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Sample records for phase insulin secretion

  1. The effect of defective early phase insulin secretion on postload glucose intolerance in impaired fasting glucose.

    PubMed

    Sargin, Mehmet; Ikiişik, Murat; Sargin, Haluk; Orçun, Asuman; Kaya, Müjgan; Gözü, Hülya; Dabak, Reşat; Bayramiçli, Oya Uygur; Yayla, Ali

    2005-10-01

    Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two risk groups for type 2 diabetes. Type 2 diabetes is characterized by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycemia may differ due to heterogeneity of the disease. Combined glucose intolerance (CGI), on the other hand, seems to represent a more advanced stage of prediabetes that bears a distinctly higher risk of progression to diabetes and its comorbidities. This study has the aim to compare isolated IFG and CGI categories with respect to the degree of early phase insulin secretion abnormalities and insulin resistance. Subjects who had IFG (fasting glucose: 110-126 mg/dl) were included in the study. A 75-g oral glucose tolerance test (OGTT) with insulin response was done and subjects were classified according to the WHO criteria. Six subjects were excluded because they had diabetic glucose tolerance. A total of 66 patients (53.4 +/- 11.1 years, female/male: 48/18) were divided into two groups according to their glucose tolerance in OGGT (Group 1: isolated IFG and group 2: CGI). Early phase insulin secretion was measured by intravenous glucose tolerance test (IVGTT) and OGTT. Insulin resistance was assessed by the R value of the homeostasis model assessment (HOMA). We did not find any statistically significant difference between groups according to age, gender, body mass index (BMI), fasting glucose, fasting insulin, insulin-AUC (0-180 min) and HOMA-R values. In OGGT there was no statistically significant difference between 0', 30', 60' and 90' insulin levels of the groups; only 120' and 180' insulin levels were higher in CGI than in IFG group (p<0.05). In IVGTT, there was no statistically significant difference between glucose levels of the groups. Furthermore, insulin response to intravenous glucose was higher in IFG than in CGI (p<0.05). Our data demonstrate that isolated IFG and CGI are similar with respect to

  2. Cephalic phase of insulin secretion in response to a meal is unrelated to family history of type 2 diabetes.

    PubMed

    Eliasson, Björn; Rawshani, Araz; Axelsen, Mette; Hammarstedt, Ann; Smith, Ulf

    2017-01-01

    The pre-absorptive cephalic phase of insulin secretion is elicited during the first ten min of a meal and before glucose levels rise. Its importance for insulin release during the post-absorptive phase has been well documented in animals but its presence or importance in man has become increasingly controversial. We here examined the presence of an early cephalic phase of insulin release in 31 well matched individuals without (n = 15) or with (n = 16) a known family history of type 2 diabetes (first-degree relatives; FDR). We also examined the potential differences in individuals with or without impaired fasting (IFG) and impaired glucose tolerance (IGT). We here demonstrate that a cephalic phase of insulin secretion was present in all individuals examined and without any differences between control persons and FDR or IFG/IGT. However, the overall importance of the cephalic phase is conjectural since it was unrelated to the subsequent post-absorptive insulin release or glucose tolerance. One of the best predictors of the incremental cephalic phase of insulin release was fasting insulin level and, thus, a relation to degree of insulin sensitivity is likely. In conclusion, an early pre-absorptive and cephalic phase of insulin release is robustly present in man. However, we could not document any relation to family history of Type 2 diabetes nor to the post-absorptive phase and, thus, confirm its importance for subsequent degree of insulin release or glucose tolerance.

  3. Cephalic phase of insulin secretion in response to a meal is unrelated to family history of type 2 diabetes

    PubMed Central

    Rawshani, Araz; Axelsen, Mette; Hammarstedt, Ann; Smith, Ulf

    2017-01-01

    The pre-absorptive cephalic phase of insulin secretion is elicited during the first ten min of a meal and before glucose levels rise. Its importance for insulin release during the post-absorptive phase has been well documented in animals but its presence or importance in man has become increasingly controversial. We here examined the presence of an early cephalic phase of insulin release in 31 well matched individuals without (n = 15) or with (n = 16) a known family history of type 2 diabetes (first-degree relatives; FDR). We also examined the potential differences in individuals with or without impaired fasting (IFG) and impaired glucose tolerance (IGT). We here demonstrate that a cephalic phase of insulin secretion was present in all individuals examined and without any differences between control persons and FDR or IFG/IGT. However, the overall importance of the cephalic phase is conjectural since it was unrelated to the subsequent post-absorptive insulin release or glucose tolerance. One of the best predictors of the incremental cephalic phase of insulin release was fasting insulin level and, thus, a relation to degree of insulin sensitivity is likely. In conclusion, an early pre-absorptive and cephalic phase of insulin release is robustly present in man. However, we could not document any relation to family history of Type 2 diabetes nor to the post-absorptive phase and, thus, confirm its importance for subsequent degree of insulin release or glucose tolerance. PMID:28288176

  4. Insulin sensitivity and first-phase insulin secretion in obese Chinese with hyperglycemia in 30 and/or 60 min during glucose tolerance tests.

    PubMed

    Hong, Jie; Zhang, Yi-Fei; Gu, Wei-qiong; Zhang, Yu-wen; Su, Yu-xia; Chi, Zhen-ni; Wang, Wei-qing; Li, Xiao-ying; Ning, Guang

    2008-01-01

    The purpose of this study was to investigate insulin sensitivity and first-phase insulin secretion in obesity with hyperglycemia in 30 and/or 60 min during oral glucose tolerance (OGTT, glucose > or = 11.1 mmol/l, post-loading hyperglycemia, PLH) in Chinese population. A total of 196 nondiabetic subjects were included in the present study, among them 99 had normal glucose tolerance (NGT, subdivided into 32 lean NGT and 67 obese NGT), 74 had obesity with impaired glucose tolerance (IGT) and 23 had obesity with PLH. A standard 75-g oral glucose tolerance test was performed after fasting and at 30 min, 1, 2 and 3 h. Insulin sensitivity index (S(I)) was assessed by the Bergman's minimal model method with frequently sampled intravenous glucose tolerance test (FSIGTT), insulin secretion was determined by acute insulin response to glucose (AIRg). The disposition index (DI), the product of AIRg and S(I) was used to determine whether AIRg was adequate to compensate for insulin resistance. S(I) was significantly equally lower in three obese subgroups. AIRg was significantly increased in obese NGT as compared with lean NGT controls, and reduced to the same extent in IGT and PLH subjects. There was no significant difference among lean NGT, IGT and PLH subjects. DI value was reduced from obese NGT individuals, IGT and PLH subjects had a similar lower level of DI. In conclusion, our present results demonstrated that the pathophysiological basis of obese subjects with PLH were clearly insulin resistance and defective in first-phase insulin secretion as that in IGT subjects in Chinese population.

  5. Cephalic phase secretion of insulin and other enteropancreatic hormones in humans.

    PubMed

    Veedfald, Simon; Plamboeck, Astrid; Deacon, Carolyn F; Hartmann, Bolette; Knop, Filip K; Vilsbøll, Tina; Holst, Jens J

    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/m(2); HbA1c: 5.1 ± 0.1%/31.4 ± 0.5 mmol/mol). Cephalic activation was elicited by modified sham feeding (MSF, aka "chew and spit") with or without atropine (1 mg bolus 45 min before MSF + 80 ng·kg(-1)·min(-1) for 2 h). To mimic incipient prandial glucose excursions, glucose levels were clamped at 6 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 and abolished the MSF response. Neither insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), nor glucagon-like peptide-1 (GLP-1) levels changed in response to MSF or atropine. Glucagon and ghrelin levels were markedly attenuated by atropine prior to and during the clamp: at t = 105 min on the atropine (ATR) + clamp (CLA) + MSF compared with the saline (SAL) + CLA and SAL + CLA + MSF days; baseline-subtracted glucagon levels were -10.7 ± 1.1 vs. -4.0 ± 1.1 and -4.7 ± 1.9 pmol/l (means ± SE), P < 0.0001, respectively; corresponding baseline-subtracted ghrelin levels were 303 ± 36 vs. 39 ± 38 and 3.7 ± 21 pg/ml (means ± SE), P < 0.0001. Glucagon and ghrelin levels were unaffected by MSF. Despite adequate PP responses, a cephalic phase response was absent for insulin, glucagon, GLP-1, GIP, and ghrelin. Copyright © 2016 the American Physiological Society.

  6. Connexin-36 Gap Junctions Regulate In Vivo First- and Second-Phase Insulin Secretion Dynamics and Glucose Tolerance in the Conscious Mouse

    PubMed Central

    Head, W. Steven; Orseth, Meredith L.; Nunemaker, Craig S.; Satin, Leslie S.; Piston, David W.; Benninger, Richard K.P.

    2012-01-01

    Insulin is secreted from the islets of Langerhans in coordinated pulses. These pulses are thought to lead to plasma insulin oscillations, which are putatively more effective in lowering blood glucose than continuous levels of insulin. Gap-junction coupling of β-cells by connexin-36 coordinates intracellular free calcium oscillations and pulsatile insulin release in isolated islets, however a role in vivo has not been shown. We test whether loss of gap-junction coupling disrupts plasma insulin oscillations and whether this impacts glucose tolerance. We characterized the connexin-36 knockout (Cx36−/−) mouse phenotype and performed hyperglycemic clamps with rapid sampling of insulin in Cx36−/− and control mice. Our results show that Cx36−/− mice are glucose intolerant, despite normal plasma insulin levels and insulin sensitivity. However, Cx36−/− mice exhibit reduced insulin pulse amplitudes and a reduction in first-phase insulin secretion. These changes are similarly found in isolated Cx36−/− islets. We conclude that Cx36 gap junctions regulate the in vivo dynamics of insulin secretion, which in turn is important for glucose homeostasis. Coordinated pulsatility of individual islets enhances the first-phase elevation and second-phase pulses of insulin. Because these dynamics are disrupted in the early stages of type 2 diabetes, dysregulation of gap-junction coupling could be an important factor in the development of this disease. PMID:22511206

  7. Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse.

    PubMed

    Head, W Steven; Orseth, Meredith L; Nunemaker, Craig S; Satin, Leslie S; Piston, David W; Benninger, Richard K P

    2012-07-01

    Insulin is secreted from the islets of Langerhans in coordinated pulses. These pulses are thought to lead to plasma insulin oscillations, which are putatively more effective in lowering blood glucose than continuous levels of insulin. Gap-junction coupling of β-cells by connexin-36 coordinates intracellular free calcium oscillations and pulsatile insulin release in isolated islets, however a role in vivo has not been shown. We test whether loss of gap-junction coupling disrupts plasma insulin oscillations and whether this impacts glucose tolerance. We characterized the connexin-36 knockout (Cx36(-/-)) mouse phenotype and performed hyperglycemic clamps with rapid sampling of insulin in Cx36(-/-) and control mice. Our results show that Cx36(-/-) mice are glucose intolerant, despite normal plasma insulin levels and insulin sensitivity. However, Cx36(-/-) mice exhibit reduced insulin pulse amplitudes and a reduction in first-phase insulin secretion. These changes are similarly found in isolated Cx36(-/-) islets. We conclude that Cx36 gap junctions regulate the in vivo dynamics of insulin secretion, which in turn is important for glucose homeostasis. Coordinated pulsatility of individual islets enhances the first-phase elevation and second-phase pulses of insulin. Because these dynamics are disrupted in the early stages of type 2 diabetes, dysregulation of gap-junction coupling could be an important factor in the development of this disease.

