintain body weight comparable to WT mice. In conclusion, taurine depletion causes enhanced glucose disposal despite lowering insulin levels and lower body weight, implying deterioration in tissue energy metabolism. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  1. A matlab framework for estimation of NLME models using stochastic differential equations: applications for estimation of insulin secretion rates.

    Science.gov (United States)

    Mortensen, Stig B; Klim, Søren; Dammann, Bernd; Kristensen, Niels R; Madsen, Henrik; Overgaard, Rune V

    2007-10-01

    The non-linear mixed-effects model based on stochastic differential equations (SDEs) provides an attractive residual error model, that is able to handle serially correlated residuals typically arising from structural mis-specification of the true underlying model. The use of SDEs also opens up for new tools for model development and easily allows for tracking of unknown inputs and parameters over time. An algorithm for maximum likelihood estimation of the model has earlier been proposed, and the present paper presents the first general implementation of this algorithm. The implementation is done in Matlab and also demonstrates the use of parallel computing for improved estimation times. The use of the implementation is illustrated by two examples of application which focus on the ability of the model to estimate unknown inputs facilitated by the extension to SDEs. The first application is a deconvolution-type estimation of the insulin secretion rate based on a linear two-compartment model for C-peptide measurements. In the second application the model is extended to also give an estimate of the time varying liver extraction based on both C-peptide and insulin measurements.

  2. Genetic predisposition to obesity is associated with insulin secretion in Chinese adults: The Cardiometabolic Risk in Chinese (CRC) study.

    Science.gov (United States)

    Liang, Jun; Sun, Yuting; Liu, Xuekui; Zhu, Yan; Pei, Ying; Wang, Yu; Qiu, Qinqin; Yang, Manqing; Qi, Lu

    2016-01-01

    The etiological role of obesity in determining diabetes risk among Asians may be different from that among Caucasians. The current study aimed to investigate the association between genetic predisposition to obesity and measures of insulin secretion and resistance in a large Chinese cohort. Study samples were from a community-based health examination survey in central China. A total of 2058 subjects with available biomarkers levels were included in the present study. A genetic risk score (GRS) of obesity was derived on the basis of thirteen Asian-specific body mass index (BMI)-associated variants. High obesity GRS was significantly associated with increased homeostasis model assessment (HOMA)-B score (β=7.309; P=0.001) but not related to measures of insulin resistance. Adjustment for age, sex, BMI, and levels of lipids did not appreciably change the results. In addition, we found significant interactions between the obesity GRS and measures of body fat distribution including waist circumference (WC; P for interaction=0.004) and neck circumference (NC; P for interaction=0.014) on HOMA-B score. Our results suggest that genetic predisposition to obesity may affect beta cell function in Chinese; and body fat distribution may modify the genetic effects. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Heart, Emma [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Palo, Meridith; Womack, Trayce [Department of Science, United States Coast Guard Academy, New London, CT, 06320 (United States); Smith, Peter J.S. [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Institute for Life Sciences, University of Southampton (United Kingdom); Gray, Joshua P., E-mail: Joshua.p.gray@uscga.edu [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Department of Science, United States Coast Guard Academy, New London, CT, 06320 (United States)

    2012-01-15

    Pancreatic β-cells release insulin in response to elevation of glucose from basal (4–7 mM) to stimulatory (8–16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H{sub 2}O{sub 2}), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H{sub 2}O{sub 2} inhibit insulin secretion. Menadione, which produces H{sub 2}O{sub 2} via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H{sub 2}O{sub 2} production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1–10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H{sub 2}O{sub 2} formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H{sub 2}O{sub 2} and menadione on insulin secretion. -- Highlights: ► Menadione stimulation or inhibition of insulin secretion is dependent upon applied glucose levels. ► Menadione-dependent H{sub 2}O{sub 2} production is proportional to applied glucose levels. ► Quinone-mediated redox cycling

  4. The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion

    International Nuclear Information System (INIS)

    Heart, Emma; Palo, Meridith; Womack, Trayce; Smith, Peter J.S.; Gray, Joshua P.

    2012-01-01

    Pancreatic β-cells release insulin in response to elevation of glucose from basal (4–7 mM) to stimulatory (8–16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H 2 O 2 ), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H 2 O 2 inhibit insulin secretion. Menadione, which produces H 2 O 2 via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H 2 O 2 production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1–10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H 2 O 2 formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H 2 O 2 and menadione on insulin secretion. -- Highlights: ► Menadione stimulation or inhibition of insulin secretion is dependent upon applied glucose levels. ► Menadione-dependent H 2 O 2 production is proportional to applied glucose levels. ► Quinone-mediated redox cycling is dependent on glycolysis

  5. Insulin and Insulin Resistance

    Science.gov (United States)

    2005-01-01

    As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalisation, urbanisation and industrialisation have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits. PMID:16278749

  6. Common variants in the type 2 diabetes KCNQ1 gene are associated with impairments in insulin secretion during hyperglycaemic glucose clamp.

    Directory of Open Access Journals (Sweden)

    Jana V van Vliet-Ostaptchouk

    Full Text Available BACKGROUND: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. METHODOLOGY: The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. PRINCIPAL FINDINGS: We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002. The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively. In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively. We found no evidence for an association of KCNQ1 with diabetic complications. CONCLUSIONS: Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.

  7. Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets.

    Science.gov (United States)

    Hall, Elin; Volkov, Petr; Dayeh, Tasnim; Esguerra, Jonathan Lou S; Salö, Sofia; Eliasson, Lena; Rönn, Tina; Bacos, Karl; Ling, Charlotte

    2014-12-03

    Epigenetic factors regulate tissue-specific expression and X-chromosome inactivation. Previous studies have identified epigenetic differences between sexes in some human tissues. However, it is unclear whether epigenetic modifications contribute to sex-specific differences in insulin secretion and metabolism. Here, we investigate the impact of sex on the genome-wide DNA methylation pattern in human pancreatic islets from 53 males and 34 females, and relate the methylome to changes in expression and insulin secretion. Glucose-stimulated insulin secretion is higher in female versus male islets. Genome-wide DNA methylation data in human islets clusters based on sex. While the chromosome-wide DNA methylation level on the X-chromosome is higher in female versus male islets, the autosomes do not display a global methylation difference between sexes. Methylation of 8,140 individual X-chromosome sites and 470 autosomal sites shows sex-specific differences in human islets. These include sites in/near AR, DUSP9, HNF4A, BCL11A and CDKN2B. 61 X-chromosome genes and 18 autosomal genes display sex-specific differences in both DNA methylation and expression. These include NKAP, SPESP1 and APLN, which exhibited lower expression in females. Functional analyses demonstrate that methylation of NKAP and SPESP1 promoters in vitro suppresses their transcriptional activity. Silencing of Nkap or Apln in clonal beta-cells results in increased insulin secretion. Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes. Chromosome-wide and gene-specific sex differences in DNA methylation associate with altered expression and insulin secretion in human islets. Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes.

  8. Indices of insulin sensitivity and secretion from a standard liquid meal test in subjects with type 2 diabetes, impaired or normal fasting glucose

    Directory of Open Access Journals (Sweden)

    Farmer Mildred V

    2009-05-01

    Full Text Available Abstract Background To provide an initial evaluation of insulin sensitivity and secretion indices derived from a standard liquid meal tolerance test protocol in subjects with normal (NFG, impaired fasting glucose (IFG or type 2 diabetes mellitus. Methods Areas under the curve (AUC for glucose, insulin and C-peptide from pre-meal to 120 min after consumption of a liquid meal were calculated, as were homeostasis model assessments of insulin resistance (HOMA2-IR and the Matsuda index of insulin sensitivity. Results Subjects with NFG (n = 19, IFG (n = 19, and diabetes (n = 35 had mean ± SEM HOMA2-IR values of 1.0 ± 0.1, 1.6 ± 0.2 and 2.5 ± 0.3 and Matsuda insulin sensitivity index values of 15.6 ± 2.0, 8.8 ± 1.2 and 6.0 ± 0.6, respectively. The log-transformed values for these variables were highly correlated overall and within each fasting glucose category (r = -0.91 to -0.94, all p Conclusion These results provide initial evidence to support the usefulness of a standard liquid meal tolerance test for evaluation of insulin secretion and sensitivity in clinical and population studies.

  9. Unprecedented high insulin secretion in a healthy human subject after intravenous glucagon-like peptide-1

    DEFF Research Database (Denmark)

    Knop, Filip K; Lund, Asger; Madsbad, Sten

    2014-01-01

    BACKGROUND: The gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are released in response to ingestion of nutrients. Both hormones are highly insulinotropic in strictly glucose-dependent fashions and glucagon-like peptide-1 is often referred...... to as one of the most insulinotropic substances known. CASE PRESENTATION: Plasma insulin and C-peptide concentrations were measured in a healthy Caucasian male (age: 53 years; body mass index: 28.6 kg/m2; fasting plasma glucose: 5.7 mM; 2 h plasma glucose value following 75 g-oral glucose tolerance test: 3...

  10. Validation of methods for measurement of insulin secretion in humans in vivo

    DEFF Research Database (Denmark)

    Kjems, L L; Christiansen, E; Vølund, A

    2000-01-01

    )-considered the "gold standard"-and the combined model (by Vølund et al.). The deconvolution method is a 2-day method, which generally requires separate assessment of C-peptide kinetics, whereas the combined model is a single-day method that uses insulin and C-peptide data from a single test of interest. The validity...... the combined model and the deconvolution method were accurate, i.e., recovery of true ISR was not significantly different from 100%. Furthermore, both maximal and total ISRs from the combined model were strongly correlated to those obtained by the deconvolution method (r = 0.89 and r = 0.82, respectively...

  11. Improved insulin secretion following intrapancreatic UCB transplantation in patients with T2DM.

    Science.gov (United States)

    Tong, Qiang; Duan, Lian; Xu, Zihui; Wang, Hui; Wang, Xiaocui; Li, Zhongjun; Zhang, Weizhen; Zheng, Hongting

    2013-09-01

    Transplantation with stem cells has been reported as a potential treatment for diabetes. However, there are few reports examining transplantation with umbilical cord blood (UCB) in type 2 diabetes (T2DM). The aim of the study was to evaluate the efficacy of intrapancreatic UCB transplantation in patients with T2DM. Three patients were enrolled in the study, which was performed in a hospital setting from 2010 to 2012, and the duration of follow-up was approximately 6 months. UCB cells were infused by microcatheter into the dorsal pancreatic artery in 3 T2DM patients with different diabetic histories. Blood glucose (including 72-h continuous blood glucose), C-peptide, hemoglobin A1c, the requirement for insulin, and transplant complications were monitored before and after transplantation. After the transplantation, C-peptide levels had increased in all of the patients. In addition, the 72-hour continuous blood glucose monitoring results obtained after transplantation revealed that levels were more stable than before transplantation for all of the patients (P insulin were reduced in all patients after transplantation. UCB transplantation may be an approach that could somewhat improve C-peptide levels in patients with T2DM.

  12. Cephalic phase secretion of insulin and other enteropancreatic hormones in humans

    DEFF Research Database (Denmark)

    Veedfald, Simon; Plamboeck, Astrid; Deacon, Carolyn F

    2016-01-01

    Enteropancreatic hormone secretion is thought to include a cephalic phase, but the evidence in humans is ambiguous. We studied vagally induced gut hormone responses with and without muscarinic blockade in 10 glucose-clamped healthy men (age: 24.5 ± 0.6 yr, means ± SE; body mass index: 24.0 ± 0.5 kg...... mmol/l on all days. The meal stimulus for the MSF consisted of an appetizing breakfast. Participants (9/10) also had a 6 mmol/l glucose clamp without MSF. Pancreatic polypeptide (PP) levels rose from 6.3 ± 1.1 to 19.9 ± 6.8 pmol/l (means ± SE) in response to MSF and atropine lowered basal PP levels...

  13. A Novel Long-Acting Glucagon-Like Peptide-1 Agonist with Improved Efficacy in Insulin Secretion and β-Cell Growth

    Directory of Open Access Journals (Sweden)

    Hee Young Kim

    2014-09-01

    Full Text Available BackgroundGlucagon-like peptide-1 (GLP-1 is an incretin hormone produced by cleavage of proglucagon in intestinal L-cells. In the pancreas, GLP-1 stimulates post-prandial insulin secretion, promotes insulin biosynthesis, and improves insulin sensitivity. Because of its insulinotropic activity, GLP-1 has been considered a good candidate drug for treatment of diabetes mellitus. However, clinical use of GLP-1 has been limited by its short half-life, as a result of rapid degradation by dipeptidyl peptidase-IV (DPP-IV.MethodsWe designed a novel GLP-1 analog, Xenopus GLP-1 (xGLP-E4. The Ala residue in the second position of xGLP was replaced with a Ser residue to increase the half-life in the body. The C-terminal tail of exendin-4 was added to enhance the binding affinity for the GLP-1 receptor (GLP1R. The potency of GLP-1 and its analogs was determined by luciferase assay. The stability of GLP1R agonists was evaluated by determining the activity of agonists that had been preincubated in the presence of fetal bovine serum, which contains innate DPP-IV activity. The effects of xGLP-E4 on insulin secretion and β-cell growth were investigated using insulin enzyme-linked immunosorbent assay and cell counting.ResultsxGLP-E4 exhibited improved stability against DPP-IV activity and increased potency to GLP1R, compared with GLP-1. An increase in glucose-dependent insulin secretion was observed in xGLP-E4-treated pancreatic β-cells. The effect of xGLP-E4 on β-cell growth was greater than that of GLP-1.ConclusionWe developed a novel GLP-1 analog, xGLP-E4, that shows prolonged longevity and improved efficacy. This analog is a potential candidate for treatment of type 2 diabetes.

  14. Effects of CaMKII-Mediated Phosphorylation of Ryanodine Receptor Type 2 on Islet Calcium Handling, Insulin Secretion, and Glucose Tolerance

    Science.gov (United States)

    Dixit, Sayali S.; Wang, Tiannan; Manzano, Eiffel John Q.; Yoo, Shin; Lee, Jeongkyung; Chiang, David Y.; Ryan, Nicole; Respress, Jonathan L.; Yechoor, Vijay K.; Wehrens, Xander H. T.

    2013-01-01

    Altered insulin secretion contributes to the pathogenesis of type 2 diabetes. This alteration is correlated with altered intracellular Ca2+-handling in pancreatic β cells. Insulin secretion is triggered by elevation in cytoplasmic Ca2+ concentration ([Ca2+]cyt) of β cells. This elevation in [Ca2+]cyt leads to activation of Ca2+/calmodulin-dependent protein kinase II (CAMKII), which, in turn, controls multiple aspects of insulin secretion. CaMKII is known to phosphorylate ryanodine receptor 2 (RyR2), an intracellular Ca2+-release channel implicated in Ca2+-dependent steps of insulin secretion. Our data show that RyR2 is CaMKII phosphorylated in a pancreatic β-cell line in a glucose-sensitive manner. However, it is not clear whether any change in CaMKII-mediated phosphorylation underlies abnormal RyR2 function in β cells and whether such a change contributes to alterations in insulin secretion. Therefore, knock-in mice with a mutation in RyR2 that mimics its constitutive CaMKII phosphorylation, RyR2-S2814D, were studied. This mutation led to a gain-of-function defect in RyR2 indicated by increased basal RyR2-mediated Ca2+ leak in islets of these mice. This chronic in vivo defect in RyR2 resulted in basal hyperinsulinemia. In addition, S2814D mice also developed glucose intolerance, impaired glucose-stimulated insulin secretion and lowered [Ca2+]cyt transients, which are hallmarks of pre-diabetes. The glucose-sensitive Ca2+ pool in islets from S2814D mice was also reduced. These observations were supported by immunohistochemical analyses of islets in diabetic human and mouse pancreata that revealed significantly enhanced CaMKII phosphorylation of RyR2 in type 2 diabetes. Together, these studies implicate that the chronic gain-of-function defect in RyR2 due to CaMKII hyperphosphorylation is a novel mechanism that contributes to pathogenesis of type 2 diabetes. PMID:23516528

  15. Effect of single physical exercise at 35% VO2 max. intensity on secretion activity of pancreas β-cells and 125J-insulin binding and degradation ability by erythrocyte receptors in children with diabetes mellitus

    International Nuclear Information System (INIS)

    Szczesniak, L.; Rychlewski, T.; Banaszak, F.; Kasprzak, Z.; Walczak, M.

    1994-01-01

    In this report we showed research results of effect of single physical exercise on cycloergometer at 35% VO 2 max. intensity on 125 J-insulin binding and degradation ability by erythrocyte receptors in children with diabetes mellitus, secreting and non-secreting endogenous insulin. Insulin secretion was evaluated by measurement of C-peptide by Biodet test (Serono) of sensitivity threshold at 0.3 μg/ml. We indicated in children non-secreting endogenous insulin (n=32) there is statistically essential lower 125 J-insulin binding with erythrocyte receptor in comparison to children group with C-peptide. Physical exercise on cycloergometer at 35% VO 2 max. intensity caused different reaction in range of physiological indices, like acid-base parameters, level of glucose and 125 J-insulin binding and degradation. In children devoid of endogenous insulin we indicated statistically nonessential changes in 125 J-insulin degradation by non-impaired erythrocytes and by hemolizate, as well. 125 J-insulin binding after physical exercise increased in both groups, though change amplitude was different. Obtained research results allowed us to conclude, in children with I-type diabetes, that in dependence of impairment degree of pancreas βcells sensitivity of insulin receptor and/or number of receptors on erythrocyte surface is different

  16. Insulin-like growth factor--phosphatidylinositol 3 kinase signaling in canine cortisol-secreting adrenocortical tumors.

    Science.gov (United States)

    Kool, M M J; Galac, S; van der Helm, N; Corradini, S; Kooistra, H S; Mol, J A

    2015-01-01

    Hypercortisolism is a common endocrine disorder in dogs, caused by a cortisol-secreting adrenocortical tumor (AT) in approximately 15% of cases. In adrenocortical carcinomas of humans, activation of the phosphatidylinositol 3 kinase (PI3K) signaling pathway by insulin-like growth factor (IGF) signaling represents a promising therapeutic target. To investigate the involvement of PI3K signaling in the pathogenesis of ATs in dogs and to identify pathway components that may hold promise as future therapeutic targets or as prognostic markers. Analyses were performed on 36 canine cortisol-secreting ATs (11 adenomas and 25 carcinomas) and 15 normal adrenal glands of dogs. mRNA expression analysis was performed for PI3K target genes, PI3K inhibitor phosphatase and tensin homolog (PTEN), IGFs, IGF receptors, IGF binding proteins and epidermal growth factor receptors. Mutation analysis was performed on genes encoding PTEN and PI3K catalytic subunit (PIK3CA). Target gene expression indicated PI3K activation in carcinomas, but not in adenomas. No amino acid-changing mutations were detected in PTEN or PIK3CA and no significant alterations in IGF-II or IGFR1 expression were detected. In carcinomas, ERBB2 expression tended to be higher than in normal adrenal glands, and higher expression of inhibitor of differentiation 1 and 2 (ID1 and ID2) was detected in carcinomas with recurrence within 2.5 years after adrenalectomy. Based on these results, ERBB2 might be a promising therapeutic target in ATs in dogs, whereas ID1 and 2 might be valuable as prognostic markers and therapeutic targets. Copyright © 2015 by the American College of Veterinary Internal Medicine.

  17. Glucose-stimulated prehepatic insulin secretion is associated with circulating alanine, triglyceride, glucagons, lactate and TNF-alfa in patients with HIV-lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Pedersen, SB

    2006-01-01

    and ISREG0-10 min. Increased concentrations of the nonglucose insulin secretagogues triglyceride (+124%), alanine (+35%) and glucagon (+88%), and also lactate (+96%) and tumour necrosis factor (TNF)-alpha (+62%) were observed in the 10 LIPO patients with aberrations in FISR and ISREG0-10 min compared...... with the remaining HIV-infected patients (all Palanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients....