  8. Effect of intensive insulin therapy on first-phase insulin secretion in newly diagnosed type 2 diabetic patients with a family history of the disease

    PubMed Central

    LI, QING; WANG, LUAN; XIAO, LIN; WANG, ZHONGCHAO; WANG, FANG; YU, XIAOLONG; YAN, SHENGLI; WANG, YANGANG

    2015-01-01

    Intensive insulin treatment is known to improve β-cell function in the majority of patients with newly diagnosed type 2 diabetes mellitus (T2DM), and family history (FH) is known to be an important independent risk factor for T2DM. Thus, the aim of the present study was to investigate the difference in first-phase insulin secretion and the effect of intensive insulin therapy on the improvement of β-cell function between T2DM patients with and without a FH of diabetes. Patients with newly diagnosed T2DM and healthy controls were divided into groups according to their FH of diabetes. Improvement in β-cell function was evaluated with an arginine stimulation test after two weeks of continuous subcutaneous insulin infusion (CSII). Compared with the control group, the level of fasting insulin and the homeostasis model assessment of insulin resistance (HOMA2-IR) were higher in the DM group, while the homeostasis model assessment of β-cell insulin secretion (HOMA2-%β) and the first-phase peak ratio were lower (P<0.05). In addition, the first-phase peak ratio in the FH- control group was higher compared with that in the FH+ control group (P=0.023). Following CSII, all the patients achieved excellent blood glucose control in 6.2±3.6 days, without severe adverse effects. In the DM groups, the fasting insulin level and HOMA2-IR were lower, while the HOMA2-%β and first-phase peak ratio were higher, when compared with the values prior to treatment, particularly in the FH- DM group. The HOMA2-%β in the FH+ DM group was lower compared with the FH- DM group (P=0.027). Therefore, T2DM patients with and without a FH of the disease were shown to have a good response to CSII in the improvement of insulin resistance and β-cell function; however, the improvements were less significant in patients with a FH compared with patients without a FH of diabetes. PMID:25574243

  9. Evaluation of insulin sensitivity and secretion in primary aldosteronism.

    PubMed

    Watanabe, Daisuke; Yatabe, Midori; Ichihara, Atsuhiro

    In primary aldosteronism (PA), insulin response to glucose is not fully understood. Insulin action was elucidated using indices in 32 PA and 21 essential hypertension (EH) patients. These patients were evaluated using homeostasis model assessment (HOMA) indices, quantitative insulin sensitivity check index (QUICKI), and insulinogenic index (IGI), which were expressed for insulin sensitivity/secretion and the early phase of insulin secretion. Insulin sensitivity and early phase of insulin secretion were decreased in PA, and there was a negative correlation between serum potassium concentration and insulin sensitivity indices. These findings suggest that glucose intolerance in PA may be caused by hypokalemia-induced insulin resistance and hypokalemia-independent impairment of early-phase insulin secretion.

  10. Oscillatory control of insulin secretion.

    PubMed

    Tengholm, Anders; Gylfe, Erik

    2009-01-15

    Pancreatic beta-cells possess an inherent ability to generate oscillatory signals that trigger insulin release. Coordination of the secretory activity among beta-cells results in pulsatile insulin secretion from the pancreas, which is considered important for the action of the hormone in the target tissues. This review focuses on the mechanisms underlying oscillatory control of insulin secretion at the level of the individual beta-cell. Recent studies have demonstrated that oscillations of the cytoplasmic Ca(2+) concentration are synchronized with oscillations in beta-cell metabolism, intracellular cAMP concentration, phospholipase C activity and plasma membrane phosphoinositide lipid concentrations. There are complex interdependencies between the different messengers and signalling pathways that contribute to amplitude regulation and shaping of the insulin secretory response to nutrient stimuli and neurohormonal modulators. Several of these pathways may be important pharmacological targets for improving pulsatile insulin secretion in type 2 diabetes.

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

    PubMed

    Wood, Andrew R; Jonsson, Anna; Jackson, Anne U; Wang, Nan; van Leewen, Nienke; Palmer, Nicholette D; Kobes, Sayuko; Deelen, Joris; Boquete-Vilarino, Lorena; Paananen, Jussi; Stančáková, Alena; Boomsma, Dorret I; de Geus, Eco J C; Eekhoff, Elisabeth M W; Fritsche, Andreas; Kramer, Mark; Nijpels, Giel; Simonis-Bik, Annemarie; van Haeften, Timon W; Mahajan, Anubha; Boehnke, Michael; Bergman, Richard N; Tuomilehto, Jaakko; Collins, Francis S; Mohlke, Karen L; Banasik, Karina; Groves, Christopher J; McCarthy, Mark I; Pearson, Ewan R; Natali, Andrea; Mari, Andrea; Buchanan, Thomas A; Taylor, Kent D; Xiang, Anny H; Gjesing, Anette P; Grarup, Niels; Eiberg, Hans; Pedersen, Oluf; Chen, Yii-Derr; Laakso, Markku; Norris, Jill M; Smith, Ulf; Wagenknecht, Lynne E; Baier, Leslie; Bowden, Donald W; Hansen, Torben; Walker, Mark; Watanabe, Richard M; 't Hart, Leen M; Hanson, Robert L; Frayling, Timothy M

    2017-08-01

    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 intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits. © 2017 by the American Diabetes Association.

  12. Rp-cAMPS Prodrugs Reveal the cAMP Dependence of First-Phase Glucose-Stimulated Insulin Secretion

    PubMed Central

    Schwede, Frank; Chepurny, Oleg G.; Kaufholz, Melanie; Bertinetti, Daniela; Leech, Colin A.; Cabrera, Over; Zhu, Yingmin; Mei, Fang; Cheng, Xiaodong; Manning Fox, Jocelyn E.; MacDonald, Patrick E.; Genieser, Hans-G.; Herberg, Friedrich W.

    2015-01-01

    cAMP-elevating agents such as the incretin hormone glucagon-like peptide-1 potentiate glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. However, a debate has existed since the 1970s concerning whether or not cAMP signaling is essential for glucose alone to stimulate insulin secretion. Here, we report that the first-phase kinetic component of GSIS is cAMP-dependent, as revealed through the use of a novel highly membrane permeable para-acetoxybenzyl (pAB) ester prodrug that is a bioactivatable derivative of the cAMP antagonist adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS). In dynamic perifusion assays of human or rat islets, a step-wise increase of glucose concentration leads to biphasic insulin secretion, and under these conditions, 8-bromoadenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer, 4-acetoxybenzyl ester (Rp-8-Br-cAMPS-pAB) inhibits first-phase GSIS by up to 80%. Surprisingly, second-phase GSIS is inhibited to a much smaller extent (≤20%). Using luciferase, fluorescence resonance energy transfer, and bioluminescence resonance energy transfer assays performed in living cells, we validate that Rp-8-Br-cAMPS-pAB does in fact block cAMP-dependent protein kinase activation. Novel effects of Rp-8-Br-cAMPS-pAB to block the activation of cAMP-regulated guanine nucleotide exchange factors (Epac1, Epac2) are also validated using genetically encoded Epac biosensors, and are independently confirmed in an in vitro Rap1 activation assay using Rp-cAMPS and Rp-8-Br-cAMPS. Thus, in addition to revealing the cAMP dependence of first-phase GSIS from human and rat islets, these findings establish a pAB-based chemistry for the synthesis of highly membrane permeable prodrug derivatives of Rp-cAMPS that act with micromolar or even nanomolar potency to inhibit cAMP signaling in living cells. PMID:26061564

  13. Rp-cAMPS Prodrugs Reveal the cAMP Dependence of First-Phase Glucose-Stimulated Insulin Secretion.

    PubMed

    Schwede, Frank; Chepurny, Oleg G; Kaufholz, Melanie; Bertinetti, Daniela; Leech, Colin A; Cabrera, Over; Zhu, Yingmin; Mei, Fang; Cheng, Xiaodong; Manning Fox, Jocelyn E; MacDonald, Patrick E; Genieser, Hans-G; Herberg, Friedrich W; Holz, George G

    2015-07-01

    cAMP-elevating agents such as the incretin hormone glucagon-like peptide-1 potentiate glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. However, a debate has existed since the 1970s concerning whether or not cAMP signaling is essential for glucose alone to stimulate insulin secretion. Here, we report that the first-phase kinetic component of GSIS is cAMP-dependent, as revealed through the use of a novel highly membrane permeable para-acetoxybenzyl (pAB) ester prodrug that is a bioactivatable derivative of the cAMP antagonist adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS). In dynamic perifusion assays of human or rat islets, a step-wise increase of glucose concentration leads to biphasic insulin secretion, and under these conditions, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer, 4-acetoxybenzyl ester (Rp-8-Br-cAMPS-pAB) inhibits first-phase GSIS by up to 80%. Surprisingly, second-phase GSIS is inhibited to a much smaller extent (≤20%). Using luciferase, fluorescence resonance energy transfer, and bioluminescence resonance energy transfer assays performed in living cells, we validate that Rp-8-Br-cAMPS-pAB does in fact block cAMP-dependent protein kinase activation. Novel effects of Rp-8-Br-cAMPS-pAB to block the activation of cAMP-regulated guanine nucleotide exchange factors (Epac1, Epac2) are also validated using genetically encoded Epac biosensors, and are independently confirmed in an in vitro Rap1 activation assay using Rp-cAMPS and Rp-8-Br-cAMPS. Thus, in addition to revealing the cAMP dependence of first-phase GSIS from human and rat islets, these findings establish a pAB-based chemistry for the synthesis of highly membrane permeable prodrug derivatives of Rp-cAMPS that act with micromolar or even nanomolar potency to inhibit cAMP signaling in living cells.

  14. ERAD-icating mutant insulin promotes functional insulin secretion.

    PubMed

    Moore, Daniel J

    2017-01-18

    Overexpression of a chaperone protein liberates functional insulin from a misfolded mutant partner to improve insulin secretion. Copyright © 2017, American Association for the Advancement of Science.

  15. Molecular Mechanisms of Insulin Secretion and Insulin Action.

    ERIC Educational Resources Information Center

    Flatt, Peter R.; Bailey, Clifford J.

    1991-01-01

    Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

  16. Molecular Mechanisms of Insulin Secretion and Insulin Action.

    ERIC Educational Resources Information Center

    Flatt, Peter R.; Bailey, Clifford J.

    1991-01-01

    Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

  17. Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass.

    PubMed

    Martinussen, Christoffer; Bojsen-Møller, Kirstine N; Dirksen, Carsten; Jacobsen, Siv H; Jørgensen, Nils B; Kristiansen, Viggo B; Holst, Jens J; Madsbad, Sten

    2015-03-15

    Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic β-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose 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 oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-β already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic β-cell function per se, reflected in enhanced 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. Copyright © 2015 the American Physiological Society.

  18. High-fat diet with stress impaired islets' insulin secretion by reducing plasma estradiol and pancreatic GLUT2 protein levels in rats' proestrus phase.

    PubMed

    Salimi, M; Zardooz, H; Khodagholi, F; Rostamkhani, F; Shaerzadeh, F

    2016-10-01

    This study was conducted to determine whether two estrus phases (proestrus and diestrus) in female rats may influence the metabolic response to a high-fat diet and/or stress, focusing on pancreatic insulin secretion and content. Animals were divided into high-fat and normal diet groups, then each group was subdivided into stress and non-stress groups, and finally, each one of these was divided into proestrus and diestrus subgroups. At the end of high-fat diet treatment, foot-shock stress was applied to the animals. Then, blood samples were taken to measure plasma factors. Finally, the pancreas was removed for determination of glucose transporter 2 (GLUT2) protein levels and assessment of insulin content and secretion of the isolated islets. In the normal and high-fat diet groups, stress increased plasma corticosterone concentration in both phases. In both study phases, high-fat diet consumption decreased estradiol and increased leptin plasma levels. In the high-fat diet group in response to high glucose concentration, a reduction in insulin secretion was observed in the proestrus phase compared with the same phase in the normal diet group in the presence and absence of stress. Also, high-fat diet decreased the insulin content of islets in the proestrus phase compared with the normal diet. High-fat diet and/or stress caused a reduction in islet GLUT2 protein levels in both phases. In conclusion, it seems possible that high-fat diet alone or combined with foot-shock, predispose female rats to impaired insulin secretion, at least in part, by interfering with estradiol levels in the proestrus phase and decreasing pancreatic GLUT2 protein levels.