  18. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers

    DEFF Research Database (Denmark)

    Nauck, Michael A; Heimesaat, Markus M; Behle, Kai

    2002-01-01

    .97). The other counterregulatory hormones and autonomic or neuroglucopenic symptom scores increased, and cognitive functions decreased with decreasing glucose concentrations, but there were no significant differences comparing experiments with GLP-1 or placebo, except for a significant reduction of GH responses...... and neuroglucopenic symptoms were assessed, and cognitive function was tested at each plateau. Insulin secretion rates were estimated by deconvolution (two-compartment model of C-peptide kinetics). At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1 (P...

  19. Characterization of the Molecular Mechanisms Underlying Glucose Stimulated Insulin Secretion from Isolated Pancreatic β-cells Using Post-translational Modification Specific Proteomics (PTMomics)

    DEFF Research Database (Denmark)

    Kang, Taewook; Jensen, Pia; Huang, Honggang

    2018-01-01

    understanding of glucose-stimulated insulin secretion (GSIS) mechanisms under normal conditions is a prerequisite for developing better interventions against diabetes. Here, we aimed at identifying novel signaling pathways involved in the initial release of insulin from PBCs after glucose stimulation using......-cell interaction, cell movement, cell-ECM interaction and Focal Adhesion (e.g. integrins, semaphorins, and plexins) were found regulated at the level of sialylation, but not in protein expression. Collectively, we believe that this comprehensive Proteomics and PTMomics survey of signaling pathways taking place...

  20. Glucose-stimulated prehepatic insulin secretion is associated with circulating alanine, triglyceride, glucagon, lactate and TNF-alpha in patients with HIV-lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, S B; Andersen, O; Pedersen, S B

    2006-01-01

    and ISREG0-10 min. Increased concentrations of the nonglucose insulin secretagogues triglyceride (+124%), alanine (+35%) and glucagon (+88%), and also lactate (+96%) and tumour necrosis factor (TNF)-alpha (+62%) were observed in the 10 LIPO patients with aberrations in FISR and ISREG0-10 min compared...... with the remaining HIV-infected patients (all Ptriglyceride, alanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients....

  1. Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation.

    Science.gov (United States)

    Merli, M; Leonetti, F; Riggio, O; Valeriano, V; Ribaudo, M C; Strati, F; Tisone, G; Casciani, C U; Capocaccia, L; Sprati, F

    1999-09-01

    Cirrhosis is often associated with insulin resistance and glucose intolerance. We evaluated if these alterations are restored by liver transplantation (LT). Glucose tolerance (oral glucose tolerance test [OGTT]), peripheral insulin sensitivity (euglycemic insulin clamp technique), glucose oxidation (indirect calorimetry), nonoxidative glucose disposal, and insulin secretion (hyperglycemic clamp technique) were measured in 6 patients (Group 1) before and 6 months after LT, in 12 patients (Group 2) who underwent LT 6 to 30 months previously, and in 6 healthy individuals (controls). In Group 1, glucose tolerance and insulin sensitivity (3.24 +/- 0.37 mg/kg/min) were normalized after LT (8.6 +/- 0.77 mg/kg/min; P <.0001; P = not significant vs. controls). The improved insulin-mediated glucose uptake was the result of a normalization of nonoxidative glucose disposal. Fasting insulin and C-peptide decreased from 24.6 +/- 3.3 microU/mL and 4.37 +/- 0.46 ng/dL, respectively, to 12.7 +/- 1.9 microU/mL and 2.46 +/- 0.5 ng/dL (controls: 10.0 +/- 3 microU/mL and 1.45 +/- 0.34 ng/dL). The glucose-induced increase of insulin concentration, which was higher before LT, showed a significant reduction, although the first phase of beta-cell secretion remained significantly higher compared with that of controls. All these findings were also confirmed in Group 2. The present data indicate that LT normalizes glucose tolerance and insulin sensitivity in cirrhotic patients through an improvement of both hepatic glucose clearance and the peripheral glucose disposal. The latter effect may be the result of the correction of chronic hyperinsulinemia. An increased first-phase beta-cell insulin secretion in response to high glucose levels persists, suggesting that a memory of previous insulin resistance is maintained.

  2. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal

    DEFF Research Database (Denmark)

    Willms, B; Werner, J; Holst, J J

    1996-01-01

    yr; body mass index, 30.0 +/- 5.2 kg/m2; hemoglobin A1c, 10.5 +/- 1.2%) were studied in the fasting state (plasma glucose, 11.1 +/- 1.1 mmol/L). A liquid meal of 400 mL containing 8% amino acids and 50 g sucrose (327 Kcal) was administered at time zero by a nasogastric tube. Gastric volume......The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 +/- 6...... to normal fasting values (5.4 +/- 0.7 mmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together...

  3. Postoperative myocardial performance during glucose-induced hypophosphatemia

    DEFF Research Database (Denmark)

    Rasmussen, A; Buus, S; Hessov, I

    1985-01-01

    Long-lasting hypophosphatemia was previously found to diminish myocardial performance. The present study aimed to elucidate if postoperative glucose-induced hypophosphatemia is of importance for myocardial performance. Sixteen patients undergoing elective colonic or rectal surgery were given 100 g...... glucose intravenously (as 20% glucose solution) on the first and second postoperative days. The infusion rate was 0.3 g/kg/hour. On both days the glucose infusion caused significant fall in P-phosphate (0.94 to 0.67 and 0.71 to 0.47 mmol/l, respectively). No changes were seen in P-calcium, P-potassium....... As the preload (central venous pressure) and the afterload (arterial pressure) similarly were unchanged by the glucose infusion, glucose-induced hypophosphatemia following elective surgery was judged to lack importance for the myocardial performance....

  4. High normal HbA(1c) levels were associated with impaired insulin secretion without escalating insulin resistance in Japanese individuals: the Toranomon Hospital Health Management Center Study 8 (TOPICS 8).

    Science.gov (United States)

    Heianza, Y; Arase, Y; Fujihara, K; Tsuji, H; Saito, K; Hsieh, S D; Kodama, S; Shimano, H; Yamada, N; Hara, S; Sone, H

    2012-10-01

    We aimed to characterize the association of insulin resistance, impaired insulin secretion and β-cell dysfunction in relation to HbA(1c) levels in a non-diabetic range in Japanese individuals without clinically diagnosed diabetes. This cross-sectional study included 1444 individuals without a history of outpatient treatment of diabetes or use of insulin or oral hypoglycaemic agents. The homeostasis model assessment of insulin resistance and beta-cell function, insulinogenic index, Matsuda index and disposition index were calculated using data from 75-g oral glucose tolerance tests and compared across quintile (Q) categories of HbA(1c) levels. Fasting plasma glucose and 30-min and 60-min plasma glucose (PG) levels were significantly higher when HbA(1c) exceeded 36 mmol/mol (5.4%). A HbA(1c) concentration of 36-37 mmol/mol (5.4-5.5%) (Q3) was significantly associated with a 15% lower homeostasis model assessment of β-cell function value and 31% lower insulinogenic index value compared with HbA(1c) ≤ 32 mmol/mol (≤ 5.1%) (Q1) (P insulin resistance was not significantly elevated and the Matsuda index was not significantly lower unless HbA(1c) exceeded 41 mmol/mol (5.9%). Individuals with HbA(1c) ≥ 41 mmol/mol (≥ 5.9%) (Q5) had a 69% lower disposition index than those with a HbA(1c) concentration of ≤ 32 mmol/mol (≤ 5.1%) (Q1). Elevated HbA(1c) levels ≥ 41 mmol/mol (≥ 5.9%) were associated with substantial reductions in insulin secretion, insulin sensitivity and β-cell dysfunction in Japanese individuals not treated for diabetes. High normal HbA(1c) levels of 36-40 mmol/mol (5.4-5.8%) were also associated with impaired insulin secretion without marked insulin resistance in Japanese individuals. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  5. [Effect of L-arginine supplementation on secretion of human growth hormone and insulin-like growth factor in adults].

    Science.gov (United States)

    Fayh, Ana Paula Trussardi; Friedman, Rogério; Sapata, Katiuce Borges; Oliveira, Alvaro Reischak de

    2007-06-01

    Based on presumptions that the infusion of amino acids can augment the release of human growth hormone (hGH) and that this metabolism is related with secretion of insulin-like growth factor I (IGF-I), the purpose of this study was to verify the effect of L-arginine supplementation on GH and IGF-I in adults. Seventeen male individuals participated on the study and were randomized to receive L-arginine (n= 10) or placebo (n= 7), seven grams per day for seven days. Before and after the supplementation period, the volunteers realized blood collection in fasting to verify both GH and IGF-I levels, as well as urine collection to verify urea excretion. At the end of the experimental period, it was verified that the group that received L-arginine augmented the urea in urine excretion (to 2684.1 +/- 475.2 mg/dl from 2967.2 +/- 409.7 mg/dl, p= 0.002), therefore it did not alter significantly the release of hormones evaluated. The group which received placebo did not alter significantly any evaluated parameters. The L-arginine supplementation during seven days was ineffective to augment both GH and IGF-I release in individual male adults.

  6. Cucurbita ficifolia Bouché increases insulin secretion in RINm5F cells through an influx of Ca(2+) from the endoplasmic reticulum.

    Science.gov (United States)

    Miranda-Perez, Maria Elizabeth; Ortega-Camarillo, Clara; Del Carmen Escobar-Villanueva, Maria; Blancas-Flores, Gerardo; Alarcon-Aguilar, Francisco Javier

    2016-07-21

    Cucurbita ficifolia Bouché(C. ficifolia) is a plant used in Mexican traditional medicine to control type 2 diabetes (T2D). The hypoglycemic effect of the fruit of C. ficifolia has been demonstrated in different experimental models and in T2D patients. It has been proposed that D-chiro-inositol (DCI) is the active compound of the fruit. Additionally, it has been reported that C. ficifolia increases the mRNA expression of insulin and Kir 6.2 (a component of the ATP-sensitive potassium (K(+)ATP) channel, which is activated by sulphonylurea) in RINm5F cells. However, it remains unclear whether C. ficifolia and DCI causes the secretion of insulin by increasing the concentration of intracellular calcium ([Ca(2+)]i) through K(+)ATP channel blockage or from the reservoir in the endoplasmic reticulum (ER). The aqueous extract of C. ficifolia was obtained and standardized with regard to its DCI content. RINm5F pancreatic β-cells were incubated with different concentrations (50, 100, 200 and 400μM) of DCI alone or C. ficifolia (9, 18, 36 and 72µg of extract/mL), and the [Ca(2+)]i of the cells was quantified. The cells were preloaded with the Ca(2+) fluorescent dye fluo4-acetoxymethyl ester (AM) and visualized by confocal microscopy. Insulin secretion was measured by an ELISA method. Subsequently, the effect of C. ficifolia on the K(+)ATP channel was evaluated. In this case, the blocker activator diazoxide was used to inhibit the C. ficifolia-induced calcium influx. In addition, the inositol 1,4,5-trisphosphate (IP3)-receptor-selective inhibitor 2-amino-thoxydiphenylborate (2-APB) was used to inhibit the influx of calcium from the ER that was induced by C. ficifolia. It was found that DCI alone did not increase [Ca(2+)]i or insulin secretion. In contrast, treatment with C. ficifolia increased [Ca(2+)]i 10-fold compared with the control group. Insulin secretion increased by 46.9%. In the presence of diazoxide, C. ficifolia decreased [Ca(2+)]i by 50%, while insulin secretion

  7. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

    DEFF Research Database (Denmark)

    Guigas, B.; van Weenen, J. E. D.; van Leeuwen, N.

    2014-01-01

    functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort......Aims Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic beta-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. Methods Four potentially....... In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. Results rs1800497 at the DRD2/ANKK1 locus was associated...

  8. Ghrelin stimulation of growth hormone isoforms: parallel secretion of total and 20-kDa growth hormone and relation to insulin sensitivity in healthy humans.

    Science.gov (United States)

    Tong, Jenny; D'Alessio, David; Ramisch, Juliane; Davis, Harold W; Stambrook, Elizabeth; Tschöp, Matthias H; Bidlingmaier, Martin

    2012-09-01

    The 20-kDa human GH (hGH) is produced in the pituitary by alternative splicing of the hGH-N gene. The 20-kDa hGH promotes growth similarly to 22-kDa or total hGH, the predominant form in circulation, but the relative effects of these isoforms on glucose metabolism have been debated. To investigate the effect of ghrelin on 20-kDa and total hGH secretion in healthy, nonobese subjects. We also studied associations between basal GH concentration and fasting glucose and insulin as well as between dynamic GH secretion and insulin sensitivity. Synthetic human acyl ghrelin (0.2 or 0.6 nmol/kg · h) or saline was infused in random order in 14 healthy subjects (six males, eight females; age 27.7 ± 6.3 yr; body mass index 22.0 ± 2.7 kg/m(2), mean ± SEM) on 3 separate days. Ghrelin was infused for 45 min to achieve steady-state levels and continued through a 3-h frequently sampled i.v. glucose tolerance test. Insulin sensitivity index was quantified using the minimal model of glucose kinetics. Basal 20-kDa and total GH concentrations were 0.4 ± 0.1 and 2.2 ± 0.4 ng/ml, respectively, with a 20-kDa to total GH ratio of 0.13 ± 0.02. Females had significantly higher baseline GH levels. Ghrelin administration increased 20-kDa and total GH levels in a parallel and dose-dependent fashion, with no significant change in the ratio of the isoforms. Basal 20-kDa and total GH levels were negatively correlated with fasting glucose, insulin, and homeostasis model assessment of insulin resistance. During the frequently sampled iv glucose tolerance test, GH secretion was positively correlated with insulin sensitivity index with saline infusion. Ghrelin dose-dependently increases endogenous 20-kDa and total GH secretion in a parallel fashion in healthy subjects. Both basal and stimulated levels of the different GH isoforms were positively associated with insulin sensitivity in this cohort of healthy men and women.

  9. Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs.

    Science.gov (United States)

    Salama, Apolline; Mosser, Mathilde; Lévêque, Xavier; Perota, Andrea; Judor, Jean-Paul; Danna, Corentin; Pogu, Sylvie; Mouré, Anne; Jégou, Dominique; Gaide, Nicolas; Abadie, Jérôme; Gauthier, Olivier; Concordet, Jean-Paul; Le Bas-Bernardet, Stéphanie; Riochet, David; Le Berre, Ludmilla; Hervouet, Jérémy; Minault, David; Weiss, Pierre; Guicheux, Jérôme; Brouard, Sophie; Bosch, Steffi; Lagutina, Irina; Duchi, Roberto; Lazzari, Giovanna; Cozzi, Emanuele; Blancho, Gilles; Conchon, Sophie; Galli, Cesare; Soulillou, Jean-Paul; Bach, Jean-Marie

    2017-04-01

    Xenocell therapy from neonate or adult pig pancreatic islets is one of the most promising alternatives to allograft in type 1 diabetes for addressing organ shortage. In humans, however, natural and elicited antibodies specific for pig xenoantigens, α-(1,3)-galactose (GAL) and N -glycolylneuraminic acid (Neu5Gc), are likely to significantly contribute to xenoislet rejection. We obtained double-knockout (DKO) pigs lacking GAL and Neu5Gc. Because Neu5Gc -/- mice exhibit glycemic dysregulations and pancreatic β-cell dysfunctions, we evaluated islet function and glucose metabolism regulation in DKO pigs. Isolation of islets from neonate piglets yielded identical islet equivalent quantities to quantities obtained from control wild-type pigs. In contrast to wild-type islets, DKO islets did not induce anti-Neu5Gc antibody when grafted in cytidine monophosphate- N -acetylneuraminic acid hydroxylase KO mice and exhibited in vitro normal insulin secretion stimulated by glucose and theophylline. Adult DKO pancreata showed no histological abnormalities, and immunostaining of insulin and glucagon was similar to that from wild-type pancreata. Blood glucose, insulin, C-peptide, the insulin-to-glucagon ratio, and HOMA-insulin resistance in fasted adult DKO pigs and blood glucose and C-peptide changes after intravenous glucose or insulin administration were similar to wild-type pigs. This first evaluation of glucose homeostasis in DKO pigs for two major xenoantigens paves the way to their use in (pre)clinical studies. © 2017 by the American Diabetes Association.

  10. Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion.

    Directory of Open Access Journals (Sweden)

    Yuko Nakagawa

    Full Text Available BACKGROUND: Sweet taste receptor is expressed in the taste buds and enteroendocrine cells acting as a sugar sensor. We investigated the expression and function of the sweet taste receptor in MIN6 cells and mouse islets. METHODOLOGY/PRINCIPAL FINDINGS: The expression of the sweet taste receptor was determined by RT-PCR and immunohistochemistry. Changes in cytoplasmic Ca(2+ ([Ca(2+](c and cAMP ([cAMP](c were monitored in MIN6 cells using fura-2 and Epac1-camps. Activation of protein kinase C was monitored by measuring translocation of MARCKS-GFP. Insulin was measured by radioimmunoassay. mRNA for T1R2, T1R3, and gustducin was expressed in MIN6 cells. In these cells, artificial sweeteners such as sucralose, succharin, and acesulfame-K increased insulin secretion and augmented secretion induced by glucose. Sucralose increased biphasic increase in [Ca(2+](c. The second sustained phase was blocked by removal of extracellular calcium and addition of nifedipine. An inhibitor of inositol(1, 4, 5-trisphophate receptor, 2-aminoethoxydiphenyl borate, blocked both phases of [Ca(2+](c response. The effect of sucralose on [Ca(2+](c was inhibited by gurmarin, an inhibitor of the sweet taste receptor, but not affected by a G(q inhibitor. Sucralose also induced sustained elevation of [cAMP](c, which was only partially inhibited by removal of extracellular calcium and nifedipine. Finally, mouse islets expressed T1R2 and T1R3, and artificial sweeteners stimulated insulin secretion. CONCLUSIONS: Sweet taste receptor is expressed in beta-cells, and activation of this receptor induces insulin secretion by Ca(2+ and cAMP-dependent mechanisms.

  11. PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells.

    Directory of Open Access Journals (Sweden)

    Hyo-Sup Kim

    Full Text Available BACKGROUND: It has been reported that peroxisome proliferator-activated receptor (PPAR-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells. METHODS: Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ and/or adenoviral PPAR-γ overexpression. OLETF rats were treated with RGZ. RESULTS: PPAR-γ activation with RGZ and/or adenoviral PPAR-γ overexpression increased free fatty acid (FFA receptor GPR40 expression, and increased insulin secretion and intracellular calcium mobilization, and was blocked by the PLC inhibitors, GPR40 RNA interference, and GLUT2 RNA interference. As a downstream signaling pathway of intracellular calcium mobilization, the phosphorylated levels of CaMKII and CREB, and the downstream IRS-2 and phospho-Akt were significantly increased. Despite of insulin receptor RNA interference, the levels of IRS-2 and phospho-Akt was still maintained with PPAR-γ activation. In addition, the β-cell specific gene expression, including Pdx-1 and FoxA2, increased in a GPR40- and GLUT2-dependent manner. The levels of GPR40, phosphorylated CaMKII and CREB, and β-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-γ antagonist. Finally, PPAR-γ activation up-regulated β-cell gene expressions through FoxO1 nuclear exclusion, independent of the insulin signaling pathway. Based on immunohistochemical staining, the GLUT2, IRS-2, Pdx-1, and GPR40 were more strongly expressed in islets from RGZ-treated OLETF rats compared to control islets. CONCLUSION: These observations suggest that PPAR-γ activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene up-regulation.