  19. Clinical Results of an Automated Artificial Pancreas Using Technosphere Inhaled Insulin to Mimic First-Phase Insulin Secretion

    PubMed Central

    Zisser, Howard; Dassau, Eyal; Lee, Justin J.; Harvey, Rebecca A.; Bevier, Wendy; Doyle, Francis J.

    2015-01-01

    Objective: The purpose of this study was to investigate whether or not adding a fixed preprandial dose of inhaled insulin to a fully automated closed loop artificial pancreas would improve the postprandial glucose control without adding an increased risk of hypoglycemia. Research Design and Methods: Nine subjects with T1DM were recruited for the study. The patients were on closed-loop control for 24 hours starting around 4:30 pm. Mixed meals (~50 g CHO) were given at 6:30 pm and 7:00 am the following day. For the treatment group each meal was preceded by the inhalation of one 10 U dose of Technosphere Insulin (TI). Subcutaneous insulin delivery was controlled by a zone model predictive control algorithm (zone-MPC). At 11:00 am, the patient exercised for 30 ± 5 minutes at 50% of predicted heart rate reserve. Results: The use of TI resulted in increasing the median percentage time in range (70-180 mg/dl, BG) during the 5-hour postprandial period by 21.6% (81.6% and 60% in the with/without TI cases, respectively, P = .06) and reducing the median postprandial glucose peak by 33 mg/dl (172 mg/dl and 205 mg/dl in the with and without TI cases, respectively, P = .004). The median percentage time in range 80-140 mg/dl during the entire study period was 67.5% as compared to percentage time in range without the use of TI of 55.2% (P = .03). Conclusions: Adding preprandial TI (See video supplement) to an automated closed-loop AP system resulted in superior postprandial control as demonstrated by lower postprandial glucose exposure without addition hypoglycemia. PMID:25901023

  20. Combination of Peptide YY3–36 with GLP-17–36 amide Causes an Increase in First-Phase Insulin Secretion after IV Glucose

    PubMed Central

    Tan, Tricia M.; Salem, Victoria; Troke, Rachel C.; Alsafi, Ali; Field, Benjamin C. T.; De Silva, Akila; Misra, Shivani; Baynes, Kevin C. R.; Donaldson, Mandy; Minnion, James; Ghatei, Mohammad A.; Godsland, Ian F.

    2014-01-01

    Context: The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY3–36 and GLP-17–36 amide, on glucose homeostasis are unknown. Objective: This study sought to investigate the acute effects of PYY3–36 and GLP-17–36 amide, individually and in combination, on insulin secretion and sensitivity. Setting and Design: Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY3–36 alone, GLP-17–36 amide alone, and a combination of PYY3–36 and GLP-17–36 amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility. Results: PYY3–36 alone caused a small but nonsignificant increase in AIRg. GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide did increase AIRg significantly. No significant differences in SI were observed with any intervention. Conclusions: PYY3–36 lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY3–36 and GLP-17–36 amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI. PMID:25144632

  1. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance.

    PubMed

    van Poppel, P C M; van Asseldonk, E J P; Holst, J J; Vilsbøll, T; Netea, M G; Tack, C J

    2014-12-01

    Inflammation at the level of the β cell appears to be involved in progressive β-cell dysfunction in type 2 diabetes. We assessed the effect of blocking interleukin-1 (IL-1) by anakinra [recombinant human interleukin-1 receptor antagonist (IL-1Ra)] on β-cell function. Sixteen participants with impaired glucose tolerance were treated with 150 mg anakinra daily for 4 weeks in a double blind, randomized, placebo-controlled cross-over study with a wash-out period of 4 weeks. At the end of each treatment period, oral glucose tolerance tests (OGTTs) and hyperglycaemic clamps were performed. First-phase insulin secretion improved after anakinra treatment compared with placebo, 148 ± 20 versus 123 ± 14 mU/l, respectively (p = 0.03), and the insulinogenic index was higher after anakinra treatment. These results support the concept of involvement of IL-1β in the (progressive) decrease of insulin secretion capacity associated with type 2 diabetes.

  2. Insulin secretion in children with growth retardation.

    PubMed

    Boscherini, B; Finocchi, G; Lostia, O; Mancuso, G; Montani, P; Pasquino, A M; Rezza, E; Rocchio, J; Taggi, F; Zorretta, D

    1977-12-30

    The effect of tolbutamide administration on insulin secretion was studied in 69 children with growth retardation. Diminished insulin secretion was found in all the patients, compared to the control group. This insulin deficit was most evident in patients with isolated, total GH deficiency and least evident in children with idiopathic short stature. Intermediate values were found in dwarfism due to isolated, partial GH deficiency. These results favour the hypothesis that hypoinsulinism contributes to the somatotropin deficiency in causing growth retardation.

  3. Insulin and Glucagon Secretion In Vitro

    NASA Technical Reports Server (NTRS)

    Rajan, Arun S.

    1998-01-01

    Long-duration space flight is associated with many physiological abnormalities in astronauts. In particular, altered regulation of the hormones insulin and glucagon may contribute to metabolic disturbances such as increased blood sugar levels, which if persistently elevated result in toxic effects. These changes are also observed in the highly prevalent disease diabetes, which affects 16 million Americans and consumes over $100 billion in annual healthcare costs. By mimicking the microgravity environment of space in the research laboratory using a NASA-developed bioreactor, one can study the physiology of insulin and glucagon secretion and determine if there are alterations in these cellular processes. The original specific objectives of the project included: (1) growing ('cell culture') of pancreatic islet beta and alpha cells that secrete insulin and glucagon respectively, in the NASA bioreactor; (2) examination of the effects of microgravity on insulin and glucagon secretion; and (3) study of molecular mechanisms of insulin and glucagon secretion if altered by microgravity.

  4. Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics.

    PubMed

    Benninger, Richard K P; Piston, David W

    2014-08-01

    Coordinated pulses of electrical activity and insulin secretion are a hallmark of the islet of Langerhans. These coordinated behaviors are lost when β cells are dissociated, which also leads to increased insulin secretion at low glucose levels. Islets without gap junctions exhibit asynchronous electrical activity similar to dispersed cells, but their secretion at low glucose levels is still clamped off, putatively by a juxtacrine mechanism. Mice lacking β cell gap junctions have near-normal average insulin levels, but are glucose intolerant due to reduced first-phase and pulsatile insulin secretion, illustrating the importance of temporal dynamics. Here, we review the quantitative data on islet synchronization and the current mathematical models that have been developed to explain these behaviors and generate greater understanding of the underlying mechanisms. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Cellular Communication and Heterogeneity in Pancreatic Islet Insulin Secretion Dynamics

    PubMed Central

    Benninger, Richard K.P.; Piston, David W.

    2014-01-01

    Coordinated pulses of electrical activity and insulin secretion are a hallmark of the islet of Langerhans. These coordinated behaviors are lost when β-cells are dissociated, which also leads to increased insulin secretion at low glucose. Islets without gap junctions exhibit asynchronous electrical activity similar to dispersed cells, but their secretion at low glucose is still clamped off, putatively by a juxtacrine mechanism. Mice lacking β-cell gap junctions have near-normal average insulin levels, but are glucose intolerant due to reduced first-phase and pulsatile insulin secretion, illustrating the importance of temporal dynamics. We review the quantitative data on islet synchronization and the current mathematical models that have been developed to explain these behaviors and generate greater understanding of the underlying mechanisms. PMID:24679927

  6. First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery.

    PubMed

    Salinari, Serenella; Bertuzzi, Alessandro; Asnaghi, Simone; Guidone, Caterina; Manco, Melania; Mingrone, Geltrude

    2009-03-01

    The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery. Peripheral insulin sensitivity and beta-cell function after either intravenous (IVGTT) or oral glucose tolerance (OGTT) tests and minimal model analysis were assessed in nine obese, type 2 diabetic subjects before and 1 month after biliopancreatic diversion and compared with those in six normal-weight control subjects. Insulin-dependent whole-body glucose disposal was measured by the euglycemic clamp, and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were also measured. The first phase of insulin secretion after the IVGTT was fully normalized after the operation. The disposition index from OGTT data was increased about 10-fold and became similar to the values found in control subjects, and the disposition index from IVGTT data increased about 3.5-fold, similarly to what happened after the euglycemic clamp. The area under the curve (AUC) for GIP decreased about four times (from 3,000 +/- 816 to 577 +/- 155 pmol x l(-1) x min, P < 0.05). On the contrary, the AUC for GLP1 almost tripled (from 150.4 +/- 24.4 to 424.4 +/- 64.3 pmol x l(-1) . min, P < 0.001). No significant correlation was found between GIP or GLP1 percent changes and modification of the sensitivity indexes independently of the route of glucose administration. Restoration of the first-phase insulin secretion and normalization of insulin sensitivity in type 2 diabetic subjects after malabsorptive bariatric surgery seem to be related to the reduction of the effect of some intestinal factor(s) resulting from intestinal bypass.

  7. Simultaneous measurement of insulin sensitivity, insulin secretion and the disposition index in conscious unhandled mice

    PubMed Central

    Alonso, L. C.; Watanabe, Y.; Stefanovski, D.; Lee, E. J.; Singamsetty, S.; Romano, L. C.; Zou, B.; Garcia-Ocana, A.; Bergman, R. N.; O’Donnell, C. P.

    2012-01-01

    Of the parameters that determine glucose disposal and progression to diabetes in humans: first-phase insulin secretion, glucose effectiveness, insulin sensitivity, and the disposition index, only insulin sensitivity can be reliably measured in conscious mice. To determine the importance of the other parameters in murine glucose homeostasis in lean and obese states, we developed the frequently sampled intravenous glucose tolerance test (FSIVGTT) for use in unhandled mice. We validated the conscious FSIVGTT against the euglycemic clamp for measuring insulin sensitivity in lean and obese mice. Insulin resistant mice had increased first-phase insulin secretion, decreased glucose effectiveness and a reduced disposition index, qualitatively similar to humans. Intriguingly, while insulin secretion explained most of the variation in glucose disposal in lean mice, glucose effectiveness and the disposition index more strongly predicted glucose disposal in obese mice. Disposition index curves identified individual diet-induced obese mice as having compensated or decompensated insulin secretion. Conscious FSIVGTT opens the door to apply mouse genetics to the determinants of in vivo insulin secretion, glucose effectiveness and disposition index, and further validates the mouse as a model of metabolic disease. PMID:22331130

  8. Stimulation of leptin secretion by insulin

    PubMed Central

    Tsai, Minglun; Asakawa, Akihiro; Amitani, Haruka; Inui, Akio

    2012-01-01

    Leptin has a crucial role in regulating food intake and maintaining metabolic homeostasis. Although little is known about the process of leptin secretion, insulin, which has an important role in the metabolism of glucose and lipids, is believed to regulate leptin secretion through a posttranscriptional mechanism in the short term, and via glucose metabolism in the long term. The gastric mucosa secretes leptin, but this mechanism has not been completely elucidated. Understanding the mechanism of insulin-regulated leptin secretion could lead to the development of new treatment methods for obesity and its comorbidities, which are serious public health concerns. PMID:23565488

  9. A mathematical model of insulin secretion.

    PubMed

    Shannon, A G; Hogg, J M; Ollerton, R L; Luzio, S; Owens, D R

    1994-01-01

    Diabetes mellitus is a chronic state of excessive blood glucose levels (hyperglycaemia), which may result from many environmental and genetic factors, often acting jointly. The major regulator of glucose concentration in the blood is insulin. It is known that about 50% of the insulin is taken up by the liver on passing through it after secretion from the pancreas. The precise value of this fractional uptake is not known, so the prehepatic insulin secretion rates cannot be readily estimated from the plasma insulin concentration levels. By utilizing the equimolar secretion of insulin and connecting peptide (C-peptide) from the pancreas, a noninvasive method has been formulated. This was based on a compartmental model which involved the pancreas, liver, and plasma. The resulting differential equation yielded a gamma variate solution which could be readily linearized. The model was then tested on 56 normal (51 nonobese and 5 obese) subjects, and three groups of subjects with diabetes who could be labelled as mild, moderate, and severe (based on the fasting plasma glucose concentration) with 83, 88, and 64 subjects respectively. We have focused on the human patient environment of the clinician to produce a distinct model which gave a consistent pattern within all four groups with good fits between observed and theoretical values of the plasma insulin levels. The consequent rates for insulin secretion were consistent across the groups and were clinically meaningful.