  12. Sensitive and specific markers for insulin resistance, hyperandrogenemia, and inappropriate gonadotrophin secretion in women with polycystic ovary syndrome: a case-control study from Bahrain

    Directory of Open Access Journals (Sweden)

    Al-Ayadhi MA

    2012-05-01

    Full Text Available Jamal Golbahar,1,2,* Maha Al-Ayadhi,2,* Negalla Mohan Das,2 Khalid Gumaa,2 1Department of Molecular Medicine, Al-Jawhara Centre for Genetic Diagnosis and Research, 2Department of Medical Biochemistry, College of Medicine and Medical Sciences, AGU, Manama, Bahrain *These authors contributed equally to this articleBackground: In women with polycystic ovary syndrome (PCOS, despite a high prevalence of insulin resistance, hyperandrogenemia, and disturbances in the secretion of gonadotrophin, the principal causes of biochemical abnormalities and the best endocrine markers for PCOS have not been fully identified.Subjects and methods: Serum levels of insulin, glucose, follicle-stimulating hormone (FSH, luteinizing hormone (LH, total testosterone, estrogen, sex hormone-binding capacity (SHBG, and other related indices such as homeostasis model assessment, insulin glucose ratios, LH/FSH ratios, and the free androgen index (FAI were determined and compared in women with PCOS (n = 50 and women without PCOS (n = 50.Results: In multivariate logistic regression analyses, among all insulin resistance indices, only hyperinsulinemia (odds ratio [OR] = 2.6; confidence interval [CI]: 1.3–5.2; P = 0.008 was significantly and independently associated with PCOS when adjusted for body mass index (BMI, hyperandrogenemia, and LH/FSH ratios. The LH/FSH ratio (OR = 5.4; CI: 1.2–23.0, P = 0.03 was the only marker among those indices for inappropriate gonadotrophin secretion that significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. Among those indices for hyperandrogenemia, FAI (OR = 1.1; CI: 1.0–2.7; P = 0.02 and SHBG (OR = 1.2; CI: 1.2–3.4; P = 0.03 were significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. In addition, receiver operating characteristic analysis showed that the best predictive markers for PCOS were insulin (area under the curve [AUC] = 0.944; CI: 0.887–0

  13. Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes.

    Science.gov (United States)

    Wice, Burton M; Reeds, Dominic N; Tran, Hung D; Crimmins, Dan L; Patterson, Bruce W; Dunai, Judit; Wallendorf, Michael J; Ladenson, Jack H; Villareal, Dennis T; Polonsky, Kenneth S

    2012-07-01

    Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion (GSIS). This response is blunted in type 2 diabetes (T2DM). Xenin-25 is a 25-amino acid neurotensin-related peptide that amplifies GIP-mediated GSIS in hyperglycemic mice. This study determines if xenin-25 amplifies GIP-mediated GSIS in humans with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or T2DM. Each fasting subject received graded glucose infusions to progressively raise plasma glucose concentrations, along with vehicle alone, GIP, xenin-25, or GIP plus xenin-25. Plasma glucose, insulin, C-peptide, and glucagon levels and insulin secretion rates (ISRs) were determined. GIP amplified GSIS in all groups. Initially, this response was rapid, profound, transient, and essentially glucose independent. Thereafter, ISRs increased as a function of plasma glucose. Although magnitudes of insulin secretory responses to GIP were similar in all groups, ISRs were not restored to normal in subjects with IGT and T2DM. Xenin-25 alone had no effect on ISRs or plasma glucagon levels, but the combination of GIP plus xenin-25 transiently increased ISR and plasma glucagon levels in subjects with NGT and IGT but not T2DM. Since xenin-25 signaling to islets is mediated by a cholinergic relay, impaired islet responses in T2DM may reflect defective neuronal, rather than GIP, signaling.

  14. Self-Transducible Bimodal PDX1-FOXP3 Protein Lifts Insulin Secretion and Curbs Autoimmunity, Boosting Tregs in Type 1 Diabetic Mice.

    Science.gov (United States)

    Amatya, Christina; Radichev, Ilian A; Ellefson, Jacob; Williams, Mark; Savinov, Alexei Y

    2018-01-03

    Type 1 diabetes (T1D) is characterized by massive destruction of insulin-producing β cells by autoreactive T lymphocytes, arising via defective immune tolerance. Therefore, effective anti-T1D therapeutics should combine autoimmunity-preventing and insulin production-restoring properties. We constructed a cell-permeable PDX1-FOXP3-TAT fusion protein (FP) composed of two transcription factors: forkhead box P3 (FOXP3), the master regulator of differentiation and functioning of self-tolerance-promoting Tregs, and pancreatic duodenal homeobox-1 (PDX1), the crucial factor supporting β cell development and maintenance. The FP was tested in vitro and in a non-obese diabetic mouse T1D model. In vitro, FP converted naive CD4 + T cells into a functional "Treg-like" subset, which suppressed cytokine secretion, downregulated antigen-specific responses, and curbed viability of diabetogenic effector cells. In hepatic stem-like cells, FP potentiated endocrine transdifferentiation, inducing expression of Insulin2 and other β lineage-specific genes. In vivo, FP administration to chronically diabetic mice triggered (1) a significant elevation of insulin and C-peptide levels, (2) the formation of insulin-containing cell clusters in livers, and (3) a systemic anti-inflammatory shift (higher Foxp3 + CD4 + CD25 + T cell frequencies, elevated rates of IL-10-producing cells, and reduced rates of IFN-γ-secreting cells). Overall, in accordance with its design, PDX1-FOXP3-TAT FP delivered both Treg-stabilizing anti-autoimmune and de novo insulin-producing effects, proving its anti-T1D therapeutic potential. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  15. Sequential signaling cascade of IL-6 and PGC-1α is involved in high glucose-induced podocyte loss and growth arrest

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Il; Park, Soo Hyun, E-mail: parksh@chonnam.ac.kr

    2013-06-14

    Highlights: •The pathophysiological role of IL-6 in high glucose-induced podocyte loss. •The novel role of PGC-1α in the development of diabetic nephropathy. •Signaling of IL-6 and PGC-1α in high glucose-induced dysfunction of podocyte. -- Abstract: Podocyte loss, which is mediated by podocyte apoptosis, is implicated in the onset of diabetic nephropathy. In this study, we investigated the involvement of interleukin (IL)-6 in high glucose-induced apoptosis of rat podocytes. We also examined the pathophysiological role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in this system. High glucose treatment induced not only podocyte apoptosis but also podocyte growth arrest. High glucose treatment also increased IL-6 secretion and activated IL-6 signaling. The high glucose-induced podocyte apoptosis was blocked by IL-6 neutralizing antibody. IL-6 treatment or overexpression induced podocyte apoptosis and growth arrest, and IL-6 siRNA transfection blocked high glucose-induced podocyte apoptosis and growth arrest. Furthermore, high glucose or IL-6 treatment increased PGC-1α expression, and PGC-1α overexpression also induced podocyte apoptosis and growth arrest. PGC-1α siRNA transfection blocked high glucose-induced podocyte apoptosis and growth arrest. Collectively, these findings showed that high glucose promoted apoptosis and cell growth arrest in podocytes via IL-6 signaling. In addition, PGC-1α is involved in podocyte apoptosis and cell growth arrest. Therefore, blocking IL-6 and its downstream mediators such as IL6Rα, gp130 and PGC-1α may attenuate the progression of diabetic nephropathy.

  16. Chronic Reduction of the Cytosolic or Mitochondrial NAD(P)-malic Enzyme Does Not Affect Insulin Secretion in a Rat Insulinoma Cell Line*

    Science.gov (United States)

    Brown, Laura J.; Longacre, Melissa J.; Hasan, Noaman M.; Kendrick, Mindy A.; Stoker, Scott W.; MacDonald, Michael J.

    2009-01-01

    The cytosolic malic enzyme (ME1) has been suggested to augment insulin secretion via the malate-pyruvate and/or citrate-pyruvate shuttles, through the production of NADPH or other metabolites. We used selectable vectors expressing short hairpin RNA (shRNA) to stably decrease Me1 mRNA levels by 80–86% and ME1 enzyme activity by 78–86% with either of two shRNAs in the INS-1 832/13 insulinoma cell line. Contrary to published short term ME1 knockdown experiments, our long term targeted cells showed normal insulin secretion in response to glucose or to glutamine plus 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid. We found no increase in the mRNAs and enzyme activities of the cytosolic isocitrate dehydrogenase or glucose-6-phosphate dehydrogenase, which also produce cytosolic NADPH. There was no compensatory induction of the mRNAs for the mitochondrial malic enzymes Me2 or Me3. Interferon pathway genes induced in preliminary small interfering RNA experiments were not induced in the long term shRNA experiments. We repeated our study with an improved vector containing Tol2 transposition sequences to produce a higher rate of stable transferents and shortened time to testing, but this did not alter the results. We similarly used stably expressed shRNA to reduce mitochondrial NAD(P)-malic enzyme (Me2) mRNA by up to 95%, with severely decreased ME2 protein and a 90% decrease in enzyme activity. Insulin release to glucose or glutamine plus 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid remained normal. The maintenance of robust insulin secretion after lowering expression of either one of these malic enzymes is consistent with the redundancy of pathways of pyruvate cycling and/or cytosolic NADPH production in insulinoma cells. PMID:19858194

  17. Chronic reduction of the cytosolic or mitochondrial NAD(P)-malic enzyme does not affect insulin secretion in a rat insulinoma cell line.

    Science.gov (United States)

    Brown, Laura J; Longacre, Melissa J; Hasan, Noaman M; Kendrick, Mindy A; Stoker, Scott W; Macdonald, Michael J

    2009-12-18

    The cytosolic malic enzyme (ME1) has been suggested to augment insulin secretion via the malate-pyruvate and/or citrate-pyruvate shuttles, through the production of NADPH or other metabolites. We used selectable vectors expressing short hairpin RNA (shRNA) to stably decrease Me1 mRNA levels by 80-86% and ME1 enzyme activity by 78-86% with either of two shRNAs in the INS-1 832/13 insulinoma cell line. Contrary to published short term ME1 knockdown experiments, our long term targeted cells showed normal insulin secretion in response to glucose or to glutamine plus 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid. We found no increase in the mRNAs and enzyme activities of the cytosolic isocitrate dehydrogenase or glucose-6-phosphate dehydrogenase, which also produce cytosolic NADPH. There was no compensatory induction of the mRNAs for the mitochondrial malic enzymes Me2 or Me3. Interferon pathway genes induced in preliminary small interfering RNA experiments were not induced in the long term shRNA experiments. We repeated our study with an improved vector containing Tol2 transposition sequences to produce a higher rate of stable transferents and shortened time to testing, but this did not alter the results. We similarly used stably expressed shRNA to reduce mitochondrial NAD(P)-malic enzyme (Me2) mRNA by up to 95%, with severely decreased ME2 protein and a 90% decrease in enzyme activity. Insulin release to glucose or glutamine plus 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid remained normal. The maintenance of robust insulin secretion after lowering expression of either one of these malic enzymes is consistent with the redundancy of pathways of pyruvate cycling and/or cytosolic NADPH production in insulinoma cells.

  18. Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells.

    Science.gov (United States)

    Najem, Dema; Bamji-Mirza, Michelle; Yang, Ze; Zhang, Wandong

    2016-06-01

    Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) toxicity, tau pathology, insulin resistance, neuroinflammation, and dysregulation of cholesterol homeostasis, all of which play roles in neurodegeneration. Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes. In this study, we investigated possible relationships among insulin signaling and cholesterol biosynthesis, along with the effects of Aβ42 on these pathways in vitro. We found that neuroblastoma 2a (N2a) cells transfected with the human gene encoding amyloid-β protein precursor (AβPP) (N2a-AβPP) produced Aβ and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment, and by increased phosphorylation of insulin receptor subunit-1 at serine 612 (p-IRS-S612) as compared to parental N2a cells. Treatment of human neuroblastoma SH-SY5Y cells with Aβ42 also increased p-IRS-S612, suggesting that Aβ42 is responsible for insulin resistance. The insulin resistance was alleviated when N2a-AβPP cells were treated with higher insulin concentrations. Insulin increased Aβ release from N2a-AβPP cells, by which it may promote Aβ clearance. Insulin increased cholesterol-synthesis gene expression in SH-SY5Y and N2a cells, including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) through sterol-regulatory element-binding protein-2 (SREBP2). While Aβ42-treated SH-SY5Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses, they also showed down-regulation of neuro-protective/anti-inflammatory DHCR24. These results suggest that Aβ42 may cause insulin resistance, activate JNK for c-Jun phosphorylation, and lead to dysregulation of cholesterol homeostasis, and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote A

  19. Differential patterns of insulin secretion and sensitivity in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease versus patients with type 2 diabetes mellitus alone.

    Science.gov (United States)

    Chai, Shang-Yu; Pan, Xiao-Yu; Song, Ke-Xiu; Huang, Yue-Ye; Li, Fei; Cheng, Xiao-Yun; Qu, Shen

    2014-01-07

    Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) often coexist and have adverse outcomes. The aim of our study was to elucidate metabolic abnormalities in patients with DM-NAFLD versus those with T2DM alone. Patients were divided into two groups: 26 T2DM patients with NAFLD and 26 gender-, age-, and body mass index-matched patients with T2DM alone. Patients took a 75-g oral glucose tolerance test (OGTT), which measured serum insulin and C-peptide (C-p) levels at baseline (0 min), 30 min, 60 min, and 120 min after glucose challenge. Patients with DM-NAFLD or T2DM alone had similar blood glucose levels. β-cell hypersecretion was more obvious in patients with DM-NAFLD. In addition, fasting, early-phase, and late-phase C-peptide levels were significantly increased in patients with DM-NAFLD (ΔC-p 0-30 min, P insulin resistance during the OGTT did not differ significantly between groups. Hepatic insulin sensitivity independently contributed to the early phase (0-30 min) of the OGTT in patients with T2DM and NAFLD, whereas a significant deficit in late insulin secretion independently contributed to the 30-120 min glucose status in patients with T2DM only. In patients with similar levels of insulin resistance and hyperglycemia, DM-NAFLD was associated with higher serum insulin levels than T2DM alone. Hyperinsulinemia is caused mainly by β-cell hypersecretion. The present study demonstrates pathophysiological differences in mechanisms of insulin resistance in patients with DM-NAFLD versus T2DM alone.

  20. The influence of INS VNTR class III allele on auxological parameters, glucose, insulin, lipids, and adipocytokines secretion in prepubertal children born small for gestational age.

    Science.gov (United States)

    Stawerska, Renata; Szałapska, Małgorzata; Borowiec, Maciej; Antosik, Karolina; Młynarski, Wojciech; Lewiński, Andrzej

    2016-01-01

    The insulin gene variable number of tandem repeats (INS VNTR) class III allele has been implicated in lower birth weight, obesity, and insulin resistance. We assessed its influence on birth weight in the Polish population and on the current body mass and metabolic profile in prepubertal children born small for gestational age (SGA). DNA for genotyping of INS VNTR was available for 123 subjects born SGA and 132 born appropriate for gestational age (AGA). We identified two alleles: class I and class III. Next, in 112 prepubertal (aged: 6.8 ± 1.38 years) SGA children, the auxological measurements, fasting serum C-peptide, triglycerides, cholesterol, ghrelin, leptin, adiponectin, resistin, cortisol, and insulin-like growth factor type I (IGF-I) concentrations, as well as glucose and insulin during oral glucose tolerance test (OGTT), were assessed and insulin resistance indices were calculated. The results were analysed depending on INS VNTR variants. The occurrence of individual INS VNTR variants were similar in the SGA and AGA groups. In prepubertal SGA children, we did not observe any statistical differences as regards birth weight, body mass, lipids, or adipocytokine concentrations among I/I, I/III, and III/III class groups. The concentration of insulin in 120' of OGTT was significantly higher in class III homozygous than in class I homozygous individuals. Variant INS VNTR class III was shown not to be associated in any essential way with birth weight in the Polish population. Among prepubertal SGA children, the presence of INS VNTR class III is related to higher insulin secretion during OGTT. (Endokrynol Pol 2016; 67 (6): 585-591).

  1. Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

    Science.gov (United States)

    Cheurfa, N; Brenner, G M; Reis, A F; Dubois-Laforgue, D; Roussel, R; Tichet, J; Lantieri, O; Balkau, B; Fumeron, F; Timsit, J; Marre, M; Velho, G

    2011-03-01

    We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

  2. Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism.

    Science.gov (United States)

    Roomp, Kirsten; Kristinsson, Hjalti; Schvartz, Domitille; Ubhayasekera, Kumari; Sargsyan, Ernest; Manukyan, Levon; Chowdhury, Azazul; Manell, Hannes; Satagopam, Venkata; Groebe, Karlfried; Schneider, Reinhard; Bergquist, Jonas; Sanchez, Jean-Charles; Bergsten, Peter

    2017-01-01

    Studies on the pathophysiology of type 2 diabetes mellitus (T2DM) have linked the accumulation of lipid metabolites to the development of beta-cell dysfunction and impaired insulin secretion. In most in vitro models of T2DM, rodent islets or beta-cell lines are used and typically focus is on specific cellular pathways or organs. Our aim was to, firstly, develop a combined lipidomics and proteomics approach for lipotoxicity in isolated human islets and, secondly, investigate if the approach could delineate novel and/ or confirm reported mechanisms of lipotoxicity. To this end isolated human pancreatic islets, exposed to chronically elevated palmitate concentrations for 0, 2 and 7 days, were functionally characterized and their levels of multiple targeted lipid and untargeted protein species determined. Glucose-stimulated insulin secretion from the islets increased on day 2 and decreased on day 7. At day 7 islet insulin content decreased and the proinsulin to insulin content ratio doubled. Amounts of cholesterol, stearic acid, C16 dihydroceramide and C24:1 sphingomyelin, obtained from the lipidomic screen, increased time-dependently in the palmitate-exposed islets. The proteomic screen identified matching changes in proteins involved in lipid biosynthesis indicating up-regulated cholesterol and lipid biosynthesis in the islets. Furthermore, proteins associated with immature secretory granules were decreased when palmitate exposure time was increased despite their high affinity for cholesterol. Proteins associated with mature secretory granules remained unchanged. Pathway analysis based on the protein and lipid expression profiles implicated autocrine effects of insulin in lipotoxicity. Taken together the study demonstrates that combining different omics approaches has potential in mapping of multiple simultaneous cellular events. However, it also shows that challenges exist for effectively combining lipidomics and proteomics in primary cells. Our findings provide

  3. Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism.

    Directory of Open Access Journals (Sweden)

    Kirsten Roomp

    Full Text Available Studies on the pathophysiology of type 2 diabetes mellitus (T2DM have linked the accumulation of lipid metabolites to the development of beta-cell dysfunction and impaired insulin secretion. In most in vitro models of T2DM, rodent islets or beta-cell lines are used and typically focus is on specific cellular pathways or organs. Our aim was to, firstly, develop a combined lipidomics and proteomics approach for lipotoxicity in isolated human islets and, secondly, investigate if the approach could delineate novel and/ or confirm reported mechanisms of lipotoxicity. To this end isolated human pancreatic islets, exposed to chronically elevated palmitate concentrations for 0, 2 and 7 days, were functionally characterized and their levels of multiple targeted lipid and untargeted protein species determined. Glucose-stimulated insulin secretion from the islets increased on day 2 and decreased on day 7. At day 7 islet insulin content decreased and the proinsulin to insulin content ratio doubled. Amounts of cholesterol, stearic acid, C16 dihydroceramide and C24:1 sphingomyelin, obtained from the lipidomic screen, increased time-dependently in the palmitate-exposed islets. The proteomic screen identified matching changes in proteins involved in lipid biosynthesis indicating up-regulated cholesterol and lipid biosynthesis in the islets. Furthermore, proteins associated with immature secretory granules were decreased when palmitate exposure time was increased despite their high affinity for cholesterol. Proteins associated with mature secretory granules remained unchanged. Pathway analysis based on the protein and lipid expression profiles implicated autocrine effects of insulin in lipotoxicity. Taken together the study demonstrates that combining different omics approaches has potential in mapping of multiple simultaneous cellular events. However, it also shows that challenges exist for effectively combining lipidomics and proteomics in primary cells. Our

  4. Establishing a Large-Animal Model for In Vivo Reprogramming of Bile Duct Cells into Insulin-Secreting Cells to Treat Diabetes.