  10. Type 2 Diabetes–Associated K+ Channel TALK-1 Modulates β-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis

    PubMed Central

    Vierra, Nicholas C.; Dadi, Prasanna K.; Jeong, Imju; Dickerson, Matthew; Powell, David R.

    2015-01-01

    Two-pore domain K+ (K2P) channels play an important role in tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TWIK-related alkaline pH-activated K2P (TALK)-1 is linked to type 2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 channels are expressed in mouse and human β-cells, where they serve as key regulators of electrical excitability and GSIS. We find that the rs1535500 polymorphism, which results in an alanine-to-glutamate substitution in the C-terminus of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in β-cell membrane potential depolarization, increased islet Ca2+ influx, and enhanced second-phase GSIS. Moreover, mice lacking TALK-1 channels are resistant to high-fat diet–induced elevations in fasting glycemia. These findings reveal TALK-1 channels as important modulators of second-phase insulin secretion and suggest a clinically relevant mechanism for rs1535500, which may increase type 2 diabetes risk by limiting GSIS. PMID:26239056

  11. Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates β-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis.

    PubMed

    Vierra, Nicholas C; Dadi, Prasanna K; Jeong, Imju; Dickerson, Matthew; Powell, David R; Jacobson, David A

    2015-11-01

    Two-pore domain K+ (K2P) channels play an important role in tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TWIK-related alkaline pH-activated K2P (TALK)-1 is linked to type 2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 channels are expressed in mouse and human β-cells, where they serve as key regulators of electrical excitability and GSIS. We find that the rs1535500 polymorphism, which results in an alanine-to-glutamate substitution in the C-terminus of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in β-cell membrane potential depolarization, increased islet Ca2+ influx, and enhanced second-phase GSIS. Moreover, mice lacking TALK-1 channels are resistant to high-fat diet-induced elevations in fasting glycemia. These findings reveal TALK-1 channels as important modulators of second-phase insulin secretion and suggest a clinically relevant mechanism for rs1535500, which may increase type 2 diabetes risk by limiting GSIS.

  12. [Prostaglandins, insulin secretion and diabetes mellitus].

    PubMed

    Giugliano, D; Torella, R; Scheen, A J; Lefebvre, P J; D'Onofrio, F

    1988-12-01

    The islets of Langerhans have the enzymatic equipment permitting the synthesis of the metabolites of arachidonic acid: cyclo-oxygenase and lipo-oxygenase. Numerous studies have shown that cyclo-oxygenase derivatives, mainly PGE2, reduce the insulin response to glucose whereas lipo-oxygenase derivatives, mainly 15-HPETE, stimulate insulin secretion. So, for instance, drugs that increase prostaglandins synthesis as colchicine or furosemide inhibit insulin secretion while non steroid anti-inflammator drugs, mainly salicylates, which inhibit cyclo-oxygenase, enhance the insulin response to various stimuli. In type-2 (non insulin-dependent) diabetes, an increased sensitivity to endogenous prostaglandins has been proposed as a possible cause for the insulin secretion defect which characterizes this disease. Play in favor of this hypothesis the fact that the administration of PGE inhibits the insulin response to arginine in type-2 diabetics but not in normal subject and the fact that the administration of salicylates could improve the insulin response to glucose in some of these patients.

  13. Insulin reciprocally regulates glucagon secretion in humans.

    PubMed

    Cooperberg, Benjamin A; Cryer, Philip E

    2010-11-01

    We tested the hypothesis that an increase in insulin per se, i.e., in the absence of zinc, suppresses glucagon secretion during euglycemia and that a decrease in insulin per se stimulates glucagon secretion during hypoglycemia in humans. We measured plasma glucagon concentrations in patients with type 1 diabetes infused with the zinc-free insulin glulisine on three occasions. Glulisine was infused with clamped euglycemia (∼95 mg/dl [5.3 mmol/l]) from 0 to 60 min on all three occasions. Then, glulisine was discontinued with clamped euglycemia or with clamped hypoglycemia (∼55 mg/dl [3.0 mmol/l]) or continued with clamped hypoglycemia from 60 to 180 min. Plasma glucagon concentrations were suppressed by -13 ± 3, -9 ± 3, and -12 ± 2 pg/ml (-3.7 ± 0.9, -2.6 ± 0.9, and -3.4 ± 0.6 pmol/l), respectively, (all P < 0.01) during zinc-free hyperinsulinemic euglycemia over the first 60 min. Glucagon levels remained suppressed following a decrease in zinc-free insulin with euglycemia (-14 ± 3 pg/ml [-4.0 ± 0.9 pmol/l]) and during sustained hyperinsulinemia with hypoglycemia (-14 ± 2 pg/ml [-4.0 ± 0.6 pmol/l]) but increased to -3 ± 3 pg/ml (-0.9 ± 0.9 pmol/l) (P < 0.01) following a decrease in zinc-free insulin with hypoglycemia over the next 120 min. These data indicate that an increase in insulin per se suppresses glucagon secretion and a decrease in insulin per se, in concert with a low glucose concentration, stimulates glucagon secretion. Thus, they document that insulin is a β-cell secretory product that, in concert with glucose and among other signals, reciprocally regulates α-cell glucagon secretion in humans.

  14. THE HYPOPHYSIS AND SECRETION OF INSULIN

    PubMed Central

    Houssay, B. A.; Foglia, V. G.; Smyth, F. S.; Rietti, C. T.; Houssay, A. B.

    1942-01-01

    The ability of the pancreas, from various types of dogs, to correct diabetic hyperglycemia has been studied (Table XI). The pancreas from one animal was united by a vascular union with the neck blood vessels of another dog which had been pancreatectomized for 20 hours. The time necessary to reduce the blood sugar level to 120 mg. per cent was determined. 1. Pancreas from 6 hypophysectomized dogs produced a normal insulin secretion, showing that an anterior pituitary hormone is not necessary for its production or maintenance. 2. In 14 of 17 normal dogs given anterior pituitary extract for 3 or more consecutive days and presenting diabetes (fasting blood sugar 150 mg. per cent or more) the pancreas showed diminished insulin production. 3. In animals which remained diabetic after discontinuing the injections of hypophyseal extract, the pancreas islands were markedly pathologic and the insulin secretion was practically nil. 4. When hyperglycemia existed on the 2nd to 5th day but fell later, the insulin secretion of 5 dogs was normal in 2, supernormal in 1, and less than normal in 2. Histologic examination showed a restoration of beta cells. 5. In 14 dogs resistant to the diabetogenic action of anterior pituitary extract, as shown by little or no change in blood sugar, the pancreatic secretion of insulin was normal in 6 cases, supernormal in 3, and subnormal in 5 cases. Clear signs of hyperfunction of B cells were observed. In 6 resistant animals a high blood sugar (150 mg. per cent) appeared shortly before transplanting, but insulin secretion was normal in 4, supernormal in 1, and subnormal in 1 case. 6. With one injection of extract and 1 day of hyperglycemia the capacity of the pancreas to secrete insulin was not altered. 7. A high blood sugar level lasting 4 days does not alter the islets. The hypophyseal extract acts, therefore, by some other mechanism. In normal dogs, the continuous intravenous infusion of glucose for 4 days maintained the blood sugar at levels as

  15. First-phase insulin secretion has limited impact on postprandial glycemia in subjects with type 2 diabetes: correlations between hyperglycemic glucose clamp and meal test.

    PubMed

    Rave, Klaus; Sidharta, Patricia N; Dingemanse, Jasper; Heinemann, Lutz; Roggen, Kerstin

    2010-02-01

    Lack of first-phase insulin (INS) secretion is regarded as causative for high postprandial glucose excursions in subjects with type 2 diabetes. We aimed to determine the impact of early INS secretion on postprandial glycemia. Twenty subjects with type 2 diabetes (age 54 +/- 8 years, body mass index 28.7 +/- 2.7 kg/m(2) [mean +/- SD]) underwent a hyperglycemic glucose clamp and a meal test twice separated by a washout period of 4 weeks. Multiple regression analysis was used to identify determinants of postprandial glycemia. During hyperglycemic glucose clamps eight subjects showed a preserved first-phase INS secretion (P1+), whereas 12 subjects showed none (P1-). Both subject groups differed in fasting blood glucose (BG) (116 +/- 7 vs. 147 +/- 31 mg/dL, P = 0.011) and glycosylated hemoglobin (6.0 +/- 0.4 vs. 6.7 +/- 0.8, P = 0.041). Total INS secretory response during glucose clamps was higher in P1+ than P1- (INS-area under the concentration vs. time curve [AUC](0-120 min) 6.7 +/- 2.7 vs. 3.2 +/- 2.1 mU.min/mL; P = 0.006). During meal tests, however, INS-AUC(0-120 min) was similar between P1+ and P1-, whereas early INS secretion was still different (INS-AUC(0-60 min) 3.9 +/- 1.8 vs. 2.1 +/- 1.0 mU.min/mL; P = 0.031). Despite higher INS-AUC(0-60 min) in P1+, early postprandial BG was comparable between groups (BG-AUC(0-60 min) 1.5 +/- 0.5 vs. 1.6 +/- 0.6 g.min/dL; difference not significant). Multiple regression analyses showed no impact of first-phase INS secretion on postprandial glycemia, either in P1+ or in P1-. Nevertheless, in P1-, but not in P1+, postprandial glycemia was negatively correlated with INS sensitivity (R(2) = 0.83, P < 0.001). This study, correlating results of hyperglycemic glucose clamps with meal tests, shows that a preserved first-phase INS secretion has only a limited impact on postprandial glucose excursions in a group of subjects in early-stage type 2 diabetes.

  16. Nutrient regulation of insulin secretion and action.

    PubMed

    Newsholme, Philip; Cruzat, Vinicius; Arfuso, Frank; Keane, Kevin

    2014-06-01

    Pancreatic β-cell function is of critical importance in the regulation of fuel homoeostasis, and metabolic dysregulation is a hallmark of diabetes mellitus (DM). The β-cell is an intricately designed cell type that couples metabolism of dietary sources of carbohydrates, amino acids and lipids to insulin secretory mechanisms, such that insulin release occurs at appropriate times to ensure efficient nutrient uptake and storage by target tissues. However, chronic exposure to high nutrient concentrations results in altered metabolism that impacts negatively on insulin exocytosis, insulin action and may ultimately lead to development of DM. Reduced action of insulin in target tissues is associated with impairment of insulin signalling and contributes to insulin resistance (IR), a condition often associated with obesity and a major risk factor for DM. The altered metabolism of nutrients by insulin-sensitive target tissues (muscle, adipose tissue and liver) can result in high circulating levels of glucose and various lipids, which further impact on pancreatic β-cell function, IR and progression of the metabolic syndrome. Here, we have considered the role played by the major nutrient groups, carbohydrates, amino acids and lipids, in mediating β-cell insulin secretion, while also exploring the interplay between amino acids and insulin action in muscle. We also focus on the effects of altered lipid metabolism in adipose tissue and liver resulting from activation of inflammatory processes commonly observed in DM pathophysiology. The aim of this review is to describe commonalities and differences in metabolism related to insulin secretion and action, pertinent to the development of DM. © 2014 Society for Endocrinology.