    Science.gov (United States)

    Hill, Caitlin M; Banga, Anannya; Abrahante, Juan E; Yuan, Ce; Mutch, Lucas A; Janecek, Jody; O'Brien, Timothy; Graham, Melanie L; Dutton, James R

    2017-06-01

    Type 1 diabetes manifests as autoimmune destruction of beta cells requiring metabolic management with an exogenous replacement of insulin, either by repeated injection of recombinant insulin or by transplantation of allogeneic islets from cadaveric donors. Both of these approaches have severe limitations. Repeated insulin injection requires intensive blood glucose monitoring, is expensive, and is associated with decreased quality-of-life measures. Islet transplantation, while highly effective, is severely limited by shortage of donor organs. Clinical translation of beta cells derived from pluripotent stem cells is also not yet a reality, and alternative approaches to solving the replacement of lost beta cell function are required. In vivo direct reprogramming offers an attractive approach to generating new endogenous insulin-secreting cells by permanently altering the phenotype of somatic cells after transient expression of transcription factors. Previously, we have successfully restored control of blood glucose in diabetic mice by reprogramming liver cells into glucose-sensitive insulin-secreting cells after the transient, simultaneous delivery of three transcription factors (Pdx1, Ngn3, and MafA) to the liver of diabetic mice, using an adenoviral vector (Ad-PNM). Establishing a clinically relevant, large-animal model is a critical next step in translating this approach beyond the proof-of-principle stage in rodents and allowing investigation of vector design, dose and delivery, host response to vector infusion, and establishment of suitable criteria for measuring safety and efficacy. In this feasibility study we infused Ad-PNM into the liver of three diabetic cynomolgus macaques via portal vein catheter. Vector presence and cargo gene and protein expression were detected in liver tissue after infusion with no adverse effects. Refinement of immune suppression significantly extended the period of exogenous PNM expression. This pilot study establishes the

  5. Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells

    Science.gov (United States)

    Emlet, David R.; Pastor-Soler, Nuria; Marciszyn, Allison; Wen, Xiaoyan; Gomez, Hernando; Humphries, William H.; Morrisroe, Seth; Volpe, Jacob K.

    2017-01-01

    We have characterized the expression and secretion of the acute kidney injury (AKI) biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in human kidney epithelial cells in primary cell culture and tissue. We established cell culture model systems of primary kidney cells of proximal and distal tubule origin and observed that both proteins are indeed expressed and secreted in both tubule cell types in vitro. However, TIMP-2 is both expressed and secreted preferentially by cells of distal tubule origin, while IGFBP7 is equally expressed across tubule cell types yet preferentially secreted by cells of proximal tubule origin. In human kidney tissue, strong staining of IGFBP7 was seen in the luminal brush-border region of a subset of proximal tubule cells, and TIMP-2 stained intracellularly in distal tubules. Additionally, while some tubular colocalization of both biomarkers was identified with the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, both biomarkers could also be seen alone, suggesting the possibility for differential mechanistic and/or temporal profiles of regulation of these early AKI biomarkers from known markers of injury. Last, an in vitro model of ischemia-reperfusion demonstrated enhancement of secretion of both markers early after reperfusion. This work provides a rationale for further investigation of these markers for their potential role in the pathogenesis of acute kidney injury. PMID:28003188

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

    Science.gov (United States)

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

    2016-06-01

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

  7. V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog A Synthetic Modified mRNA Drives Reprogramming of Human Pancreatic Duct-Derived Cells Into Insulin-Secreting Cells

    Science.gov (United States)

    Corritore, Elisa; Lee, Yong-Syu; Pasquale, Valentina; Liberati, Daniela; Hsu, Mei-Ju; Lombard, Catherine Anne; Van Der Smissen, Patrick; Vetere, Amedeo; Bonner-Weir, Susan; Piemonti, Lorenzo; Sokal, Etienne

    2016-01-01

    β-Cell replacement therapy represents the most promising approach to restore β-cell mass and glucose homeostasis in patients with type 1 diabetes. Safety and ethical issues associated with pluripotent stem cells stimulated the search for adult progenitor cells with endocrine differentiation capacities. We have already described a model for expansion and differentiation of human pancreatic duct-derived cells (HDDCs) into insulin-producing cells. Here we show an innovative and robust in vitro system for large-scale production of β-like cells from HDDCs using a nonintegrative RNA-based reprogramming technique. Synthetic modified RNAs for pancreatic transcription factors (pancreatic duodenal homeobox 1, neurogenin3, and V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A [MAFA]) were manufactured and daily transfected in HDDCs without strongly affecting immune response and cell viability. MAFA overexpression was efficient and sufficient to induce β-cell differentiation of HDDCs, which acquired a broad repertoire of mature β-cell markers while downregulating characteristic epithelial-mesenchymal transition markers. Within 7 days, MAFA-reprogrammed HDDC populations contained 37% insulin-positive cells and a proportion of endocrine cells expressing somatostatin and pancreatic polypeptide. Ultrastructure analysis of differentiated HDDCs showed both immature and mature insulin granules with light-backscattering properties. Furthermore, in vitro HDDC-derived β cells (called β-HDDCs) secreted human insulin and C-peptide in response to glucose, KCl, 3-isobutyl-1-methylxanthine, and tolbutamide stimulation. Transplantation of β-HDDCs into diabetic SCID-beige mice confirmed their functional glucose-responsive insulin secretion and their capacity to mitigate hyperglycemia. Our data describe a new, reliable, and fast procedure in adult human pancreatic cells to generate clinically relevant amounts of new β cells with potential to reverse diabetes. Significance

  8. G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1.

    Science.gov (United States)

    Ferdaoussi, M; Bergeron, V; Zarrouki, B; Kolic, J; Cantley, J; Fielitz, J; Olson, E N; Prentki, M; Biden, T; MacDonald, P E; Poitout, V

    2012-10-01

    Activation of the G protein-coupled receptor (GPR)40 by long-chain fatty acids potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, and GPR40 agonists are in clinical development for type 2 diabetes therapy. GPR40 couples to the G protein subunit Gα(q/11) but the signalling cascade activated downstream is unknown. This study aimed to determine the mechanisms of GPR40-dependent potentiation of GSIS by fatty acids. Insulin secretion in response to glucose, oleate or diacylglycerol (DAG) was assessed in dynamic perifusions and static incubations in islets from wild-type (WT) and Gpr40 (-/-) mice. Depolymerisation of filamentous actin (F-actin) was visualised by phalloidin staining and epifluorescence. Pharmacological and molecular approaches were used to ascertain the roles of protein kinase D (PKD) and protein kinase C delta in GPR40-mediated potentiation of GSIS. Oleate potentiates the second phase of GSIS, and this effect is largely dependent upon GPR40. Accordingly, oleate induces rapid F-actin remodelling in WT but not in Gpr40 (-/-) islets. Exogenous DAG potentiates GSIS in both WT and Gpr40 (-/-) islets. Oleate induces PKD phosphorylation at residues Ser-744/748 and Ser-916 in WT but not Gpr40 (-/-) islets. Importantly, oleate-induced F-actin depolymerisation and potentiation of GSIS are lost upon pharmacological inhibition of PKD1 or deletion of Prkd1. We conclude that the signalling cascade downstream of GPR40 activation by fatty acids involves activation of PKD1, F-actin depolymerisation and potentiation of second-phase insulin secretion. These results provide important information on the mechanisms of action of GPR40, a novel drug target for type 2 diabetes.

  9. Oral delivery of bioencapsulated exendin-4 expressed in chloroplasts lowers blood glucose level in mice and stimulates insulin secretion in beta-TC6 cells.

    Science.gov (United States)

    Kwon, Kwang-Chul; Nityanandam, Ramya; New, James S; Daniell, Henry

    2013-01-01

    Glucagon-like peptide (GLP-1) increases insulin secretion but is rapidly degraded (half-life: 2 min in circulation). GLP-1 analogue, exenatide (Byetta) has a longer half-life (3.3-4 h) with potent insulinotropic effects but requires cold storage, daily abdominal injections with short shelf life. Because patients with diabetes take >60 000 injections in their life time, alternative delivery methods are highly desired. Exenatide is ideal for oral delivery because insulinotropism is glucose dependent, with reduced risk of hypoglycaemia even at higher doses. Therefore, exendin-4 (EX4) was expressed as a cholera toxin B subunit (CTB)-fusion protein in tobacco chloroplasts to facilitate bioencapsulation within plant cells and transmucosal delivery in the gut via GM1 receptors present in the intestinal epithelium. The transgene integration was confirmed by PCR and Southern blot analysis. Expression level of CTB-EX4 reached up to 14.3% of total leaf protein (TLP). Lyophilization of leaf material increased therapeutic protein concentration by 12- to 24-fold, extended their shelf life up to 15 months when stored at room temperature and eliminated microbes present in fresh leaves. The pentameric structure, disulphide bonds and functionality of CTB-EX4 were well preserved in lyophilized materials. Chloroplast-derived CTB-EX4 showed increased insulin secretion similar to the commercial EX4 in beta-TC6, a mouse pancreatic cell line. Even when 5000-fold excess dose of CTB-EX4 was orally delivered, it stimulated insulin secretion similar to the intraperitoneal injection of commercial EX4 but did not cause hypoglycaemia in mice. Oral delivery of the bioencapsulated EX4 should eliminate injections, increase patient compliance/convenience and significantly lower their cost. © 2012 The Authors Plant Biotechnology Journal © 2012 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

  10. Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion.

    Directory of Open Access Journals (Sweden)

    Naoya Murao

    Full Text Available Incretins (GLP-1 and GIP potentiate insulin secretion through cAMP signaling in pancreatic β-cells in a glucose-dependent manner. We recently proposed a mechanistic model of incretin-induced insulin secretion (IIIS that requires two critical processes: 1 generation of cytosolic glutamate through the malate-aspartate (MA shuttle in glucose metabolism and 2 glutamate transport into insulin granules by cAMP signaling to promote insulin granule exocytosis. To directly prove the model, we have established and characterized CRISPR/Cas9-engineered clonal mouse β-cell lines deficient for the genes critical in these two processes: aspartate aminotransferase 1 (AST1, gene symbol Got1, a key enzyme in the MA shuttle, which generates cytosolic glutamate, and the vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3, gene symbol Slc17a7, Slc17a6, and Slc17a8, respectively, which participate in glutamate transport into secretory vesicles. Got1 knockout (KO β-cell lines were defective in cytosolic glutamate production from glucose and showed impaired IIIS. Unexpectedly, different from the previous finding that global Slc17a7 KO mice exhibited impaired IIIS from pancreatic islets, β-cell specific Slc17a7 KO mice showed no significant impairment in IIIS, as assessed by pancreas perfusion experiment. Single Slc17a7 KO β-cell lines also retained IIIS, probably due to compensatory upregulation of Slc17a6. Interestingly, triple KO of Slc17a7, Slc17a6, and Slc17a8 diminished IIIS, which was rescued by exogenously introduced wild-type Slc17a7 or Slc17a6 genes. The present study provides direct evidence for the essential roles of AST1 and VGLUTs in β-cell glutamate signaling for IIIS and also shows the usefulness of the CRISPR/Cas9 system for studying β-cells by simultaneous disruption of multiple genes.

  11. Variants within the calpain-10 gene on chromosome 2q37 (NIDDM1) and relationships to type 2 diabetes, insulin resistance, and impaired acute insulin secretion among Scandinavian Caucasians

    DEFF Research Database (Denmark)

    Rasmussen, Søren K; Urhammer, Søren A; Berglund, Lars Erik

    2002-01-01

    Variations in the calpain-10 gene (CAPN10) have been identified among Mexican-Americans, and an at-risk haplotype combination (112/121) defined by three polymorphisms, UCSNP-43, -19, and -63, confers increased risk of type 2 diabetes. Here we examine the three polymorphisms in 1,594 Scandinavian...... subjects, including 409 type 2 diabetic patients, 200 glucose-tolerant control subjects, 322 young healthy subjects, 206 glucose-tolerant offspring of diabetic patients, and 457 glucose-tolerant 70-year-old men. The frequency of the 112/121 combination was not significantly different in 409 type 2 diabetic...... the CAPN10 variants and type 2 diabetes, insulin resistance, or impaired insulin secretion....

  12. Insulin-like growth factor-I feedback regulation of growth hormone and luteinizing hormone secretion in the pig: evidence for a pituitary site of action.

    Science.gov (United States)

    Barb, C R; Hausman, G J

    2009-06-01

    Three experiments (EXP) were conducted to determine the role of insulin-like growth factor-I (IGF-I) in the control of growth hormone (GH) and LH secretion. In EXP I, prepuberal gilts, 65 ± 6 kg body weight and 140 days of age received intracerebroventricular (ICV) injections of saline (n = 4), 25 μg (n = 4) or 75 μg (n = 4) IGF-I and jugular blood samples were collected. In EXP II, anterior pituitary cells in culture collected from 150-day-old prepuberal gilts (n = 6) were challenged with 0.1, 10 or 1000 nM [Ala15]-h growth hormone-releasing hormone-(1-29)NH2 (GHRH), or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 1000 nM GHRH. Secreted GH was measured at 4 and 24 h after treatment. In EXP III, anterior pituitary cells in culture collected from 150-day-old barrows (n = 5) were challenged with 10, 100 or 1000 nM gonadotropin-releasing hormone (GnRH) or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 100 nM GnRH. Secreted LH was measured at 4 h after treatment. In EXP I, serum GH and LH concentrations were unaffected by ICV IGF-I treatment. In EXP II, relative to control all doses of GHRH increased (P 0.1). In conclusion, under these experimental conditions the results suggest that the pituitary is the putative site for IGF-I modulation of GH and LH secretion. Further examination of the role of IGF-I on GH and LH secretion is needed to understand the inhibitory and stimulatory action of IGF-I on GH and LH secretion.

  13. The zinc transporter ZNT3 co-localizes with insulin in INS-1E pancreatic beta cells and influences cell survival, insulin secretion capacity, and ZNT8 expression

    DEFF Research Database (Denmark)

    Smidt, Kamille; Larsen, Agnete; Brønden, Andreas

    2016-01-01

    Zinc trafficking in pancreatic beta cells is tightly regulated by zinc transporting (ZNTs) proteins. The role of different ZNTs in the beta cells is currently being clarified. ZNT8 transports zinc into insulin granules and is critical for a correct insulin crystallization and storage...... in the granules whereas ZNT3 knockout negatively affects beta cell function and survival. Here, we describe for the first time the sub-cellular localization of ZNT3 by immuno-gold electron microscopy and supplement previous data from knockout experiments with investigations of the effect of ZNT3 in a pancreatic...... beta cell line, INS-1E overexpressing ZNT3. In INS-1E cells, we found that ZNT3 was abundant in insulin containing granules located close to the plasma membrane. The level of ZNT8 mRNA was significantly decreased upon over-expression of ZNT3 at different glucose concentrations (5, 11 and 21 mM glucose...

  14. The H+/K+ ATPase Inhibitor SCH-28080 Inhibits Insulin Secretion and Induces Cell Death in INS-1E Rat Insulinoma Cells

    Directory of Open Access Journals (Sweden)

    Martin Jakab

    2017-10-01

    Full Text Available Background/Aims: Glucose-stimulated insulin secretion (GSIS of pancreatic β-cells involves glucose uptake and metabolism, closure of KATP channels and depolarization of the cell membrane potential (Vmem, activation of voltage-activated Ca2+ currents (ICav and influx of Ca2+, which eventually triggers hormone exocytosis. Beside this classical pathway, KATP-independent mechanisms such as changes in intracellular pH (pHi or cell volume, which also affect β-cell viability, can elicit or modify insulin release. In β-cells the regulation of pHi is mainly accomplished by Na+/H+ exchangers (NHEs. To investigate if other proton extrusion mechanisms than NHEs are involved in pH regulation, we tested for the presence of the non-gastric H+/K+ ATPase in rat insulinoma cells and assessed effects of the H+/K+ ATPase inhibitor SCH-28080 on insulin secretion, cell viability and apoptosis. Methods: In INS-1E cell cultures, H+/K+ ATPase gene and protein expression was analyzed by reverse transcription PCR and Western blotting. Intracellular pH (pHi recovery after acute acidic load was measured by NH4Cl prepulsing using BCECF. Insulin secretion was determined by ELISA from the cell culture supernatant. Vmem, K+ and Ca2+ currents were recorded using patch clamp. Overall cell responses were determined using resazurin (viability and cytotoxicity assays. The mean cell volume (MCV, cell granularity (side-scatter; SSC, phosphatidylserine (PS exposure, cell membrane integrity, caspase activity and the mitochondrial membrane potential (ΔΨm were measured by flow cytometry. Results: We found that the α-subunit of the non-gastric H+/K+ ATPase (HKα2 is expressed on mRNA and protein level. However, compared to rat colon tissue, in INS-1E cells mRNA abundance was very low. In NH4Cl prepulsing experiments no K+-dependent pHi recovery was observed under Na+-free extracellular conditions. Nonetheless within 1 h, 20 µM SCH-28080 inhibited GSIS by ∼50%, while basal release

  15. The GTPase Rab37 Participates in the Control of Insulin Exocytosis.

    Directory of Open Access Journals (Sweden)

    Sanda Ljubicic

    Full Text Available Rab37 belongs to a subclass of Rab GTPases regulating exocytosis, including also Rab3a and Rab27a. Proteomic studies indicate that Rab37 is associated with insulin-containing large dense core granules of pancreatic β-cells. In agreement with these observations, we detected Rab37 in extracts of β-cell lines and human pancreatic islets and confirmed by confocal microscopy the localization of the GTPase on insulin-containing secretory granules. We found that, as is the case for Rab3a and Rab27a, reduction of Rab37 levels by RNA interference leads to impairment in glucose-induced insulin secretion and to a decrease in the number of granules in close apposition to the plasma membrane. Pull-down experiments revealed that, despite similar functional effects, Rab37 does not interact with known Rab3a or Rab27a effectors and is likely to operate through a different mechanism. Exposure of insulin-secreting cells to proinflammatory cytokines, fatty acids or oxidized low-density lipoproteins, mimicking physiopathological conditions that favor the development of diabetes, resulted in a decrease in Rab37 expression. Our data identify Rab37 as an additional component of the machinery governing exocytosis of β-cells and suggest that impaired expression of this GTPase may contribute to defective insulin release in pre-diabetic and diabetic conditions.

  16. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    Science.gov (United States)

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways. Copyright © 2016 the American Physiological Society.

  17. In vitro effects of bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), or VO(dmpp)2, on insulin secretion in pancreatic islets of type 2 diabetic Goto-Kakizaki rats.

    Science.gov (United States)

    Pelletier, Julien; Domingues, Neuza; Castro, M Margarida C A; Östenson, Claes-Göran

    2016-01-01

    Vanadium compounds have been explored as therapy of diabetes, and most studies have focussed on insulin mimetic effects, i.e. reducing hyperglycemia by improving glucose sensitivity and thus glucose uptake in sensitive tissues. We have recently shown that bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), VO(dmpp)2, has promising effects when compared to another vanadium compound, bis(maltolato)oxidovanadium(IV), BMOV, and insulin itself, in isolated adipocytes and in vivo in Goto-Kakizaki (GK) rats, an animal model of hereditary type 2 diabetes (T2D).We now have investigated in GK rats whether VO(dmpp)2 also modulates another important defect in T2D, impaired insulin secretion. VO(dmpp)2, but not BMOV, stimulated insulin secretion from isolated GK rat pancreatic islets at high, 16.7mM, but not at low–normal, 3.3 mM, glucose concentration. Mechanistic studies demonstrate that the insulin releasing effect of VO(dmpp)2 is due to its interaction with several steps in the stimulus-secretion coupling for glucose, including islet glucose metabolism and K-ATP channels, L-type Ca2+ channels, modulation by protein kinases A and C, as well as the exocytotic machinery. In conclusion, VO(dmpp)2 exhibits properties of interest for treatment of the insulin secretory defect in T2D, in addition to its well-described insulin mimetic activity.

  18. Early enhancements of hepatic and later of peripheral insulin sensitivity combined with increased postprandial insulin secretion contribute to improved glycemic control after Roux-en-Y gastric bypass

    DEFF Research Database (Denmark)

    Bojsen-Møller, Kirstine N; Dirksen, Carsten; Jørgensen, Nils Bruun

    2014-01-01

    Roux-en-Y gastric bypass (RYGB) improves glycemic control within days after surgery, and changes in insulin sensitivity and beta-cell function are likely to be involved. We studied 10 obese patients with type 2 diabetes and 10 obese glucose tolerant subjects before, 1 week, 3 months and 1 year...

  19. Impact of objectively measured sedentary behaviour on changes in insulin resistance and secretion over 3 years in the RISC study

    DEFF Research Database (Denmark)

    Lahjibi, E; Heude, B; Dekker, J M

    2013-01-01

    The importance of reducing sedentary time is increasingly being recognized in the prevention of diabetes and cardiovascular disease. Despite this, the prospective association between sedentary time and physical activity with insulin sensitivity and cardiometabolic risk factors has been little stu...

  20. BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt.

    Science.gov (United States)

    Karandrea, Shpetim; Yin, Huquan; Liang, Xiaomei; Heart, Emma A

    2017-12-01

    PBDEs (polybrominated diphenyl ethers) are environmental pollutants that have been linked to the development of type 2 diabetes, however, the precise mechanisms are not clear. Particularly, their direct effect on insulin secretion is unknown. In this study, we show that two PBDE congeners, BDE-47 and BDE-85, potentiate glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells. This effect of BDE-47 and BDE-85 on GSIS was dependent on thyroid receptor (TR). Both BDE-47 and BDE-85 (10μM) activated Akt during an acute exposure. The activation of Akt by BDE-47 and BDE-85 plays a role in their potentiation of GSIS, as pharmacological inhibition of PI3K, an upstream activator of Akt, significantly lowers GSIS compared to compounds alone. This study shows that BDE-47 and BDE-85 directly act on pancreatic β-cells to stimulate GSIS, and that this effect is mediated by the thyroid receptor (TR) and Akt activation. Copyright © 2017. Published by Elsevier B.V.

  1. Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion.

    Science.gov (United States)

    Branco, Renato Chaves Souto; Camargo, Rafael Ludemann; Batista, Thiago Martins; Vettorazzi, Jean Franciesco; Borck, Patrícia Cristine; Dos Santos-Silva, Junia Carolina Rebelo; Boschero, Antonio Carlos; Zoppi, Cláudio Cesar; Carneiro, Everardo Magalhães

    2017-09-01

    Taurine (Tau) restores β-cell function in obesity; however, its action is lost in malnourished obese rodents. Here, we investigated the mechanisms involved in the lack of effects of Tau in this model. C57BL/6 mice were fed a control diet (CD) (14% protein) or a protein-restricted diet (RD) (6% protein) for 6 wk. Afterward, mice received a high-fat diet (HFD) for 8 wk [CD + HFD (CH) and RD + HFD (RH)] with or without 5% Tau supplementation after weaning on their drinking water [CH + Tau (CHT) and RH + Tau (RHT)]. The HFD increased insulin secretion through mitochondrial metabolism in CH and RH. Tau prevented all those alterations in CHT only. The expression of the taurine transporter (Tau-T), as well as Tau content in pancreatic islets, was increased in CH but had no effect on RH. Protein malnutrition programs β cells and impairs Tau-induced restoration of mitochondrial metabolism and biogenesis. This may be associated with modulation of the expression of Tau-T in pancreatic islets, which may be responsible for the absence of effect of Tau in protein-malnourished obese mice.-Branco, R. C. S., Camargo, R. L., Batista, T. M., Vettorazzi, J. F., Borck, P. C., dos Santos-Silva, J. C. R., Boschero, A. C., Zoppi, C. C., Carneiro, E. M. Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion. © FASEB.

  2. Generation of glucose-sensitive insulin-secreting beta-like cells from human embryonic stem cells by incorporating a synthetic lineage-control network.

    Science.gov (United States)

    Saxena, Pratik; Bojar, Daniel; Zulewski, Henryk; Fussenegger, Martin

    2017-10-10

    We previously reported novel technology to differentiate induced pluripotent stem cells (IPSCs) into glucose-sensitive insulin-secreting beta-like cells by engineering a synthetic lineage-control network regulated by the licensed food additive vanillic acid. This genetic network was able to program intricate expression dynamics of the key transcription factors Ngn3 (neurogenin 3, OFF-ON-OFF), Pdx1 (pancreatic and duodenal homeobox 1, ON-OFF-ON) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A, OFF-ON) to guide the differentiation of IPSC-derived pancreatic progenitor cells to beta-like cells. In the present study, we show for the first time that this network can also program the expression dynamics of Ngn3, Pdx1 and MafA in human embryonic stem cell (hESC)-derived pancreatic progenitor cells and drive differentiation of these cells into glucose-sensitive insulin-secreting beta-like cells. Therefore, synthetic lineage-control networks appear to be a robust methodology for differentiating pluripotent stem cells into somatic cell types for basic research and regenerative medicine. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Relative importance of first- and second-phase insulin secretion in glucose homeostasis in conscious dog. II. Effects on gluconeogenesis.

    Science.gov (United States)

    Steiner, K E; Mouton, S M; Williams, P E; Lacy, W W; Cherrington, A D

    1986-07-01

    The normal pancreatic response to an exogenous glucagon infusion is a biphasic release of insulin. In our study the ability of each component of insulin release to counter the effects of the glucagon on gluconeogenesis and alanine metabolism was assessed by mimicking first- and/or second-phase insulin release with infusions of somatostatin and intraportal insulin. When a fourfold increase in glucagon was brought about in the presence of fixed basal insulin release, there was a large increase in overall glucose production and gluconeogenesis. The increase in the conversion of [14C]alanine into [14C]glucose (169 +/- 42%, P less than .05) was accompanied by an increase in the fractional extraction of alanine by the liver (FEA 0.32 +/- 0.06 to 0.66 +/- 0.10, P less than .05) and net hepatic alanine uptake (NHAU 2.97 +/- 0.45 to 4.61 +/- 0.48 mumol . kg-1 . min-1, P less than .05). Simulated first-phase insulin release had no effect on the ability of glucagon to increase FEA (0.32 +/- 0.03 to 0.66 +/- 0.03, P less than .05) or NHAU (3.69 +/- 0.80 to 5.10 +/- 0.69 mumol . kg-1 . min-1, P less than .05) but did limit the increase in overall gluconeogenic conversion (114 +/- 37%). Second-phase insulin release had no effect on either the glucagon-induced increase in FEA (0.35 +/- 0.08 to 0.73 +/- 0.04) or NHAU (3.35 +/- 0.92 to 5.13 +/- 0.85 mumol . kg-1 . min-1) but completely inhibited the increase in overall gluconeogenic conversion.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. The Ia-2β intronic miRNA, miR-153, is a negative regulator of insulin and dopamine secretion through its effect on the Cacna1c gene in mice.

    Science.gov (United States)

    Xu, Huanyu; Abuhatzira, Liron; Carmona, Gilberto N; Vadrevu, Suryakiran; Satin, Leslie S; Notkins, Abner L

    2015-10-01

    miR-153 is an intronic miRNA embedded in the genes that encode IA-2 (also known as PTPRN) and IA-2β (also known as PTPRN2). Islet antigen (IA)-2 and IA-2β are major autoantigens in type 1 diabetes and are important transmembrane proteins in dense core and synaptic vesicles. miR-153 and its host genes are co-regulated in pancreas and brain. The present experiments were initiated to decipher the regulatory network between miR-153 and its host gene Ia-2β (also known as Ptprn2). Insulin secretion was determined by ELISA. Identification of miRNA targets was assessed using luciferase assays and by quantitative real-time PCR and western blots in vitro and in vivo. Target protector was also employed to evaluate miRNA target function. Functional studies revealed that miR-153 mimic suppresses both glucose- and potassium-induced insulin secretion (GSIS and PSIS, respectively), whereas miR-153 inhibitor enhances both GSIS and PSIS. A similar effect on dopamine secretion also was observed. Using miRNA target prediction software, we found that miR-153 is predicted to target the 3'UTR region of the calcium channel gene, Cacna1c. Further studies confirmed that Cacna1c mRNA and protein are downregulated by miR-153 mimics and upregulated by miR-153 inhibitors in insulin-secreting freshly isolated mouse islets, in the insulin-secreting mouse cell line MIN6 and in the dopamine-secreting cell line PC12. miR-153 is a negative regulator of both insulin and dopamine secretion through its effect on Cacna1c expression, which suggests that IA-2β and miR-153 have opposite functional effects on the secretory pathway.

  5. Use of anesthesia dramatically alters the oral glucose tolerance and insulin secretion in C57Bl/6 mice

    DEFF Research Database (Denmark)

    Windeløv, Johanne A; Pedersen, Jens; Holst, Jens J

    2016-01-01

    Evaluation of the impact of anesthesia on oral glucose tolerance in mice. Anesthesia is often used when performing OGTT in mice to avoid the stress of gavage and blood sampling, although anesthesia may influence gastrointestinal motility, blood glucose, and plasma insulin dynamics. C57Bl/6 mice...... in the time frame -15 to +150 min. Plasma insulin concentration was measured at time 0 and 20 min. All four anesthetic regimens resulted in impaired glucose tolerance compared to saline/no anesthesia. (1) hypnorm/midazolam increased insulin concentrations and caused an altered glucose tolerance; (2) ketamine...... regimens altered the oral glucose tolerance, and we conclude that anesthesia should not be used when performing metabolic studies in mice....

  6. Cholinergic signaling mediates the effects of xenin-25 on secretion of pancreatic polypeptide but not insulin or glucagon in humans with impaired glucose tolerance.

    Directory of Open Access Journals (Sweden)

    Songyan Wang

    Full Text Available We previously demonstrated that infusion of an intestinal peptide called xenin-25 (Xen amplifies the effects of glucose-dependent insulinotropic polypeptide (GIP on insulin secretion rates (ISRs and plasma glucagon levels in humans. However, these effects of Xen, but not GIP, were blunted in humans with type 2 diabetes. Thus, Xen rather than GIP signaling to islets fails early during development of type 2 diabetes. The current crossover study determines if cholinergic signaling relays the effects of Xen on insulin and glucagon release in humans as in mice. Fasted subjects with impaired glucose tolerance were studied. On eight separate occasions, each person underwent a single graded glucose infusion- two each with infusion of albumin, Xen, GIP, and GIP plus Xen. Each infusate was administered ± atropine. Heart rate and plasma glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide (PP levels were measured. ISRs were calculated from C-peptide levels. All peptides profoundly increased PP responses. From 0 to 40 min, peptide(s infusions had little effect on plasma glucose concentrations. However, GIP, but not Xen, rapidly and transiently increased ISRs and glucagon levels. Both responses were further amplified when Xen was co-administered with GIP. From 40 to 240 min, glucose levels and ISRs continually increased while glucagon concentrations declined, regardless of infusate. Atropine increased resting heart rate and blocked all PP responses but did not affect ISRs or plasma glucagon levels during any of the peptide infusions. Thus, cholinergic signaling mediates the effects of Xen on insulin and glucagon release in mice but not humans.

  7. Cholinergic signaling mediates the effects of xenin-25 on secretion of pancreatic polypeptide but not insulin or glucagon in humans with impaired glucose tolerance.

    Science.gov (United States)

    Wang, Songyan; Oestricker, Lauren Z; Wallendorf, Michael J; Sterl, Karin; Dunai, Judit; Kilpatrick, C Rachel; Patterson, Bruce W; Reeds, Dominic N; Wice, Burton M

    2018-01-01

    We previously demonstrated that infusion of an intestinal peptide called xenin-25 (Xen) amplifies the effects of glucose-dependent insulinotropic polypeptide (GIP) on insulin secretion rates (ISRs) and plasma glucagon levels in humans. However, these effects of Xen, but not GIP, were blunted in humans with type 2 diabetes. Thus, Xen rather than GIP signaling to islets fails early during development of type 2 diabetes. The current crossover study determines if cholinergic signaling relays the effects of Xen on insulin and glucagon release in humans as in mice. Fasted subjects with impaired glucose tolerance were studied. On eight separate occasions, each person underwent a single graded glucose infusion- two each with infusion of albumin, Xen, GIP, and GIP plus Xen. Each infusate was administered ± atropine. Heart rate and plasma glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide (PP) levels were measured. ISRs were calculated from C-peptide levels. All peptides profoundly increased PP responses. From 0 to 40 min, peptide(s) infusions had little effect on plasma glucose concentrations. However, GIP, but not Xen, rapidly and transiently increased ISRs and glucagon levels. Both responses were further amplified when Xen was co-administered with GIP. From 40 to 240 min, glucose levels and ISRs continually increased while glucagon concentrations declined, regardless of infusate. Atropine increased resting heart rate and blocked all PP responses but did not affect ISRs or plasma glucagon levels during any of the peptide infusions. Thus, cholinergic signaling mediates the effects of Xen on insulin and glucagon release in mice but not humans.

  8. Sustained Decrease of Early-Phase Insulin Secretion in Japanese Women with Gestational Diabetes Mellitus who Developed Impaired Glucose Tolerance and Impaired Fasting Glucose Postpartum

    Directory of Open Access Journals (Sweden)

    Hiroko Katayama

    2015-01-01

    Full Text Available Objective The aim of this study was to compare glucose intolerance in the antenatal and the postpartum periods using a 75-g oral glucose tolerance test (OGTT in the Japanese women with gestational diabetes mellitus (GDM using a retrospective design. Patients and Methods Data were obtained from 85 Japanese women with GDM who delivered from April 2011 through April 2015 and who underwent an OGTT 6–14 weeks postpartum. The women were divided into two groups based on the results of the postpartum OGTT: one group with normal glucose tolerance (NGT and the other with impaired glucose tolerance (IGT as well as impaired fasting glucose (IFG. We analyzed the associations between postpartum IGT–IFG and various factors. Results Antenatally, a significant difference was observed between the groups only in the 1-hour plasma glucose level of the 75-g OGTT. Postpartum results of plasma glucose level were significantly higher at 0.5, 1, and 2 hours in the IGT–IFG group than those in the NGT group. Moreover, a significant decrease in the levels of 0.5-hour immunoreactive insulin and insulinogenic index was observed in the IGT–IFG group compared to those in the NGT group. Homeostasis model assessment-insulin resistance and homeostasis model assessment β-cell function of both groups were found to significantly decrease in the postpartum period; however, there was no significant change in the insulinogenic index of either group. Conclusions Our study clearly showed that the postpartum IGT and IFG levels of Japanese women with GDM are affected by impaired early-phase insulin secretion; however, insulin resistance promptly improves.

  9. Zinc Supplementation Does Not Alter Indicators of Insulin Secretion and Sensitivity in Black and White Female Adolescents.

    Science.gov (United States)

    Lobene, Andrea J; Kindler, Joseph M; Jenkins, Nathan T; Pollock, Norman K; Laing, Emma M; Grider, Arthur; Lewis, Richard D

    2017-07-01

    Background: Zinc is a micronutrient involved in the production of, and peripheral sensitivity to, pancreatic β cell-derived insulin. To our knowledge, the effect of zinc supplementation on insulin outcomes, and potential risk of diabetes, in otherwise healthy children in the United States has not been investigated. Objective: The objective of this study was to determine the influence of zinc supplementation on insulin outcomes in black and white girls in the early stages of adolescence. A secondary objective was to determine relations between baseline zinc concentrations and insulin outcomes. Methods: Healthy black and white girls aged 9-11 y were randomly assigned to daily supplementation of zinc (9 mg elemental Zn/d; n = 75; blacks: n = 35) or placebo ( n = 72; blacks: n = 32) for 4 wk. Fasting serum insulin, glucose, and C-peptide were assessed at baseline and at 4 wk. C-peptide and glucose values were used to calculate the computer model-derived homeostatic model assessment of insulin resistance (HOMA2-IR). Changes in outcome measures were compared by using repeated-measures, mixed-model ANOVA. Results: Baseline plasma zinc was not correlated with C-peptide ( r = -0.07), insulin ( r = -0.06), or HOMA2-IR ( r = -0.09) (all P > 0.05) after controlling for race and age. Treatment × time interactions for C-peptide and HOMA2-IR were not significant (both P > 0.05). Although the treatment × race × time interactions for C-peptide and HOMA2-IR were not significant (both P = 0.08), black girls who received the placebo experienced slight increases in C-peptide (15.7%) and HOMA2-IR (17.7%) ( P = 0.06). Conclusions: Four weeks of zinc supplementation had no effect on insulin outcomes in healthy black and white early-adolescent girls, although C-peptide and HOMA2-IR tended to increase in black girls who received placebo. Additional trials that are appropriately powered should further explore the effect of zinc on markers of diabetes risk, and whether race affects this

  10. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion.

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    Tasnim Dayeh

    2014-03-01

    Full Text Available Impaired insulin secretion is a hallmark of type 2 diabetes (T2D. Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, β- and α-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3'UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea were hypermethylated in human islets, β- and α-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (∼ 7% and overrepresented in the open sea (∼ 60%. 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal β- and α-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These

  11. Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and β-cell apoptosis

    DEFF Research Database (Denmark)

    Berchtold, Lukas Adrian; Størling, Zenia Marian; Ortis, Fernanda

    2011-01-01

    genes in T1D, including the INS gene. An unexpected top-scoring candidate gene was huntingtin-interacting protein (HIP)-14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulin-positive cells in islets of Langerhans. RNAi...

  12. Black Seed Thymoquinone Improved Insulin Secretion, Hepatic Glycogen Storage, and Oxidative Stress in Streptozotocin-Induced Diabetic Male Wistar Rats

    Directory of Open Access Journals (Sweden)

    Heba M. A. Abdelrazek

    2018-01-01

    Full Text Available Diabetes mellitus is one of the metabolic diseases having several complications. Nigella sativa oil (NSO might have beneficial effects in the treatment of diabetic complications. Thirty-two mature male Wistar rats were equally divided into four experimental groups: control, control NSO 2 mL/kg, streptozotocin- (STZ- induced diabetic, and diabetic (STZ-induced treated with oral NSO 2 mg/kg for 30 days. Fasting blood glucose (FBG, insulin, and lipid profile levels were determined. Pancreatic and hepatic tissues were used for catalase and GSH. Histopathology, hepatic glycogen contents, insulin immunohistochemistry, and pancreatic islet morphometry were performed. NSO 2 mL/kg was noticed to decrease (P<0.05 FBG and increase (P<0.05 insulin levels in diabetic rats than in diabetic nontreated animals. Lipid profile showed significant (P<0.5 improvement in diabetic rats that received NSO 2 mL/kg than in the diabetic group. Both pancreatic and hepatic catalase and GSH activities revealed a significant (P<0.05 increment in the diabetic group treated with NSO than in the diabetic animals. NSO improved the histopathological picture and hepatic glycogen contents of the diabetic group as well as increased (P<0.05 insulin immunoreactive parts % and mean pancreatic islet diameter. NSO exerts ameliorative and therapeutic effects on the STZ-induced diabetic male Wistar rats.

  13. Intrinsic insulin secretion capacity might be preserved by discontinuing anti-programmed cell death protein 1 antibody treatment in 'anti-programmed cell death protein 1 antibody-induced' fulminant type 1 diabetes.

    Science.gov (United States)

    Sakai, Gota; Saito, Daigo; Nakajima, Ritsuko; Hatano, Masako; Noguchi, Yuichi; Kurihara, Susumu; Katayama, Shigehiro; Inoue, Ikuo; Noda, Mitsuhiko; Shimada, Akira

    2018-03-01

    Intrinsic insulin secretion capacity may be preserved by discontinuing anti-PD-1 antibody treatment in 'anti-PD-1 antibody-induced'fulminant type 1 diabetes. © 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  14. PYY-Dependent Restoration of Impaired Insulin and Glucagon Secretion in Type 2 Diabetes following Roux-En-Y Gastric Bypass Surgery

    Directory of Open Access Journals (Sweden)

    Reshma D. Ramracheya

    2016-05-01

    Full Text Available Roux-en-Y gastric bypass (RYGB is a weight-reduction procedure resulting in rapid resolution of type 2 diabetes (T2D. The role of pancreatic islet function in this restoration of normoglycemia has not been fully elucidated. Using the diabetic Goto-Kakizaki (GK rat model, we demonstrate that RYGB restores normal glucose regulation of glucagon and insulin secretion and normalizes islet morphology. Culture of isolated islets with serum from RYGB animals mimicked these effects, implicating a humoral factor. These latter effects were reversed following neutralization of the gut hormone peptide tyrosine tyrosine (PYY but persisted in the presence of a glucagon-like peptide-1 (GLP-1 receptor antagonist. The effects of RYGB on secretion were replicated by chronic exposure of diabetic rat islets to PYY in vitro. These findings indicate that the mechanism underlying T2D remission may be mediated by PYY and suggest that drugs promoting PYY release or action may restore pancreatic islet function in T2D.