  17. Effect of tequila on homocysteine, insulin secretion, insulin sensitivity, and metabolic profile in healthy men.

    PubMed

    González-Ortiz, Manuel; Pascoe-González, Sara; Kam-Ramos, Angélica M; Martínez-Abundis, Esperanza

    2005-01-01

    The purpose of this study is to identify the effect of a low dose of tequila on homocysteine, insulin secretion, insulin sensitivity, and metabolic profile in healthy young men. An open clinical trial was carried out in eight healthy nonobese, young male volunteers. The study was divided in two phases. The first one evaluated metabolic changes, including insulin secretion and sensitivity due to acute administration of 30 ml of straight tequila. The second phase of the study evaluated metabolic effects due to the daily administration of 30 ml of tequila during 30 days. There were no significant metabolic changes after the single oral administration of 30 ml of straight tequila. After the administration of tequila during 30 days, a significant increase in homocysteine levels and a tendency to increase the glucose concentration and to decrease the insulin sensitivity were found. Detrimental metabolic changes were observed with the daily administration of 30 ml of tequila during 30 days.

  18. Cardiorespiratory fitness predicts insulin action and secretion in healthy individuals.

    PubMed

    Larsen, Filip J; Anderson, Martin; Ekblom, Björn; Nyström, Thomas

    2012-01-01

    Long-term cardiorespiratory fitness (CRF) and the development of type 2 diabetes mellitus are inversely correlated. Here, we examined the relationships between peak oxygen uptake (VO(2)peak), on the one hand, and glucose infusion rate at rest (GIR(rest)) and during exercise (GIR(exercise)), as well as insulin secretion (both the early and late phases of response [area under the curve {AUC}(insulin)]), on the other. Eight male and 4 female healthy, lean, nonsmoking volunteers were recruited. The VO(2)peak was measured during graded exercise on a cycle ergometer until exhaustion was reached. The GIR(rest) and GIR(exercise) were determined using a euglycemic-hyperinsulinemic clamp, and insulin secretion at rest was evaluated with an intravenous glucose tolerance test. The VO(2)peak correlated positively to GIR(rest) (r = 0.81, P = .001) and GIR(exercise) (r = 0.87, P < .001) and negatively to AUC(insulin) (r = -0.64, P = .03). The respiratory exchange ratio (RER) during insulin infusion was positively correlated to GIR(rest) (r = 0.83, P < .001) and GIR(exercise) (r = 0.86, P < .01) and negatively correlated to both the early insulin response (r = -0.86, P < .0001) and AUC(insulin) (r = -0.87, P = .001). The VO(2)peak accounted for 45% of the variability in RER (R(2) = 0.45, P = .035). In this healthy population, CRF and RER were highly correlated to insulin sensitivity and secretion, as well as to the ability to alter the substrate being oxidized during exercise. These findings highlight the importance of good CRF to maintaining normal insulin action.

  19. Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Sensitivity.

    PubMed

    Ramakrishnan, Sadeesh K; Russo, Lucia; Ghanem, Simona S; Patel, Payal R; Oyarce, Ana Maria; Heinrich, Garrett; Najjar, Sonia M

    2016-11-11

    High fat diet reduces the expression of CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a transmembrane glycoprotein that promotes insulin clearance and down-regulates fatty acid synthase activity in the liver upon its phosphorylation by the insulin receptor. Because peroxisome proliferator-activated receptor α (PPARα) transcriptionally suppresses CEACAM1 expression, we herein examined whether high fat down-regulates CEACAM1 expression in a PPARα-dependent mechanism. By activating PPARα, the lipid-lowering drug fenofibrate reverses dyslipidemia and improves insulin sensitivity in type 2 diabetes in part by promoting fatty acid oxidation. Despite reducing glucose-stimulated insulin secretion, fenofibrate treatment does not result in insulin insufficiency. To examine whether this is mediated by a parallel decrease in CEACAM1-dependent hepatic insulin clearance pathways, we fed wild-type and Pparα(-/-) null mice a high fat diet supplemented with either fenofibrate or Wy14643, a selective PPARα agonist, and examined their effect on insulin metabolism and action. We demonstrated that the decrease in insulin secretion by fenofibrate and Wy14643 is accompanied by reduction in insulin clearance in wild-type but not Pparα(-/-) mice, thereby maintaining normoinsulinemia and insulin sensitivity despite continuous high fat intake. Intact insulin secretion in L-CC1 mice with protected hepatic insulin clearance and CEACAM1 levels provides in vivo evidence that insulin secretion responds to changes in insulin clearance to maintain physiologic insulin and glucose homeostasis. These results also emphasize the relevant role of hepatic insulin extraction in regulating insulin sensitivity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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

    PubMed Central

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

    2015-01-01

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

  1. Mechanism by which cyproheptadine inhibits insulin secretion.

    PubMed Central

    Donatsch, P.; Lowe, D. A.; Richardson, B. P.; Taylor, P.

    1980-01-01

    1 Isolated islets of Langerhans from the rat have been used in studies designed to elucidate the mechanism by which cyproheptadine inhibits insulin secretion. 2 D-Glucose and tolbutamide, both of which require extracellular Ca2+ to produce insulin release, failed to evoke a secretory response from islets pretreated with cyproheptadine. Conversely veratridine, the calcium ionophore A23187 and theophylline, all of which are capable of mobilizing sufficient intracellular Ca2+ to evoke insulin secretion in the absence of extracellular Ca2+, produced similar responses from cyproheptadine pretreated and control islets. 3 Cyproheptadine completely inhibited Ca2+ uptake induced by D-glucose and high Ko+, two agents which depolarize the islet beta-cell membrane, whilst Ca2+ uptake elicited by removal of extracellular Na+ (i.e. Na+-Ca2+ counter transport) was only slightly reduced. 4 A significant increase in Na+ uptake produced by veratridine was sensitive to tetrodoxin but only partially reduced by cyproheptadine. 5 These results suggest that cyproheptadine inhibits depolarization-dependent calcium entry into pancreatic beta-cells. PMID:7002245

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

    PubMed

    Arora, G P; Almgren, P; Thaman, R G; Pal, A; Groop, L; Vaag, A; Prasad, R B; Brøns, C

    2017-10-01

    The relative roles(s) of impaired insulin secretion vs. insulin resistance in the development of gestational diabetes mellitus depend upon multiple risk factors and diagnostic criteria. Here, we explored their relative contribution to gestational diabetes as defined by the WHO 1999 (GDM1999) and adapted WHO 2013 (GDM2013) criteria, excluding the 1-h glucose value, in a high-risk Indian population from Punjab. 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. Gestational diabetes defined using both criteria was associated with decreased insulin secretion compared with pregnant women with normal glucose tolerance. Women with gestational diabetes defined by the adapted GDM2013, but not GDM1999 criteria, were more insulin resistant than pregnant women with normal glucose tolerance, and furthermore displayed lower insulin secretion than GDM1999 women. Urban habitat, illiteracy, high age and low BMI were independently associated with reduced insulin secretion, whereas Sikh religion, increasing age and BMI, as well as a family history of diabetes were independently associated with increased insulin resistance. Gestational diabetes risk factors influence insulin secretion and action in North Indian women in a differential manner. Gestational diabetes classified using the adapted GDM2013 compared with GDM1999 criteria is associated with more severe impairments of insulin secretion and action. © 2017 Diabetes UK.

  3. Cephalic phase insulin release in bulimia.

    PubMed

    Moyer, A; Rodin, J; Cummings, N

    1993-11-01

    Cephalic phase secretions are associated with the sight, smell, and taste of food, as opposed to its postingestional consequences. These secretions are thought to influence metabolism and eating behavior. Cephalic phase insulin release (CPIR), in particular, might be related to hunger and overeating. It was hypothesized that bulimics, who often show endocrine abnormalities, may have an altered CPIR that, in turn, might be related to the precipitation and maintenance of binges. This study investigated whether (1) the profile or magnitude of the CPIR in bulimics differs from that of non-eating disordered controls, (2) food ingestion alters subsequent CPIR, and (3) mood and desire to binge are related to CPIR. Findings indicated little abnormality in bulimics' profile of insulin secretion. Although biological variables were not related to hunger or desire to binge, for bulimics, dysphoric moods were. The results may suggest more complex determinants of binge eating than physiological state alone.

  4. Vitamin D, Insulin Secretion, Sensitivity, and Lipids

    PubMed Central

    Grimnes, Guri; Figenschau, Yngve; Almås, Bjørg; Jorde, Rolf

    2011-01-01

    OBJECTIVE Vitamin D deficiency is associated with an unfavorable metabolic profile in observational studies. The intention was to compare insulin sensitivity (the primary end point) and secretion and lipids in subjects with low and high serum 25(OH)D (25-hydroxyvitamin D) levels and to assess the effect of vitamin D supplementation on the same outcomes among the participants with low serum 25(OH)D levels. RESEARCH DESIGN AND METHODS Participants were recruited from a population-based study (the Tromsø Study) based on their serum 25(OH)D measurements. A 3-h hyperglycemic clamp was performed, and the participants with low serum 25(OH)D levels were thereafter randomized to receive capsules of 20,000 IU vitamin D3 or identical-looking placebo twice weekly for 6 months. A final hyperglycemic clamp was then performed. RESULTS The 52 participants with high serum 25(OH)D levels (85.6 ± 13.5 nmol/L [mean ± SD]) had significantly higher insulin sensitivity index (ISI) and lower HbA1c and triglycerides (TGs) than the 108 participants with low serum 25(OH)D (40.3 ± 12.8 nmol/L), but the differences in ISI and TGs were not significant after adjustments. After supplementation, serum 25(OH)D was 142.7 ± 25.7 and 42.9 ± 17.3 nmol/L in 49 of 51 completing participants randomized to vitamin D and 45 of 53 randomized to placebo, respectively. At the end of the study, there were no statistically significant differences in the outcome variables between the two groups. CONCLUSIONS Vitamin D supplementation to apparently healthy subjects with insufficient serum 25(OH)D levels does not improve insulin sensitivity or secretion or serum lipid profile. PMID:21911741

  5. Secretagogin affects insulin secretion in pancreatic β-cells by regulating actin dynamics and focal adhesion

    PubMed Central

    Yang, Seo-Yun; Lee, Jae-Jin; Lee, Jin-Hee; Lee, Kyungeun; Oh, Seung Hoon; Lim, Yu-Mi; Lee, Myung-Shik; Lee, Kong-Joo

    2016-01-01

    Secretagogin (SCGN), a Ca2+-binding protein having six EF-hands, is selectively expressed in pancreatic β-cells and neuroendocrine cells. Previous studies suggested that SCGN enhances insulin secretion by functioning as a Ca2+-sensor protein, but the underlying mechanism has not been elucidated. The present study explored the mechanism by which SCGN enhances glucose-induced insulin secretion in NIT-1 insulinoma cells. To determine whether SCGN influences the first or second phase of insulin secretion, we examined how SCGN affects the kinetics of insulin secretion in NIT-1 cells. We found that silencing SCGN suppressed the second phase of insulin secretion induced by glucose and H2O2, but not the first phase induced by KCl stimulation. Recruitment of insulin granules in the second phase of insulin secretion was significantly impaired by knocking down SCGN in NIT-1 cells. In addition, we found that SCGN interacts with the actin cytoskeleton in the plasma membrane and regulates actin remodelling in a glucose-dependent manner. Since actin dynamics are known to regulate focal adhesion, a critical step in the second phase of insulin secretion, we examined the effect of silencing SCGN on focal adhesion molecules, including FAK (focal adhesion kinase) and paxillin, and the cell survival molecules ERK1/2 (extracellular-signal-regulated kinase 1/2) and Akt. We found that glucose- and H2O2-induced activation of FAK, paxillin, ERK1/2 and Akt was significantly blocked by silencing SCGN. We conclude that SCGN controls glucose-stimulated insulin secretion and thus may be useful in the therapy of Type 2 diabetes. PMID:27095850

  6. Peroxiredoxin 4 Improves Insulin Biosynthesis and Glucose-induced Insulin Secretion in Insulin-secreting INS-1E Cells*