  15. Differential Acute Impacts of Sleeve Gastrectomy, Roux-en-Y Gastric Bypass Surgery and Matched Caloric Restriction Diet on Insulin Secretion, Insulin Effectiveness and Non-Esterified Fatty Acid Levels Among Patients with Type 2 Diabetes.

    Science.gov (United States)

    Thomas, Felicity; Smith, Greg C; Lu, Jun; Babor, Richard; Booth, Michael; Beban, Grant; Chase, J Geoffrey; Murphy, Rinki

    2016-08-01

    Bariatric surgery is an increasingly common option for control of type 2 diabetes (T2D) and obesity. Mechanisms underlying rapid improvement of T2D after different types of bariatric surgery are not clear. Caloric deprivation and altered levels of non-esterified fatty acid (NEFA) have been proposed. This study examines how sleeve gastrectomy (SG), Roux-en-Y gastric bypass (GBP) or matched hypocaloric diet (DT) achieves improvements in T2D by characterising components of the glucose metabolism and NEFA levels before and 3 days after each intervention. Plasma samples at five time points during oral glucose tolerance test (OGTT) from subjects with T2D undergoing GBP (N = 11) or SG (N = 12) were analysed for C-peptide, insulin and glucose before surgery and 3-day post-intervention or after DT (N = 5). Fasting palmitic, linoleic, oleic and stearic acid were measured. C-peptide measurements were used to model insulin secretion rate (ISR) using deconvolution. Subjects who underwent GBP surgery experienced the greatest improvement in glycaemia (median reduction in blood glucose (BG) from basal by 29 % [IQR -57, -18]) and the greatest reduction in all NEFA measured. SG achieved improvement in glycaemia with lower ISR and reduction in all but palmitoleic acid. DT subjects achieved improvement in glycaemia with an increase in ISR, 105 % [IQR, 20, 220] and stearic acid. GBP, SG and DT each improve glucose metabolism through different effects on pancreatic beta cell function, insulin sensitivity and free fatty acids.

  16. Dieta hiperlipídica e capacidade secretória de insulina em ratos High-fat diet and secretory capacity of insulin in rats

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    Ana Cláudia Garcia de Oliveira Duarte

    2006-06-01

    the effects of continuous feeding of rats with a palatable high-fat diet on: body weight gain, adiposity, liver and muscle glycogen content, blood glucose and insulin levels, and pancreatic morphology and insulin secretion by in vitro isolated pancreatic beta cells. METHODS: Male Wistar rats (21 days old were fed with a palatable high-fat diet or a chow diet during 15wk. Body weight and food intake were recorded daily whereas blood glucose and insulin were analyzed weekly. After they were killed, pancreas, liver, gastrocnemius muscle and adipose tissues were removed and weighted. Morphology analysis of pancreatic tissue sections was performed using light microscopy. Serum insulin and the insulin secreted by isolated pancreatic islets, incubated for 90min under different concentrations of glucose, were analyzed by radioimmunoassay. RESULTS: The palatable high-fat diet increased adiposity, body weight gain and liver glycogen content when compared with the animals fed with a chow diet. Blood glucose and insulin levels did not differ between groups. The insulin secretion from isolated islets increased in the high-fat diet group only at physiological concentrations of glucose (G= 8.3mM. The size of the pancreas of rats receiving the high-fat diet decreased, although the number of beta cells increased. In addition, the lumen of pancreatic vessels was narrower compared with control islets. CONCLUSION: The obesity resulting from a high-fat diet did not alter the blood glucose and insulin levels of fasted rats. Despite the morphological alterations of the pancreas, normal blood glucose concentration in rats receiving a high-fat diet remained at physiological range due to a preserved secretory capacity of the pancreatic islets.

  17. Reversible immortalization of Nestin-positive precursor cells from pancreas and differentiation into insulin-secreting cells

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Pei; Li, Li; Qi, Hui [The Clinical Medical Research Center, The Second Clinical Medical College (Shenzhen People' s Hospital), Jinan University, 518020 Shenzhen (China); Zhou, Han-xin [Department of General Surgery, First Hospital (Shenzhen Second People' s Hospital) of Shenzhen University, 518020 Shenzhen (China); Deng, Chun-yan [The Clinical Medical Research Center, The Second Clinical Medical College (Shenzhen People' s Hospital), Jinan University, 518020 Shenzhen (China); Li, Fu-rong, E-mail: frli62@yahoo.com [The Clinical Medical Research Center, The Second Clinical Medical College (Shenzhen People' s Hospital), Jinan University, 518020 Shenzhen (China); Shenzhen Institution of Gerontology, 518020 Shenzhen (China)

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer The NPPCs from mouse pancreas were isolated. Black-Right-Pointing-Pointer Tet-on system for SV40 large in NPPCs was used to get RINPPCs. Black-Right-Pointing-Pointer The RINPPCs can undergo at least 80 population doublings without senescence. Black-Right-Pointing-Pointer The RINPPCs can be induced to differentiate into insulin-producing cells. Black-Right-Pointing-Pointer The combination of GLP-1 and sodium butyrate promoted the differentiation process. -- Abstract: Pancreatic stem cells or progenitor cells posses the ability of directed differentiation into pancreatic {beta} cells. However, these cells usually have limited proliferative capacity and finite lifespan in vitro. In the present study, Nestin-positive progenitor cells (NPPCs) from mouse pancreas that expressed the pancreatic stem cells or progenitor cell marker Nestin were isolated to obtain a sufficient number of differentiated pancreatic {beta} cells. Tet-on system for SV40 large T-antigen expression in NPPCs was used to achieve reversible immortalization. The reversible immortal Nestin-positive progenitor cells (RINPPCs) can undergo at least 80 population doublings without senescence in vitro while maintaining their biological and genetic characteristics. RINPPCs can be efficiently induced to differentiate into insulin-producing cells that contain a combination of glucagon-like peptide-1 (GLP-1) and sodium butyrate. The results of the present study can be used to explore transplantation therapy of type I diabetes mellitus.

  18. Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus

    DEFF Research Database (Denmark)

    Kalis, Martins; Bolmeson, Caroline; Esguerra, Jonathan L.S.

    2011-01-01

    -cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(¿/wt)), RIP-Cre(+/-)Dicer1(flox/flox) mice (RIP-Cre Dicer1(¿/¿)) developed progressive hyperglycaemia and full...... revealed altered islet morphology, marked decreased ß-cell mass, reduced numbers of granules within the ß-cells and reduced granule docking in adult RIP-Cre Dicer1(¿/¿) mice. ß-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal ß-cell development as 2-week old RIP-Cre Dicer1...

  19. The GLP-1 analogue liraglutide improves first-phase insulin secretion and maximal beta-cell secretory capacity over 14 weeks of therapy in subjects with Type 2 diabetes

    DEFF Research Database (Denmark)

    Madsbad, Sten; Vilsbøll, Tina; Brock, Birgitte

    Aims: We investigated the clinical effect of liraglutide, a long- acting GLP-1 analogue, on insulin secretion in Type 2 diabetes. Methods: Thirty-nine subjects (28 completed) from a randomised trial received a hyperglycaemic clamp (20 mM) with intravenous arginine stimulation, and an insulin...... with placebo, the 1.25 and 1.9 mg/day doses of liraglutide increased maximal beta-cell secretory capacity with 6.3 pM (95% CI: 2.9–9.6) B114%, and 7.2 pM (95% CI: 3.3–11.0) B97%, respectively. These doses also increased first-phase insulin secretion relative to placebo by 11.0 pMh (95% CI: 6.6–15.4) B124...... group. Conclusion: In subjects with Type 2 diabetes, 14 weeks’ once-daily liraglutide (1.25 and 1.9 mg/day) markedly improves beta-cell function, significantly increases first-phase insulin secretion and maximal beta-cell secretory capacity....

  20. Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists.

    Science.gov (United States)

    Nakashima, Ryutaro; Yano, Tatsuya; Ogawa, Junko; Tanaka, Naomi; Toda, Narihiro; Yoshida, Masao; Takano, Rieko; Inoue, Masahiro; Honda, Takeshi; Kume, Shoen; Matsumoto, Koji

    2014-08-15

    G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic β-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Co-infusion of autologous adipose tissue derived insulin-secreting mesenchymal stem cells and bone marrow derived hematopoietic stem cells: Viable therapy for type III.C. a diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Umang G Thakkar

    2014-12-01

    Full Text Available Transition from acute pancreatitis to insulin-dependent diabetes mellitus (IDDM is a rare manifestation of primary hyperparathyroidism caused by parathyroid adenoma because of impaired glucose tolerance and suppresses insulin secretion. We report the case of a 26-year-old male with pancreatic diabetes caused by parathyroid adenoma induced chronic pancreatitis. He had serum C-peptide 0.12 ng/ml, glutamic acid decarboxylase antibody 5.0 IU/ml, and glycosylated hemoglobin (HbA1C 8.9%, and required 72 IU/day of biphasic-isophane insulin injection for uncontrolled hyperglycemia. We treated him with his own adipose tissue derived insulin-secreting mesenchymal stem-cells (IS-ADMSC along with his bone marrow derived hematopoietic stem cells (BM-HSC. Autologous IS-ADMSC + BM-HSC were infused into subcutaneous tissue, portal and thymic circulation without any conditioning. Over a follow-up of 27 months, the patient is maintaining fasting and postprandial blood sugar levels of 132 and 165 mg/dl, respectively, with HbA1C 6.8% and requiring 36 IU/day of biphasic-isophane insulin. Co-infusion of IS-ADMSC + BM-HSC offers a safe and viable therapy for type III.C.a Diabetes Mellitus.

  2. Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.

    Science.gov (United States)

    Economou, Mario A; Wu, Jiangmei; Vasilcanu, Daiana; Rosengren, Linda; All-Ericsson, Charlotta; van der Ploeg, Ingeborg; Menu, Eline; Girnita, Leonard; Axelson, Magnus; Larsson, Olle; Seregard, Stefan; Kvanta, Anders

    2008-11-01

    Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1) and its receptor, IGF-1R, have been implicated in CNV. We have previously shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in-vivo model. In this study we investigated the effect of PPP on VEGF expression both in vitro and in vivo and whether this effect has anti-angiogenic consequences in a murine CNV model. C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in choroids and retinal pigment epithelial cells (APRE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. Mice treated with PPP, administered intraperitoneally or orally, showed 22-32% (p = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroids were significantly reduced. In cultured APRE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. We could confirm that PPP reduced the level of transcriptional activity of VEGF promoter. PPP reduces IGF-1 dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the therapy of conditions associated with CNV including neovascular AMD.

  3. Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats.

    Science.gov (United States)

    Medina, Anya; Parween, Saba; Ullsten, Sara; Vishnu, Neelanjan; Siu, Yuk Ting; Quach, My; Bennet, Hedvig; Balhuizen, Alexander; Åkesson, Lina; Wierup, Nils; Carlsson, Per Ola; Ahlgren, Ulf; Lernmark, Åke; Fex, Malin

    2018-04-01

    Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available. We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells. DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 ± 121.3 vs 633.3 ± 148.7; p beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats. The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

  4. FGF-2b and h-PL Transform Duct and Non-Endocrine Human Pancreatic Cells into Endocrine Insulin Secreting Cells by Modulating Differentiating Genes

    Directory of Open Access Journals (Sweden)

    Giulia Donadel

    2017-10-01

    Full Text Available Background: Diabetes mellitus (DM is a multifactorial disease orphan of a cure. Regenerative medicine has been proposed as novel strategy for DM therapy. Human fibroblast growth factor (FGF-2b controls β-cell clusters via autocrine action, and human placental lactogen (hPL-A increases functional β-cells. We hypothesized whether FGF-2b/hPL-A treatment induces β-cell differentiation from ductal/non-endocrine precursor(s by modulating specific genes expression. Methods: Human pancreatic ductal-cells (PANC-1 and non-endocrine pancreatic cells were treated with FGF-2b plus hPL-A at 500 ng/mL. Cytofluorimetry and Immunofluorescence have been performed to detect expression of endocrine, ductal and acinar markers. Bromodeoxyuridine incorporation and annexin-V quantified cells proliferation and apoptosis. Insulin secretion was assessed by RIA kit, and electron microscopy analyzed islet-like clusters. Results: Increase in PANC-1 duct cells de-differentiation into islet-like aggregates was observed after FGF-2b/hPL-A treatment showing ultrastructure typical of islets-aggregates. These clusters, after stimulation with FGF-2b/hPL-A, had significant (p < 0.05 increase in insulin, C-peptide, pancreatic and duodenal homeobox 1 (PDX-1, Nkx2.2, Nkx6.1, somatostatin, glucagon, and glucose transporter 2 (Glut-2, compared with control cells. Markers of PANC-1 (Cytokeratin-19, MUC-1, CA19-9 were decreased (p < 0.05. These aggregates after treatment with FGF-2b/hPL-A significantly reduced levels of apoptosis. Conclusions: FGF-2b and hPL-A are promising candidates for regenerative therapy in DM by inducing de-differentiation of stem cells modulating pivotal endocrine genes.

  5. Genome-wide associations between genetic and epigenetic variation influence mRNA expression and insulin secretion in human pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Anders H Olsson

    2014-11-01

    Full Text Available Genetic and epigenetic mechanisms may interact and together affect biological processes and disease development. However, most previous studies have investigated genetic and epigenetic mechanisms independently, and studies examining their interactions throughout the human genome are lacking. To identify genetic loci that interact with the epigenome, we performed the first genome-wide DNA methylation quantitative trait locus (mQTL analysis in human pancreatic islets. We related 574,553 single nucleotide polymorphisms (SNPs with genome-wide DNA methylation data of 468,787 CpG sites targeting 99% of RefSeq genes in islets from 89 donors. We identified 67,438 SNP-CpG pairs in cis, corresponding to 36,783 SNPs (6.4% of tested SNPs and 11,735 CpG sites (2.5% of tested CpGs, and 2,562 significant SNP-CpG pairs in trans, corresponding to 1,465 SNPs (0.3% of tested SNPs and 383 CpG sites (0.08% of tested CpGs, showing significant associations after correction for multiple testing. These include reported diabetes loci, e.g. ADCY5, KCNJ11, HLA-DQA1, INS, PDX1 and GRB10. CpGs of significant cis-mQTLs were overrepresented in the gene body and outside of CpG islands. Follow-up analyses further identified mQTLs associated with gene expression and insulin secretion in human islets. Causal inference test (CIT identified SNP-CpG pairs where DNA methylation in human islets is the potential mediator of the genetic association with gene expression or insulin secretion. Functional analyses further demonstrated that identified candidate genes (GPX7, GSTT1 and SNX19 directly affect key biological processes such as proliferation and apoptosis in pancreatic β-cells. Finally, we found direct correlations between DNA methylation of 22,773 (4.9% CpGs with mRNA expression of 4,876 genes, where 90% of the correlations were negative when CpGs were located in the region surrounding transcription start site. Our study demonstrates for the first time how genome-wide genetic and

  6. Insulin release by glucagon and secretin

    DEFF Research Database (Denmark)

    Kofod, Hans; Andreu, D; Thams, P

    1988-01-01

    Secretin and glucagon potentiate glucose-induced insulin release. We have compared the effects of secretin and glucagon with that of four hybrid molecules of the two hormones on insulin release and formation of cyclic AMP (cAMP) in isolated mouse pancreatic islets. All six peptides potentiated...... the release of insulin at 10 mM D-glucose, and their effects were indistinguishable with respect to the dynamics of release, dose-response relationship, and glucose dependency. However, measurements of cAMP accumulation in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-4) M...... potentiating effects of secretin and glucagon on glucose-induced insulin release, their modes of action may be different....

  7. Growth hormone and insulin-like growth factor 1 secretions in eating disorders: Correlations with psychopathological aspects of the disorders.

    Science.gov (United States)

    Brambilla, Francesca; Santonastaso, Paolo; Caregaro, Lorenza; Favaro, Angela

    2018-05-01

    Hormonal alterations in Eating Disorders (ED) may result from the biochemical stress of malnutrition/starvation. The correlations between some hormonal impairments, particularly of the somatotropic axis, and the psychopathological aspects of ED are still undefined. We measured the plasma concentrations of the somatotropic hormone (GH) and the insulin-like growth factor-1 (IGF-1) in 136 patients with various forms of ED, 65 with restricted Anorexia Nervosa (ANR), 19 with bingeing-purging Anorexia Nervosa (ANBP), 12 with purging-non binging Anorexia Nervosa (ANP), 26 with Bulimia Nervosa (BN), 8 with ED not otherwise specified-anorexic type (EDNOS-AN), 7 with ED not otherwise specified-bulimic type (EDNOS-BN) and in 30 healthy controls. Psychological assessment of patients and controls was performed using two outpatient rating scales, the Eating Disorder Inventory-2 (EDI-2) and the Symptom Checklist-90 (SCL-90). Significant negative or positive correlations were observed between GH-IGF-1 concentrations and impairments on several EDI-2 subscales (drive for thinness, body dissatisfaction, interoceptive awareness, sense of ineffectiveness, interpersonal distrust, maturity fear) and on SCL-90 subitems (depression, hostility, obsessivity compulsivity, anxiety), suggesting a possible hormonal modulatory effect on specific aspects of ED psychopathology. Copyright © 2017. Published by Elsevier B.V.

  8. Targeted inactivation of hepatocyte growth factor receptor c-met in beta-cells leads to defective insulin secretion and GLUT-2 downregulation without alteration of beta-cell mass.

    Science.gov (United States)

    Roccisana, Jennifer; Reddy, Vasumathi; Vasavada, Rupangi C; Gonzalez-Pertusa, Jose A; Magnuson, Mark A; Garcia-Ocaña, Adolfo

    2005-07-01

    Overexpression of hepatocyte growth factor (HGF) in the beta-cell of transgenic mice enhances beta-cell proliferation, survival, and function. In the current studies, we have used conditional ablation of the c-met gene to uncover the physiological role of HGF in beta-cell growth and function. Mice in which c-met is inactivated in the beta-cell (MetCKO mice) display normal body weight, blood glucose, and plasma insulin compared with control littermates. In contrast, MetCKO mice displayed significantly diminished glucose tolerance and reduced plasma insulin after a glucose challenge in vivo. This impaired glucose tolerance in MetCKO mice was not caused by insulin resistance because sensitivity to exogenous insulin was similar in both groups. Importantly, in vitro glucose-stimulated insulin secretion in MetCKO islets was decreased by approximately 50% at high glucose concentrations compared with control islets. Furthermore, whereas insulin and glucokinase expression in MetCKO islets were normal, GLUT-2 expression was decreased by approximately 50%. These changes in beta-cell function in MetCKO mice were not accompanied by changes in total beta-cell mass, islet morphology, islet cell composition, and beta-cell proliferation. Interestingly, however, MetCKO mice display an increased number of small islets, mainly single and doublet beta-cells. We conclude that HGF/c-met signaling in the beta-cell is not essential for beta-cell growth, but it is essential for normal glucose-dependent insulin secretion.

  9. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects

    DEFF Research Database (Denmark)

    Kjems, Lise L; Holst, Jens J; Vølund, Aage

    2003-01-01

    . However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2......, 4, 6, 8, and 12 mg x kg(-1) x min(-1) over 150 min on four occasions with infusion of saline or GLP-1 at 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1). GLP-1 enhanced ISR in a dose-dependent manner during the graded glucose infusion from 332 +/- 51 to 975 +/- 198 pmol/kg in the patients with type 2...... diabetes and from 711 +/- 123 to 2,415 +/- 243 pmol/kg in the control subjects. The beta-cell responsiveness to glucose, expressed as the slope of the linear relation between ISR and the glucose concentration, increased in proportion to the GLP-1 dose to 6 times relative to saline at the highest GLP-1 dose...

  10. Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice.