    PubMed Central

    Mehmeti, Ilir; Lortz, Stephan; Elsner, Matthias; Lenzen, Sigurd

    2014-01-01

    Oxidative folding of (pro)insulin is crucial for its assembly and biological function. This process takes place in the endoplasmic reticulum (ER) and is accomplished by protein disulfide isomerase and ER oxidoreductin 1β, generating stoichiometric amounts of hydrogen peroxide (H2O2) as byproduct. During insulin resistance in the prediabetic state, increased insulin biosynthesis can overwhelm the ER antioxidative and folding capacity, causing an imbalance in the ER redox homeostasis and oxidative stress. Peroxiredoxin 4 (Prdx4), an ER-specific antioxidative peroxidase can utilize luminal H2O2 as driving force for reoxidizing protein disulfide isomerase family members, thus efficiently contributing to disulfide bond formation. Here, we examined the functional significance of Prdx4 on β-cell function with emphasis on insulin content and secretion during stimulation with nutrient secretagogues. Overexpression of Prdx4 in glucose-responsive insulin-secreting INS-1E cells significantly metabolized luminal H2O2 and improved the glucose-induced insulin secretion, which was accompanied by the enhanced proinsulin mRNA transcription and insulin content. This β-cell beneficial effect was also observed upon stimulation with the nutrient insulin secretagogue combination of leucine plus glutamine, indicating that the effect is not restricted to glucose. However, knockdown of Prdx4 had no impact on H2O2 metabolism or β-cell function due to the fact that Prdx4 expression is negligibly low in pancreatic β-cells. Moreover, we provide evidence that the constitutively low expression of Prdx4 is highly susceptible to hyperoxidation in the presence of high glucose. Overall, these data suggest an important role of Prdx4 in maintaining insulin levels and improving the ER folding capacity also under conditions of a high insulin requirement. PMID:25122762

  7. Regulation of insulin secretion and proinsulin biosynthesis by succinate.

    PubMed

    Attali, Veronique; Parnes, Marcela; Ariav, Yafa; Cerasi, Erol; Kaiser, Nurit; Leibowitz, Gil

    2006-11-01

    Succinate stimulates insulin secretion and proinsulin biosynthesis. We studied the effects of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-modulating pathways on glucose- and succinate-stimulated insulin secretion and proinsulin biosynthesis in the rat and the insulin-resistant Psammomys obesus. Disruption of the anaplerotic pyruvate/malate shuttle by phenylacetic acid inhibited glucose- and succinate-stimulated insulin secretion and succinate-stimulated proinsulin biosynthesis in both species. In contrast, phenylacetic acid failed to inhibit glucose-stimulated proinsulin biosynthesis in P. obesus islets. Inhibition of the NADPH-consuming enzyme neuronal nitric oxide synthase (nNOS) with l-N(G)-nitro-l-arginine methyl ester or with N(G)-monomethyl-l-arginine(G) doubled succinate-stimulated insulin secretion in rat islets, suggesting that succinate- and nNOS-derived signals interact to regulate insulin secretion. In contrast, nNOS inhibition had no effect on succinate-stimulated proinsulin biosynthesis in both species. In P. obesus islets, insulin secretion was not stimulated by succinate in the absence of glucose, whereas proinsulin biosynthesis was increased 5-fold. Conversely, under stimulating glucose levels, succinate doubled insulin secretion, indicating glucose-dependence. Pyruvate ester and inhibition of nNOS partially mimicked the permissive effect of glucose on succinate-stimulated insulin secretion, suggesting that anaplerosis-derived signals render the beta-cells responsive to succinate. We conclude that beta-cell anaplerosis via pyruvate carboxylase is important for glucose- and succinate-stimulated insulin secretion and for succinate-stimulated proinsulin biosynthesis. In P. obesus, pyruvate/malate shuttle dependent and independent pathways that regulate proinsulin biosynthesis coexist; the latter can maintain fuel stimulated biosynthetic activity when the succinate-dependent pathway is inhibited. nNOS signaling is a negative regulator

  8. Insulin secretion stimulated by allogeneic lymphocytes in an inbred strain of mice.

    PubMed Central

    García, J B; Venturino, M C; Alvarez, E; Fabiano de Bruno, L; Braun, M; Pivetta, O H; Basabe, J C

    1986-01-01

    Effects of intraperitoneal injection of allogeneic lymphocytes on insulin secretion were studied in incubated pancreas slices from BALB/c mice. Injection of allogeneic lymphocytes from C57BL/6J (H2b) mice increased insulin secretion, both in basal and 11-mM glucose-stimulated conditions. This effect was only present when at least 5 X 10(6) or 1 X 10(6) cells were injected (in basal and stimulated conditions, respectively). Glucose-induced insulin secretion (3.3-27.5 mM) was significantly increased in pancreata from mice injected with allogeneic lymphocytes. No effect was observed when glucose was not included in the incubation medium. Intraperitoneal injection of Dextran 70 produced no change in glucose-elicited insulin secretion. There were no differences in glucagon and somatostatin (SRIF) secretion obtained from pancreas of mice injected with allogeneic or syngeneic lymphocytes. Injection of allogeneic cells increases insulin secretion (basal and both phases of 11 mM glucose-stimulated secretion). Puromycin significantly inhibited the second phase of insulin secretion. These results suggest that: Injection of allogeneic lymphocytes raises both basal and glucose-stimulated insulin secretion. This effect seems to be connected with the major histocompatibility complex, and to be related to the number of allogeneic cells injected. Injection of allogeneic lymphocytes seems to sensitize the beta cell response to glucose stimulus. Neither glucagon nor SRIF secretion are altered by alloantigen injection. The stimulatory effect of allogeneic lymphocytes is related, at least in part, to insulin synthesis. PMID:2871044

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

    PubMed

    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.

  10. Insulin secretion from beta cells within intact islets: location matters.

    PubMed

    Hoang Do, Oanh; Thorn, Peter

    2015-04-01

    The control of hormone secretion is central to body homeostasis, and its dysfunction is important in many diseases. The key cellular steps that lead to hormone secretion have been identified, and the stimulus-secretion pathway is understood in outline for many endocrine cells. In the case of insulin secretion from pancreatic beta cells, this pathway involves the uptake of glucose, cell depolarization, calcium entry, and the triggering of the fusion of insulin-containing granules with the cell membrane. The wealth of information on the control of insulin secretion has largely been obtained from isolated single-cell studies. However, physiologically, beta cells exist within the islets of Langerhans, with structural and functional specializations that are not preserved in single-cell cultures. This review focuses on recent work that is revealing distinct aspects of insulin secretion from beta cells within the islet.

  11. Neuropeptide Y and somatostatin inhibit insulin secretion through different mechanisms

    PubMed Central

    Schwetz, Tara A.; Ustione, Alessandro

    2013-01-01

    Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to glucose elevation and G protein-coupled receptor (GPCR) activation. Neuropeptide Y (NPY) and somatostatin (SST) attenuate insulin secretion through Gi activation of Y1 and SSTR1&5 receptors, respectively. The downstream pathways altered by NPY and SST are poorly understood. Thus, we investigated these underlying mechanisms. NPY and SST increase cellular redox potential, suggesting that their inhibitory effect may not be mediated through metabolic inhibition. NPY does not affect intracellular calcium ([Ca2+]i) activity upon glucose stimulation, whereas SST alters this response. Gβγ-subunit inhibition by gallein attenuates insulin secretion but does not alter metabolism or [Ca2+]i. mSIRK-induced Gβγ activation does not modulate glucose metabolism but increases [Ca2+]i activity and potentiates insulin release. Cotreatment with gallein and NPY or SST reduces insulin secretion to levels similar to that of gallein alone. mSIRK and NPY cotreatment potentiates insulin secretion similarly to mSIRK alone, whereas mSIRK and SST treatment decreases insulin release. The data support a model where SST attenuates secretion through Gβγ inhibition of Ca2+ activity, while NPY activates a Ca2+-independent pathway mediated by Gα. GPCR ligands signal through multiple pathways to inhibit insulin secretion, and determining these mechanisms could lead to novel diabetic therapies. PMID:23211512

  12. Neuropeptide Y and somatostatin inhibit insulin secretion through different mechanisms.

    PubMed

    Schwetz, Tara A; Ustione, Alessandro; Piston, David W

    2013-01-15

    Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to glucose elevation and G protein-coupled receptor (GPCR) activation. Neuropeptide Y (NPY) and somatostatin (SST) attenuate insulin secretion through G(i) activation of Y(1) and SSTR(1&5) receptors, respectively. The downstream pathways altered by NPY and SST are poorly understood. Thus, we investigated these underlying mechanisms. NPY and SST increase cellular redox potential, suggesting that their inhibitory effect may not be mediated through metabolic inhibition. NPY does not affect intracellular calcium ([Ca(2+)](i)) activity upon glucose stimulation, whereas SST alters this response. G(βγ)-subunit inhibition by gallein attenuates insulin secretion but does not alter metabolism or [Ca(2+)](i). mSIRK-induced G(βγ) activation does not modulate glucose metabolism but increases [Ca(2+)](i) activity and potentiates insulin release. Cotreatment with gallein and NPY or SST reduces insulin secretion to levels similar to that of gallein alone. mSIRK and NPY cotreatment potentiates insulin secretion similarly to mSIRK alone, whereas mSIRK and SST treatment decreases insulin release. The data support a model where SST attenuates secretion through G(βγ) inhibition of Ca(2+) activity, while NPY activates a Ca(2+)-independent pathway mediated by G(α). GPCR ligands signal through multiple pathways to inhibit insulin secretion, and determining these mechanisms could lead to novel diabetic therapies.

  13. Suppression of Insulin Production and Secretion by a Decretin Hormone

    PubMed Central

    Alfa, Ronald W.; Park, Sangbin; Skelly, Kathleen-Rose; Poffenberger, Gregory; Jain, Nimit; Gu, Xueying; Kockel, Lutz; Wang, Jing; Liu, Yinghua; Powers, Alvin C.; Kim, Seung K.

    2015-01-01

    SUMMARY Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila orthologue of Neuromedin U receptors (NMUR), in insulin-producing cells phenocopied limostatin deficiency, and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β-cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output. PMID:25651184

  14. Effects of aldosterone on insulin sensitivity and secretion.

    PubMed

    Luther, James M

    2014-12-01

    Dr. Conn originally reported an increased risk of diabetes in patients with hyperaldosteronism in the 1950s, although the mechanism remains unclear. Aldosterone-induced hypokalemia was initially described to impair glucose tolerance by impairing insulin secretion. Correction of hypokalemia by potassium supplementation only partially restored insulin secretion and glucose tolerance, however. Aldosterone also impairs glucose-stimulated insulin secretion in isolated pancreatic islets via reactive oxygen species in a mineralocorticoid receptor-independent manner. Aldosterone-induced mineralocorticoid receptor activation also impairs insulin sensitivity in adipocytes and skeletal muscle. Aldosterone may produce insulin resistance secondarily by altering potassium, increasing inflammatory cytokines, and reducing beneficial adipokines such as adiponectin. Renin-angiotensin system antagonists reduce circulating aldosterone concentrations and also the risk of type 2 diabetes in clinical trials. These data suggest that primary and secondary hyperaldosteronism may contribute to worsening glucose tolerance by impairing insulin sensitivity or insulin secretion in humans. Future studies should define the effects of MR antagonists and aldosterone on insulin secretion and sensitivity in humans.

  15. Suppression of insulin production and secretion by a decretin hormone.

    PubMed

    Alfa, Ronald W; Park, Sangbin; Skelly, Kathleen-Rose; Poffenberger, Gregory; Jain, Nimit; Gu, Xueying; Kockel, Lutz; Wang, Jing; Liu, Yinghua; Powers, Alvin C; Kim, Seung K

    2015-02-03

    Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.

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

    PubMed

    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.