    Science.gov (United States)

    Tudurí, E; Beiroa, D; Porteiro, B; López, M; Diéguez, C; Nogueiras, R

    2015-08-01

    To investigate the role of brain glucagon-like peptide-1 (GLP-1) in pancreatic β-cell function. To determine the role of brain GLP-1 receptor (GLP-1R) on β-cell function, we administered intracerebroventricular (i.c.v.) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), in both an acute and a chronic setting. We observed that acute i.c.v. GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired glucose excursion after a glucose load. Sustained activation of central nervous system GLP-1R, however, did not produce any effect on either GSIS or glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with i.c.v. GLP-1 resulted in no differences compared with controls. In addition, in mice fed a high-fat diet we observed that acute i.c.v. GLP-1 infusion improved glucose tolerance without changes in GSIS, while chronic GLP-1R activation had no effect on glucose homeostasis. Our results indicate that, under non-clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents. © 2015 John Wiley & Sons Ltd.

  11. The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells

    DEFF Research Database (Denmark)

    Schisler, Jonathan C; Jensen, Per Bo; Harper, David Alexander Taylor

    2005-01-01

    , respectively. In class 1 cells, overexpressed Nkx6.1 suppressed glucagon expression but did not affect the levels of several other prominent beta cell transcription factors. RNA interference (RNAi)-mediated suppression of Nkx6.1 in class 3 cells resulted in a doubling of glucagon mRNA, with no effect on Pdx1...... levels, whereas suppression of Pdx1 in class 3 cells caused a 12-fold increase in glucagon transcript levels, demonstrating independent effects of Nkx6.1 and Pdx1 on glucagon expression in beta cell lines. RNAi-mediated suppression of Nkx6.1 expression in class 3 cells also caused a decrease in GSIS from...... 13.9- to 3.7-fold, whereas suppression of Pdx1 reduced absolute amounts of insulin secretion without affecting fold response. Finally, RNAi-mediated suppression of Nkx6.1 mRNA in primary rat islets was accompanied by a significant decrease in GSIS relative to control cells. In sum, our studies have...

  12. Hypothesis: Musculin is a hormone secreted by skeletal muscle, the body's largest endocrine organ. Evidence for actions on the endocrine pancreas to restrain the beta-cell mass and to inhibit insulin secretion and on the hypothalamus to co-ordinate the neuroendocrine and appetite responses to exercise.

    Science.gov (United States)

    Engler, Dennis

    2007-01-01

    Recent studies indicate that skeletal muscle may act as an endocrine organ by secreting interleukin-6 (IL-6) into the systemic circulation. From an analysis of the actions of IL-6 and of additional literature, we postulate that skeletal muscle also secretes an unidentified hormone, which we have named Musculin (Latin: musculus = muscle), which acts on the pancreatic beta-cell to restrain the size of the (beta-cell mass and to tonically inhibit insulin secretion and biosynthesis. It is suggested that the amount of Musculin secreted is determined by, and is positively correlated with, the prevailing insulin sensitivity of skeletal muscle, thereby accounting for the hyperinsulinemia that occurs in insulin resistant disorders such as type 2 diabetes mellitus, obesity, and the polycystic ovary syndrome. In addition, it is postulated that Musculin acts on the hypothalamus (arcuate nucleus, dorsomedial hypothalamic nucleus) to co-ordinate the neuroendocrine and appetite responses to exercise. However, the possibilities that Musculin may act on additional central nervous system sites and that an additional hormone(s) may be responsible for these actions are not excluded. It is suggested that a search be made for Musculin, since analogues of such a substance may be of therapeutic benefit in the treatment of the current global diabetes and obesity epidemic.

  13. Pharmacological characterization of the first in class clinical candidate PF‐05190457: a selective ghrelin receptor competitive antagonist with inverse agonism that increases vagal afferent firing and glucose‐dependent insulin secretion ex vivo

    Science.gov (United States)

    Kong, J; Chuddy, J; Stock, I A; Loria, P M; Straub, S V; Vage, C; Cameron, K O; Bhattacharya, S K; Lapham, K; McClure, K F; Zhang, Y

    2016-01-01

    Background and Purpose Ghrelin increases growth hormone secretion, gastric acid secretion, gastric motility and hunger but decreases glucose‐dependent insulin secretion and insulin sensitivity in humans. Antagonizing the ghrelin receptor has potential as a therapeutic approach in the treatment of obesity and type 2 diabetes. Therefore, the aim was to pharmacologically characterize the novel small‐molecule antagonist PF‐05190457 and assess translational pharmacology ex vivo. Experimental Approach Radioligand binding in filter and scintillation proximity assay formats were used to evaluate affinity, and europium‐labelled GTP to assess functional activity. Rat vagal afferent firing and calcium imaging in dispersed islets were used as native tissues underlying food intake and insulin secretion respectively. Key Results PF‐05190457 was a potent and selective inverse agonist on constitutively active ghrelin receptors and acted as a competitive antagonist of ghrelin action, with a human K d of 3 nM requiring 4 h to achieve equilibrium. Potency of PF‐05190457 was similar across different species. PF‐05190457 increased intracellular calcium within dispersed islets and increased vagal afferent firing in a concentration‐dependent manner with similar potency but was threefold less potent as compared with the in vitro K i in recombinant overexpressing cells. The effect of PF‐05190457 on rodent islets was comparable with glibenclamide, but glucose‐dependent and additive with the insulin secretagogue glucagon‐like peptide‐1. Conclusions and Implications Together, these data provide the pharmacological in vitro and ex vivo characterization of the first ghrelin receptor inverse agonist, which has advanced into clinical trials to evaluate the therapeutic potential of blocking ghrelin receptors in obesity and type 2 diabetes. PMID:26784385

  14. Cell death and impairment of glucose-stimulated insulin secretion induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the β-cell line INS-1E

    International Nuclear Information System (INIS)

    Piaggi, Simona; Novelli, Michela; Martino, Luisa; Masini, Matilde; Raggi, Chiara; Orciuolo, Enrico; Masiello, Pellegrino; Casini, Alessandro; De Tata, Vincenzo

    2007-01-01

    The aim of this research was to characterize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity on the insulin-secreting β-cell line INS-1E. A sharp decline of cell survival (below 20%) was observed after 1 h exposure to TCDD concentrations between 12.5 and 25 nM. Ultrastructurally, β-cell death was characterized by extensive degranulation, appearance of autophagic vacuoles, and peripheral nuclear condensation. Cytotoxic concentrations of TCDD rapidly induced a dose-dependent increase in intracellular calcium concentration. Blocking calcium entry by EGTA significantly decreased TCDD cytotoxicity. TCDD was also able to rapidly induce mitochondrial depolarization. Interestingly, 1 h exposition of INS-1E cells to very low TCDD concentrations (0.05-1 nM) dramatically impaired glucose-stimulated but not KCl-stimulated insulin secretion. In conclusion, our results clearly show that TCDD exerts a direct β-cell cytotoxic effect at concentrations of 15-25 nM, but also markedly impairs glucose-stimulated insulin secretion at concentrations 20 times lower than these. On the basis of this latter observation we suggest that pancreatic β-cells could be considered a specific and sensitive target for dioxin toxicity

  15. Association of variants in HLA-DQA1-DQB1, PTPN22, INS, and CTLA4 with GAD autoantibodies and insulin secretion in nondiabetic adults of the Botnia Prospective Study.

    Science.gov (United States)

    Andersen, Mette K; Lundgren, Virve; Isomaa, Bo; Groop, Leif; Tuomi, Tiinamaija

    2012-07-01

    Previously, we observed an association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. The aims of this study were to assess whether type 1 diabetes susceptibility gene variants explain this association and investigate the effect of the variants on insulin secretion and presence of glutamic acid decarboxylase autoantibodies (GADA) in nondiabetic adults. Polymorphisms in INS (rs689), PTPN22 (rs2476601), CTLA4 (rs3087243), and the HLA-DQA1-DQB1 regions (rs2187668 and rs7454108 tagging HLA-DQ2.5 and HLA-DQ8 respectively) were genotyped in the Botnia Prospective Study (n=2764), in which initially nondiabetic participants were followed for a mean of 8.1 years. The variants did not explain the association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. In these nondiabetic adults, HLA-DQ AND PTPN22 risk genotypes were associated with GADA (HLA-DQ2.5/HLA-DQ8 or HLA-DQ8: OR (95% CI): 1.7 (1.3-2.3), P=0.0004; PTPN22 CT/TT: OR: 1.6 (1.2-2.2), P=0.003; P values were adjusted for sex, age, BMI, and follow-up time). A higher genetic risk score was associated with lower insulin secretion (insulinogenic index: 13.27 (16.27) vs 12.69 (15.27) vs 10.98 (13.06), P=0.02) and better insulin sensitivity index (risk score of 0-1 vs 2-3 vs 4-6: 142 (111) vs 144 (118) vs 157 (127), P=0.01) at baseline and a poorer capacity to compensate for the increased insulin demand after follow-up. In nondiabetic adults, HLA-DQ2.5/HLA-DQ8 and PTPN22 CT/TT genotypes were associated with GADA.

  16. Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial.

    Science.gov (United States)

    Sawada, Takahiro; Tsubata, Hideo; Hashimoto, Naoko; Takabe, Michinori; Miyata, Taishi; Aoki, Kosuke; Yamashita, Soichiro; Oishi, Shogo; Osue, Tsuyoshi; Yokoi, Kiminobu; Tsukishiro, Yasue; Onishi, Tetsuari; Shimane, Akira; Taniguchi, Yasuyo; Yasaka, Yoshinori; Ohara, Takeshi; Kawai, Hiroya; Yokoyama, Mitsuhiro

    2016-08-26

    Recent experimental studies have revealed that n-3 fatty acids, such as eicosapentaenoic acid (EPA) regulate postprandial insulin secretion, and correct postprandial glucose and lipid abnormalities. However, the effects of 6-month EPA treatment on postprandial hyperglycemia and hyperlipidemia, insulin secretion, and concomitant endothelial dysfunction remain unknown in patients with impaired glucose metabolism (IGM) and coronary artery disease (CAD). We randomized 107 newly diagnosed IGM patients with CAD to receive either 1800 mg/day of EPA (EPA group, n = 53) or no EPA (n = 54). Cookie meal testing (carbohydrates: 75 g, fat: 28.5 g) and endothelial function testing using fasting-state flow-mediated dilatation (FMD) were performed before and after 6 months of treatment. The primary outcome of this study was changes in postprandial glycemic and triglyceridemic control and secondary outcomes were improvement of insulin secretion and endothelial dysfunction. After 6 months, the EPA group exhibited significant improvements in EPA/arachidonic acid, fasting triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). The EPA group also exhibited significant decreases in the incremental TG peak, area under the curve (AUC) for postprandial TG, incremental glucose peak, AUC for postprandial glucose, and improvements in glycometabolism categorization. No significant changes were observed for hemoglobin A1c and fasting plasma glucose levels. The EPA group exhibited a significant increase in AUC-immune reactive insulin/AUC-plasma glucose ratio (which indicates postprandial insulin secretory ability) and significant improvements in FMD. Multiple regression analysis revealed that decreases in the TG/HDL-C ratio and incremental TG peak were independent predictors of FMD improvement in the EPA group. EPA corrected postprandial hypertriglyceridemia, hyperglycemia and insulin secretion ability. This amelioration of several metabolic abnormalities was accompanied by

  17. Increase in homeostasis model assessment of insulin resistance (HOMA-IR) had a strong impact on the development of type 2 diabetes in Japanese individuals with impaired insulin secretion: the Saku study.

    Science.gov (United States)

    Morimoto, Akiko; Tatsumi, Yukako; Soyano, Fumie; Miyamatsu, Naomi; Sonoda, Nao; Godai, Kayo; Ohno, Yuko; Noda, Mitsuhiko; Deura, Kijyo

    2014-01-01

    Our aim was to assess the impact of increase in homeostasis model assessment of insulin resistance (HOMA-IR) on the development of type 2 diabetes in Japanese individuals with impaired insulin secretion (IIS). This study included 2,209 participants aged 30-69 without diabetes at baseline who underwent comprehensive medical check-ups between April 2006 and March 2007 at Saku Central Hospital. Participants were classified into eight groups according to the combination of baseline IIS status (non-IIS and IIS) and category of HOMA-IR change between the baseline and follow-up examinations (decrease, no change/small increase, moderate increase, and large increase). Type 2 diabetes was determined from fasting and 2 h post-load plasma glucose concentrations at the follow-up examination between April 2009 and March 2011. At baseline, 669 individuals (30.3%) were classified as having IIS. At follow-up, 74 individuals developed type 2 diabetes. After adjusting for confounding factors including baseline HOMA-IR values, the multivariable-adjusted odds ratios (95% confidence intervals) for type 2 diabetes in the non-IIS with a decrease (mean change in HOMA-IR: -0.47), non-IIS with a moderate increase (mean change in HOMA-IR: 0.28), non-IIS with a large increase (mean change in HOMA-IR: 0.83), IIS with a decrease (mean change in HOMA-IR: -0.36), IIS with no change/small increase (mean change in HOMA-IR: 0.08), IIS with a moderate increase (mean change in HOMA-IR: 0.27), and IIS with a large increase (mean change in HOMA-IR: 0.73) groups, relative to the non-IIS with no change/small increase (mean change in HOMA-IR: 0.08) group were 0.23 (0.04, 1.11), 1.22 (0.26, 5.72), 2.01 (0.70, 6.46), 1.37 (0.32, 4.28), 3.60 (0.83, 15.57), 5.24 (1.34, 20.52), and 7.01 (1.75, 24.18), respectively. Moderate and large increases in HOMA-IR had a strong impact on the development of type 2 diabetes among individuals with IIS in this Japanese population.

  18. Increase in homeostasis model assessment of insulin resistance (HOMA-IR had a strong impact on the development of type 2 diabetes in Japanese individuals with impaired insulin secretion: the Saku study.

    Directory of Open Access Journals (Sweden)

    Akiko Morimoto

    Full Text Available Our aim was to assess the impact of increase in homeostasis model assessment of insulin resistance (HOMA-IR on the development of type 2 diabetes in Japanese individuals with impaired insulin secretion (IIS. This study included 2,209 participants aged 30-69 without diabetes at baseline who underwent comprehensive medical check-ups between April 2006 and March 2007 at Saku Central Hospital. Participants were classified into eight groups according to the combination of baseline IIS status (non-IIS and IIS and category of HOMA-IR change between the baseline and follow-up examinations (decrease, no change/small increase, moderate increase, and large increase. Type 2 diabetes was determined from fasting and 2 h post-load plasma glucose concentrations at the follow-up examination between April 2009 and March 2011. At baseline, 669 individuals (30.3% were classified as having IIS. At follow-up, 74 individuals developed type 2 diabetes. After adjusting for confounding factors including baseline HOMA-IR values, the multivariable-adjusted odds ratios (95% confidence intervals for type 2 diabetes in the non-IIS with a decrease (mean change in HOMA-IR: -0.47, non-IIS with a moderate increase (mean change in HOMA-IR: 0.28, non-IIS with a large increase (mean change in HOMA-IR: 0.83, IIS with a decrease (mean change in HOMA-IR: -0.36, IIS with no change/small increase (mean change in HOMA-IR: 0.08, IIS with a moderate increase (mean change in HOMA-IR: 0.27, and IIS with a large increase (mean change in HOMA-IR: 0.73 groups, relative to the non-IIS with no change/small increase (mean change in HOMA-IR: 0.08 group were 0.23 (0.04, 1.11, 1.22 (0.26, 5.72, 2.01 (0.70, 6.46, 1.37 (0.32, 4.28, 3.60 (0.83, 15.57, 5.24 (1.34, 20.52, and 7.01 (1.75, 24.18, respectively. Moderate and large increases in HOMA-IR had a strong impact on the development of type 2 diabetes among individuals with IIS in this Japanese population.

  19. Regulation of insulin-like growth factor-binding protein-1 synthesis and secretion by progestin and relaxin in long term cultures of human endometrial stromal cells

    International Nuclear Information System (INIS)

    Bell, S.C.; Jackson, J.A.; Ashmore, J.; Zhu, H.H.; Tseng, L.

    1991-01-01

    The decidualized endometrium during the first trimester of pregnancy synthesizes and secretes a 32-kDa insulin-like growth factor-binding protein (termed hIGFBP-1) at high levels. IGFBP-1 is the major soluble protein product of this tissue and is principally localized to the differentiated endometrial stromal cell, the decidual cell. In the present study long term culture of stromal cells from the nonpregnant endometrium have been employed to elucidate the hormonal requirements for IGFBP-1 production. Immunoreactive IGFBP-1 was undetectable in control cultures. However, inclusion of medroxyprogesterone acetate (MPA) induced rates of 0.35 +/- 0.09 microgram/0.1 mg cell DNA.day after 20-30 days. In these cultures cells exhibited morphological changes consistent with decidual cell differentiation. In all cultures removal of MPA after exposure for 10-16 days, with or without subsequent inclusion of relaxin (RLX), increased production of IGFBP-1 450- to 4600-fold to rates of 150-710 micrograms/0.1 mg cell DNA.day or 26-131 micrograms/10(6) cells.day on days 24-26. The rates tended to be higher with the inclusion of RLX and were sustained in contrast to cultures without RLX, where rates fell by day 30. Individual cultures responded differently to RLX when added from the initiation of culture, with either a response similar to MPA alone or a cyclical change in production, achieving maximal rates of 190-290 micrograms/0.1 mg cell DNA.day. Cultures in which RLX alone induced high IGFBP-1 high production were obtained from endometrium during the progesterone-dominated luteal phase. In cultures exhibiting high rates of immunoreactive IGFBP-1 production, the protein represented their major secretory protein product. This was confirmed by [ 35 S]methionine incorporation and the presence of IGFBP-1 as the predominant protein in serum-free culture medium

  20. Buddleja officinalis inhibits high glucose-induced matrix metalloproteinase activity in human umbilical vein endothelial cells.

    Science.gov (United States)

    Lee, Yun Jung; Kang, Dae Gill; Kim, Jin Sook; Lee, Ho Sub

    2008-12-01

    The aim of the present investigation was to investigate whether an aqueous extract of Buddleja officinalis (ABO), a traditional Korean herbal medicine, suppresses the endothelial extracellular matrix degradation under high glucose condition. The incubation with high concentration of glucose (25 mM) increased significantly matrix metalloproteinase (MMP)-2/-9 expressions and activities in primary cultured human umbilical vein endothelial cells (HUVEC). Pretreatment with ABO decreased high glucose-induced increase of MMP-2/-9 activities in a dose-dependent manner. Real time qRT-PCR revealed that high glucose-induced MMP-2/-9 mRNA expression levels were attenuated by pretreatment with ABO. High glucose-induced MCP-1 and IL-8 mRNA expression levels also decreased by ABO. ABO decreased high glucose-induced hydrogen peroxide production, oxidative stress marker. These results provide new insights into the pathophysiological mechanisms for anti-inflammatory properties of ABO in vascular diseases associated with diabetes mellitus. (c) 2008 John Wiley & Sons, Ltd.

  1. Glucemia, insulinemia y secreción de insulina en ratas prepúberes hiperandrogenizadas e hiperestrogenizadas Glycemia, insulinemia and insulin secretion in prepubescent rats receiving high doses of androgens and strogens

    Directory of Open Access Journals (Sweden)

    Aimée Álvarez Álvarez

    2001-04-01

    Full Text Available Se estudió el efecto de una sobredosis de enantato de testosterona y de benzoato de estradiol en ratas machos prepúberes, sobre el comportamiento de la glucemia y la insulinemia in vivo, durante una prueba de tolerancia a la glucosa. Adicionalmente se exploró, in vitro, la capacidad de secreción de insulina estimulada por glucosa de los islotes de Langerhans de estas ratas hiperandrogenizadas e hiperestrogenizadas. Se encontró que la hiperandrogenización se acompañaba de un deterioro de la sensibilidad a la insulina, con hiperinsulinemia, que no se corresponde con un aumento de la capacidad de secreción de insulina de los islotes de Langerhans. Sin embargo, se comprobó que la hiperestrogenización no indujo cambios en los perfiles de glucemia, ni de insulinemia, ni en la capacidad de secreción de insulina de los islotes de Langerhans de este grupo de ratas hiperestrogenizadas.The effect of an overdose of testosterone heptanoate and estradiol in male prepubescent rats on the behavior of glycemia and insulinemia was studied in vivo during a glucose tolerance test. The capacity of insulin secretion stimulated by glucose from the islets of Langerhans of these rats that were administered a high dose of androgens and estrogens was explored in vitro. It was found that the high level of circulating androgens was accompanied by a deterioration of sensitivity to insulin with hyperinsulinemia that does not correspond to an increase of the insulin secreting capacity of the islets of Langerhans. However, it was demonstrated that the high level of circulating estrogens did not produce changes either in the glycemia and insulinemia profiles or in the insulin secreting capacity of the islets of Langerhans in this group of rats that received an elevated dose of estrogens.