  17. Insulin secretion abnormalities in exocrine pancreatic sufficient cystic fibrosis patients.

    PubMed

    Wooldridge, Jamie L; Szczesniak, Rhonda D; Fenchel, Matthew C; Elder, Deborah A

    2015-11-01

    The aim of this study is to assess insulin secretion in pediatric cystic fibrosis (CF) patients with exocrine pancreatic sufficiency. Glucose and insulin responses during an oral glucose tolerance test (OGTT) were measured in 146 CF patients. Patients were divided into exocrine sufficient (CF-PS) and insufficient (CF-PI) groups based on pancreatic enzyme usage and fecal elastase. A reference group included healthy, non-diabetic subjects. All CF groups showed reduced insulin secretion as measured by insulinogenic index. The CF-PS patients had normal glucose tolerance. There was a direct correlation between BMI z-score and insulin area under the curve. Patients with CF have reduced insulin secretion during an OGTT regardless of exocrine pancreatic status. The abnormal insulin secretion in all CF patients may predispose them for glucose intolerance, particularly when challenged by inflammation, infection, or nutritional deficiency. In addition, the diminished insulin secretion may contribute to increased catabolism. Lastly, the CF-related diabetes (CFRD) screening guidelines should be followed by all CF patients regardless of pancreatic status. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  18. Insulin Secretion Abnormalities in Exocrine Pancreatic Sufficient Cystic Fibrosis Patients

    PubMed Central

    Wooldridge, Jamie L.; Szczesniak, Rhonda D.; Fenchel, Matthew C.; Elder, Deborah A.

    2015-01-01

    BACKGROUND To assess insulin secretion in pediatric cystic fibrosis (CF) patients with exocrine pancreatic sufficiency. METHODS Glucose and insulin responses during an oral glucose tolerance test (OGTT) were measured in 146 CF patients. Patients were divided into exocrine sufficient (CF-PS) and insufficient (CF-PI) groups based on pancreatic enzyme usage and fecal elastase. A reference group included healthy, non-diabetic subjects. RESULTS All CF groups showed reduced insulin secretion as measured by insulinogenic index. The CF-PS patients had normal glucose tolerance. There was direct correlation between BMI z-score and insulin area under the curve. CONCLUSION Patients with CF have reduced insulin secretion during an OGTT regardless of exocrine pancreatic status. The abnormal insulin secretion in all CF patients may predispose them for glucose intolerance, particularly when challenged by inflammation, infection, or nutritional deficiency. In addition, the diminished insulin secretion may contribute to increased catabolism. Lastly, the CF-related diabetes (CFRD) screening guidelines should be followed by all CF patients regardless of pancreatic status. PMID:25754095

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

    PubMed

    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 < 0.05) than controls at birth. Fasting plasma glucose and 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.

  20. Insulin secretion after injuries of differing severity in the rat.

    PubMed Central

    Frayn, K. N.

    1976-01-01

    The effects on insulin secretion of injuries of differing severity have been studied in the rat. The injuries used were dorsal scalds to 20% and 40% of the body surface area, and a 4-h period of bilateral hind-limb ischaemia. These injuries resulted in 48 h mortality rates of 0/10, 7/10 and 5/10 respectively. Rats were studied 1-5-2 h after scalding or removal of tourniquets. The blood glucose concentration was markedly raised after all these injuries, and the plasma insulin concentration was also raised, so that the insulin to glucose ratio in any group did not differ significantly from that in non-injured controls. Injection of glucose (0-5 g/kg i.v.) induced a rise in insulin concentration in all groups, although the insulin to glucose ratio after the lethal 40% scald was lower than in control rats. It was concluded that in the rat normal insulin secretion is maintained even after lethal injuries, although some suppression of the insulin response to exogenous glucose may occur. Insulin resistance is more important in the rat than impairment of insulin secretion even at an early stage after injury. PMID:782499

  1. Size-controlled insulin-secreting cell clusters.

    PubMed

    Mendelsohn, Adam D; Nyitray, Crystal; Sena, Mark; Desai, Tejal A

    2012-12-01

    The search for an effective cure for type I diabetes from the transplantation of encapsulated pancreatic β-cell clusters has so far produced sub-optimal clinical outcomes. Previous efforts have not controlled the size of transplanted clusters, a parameter implicated in affecting long-term viability and the secretion of therapeutically sufficient insulin. Here we demonstrate a method based on covalent attachment of patterned laminin for fabricating uniformly size-controlled insulin-secreting cell clusters. We show that cluster size within the range 40-120μm in diameter affects a variety of therapeutically relevant cellular responses including insulin expression, content and secretion. Our studies elucidate two size-dependent phenomena: (1) as the cluster size increases from 40μm to 60μm, glucose stimulation results in a greater amount of insulin produced per cell; and (2) as the cluster size increases beyond 60μm, sustained glucose stimulation results in a greater amount of insulin secreted per cell. Our study describes a method for producing uniformly sized insulin-secreting cell clusters, and since larger cluster sizes risk nutrient availability limitations, our data suggest that 100-120μm clusters may provide optimal viability and efficacy for encapsulated β-cell transplants as a treatment for type I diabetes and that further in vivo evaluation is warranted.

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

    PubMed Central

    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

  3. Bombesin stimulates insulin secretion by a pancreatic islet cell line.

    PubMed Central

    Swope, S L; Schonbrunn, A

    1984-01-01

    The amphibian tetradecapeptide, bombesin (BBS) has been shown to stimulate insulin secretion both in vivo and by pancreatic islet cells in vitro. To determine whether BBS can act directly on pancreatic beta cells, we examined its effects on insulin secretion by HIT-T15 cells (HIT cells), a clonal islet cell line. Addition of 100 nM BBS to HIT cells stimulated insulin release 25-fold within 30 sec. The rapid stimulatory effect of BBS on insulin release was short-lived: the secretory rate returned to basal levels after 90 min of BBS treatment. The decrease in the rate of insulin release in the continued presence of BBS was due not to depletion of intracellular insulin stores but to specific desensitization to this peptide. Stimulation of insulin secretion by BBS was dose dependent with an ED50 value (0.51 +/- 0.15 nM) similar to the concentration of BBS-like immunoreactive material in rat plasma. Five BBS analogs, including porcine gastrin-releasing peptide, were as powerful as BBS in stimulating insulin release. The relative potencies of the analogs tested indicated that the COOH-terminal octapeptide sequence in BBS was sufficient for stimulation of release. In contrast, 14 peptides structurally unrelated to BBS did not alter insulin secretion. BBS action was synergistic with that of glucagon; insulin secretion in the presence of maximal concentrations of both peptides was greater than the additive effects of the two peptides added individually. Somatostatin inhibited BBS-stimulated release by 69 +/- 1% with an ID50 value of 3.2 +/- 0.3 nM. These results show that BBS stimulation of insulin secretion by a clonal pancreatic cell line closely parallels its effects in vivo and support the hypothesis that BBS stimulates insulin secretion by a direct effect on the pancreatic beta cell. The clonal HIT cell line provides a homogeneous cell preparation amenable for studies on the biochemical mechanisms of BBS action in the endocrine pancreas. PMID:6143320

  4. Incretin action maintains insulin secretion, but not hepatic insulin action, in people with impaired fasting glucose.

    PubMed

    Perreault, Leigh; Man, Chiara Dalla; Hunerdosse, Devon M; Cobelli, Claudio; Bergman, Bryan C

    2010-10-01

    To determine whether altered GLP-1 activity contributes to the abnormal endogenous glucose production (EGP) and insulin secretion characteristic of people with impaired fasting glucose (IFG). People with IFG (n=10) and normal glucose tolerance (NGT; n=13) underwent assessment of EGP (via [6,6-(2)H(2)]-glucose infusion). Parameters of whole body insulin action and secretion were estimated by IVGTT and OGTT. Measures of EGP and insulin secretion were made before and after sitagliptin administration. EGP was not different at baseline (glucose R(a); 1.47+/-0.08 vs. 1.46+/-0.05mg/kg/min, IFG vs. NGT, p=0.93). However, when differences in circulating insulin were accounted for (EGPXSSPI; 20.2+/-2.1 vs. 14.4+/-1.0AU, vs. NGT, p=0.03) the hepatic insulin resistance index was significantly higher in IFG. Baseline insulin action (S(i); 2.3+/-0.1x10(-4)/microU/ml vs. 3.5+/-0.4x10(-4)/microU/ml, p=0.01, IFG vs. NGT) and secretion (DI; 587+/-81x10(-4)/min vs. 1171+/-226x10(-4)/min, p=0.04, IFG vs. NGT) were impaired in IFG when evaluated by the IVGTT, but not by OGTT (insulin sensitivity 4.52+/-1.08x10(-4)dl/kg/min vs. 6.73+/-1.16x10(-4)dl/kg/min, IFG vs. NGT, p=0.16; indices of basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and total (Phi(t)) insulin secretion, p>0.07). Sitagliptin did not change EGP or insulin secretion in either group. Incretin action maintained insulin secretion, but not hepatic insulin action, in people with IFG.

  5. Lysosomal integral membrane protein Sidt2 plays a vital role in insulin secretion.

    PubMed

    Gao, Jialin; Yu, Cui; Xiong, Qianyin; Zhang, Yao; Wang, Lizhuo

    2015-01-01

    Abnormal insulin secretion results in impaired glucose tolerance and is one of the causal factors in the etiology of type 2 diabetes mellitus. Sidt2, a lysosomal integral membrane protein, plays a critical role in insulin secretion. Here, we further investigate its regulation in insulin secretion. We show that Sidt2(-/-) mice exhibit weight loss, decreased postnatal survival rate with aging, increased fasting glucose and impaired glucose tolerance. After loading high levels of glucose in their diet, Sidt2(-/-) mice produce notably lower insulin levels at the first-phase secretion compared with Sidt2(+/+) mice. Consistent with the in vivo study, INS-1 cells treated with Sidt2 siRNA produced less insulin when loaded with 16.7 mM of glucose. Only 2 of the 13 genes, synap1 and synap3 which encode soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins, showed significantly decreased expression in Sidt2(-/-) mice. In conclusion, Sdit2 may play a vital role in the regulation of insulin secretion via two SNARE proteins synap1 and syanp3.

  6. Insulin secretion is increased in non-diabetic subjects with fasting hypertriglyceridaemia.

    PubMed

    Simental-Mendía, Luis E; Rodríguez-Morán, Martha; Simental-Saucedo, Luis; Guerrero-Romero, Fernando

    2013-03-01

    The elevation of triglycerides is strongly linked with insulin resistance, but it has not been evaluated in relationship to insulin secretion. The aim of this study was to determine whether hypertriglyceridaemia is associated with abnormal insulin secretion. A cross-sectional study was carried out. Eligible subjects, apparently healthy men and non-pregnant women aged 20-65 years were recruited. According to the triglyceride levels, subjects were allocated in the groups with hypertriglyceridaemia and normotriglyceridaemia. Hypertriglyceridaemia was defined by serum triglyceride levels ≥150 mg/dL. Insulin secretion was evaluated by the first phase of insulin secretion (1st PIS) and the second phase of insulin secretion (2nd PIS). A regression linear analysis was performed to evaluate the association between hypertriglyceridaemia (independent variable) and the first and second phase insulin secretion (dependent variables). A total of 247 apparently healthy subjects were enrolled; 113 (45.7%) with hypertriglyceridaemia and 134 (54.3%) in the control group. The simple regression linear analysis showed a significant association between hypertriglyceridaemia and the 1st PIS [B = 207.0; 95% confidence interval (CI) 33.5-380.5, p = 0.02] and the 2nd PIS (B = 48.7; 95% CI 9.2-88.2, p = 0.01). A multiple regression linear analysis adjusted by age, sex, body mass index and waist circumference was performed showing that fasting hypertriglyceridaemia remained significantly associated with the 1st PIS (B = 184.3; 95% CI 13.0-355.7, p = 0.03) and the 2nd PIS (B = 43.1; 95% CI 4.2-81.9, p = 0.03). The results of this study show that hypertriglyceridaemia is associated with the increase of the 1st PIS and the 2nd PIS in apparently healthy subjects. Copyright © 2012 John Wiley & Sons, Ltd.