  2. Fatty acid-induced insulin resistance

    DEFF Research Database (Denmark)

    Le Marchand-Brustel, Y; Gual, P; Grémeaux, T

    2003-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor subs...

  3. Alteration in insulin action

    DEFF Research Database (Denmark)

    Tanti, J F; Gual, P; Grémeaux, T

    2004-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS......-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine...... to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases...

  4. Alteration in insulin action

    DEFF Research Database (Denmark)

    Tanti, J F; Gual, P; Grémeaux, T

    2004-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS...... to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases......-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine...

  5. Clinical utility of insulin and insulin analogs

    Science.gov (United States)

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

    2013-01-01

    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  6. Oxidative Stress-Responsive Apoptosis Inducing Protein (ORAIP) Plays a Critical Role in High Glucose-Induced Apoptosis in Rat Cardiac Myocytes and Murine Pancreatic β-Cells.

    Science.gov (United States)

    Yao, Takako; Fujimura, Tsutomu; Murayama, Kimie; Okumura, Ko; Seko, Yoshinori

    2017-10-18

    We previously identified a novel apoptosis-inducing humoral factor in the conditioned medium of hypoxic/reoxygenated-cardiac myocytes. We named this novel post-translationally-modified secreted-form of eukaryotic translation initiation factor 5A Oxidative stress-Responsive Apoptosis-Inducing Protein (ORAIP). We confirmed that myocardial ischemia/reperfusion markedly increased plasma ORAIP levels and rat myocardial ischemia/reperfusion injury was clearly suppressed by neutralizing anti-ORAIP monoclonal antibodies (mAbs) in vivo. In this study, to investigate the mechanism of cell injury of cardiac myocytes and pancreatic β-cells involved in diabetes mellitus (DM), we analyzed plasma ORAIP levels in DM model rats and the role of ORAIP in high glucose-induced apoptosis of cardiac myocytes in vitro. We also examined whether recombinant-ORAIP induces apoptosis in pancreatic β-cells. Plasma ORAIP levels in DM rats during diabetic phase were about 18 times elevated as compared with non-diabetic phase. High glucose induced massive apoptosis in cardiac myocytes (66.2 ± 2.2%), which was 78% suppressed by neutralizing anti-ORAIP mAb in vitro. Furthermore, recombinant-ORAIP clearly induced apoptosis in pancreatic β-cells in vitro. These findings strongly suggested that ORAIP plays a pivotal role in hyperglycemia-induced myocardial injury and pancreatic β-cell injury in DM. ORAIP will be a biomarker and a critical therapeutic target for cardiac injury and progression of DM itself.

  7. Adiponectin induced AMP-activated protein kinase impairment mediates insulin resistance in Bama mini-pig fed high-fat and high-sucrose diet

    Directory of Open Access Journals (Sweden)

    Miaomiao Niu

    2017-08-01

    Full Text Available Objective Adipose tissue is no longer considered as an inert storage organ for lipid, but instead is thought to play an active role in regulating insulin effects via secretion adipokines. However, conflicting reports have emerged regarding the effects of adipokines. In this study, we investigated the role of adipokines in glucose metabolism and insulin sensitivity in obese Bama mini-pigs. Methods An obesity model was established in Bama mini-pigs, by feeding with high-fat and high-sucrose diet for 30 weeks. Plasma glucose and blood biochemistry levels were measured, and intravenous glucose tolerance test was performed. Adipokines, including adiponectin, interleukin-6 (IL-6, resistin and tumor necrosis factor alpha (TNF-α, and glucose-induced insulin secretion were also examined by radioimmunoassay. AMP-activated protein kinase (AMPK phosphorylation in skeletal muscle, which is a useful insulin resistance marker, was examined by immunoblotting. Additionally, associations of AMPK phosphorylation with plasma adipokines and homeostasis model assessment of insulin resistance (HOMA-IR index were assessed by Pearce’s correlation analysis. Results Obese pigs showed hyperglycemia, high triglycerides, and insulin resistance. Adiponectin levels were significantly decreased (p<0.05 and IL-6 amounts dramatically increased (p<0.05 in obese pigs both in serum and adipose tissue, corroborating data from obese mice and humans. However, circulating resistin and TNF-α showed no difference, while the values of TNF-α in adipose tissue were significantly higher in obese pigs, also in agreement with data from obese humans but not rodent models. Moreover, strong associations of skeletal muscle AMPK phosphorylation with plasma adiponectin and HOMA-IR index were obtained. Conclusion AMPK impairment induced by adiponectin decrease mediates insulin resistance in high-fat and high-sucrose diet induction. In addition, Bama mini-pig has the possibility of a conformable

  8. High glucose induces inflammatory cytokine through protein kinase C-induced toll-like receptor 2 pathway in gingival fibroblasts

    International Nuclear Information System (INIS)

    Jiang, Shao-Yun; Wei, Cong-Cong; Shang, Ting-Ting; Lian, Qi; Wu, Chen-Xuan; Deng, Jia-Yin

    2012-01-01

    Highlights: ► High glucose significantly induced TLR2 expression in gingival fibroblasts. ► High glucose increased NF-κB p65 nuclear activity, IL-1β and TNF-α levels. ► PKC-α/δ-TLR2 pathway is involved in periodontal inflammation under high glucose. -- Abstract: Toll-like receptors (TLRs) play a key role in innate immune response and inflammation, especially in periodontitis. Meanwhile, hyperglycemia can induce inflammation in diabetes complications. However, the activity of TLRs in periodontitis complicated with hyperglycemia is still unclear. In the present study, high glucose (25 mmol/l) significantly induced TLR2 expression in gingival fibroblasts (p < 0.05). Also, high glucose increased nuclear factor kappa B (NF-κB) p65 nuclear activity, tumor necrosis factor-α (TNF-α) and interleukin-lβ (IL-1β) levels. Protein kinase C (PKC)-α and δ knockdown with siRNA significantly decreased TLR2 and NF-κB p65 expression (p < 0.05), whereas inhibition of PKC-β had no effect on TLR2 and NF-κB p65 under high glucose (p < 0.05). Additional studies revealed that TLR2 knockdown significantly abrogated high-glucose-induced NF-κB expression and inflammatory cytokine secretion. Collectively, these data suggest that high glucose stimulates TNF-α and IL-1β secretion via inducing TLR2 through PKC-α and PKC-δ in human gingival fibroblasts.

  9. High glucose induces inflammatory cytokine through protein kinase C-induced toll-like receptor 2 pathway in gingival fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Shao-Yun, E-mail: jiangshaoyun@yahoo.com [School of Dentistry, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin 300070 (China); Wei, Cong-Cong; Shang, Ting-Ting; Lian, Qi; Wu, Chen-Xuan [School of Dentistry, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin 300070 (China); Deng, Jia-Yin, E-mail: yazhou2991@126.com [School of Dentistry, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin 300070 (China)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer High glucose significantly induced TLR2 expression in gingival fibroblasts. Black-Right-Pointing-Pointer High glucose increased NF-{kappa}B p65 nuclear activity, IL-1{beta} and TNF-{alpha} levels. Black-Right-Pointing-Pointer PKC-{alpha}/{delta}-TLR2 pathway is involved in periodontal inflammation under high glucose. -- Abstract: Toll-like receptors (TLRs) play a key role in innate immune response and inflammation, especially in periodontitis. Meanwhile, hyperglycemia can induce inflammation in diabetes complications. However, the activity of TLRs in periodontitis complicated with hyperglycemia is still unclear. In the present study, high glucose (25 mmol/l) significantly induced TLR2 expression in gingival fibroblasts (p < 0.05). Also, high glucose increased nuclear factor kappa B (NF-{kappa}B) p65 nuclear activity, tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-l{beta} (IL-1{beta}) levels. Protein kinase C (PKC)-{alpha} and {delta} knockdown with siRNA significantly decreased TLR2 and NF-{kappa}B p65 expression (p < 0.05), whereas inhibition of PKC-{beta} had no effect on TLR2 and NF-{kappa}B p65 under high glucose (p < 0.05). Additional studies revealed that TLR2 knockdown significantly abrogated high-glucose-induced NF-{kappa}B expression and inflammatory cytokine secretion. Collectively, these data suggest that high glucose stimulates TNF-{alpha} and IL-1{beta} secretion via inducing TLR2 through PKC-{alpha} and PKC-{delta} in human gingival fibroblasts.

  10. Interference of selenium and selenoproteins with the insulin-regulated carbohydrate and lipid metabolism.

    Science.gov (United States)

    Steinbrenner, Holger

    2013-12-01

    An assumed link between supranutritional intake of the micronutrient selenium (Se) and type 2 diabetes mellitus is discussed controversially. Se concentrations in the habitual diet and in dietary supplements are probably not sufficient to induce overt diabetes in healthy individuals. On the other hand, high plasma Se and selenoprotein P (Sepp1) levels have been found to be associated with biomarkers of an impaired carbohydrate and lipid homeostasis in humans. Moreover, abundant expression of antioxidant selenoproteins due to dietary Se oversupply resulted in hyperinsulinemia and decreased insulin sensitivity in animal models. This review discusses findings from animal and cell culture studies in search of molecular mechanisms underlying an interference of Se and selenproteins such as the Se transport and supply protein Sepp1 and the hydrogen peroxide-reducing selenoenzyme glutathione peroxidase 1 (GPx1) with insulin-controlled metabolic pathways. A probable rationale derives from the positive and negative regulation of both glucose-induced insulin secretion and insulin-induced signaling by hydrogen peroxide. Se status and GPx1 expression have been reported to affect the activity of insulin-antagonistic phosphatases that are regulated by hydrogen peroxide-mediated reversible oxidation of catalytic cysteine residues. GPx1 and/or Sepp1 inhibited phosphorylation (activation) of key mediators in energy metabolism such as protein kinase B (Akt) and AMP-activated protein kinase (AMPK) in liver and/or skeletal muscle. Conversely, a dys-regulated carbohydrate metabolism in diabetes might affect plasma Se and Sepp1 levels, as the hepatic biosynthesis of Sepp1 is suppressed by insulin and stimulated under hyperglycemic conditions. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial.

    Science.gov (United States)

    Gardner, Christopher D; Trepanowski, John F; Del Gobbo, Liana C; Hauser, Michelle E; Rigdon, Joseph; Ioannidis, John P A; Desai, Manisha; King, Abby C

    2018-02-20

    Dietary modification remains key to successful weight loss. Yet, no one dietary strategy is consistently superior to others for the general population. Previous research suggests genotype or insulin-glucose dynamics may modify the effects of diets. To determine the effect of a healthy low-fat (HLF) diet vs a healthy low-carbohydrate (HLC) diet on weight change and if genotype pattern or insulin secretion are related to the dietary effects on weight loss. The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) randomized clinical trial included 609 adults aged 18 to 50 years without diabetes with a body mass index between 28 and 40. The trial enrollment was from January 29, 2013, through April 14, 2015; the date of final follow-up was May 16, 2016. Participants were randomized to the 12-month HLF or HLC diet. The study also tested whether 3 single-nucleotide polymorphism multilocus genotype responsiveness patterns or insulin secretion (INS-30; blood concentration of insulin 30 minutes after a glucose challenge) were associated with weight loss. Health educators delivered the behavior modification intervention to HLF (n = 305) and HLC (n = 304) participants via 22 diet-specific small group sessions administered over 12 months. The sessions focused on ways to achieve the lowest fat or carbohydrate intake that could be maintained long-term and emphasized diet quality. Primary outcome was 12-month weight change and determination of whether there were significant interactions among diet type and genotype pattern, diet and insulin secretion, and diet and weight loss. Among 609 participants randomized (mean age, 40 [SD, 7] years; 57% women; mean body mass index, 33 [SD, 3]; 244 [40%] had a low-fat genotype; 180 [30%] had a low-carbohydrate genotype; mean baseline INS-30, 93 μIU/mL), 481 (79%) completed the trial. In the HLF vs HLC diets, respectively, the mean 12-month macronutrient distributions were 48% vs 30% for carbohydrates

  12. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats

    DEFF Research Database (Denmark)

    Hoelmkjaer, Kirsten M.; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment...... with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose...... by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean...

  13. Differences in beta-cell function and insulin secretion in Black vs. White obese adolescents: Do incretin hormones play a role?

    Science.gov (United States)

    Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated beta-cell function and insulin hypersecretion, in response to intravenous (IV) glucose, compared with Whites. T...

  14. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats.

    Directory of Open Access Journals (Sweden)

    Kirsten M Hoelmkjaer

    Full Text Available Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all. Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4% in the exenatide group versus 3.2% (range -5.3 to 5.7% in the placebo group (P = 0.10. Body composition and adipokine levels were unaffected by exenatide (P>0.05. Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats.

  15. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats.

    Science.gov (United States)

    Hoelmkjaer, Kirsten M; Wewer Albrechtsen, Nicolai J; Holst, Jens J; Cronin, Anna M; Nielsen, Dorte H; Mandrup-Poulsen, Thomas; Bjornvad, Charlotte R

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats.

  16. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats

    Science.gov (United States)

    Hoelmkjaer, Kirsten M.; Wewer Albrechtsen, Nicolai J.; Holst, Jens J.; Cronin, Anna M.; Nielsen, Dorte H.; Mandrup-Poulsen, Thomas; Bjornvad, Charlotte R.

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats. PMID:27136422

  17. H2O2-Activated Mitochondrial Phospholipase iPLA2 gamma Prevents Lipotoxic Oxidative Stress in Synergy with UCP2, Amplifies Signaling via G-Protein-Coupled Receptor GPR40, and Regulates Insulin Secretion in Pancreatic beta-Cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Jan; Dlasková, Andrea; Zelenka, Jaroslav; Jabůrek, Martin; Ježek, Petr

    2015-01-01

    Roč. 23, č. 12 (2015), s. 958-972 ISSN 1523-0864 R&D Projects: GA ČR(CZ) GPP303/11/P320; GA ČR(CZ) GA13-02033S; GA ČR(CZ) GA13-06666S; GA ČR GA15-02051S Institutional support: RVO:67985823 Keywords : mitochondrial phospholipase iPLA2 gamma * uncoupling protein UCP2 * G-protein coupled receptor - 40 * glucose-stimulated insulin secretion * pancreatic beta cells Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 7.093, year: 2015

  18. Spirulina platensis prevents high glucose-induced oxidative stress mitochondrial damage mediated apoptosis in cardiomyoblasts.

    Science.gov (United States)

    Jadaun, Pratiksha; Yadav, Dhananjay; Bisen, Prakash Singh

    2018-04-01

    The current study was undertaken to study the effect of Spirulina platensis (Spirulina) extract on enhanced oxidative stress during high glucose induced cell death in H9c2 cells. H9c2 cultured under high glucose (33 mM) conditions resulted in a noteworthy increase in oxidative stress (free radical species) accompanied by loss of mitochondrial membrane potential, release of cytochrome c, increase in caspase activity and pro-apoptotic protein (Bax). Spirulina extract (1 μg/mL), considerably inhibited increased ROS and RNS levels, reduction in cytochrome c release, raise in mitochondrial membrane potential, decreased the over expression of proapoptotic protein Bax and suppressed the Bax/Bcl2 ratio with induced apoptosis without affecting cell viability. Overall results suggest that Spirulina extract plays preventing role against enhanced oxidative stress during high glucose induced apoptosis in cardiomyoblasts as well as related dysfunction in H9c2 cells.

  19. Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte apoptosis by regulating oxidative stress.

    Science.gov (United States)

    Jagadish, Swamy; Hemshekhar, Mahadevappa; NaveenKumar, Somanathapura K; Sharath Kumar, Kothanahally S; Sundaram, Mahalingam S; Basappa; Girish, Kesturu S; Rangappa, Kanchugarakoppal S

    2017-11-01

    Chronic hyperglycemia is one of the characteristic conditions associated with Diabetes Mellitus (DM), which often exerts deleterious effects on erythrocyte morphology and hemodynamic properties leading to anemia and diabetes-associated vascular complications. High glucose-induced over production of reactive oxygen species (ROS) can alter the blood cell metabolism and biochemical functions subsequently causing eryptosis (red blood cell death), yet another complication of concern in DM. Therefore, blocking high glucose-induced oxidative damage and subsequent eryptosis is of high importance in the better management of DM and associated vascular complications. In this study, we synthesized an oxolane derivative 1-(2,2-dimethyltetrahydrofuro[2,3][1,3]dioxol-5-yl)ethane-1,2-diol (DMTD), and demonstrated its efficacy to mitigate hyperglycemia-induced ROS generation and subsequent eryptosis. We showed that DMTD effectively inhibits high glucose-induced ROS generation, intracellular calcium levels, phosphaditylserine (PS) scrambling, calpain and band 3 activation, LDH leakage, protein glycation and lipid peroxidation, meanwhile enhances the antioxidant indices, osmotic fragility and Na + /K + -ATPase activity in erythrocytes. DMTD dose dependently decreased the glycated hemoglobin level and enhances the glucose utilization by erythrocytes in vitro. Further, DMTD alleviated the increase in ROS production, intracellular Ca 2+ level and PS externalization in the erythrocytes of human diabetic subjects and enhanced the Na + /K + -ATPase activity. Taken together, the synthesized oxolane derivative DMTD could be a novel synthetic inhibitor of high glucose-induced oxidative stress and eryptosis. Considering the present results DMTD could be a potential therapeutic to treat DM and associated complications and open new avenues in developing synthetic therapeutic targeting of DM-associated complications. Copyright © 2017. Published by Elsevier Inc.

  20. High glucose induced endothelial to mesenchymal transition in human umbilical vein endothelial cell.

    Science.gov (United States)

    Yu, Chun-Hong; Suriguga; Gong, Meng; Liu, Wen-Juan; Cui, Ning-Xuan; Wang, Ying; Du, Xin; Yi, Zong-Chun

    2017-06-01

    Studies have shown that endothelial-to-mesenchymal transition (EndMT) could contribute to the progression of diabetic nephropathy, diabetic renal fibrosis, and cardiac fibrosis. The aim of this study was to investigate the influence of high glucose and related mechanism of MAPK inhibitor or specific antioxidant on the EndMT. In vitro human umbilical vein endothelial cells (HUVEC) were cultured with 11mM, 30mM, 60mM and 120mM glucose for 0, 24, 48, 72 and 168h. Endothelial cell morphology was observed with microscope, and RT-PCR was used to detect mRNA expression of endothelial markers VE-cadherin and CD31, mesenchymal markers α-SMA and collagen I, and transforming growth factor TGF-β1. Immunofluorescence staining was performed to detect the expression of CD31 and α-SMA. The concentration of TGF-β1 in the supernatant was detected by ELISA. ERK1/2 phosphorylation level was detected by Western blot analysis. High glucose induced EndMT and increased the TGF-β1 level in HUVEC cells. Cells in high glucose for 7 days showed a significant decrease in mRNA expression of CD31 and VE-cadherin, and a significant increase in that of α-SMA and collagen I, while lost CD31 staining and acquired α-SMA staining. ERK signaling pathway blocker PD98059 significantly attenuated the high glucose-induced increase in the ERK1/2 phosphorylation level. PD98059 and NAC both inhibited high glucose-induced TGF-β1 expression and attenuated EndMT marker protein synthesis. High glucose could induce HUVEC cells to undergo EndMT. NAC and ERK signaling pathway may play important role in the regulation of the TGF-β1 biosynthesis during high glucose-induced EndMT. Copyright © 2017 Elsevier Inc. All rights reserved.