  7. Phase modulation of insulin pulses enhances glucose regulation and enables inter-islet synchronization

    PubMed Central

    Lee, Boah; Song, Taegeun; Lee, Kayoung; Kim, Jaeyoon; Han, Seungmin; Berggren, Per-Olof; Ryu, Sung Ho; Jo, Junghyo

    2017-01-01

    Insulin is secreted in a pulsatile manner from multiple micro-organs called the islets of Langerhans. The amplitude and phase (shape) of insulin secretion are modulated by numerous factors including glucose. The role of phase modulation in glucose homeostasis is not well understood compared to the obvious contribution of amplitude modulation. In the present study, we measured Ca2+ oscillations in islets as a proxy for insulin pulses, and we observed their frequency and shape changes under constant/alternating glucose stimuli. Here we asked how the phase modulation of insulin pulses contributes to glucose regulation. To directly answer this question, we developed a phenomenological oscillator model that drastically simplifies insulin secretion, but precisely incorporates the observed phase modulation of insulin pulses in response to glucose stimuli. Then, we mathematically modeled how insulin pulses regulate the glucose concentration in the body. The model of insulin oscillation and glucose regulation describes the glucose-insulin feedback loop. The data-based model demonstrates that the existence of phase modulation narrows the range within which the glucose concentration is maintained through the suppression/enhancement of insulin secretion in conjunction with the amplitude modulation of this secretion. The phase modulation is the response of islets to glucose perturbations. When multiple islets are exposed to the same glucose stimuli, they can be entrained to generate synchronous insulin pulses. Thus, we conclude that the phase modulation of insulin pulses is essential for glucose regulation and inter-islet synchronization. PMID:28235104

  8. Phase modulation of insulin pulses enhances glucose regulation and enables inter-islet synchronization.

    PubMed

    Lee, Boah; Song, Taegeun; Lee, Kayoung; Kim, Jaeyoon; Han, Seungmin; Berggren, Per-Olof; Ryu, Sung Ho; Jo, Junghyo

    2017-01-01

    Insulin is secreted in a pulsatile manner from multiple micro-organs called the islets of Langerhans. The amplitude and phase (shape) of insulin secretion are modulated by numerous factors including glucose. The role of phase modulation in glucose homeostasis is not well understood compared to the obvious contribution of amplitude modulation. In the present study, we measured Ca2+ oscillations in islets as a proxy for insulin pulses, and we observed their frequency and shape changes under constant/alternating glucose stimuli. Here we asked how the phase modulation of insulin pulses contributes to glucose regulation. To directly answer this question, we developed a phenomenological oscillator model that drastically simplifies insulin secretion, but precisely incorporates the observed phase modulation of insulin pulses in response to glucose stimuli. Then, we mathematically modeled how insulin pulses regulate the glucose concentration in the body. The model of insulin oscillation and glucose regulation describes the glucose-insulin feedback loop. The data-based model demonstrates that the existence of phase modulation narrows the range within which the glucose concentration is maintained through the suppression/enhancement of insulin secretion in conjunction with the amplitude modulation of this secretion. The phase modulation is the response of islets to glucose perturbations. When multiple islets are exposed to the same glucose stimuli, they can be entrained to generate synchronous insulin pulses. Thus, we conclude that the phase modulation of insulin pulses is essential for glucose regulation and inter-islet synchronization.

  9. Insulin secretion in the hibernating edible dormouse (Glis glis): in vivo and in vitro studies.

    PubMed

    Castex, C; Tahri, A; Hoo-Paris, R; Sutter, B C

    1984-01-01

    Plasma glucose and insulin have been studied during lethargy and spontaneous arousal of hibernating edible dormouse. During lethargy blood glucose was low while plasma insulin remained at the same level as in other seasons. Plasma glucose and insulin did not fluctuate along the phase of lethargy. During spontaneous arousal plasma insulin rose strongly from the 17 degrees C stage, reaching the higher values at 26 degrees C while blood glucose was only 85 mg/100 ml, then decreased at 37 degrees C. The effect of glucose and temperature on insulin secretion was studied using perfused pancreas preparation from hibernating edible dormice. During the rewarming of the edible dormouse pancreas the insulin release did not occur in response to the absolute extracellular glucose level but occurred in response to a B cell membrane phenomenon which was dependent on the changing rate of glucose level. The effect of glucose and temperature on insulin secretion from perfused pancreas was compared between edible dormouse and homeotherm permanent, the rat. The B cell response to glucose of the dormouse pancreas increased up to 15 degrees C whereas that of the rat only from 25 degrees C. The dormouse insulin secretion reached a peak value at the 30 degrees C of temperature, whereas that of the rat progressively increased until 37 degrees C. These results showed that some biochemical adjustment or process of acclimatization took place in the B cells of the hibernators.

  10. The bile acid sensor FXR regulates insulin transcription and secretion.

    PubMed

    Renga, Barbara; Mencarelli, Andrea; Vavassori, Piero; Brancaleone, Vincenzo; Fiorucci, Stefano

    2010-03-01

    Farnesoid X Receptor plays an important role in maintaining bile acid, cholesterol homeostasis and glucose metabolism. Here we investigated whether FXR is expressed by pancreatic beta-cells and regulates insulin signaling in pancreatic beta-cell line and human islets. We found that FXR activation induces positive regulatory effects on glucose-induced insulin transcription and secretion by genomic and non-genomic activities. Genomic effects of FXR activation relay on the induction of the glucose regulated transcription factor KLF11. Indeed, results from silencing experiments of KLF11 demonstrate that this transcription factor is essential for FXR activity on glucose-induced insulin gene transcription. In addition FXR regulates insulin secretion by non-genomic effects. Thus, activation of FXR in betaTC6 cells increases Akt phosphorylation and translocation of the glucose transporter GLUT2 at plasma membrane, increasing the glucose uptake by these cells. In vivo experiments on Non Obese Diabetic (NOD) mice demonstrated that FXR activation delays development of signs of diabetes, hyperglycemia and glycosuria, by enhancing insulin secretion and by stimulating glucose uptake by the liver. These data established that an FXR-KLF11 regulated pathway has an essential role in the regulation of insulin transcription and secretion induced by glucose.

  11. Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase.

    PubMed

    Li, Changhong; Allen, Aron; Kwagh, Jae; Doliba, Nicolai M; Qin, Wei; Najafi, Habiba; Collins, Heather W; Matschinsky, Franz M; Stanley, Charles A; Smith, Thomas J

    2006-04-14

    Insulin secretion by pancreatic beta-cells is stimulated by glucose, amino acids, and other metabolic fuels. Glutamate dehydrogenase (GDH) has been shown to play a regulatory role in this process. The importance of GDH was underscored by features of hyperinsulinemia/hyperammonemia syndrome, where a dominant mutation causes the loss of inhibition by GTP and ATP. Here we report the effects of green tea polyphenols on GDH and insulin secretion. Of the four compounds tested, epigallocatechin gallate (EGCG) and epicatechin gallate were found to inhibit GDH with nanomolar ED(50) values and were therefore found to be as potent as the physiologically important inhibitor GTP. Furthermore, we have demonstrated that EGCG inhibits BCH-stimulated insulin secretion, a process that is mediated by GDH, under conditions where GDH is no longer inhibited by high energy metabolites. EGCG does not affect glucose-stimulated insulin secretion under high energy conditions where GDH is probably fully inhibited. We have further shown that these compounds act in an allosteric manner independent of their antioxidant activity and that the beta-cell stimulatory effects are directly correlated with glutamine oxidation. These results demonstrate that EGCG, much like the activator of GDH (BCH), can facilitate dissecting the complex regulation of insulin secretion by pharmacologically modulating the effects of GDH.

  12. α-Synuclein binds the KATP channel at insulin-secretory granules and inhibits insulin secretion

    PubMed Central

    Geng, Xuehui; Lou, Haiyan; Wang, Jian; Li, Lehong; Swanson, Alexandra L.; Sun, Ming; Beers-Stolz, Donna; Watkins, Simon; Perez, Ruth G.

    2011-01-01

    α-Synuclein has been studied in numerous cell types often associated with secretory processes. In pancreatic β-cells, α-synuclein might therefore play a similar role by interacting with organelles involved in insulin secretion. We tested for α-synuclein localizing to insulin-secretory granules and characterized its role in glucose-stimulated insulin secretion. Immunohistochemistry and fluorescent sulfonylureas were used to test for α-synuclein localization to insulin granules in β-cells, immunoprecipitation with Western blot analysis for interaction between α-synuclein and KATP channels, and ELISA assays for the effect of altering α-synuclein expression up or down on insulin secretion in INS1 cells or mouse islets, respectively. Differences in cellular phenotype between α-synuclein knockout and wild-type β-cells were found by using confocal microscopy to image the fluorescent insulin biosensor Ins-C-emGFP and by using transmission electron microscopy. The results show that anti-α-synuclein antibodies labeled secretory organelles within β-cells. Anti-α-synuclein antibodies colocalized with KATP channel, anti-insulin, and anti-C-peptide antibodies. α-Synuclein coimmunoprecipitated in complexes with KATP channels. Expression of α-synuclein downregulated insulin secretion at 2.8 mM glucose with little effect following 16.7 mM glucose stimulation. α-Synuclein knockout islets upregulated insulin secretion at 2.8 and 8.4 mM but not 16.7 mM glucose, consistent with the depleted insulin granule density at the β-cell surface membranes observed in these islets. These findings demonstrate that α-synuclein interacts with KATP channels and insulin-secretory granules and functionally acts as a brake on secretion that glucose stimulation can override. α-Synuclein might play similar roles in diabetes as it does in other degenerative diseases, including Alzheimer's and Parkinson's diseases. PMID:20858756

  13. Dissecting the relationship between obesity and hyperinsulinemia: Role of insulin secretion and insulin clearance.

    PubMed

    Kim, Mee Kyoung; Reaven, Gerald M; Kim, Sun H

    2017-02-01

    The aim of this study was to better delineate the complex interrelationship among insulin resistance (IR), secretion rate (ISR), and clearance rate (ICR) to increase plasma insulin concentrations in obesity. Healthy volunteers (92 nondiabetic individuals) had an insulin suppression test to measure IR and graded-glucose infusion test to measure ISR and ICR. Obesity was defined as a body mass index (BMI) ≥30 kg/m(2) , and IR was defined as steady-state plasma glucose (SSPG) ≥10 mmol/L during the insulin suppression test. Plasma glucose and insulin concentrations, ISR, and ICR were compared in three groups: insulin sensitive/overweight; insulin sensitive/obesity; and insulin resistant/obesity. Compared with the insulin-sensitive/overweight group, the insulin-sensitive/obesity had significantly higher insulin area under the curve (AUC) and ISR AUC during the graded-glucose infusion test (P < 0.001). Glucose AUC and ICR were similar. The insulin-resistant/obesity group had higher insulin AUC and ISR AUC compared with the insulin-sensitive/obesity but also had higher glucose AUC and decreased ICR (P < 0.01). In multivariate analysis, both BMI and SSPG were significantly associated with ISR. Plasma insulin concentration and ISR are increased in individuals with obesity, irrespective of degree of IR, but a decrease in ICR is confined to the subset of individuals with IR. © 2016 The Obesity Society.

  14. Effect of Naloxon on Counter Insulin Hormone Secretion in Insulin-Induced Hypoglycemia

    PubMed Central

    Ju, Yeong Shil; Kim, Sung Woon; Yang, In Myung; Kim, Jin Woo; Kim, Young Seol; Choi, Young Kil

    1987-01-01

    To investigate the normal physiologic role of endogenous opiates in glucose homeostasis and as a preliminary study for clarifying the association of endogenous opites with pathophysilogy of NIDDM, we obseved the changes in the secretion of counter-insulin hormones in response to insulin-induced hypoglycemia with or without naloxone. The results were as follows: Blood glucose was decreased significantly more rapidly with naloxone infusion than after insulin alone, which seems to play a role in the early responses of ACTH and GH.Not only was the more rapid response of ACTH and GH, but also the prolonged secretion of ACTH and Cortisol were observed after administration of insulin and naloxone. We concluded that endogenous opiates may be involved in the feedback regulation of secretion of ACTH and GH during hypoglycemia either at hypophysis or hypothalamus, and involved in glucose homeostasis via a certain direct mechanism other than regulation of counter hormone secretion. PMID:2856480

  15. Functional Role of Serotonin in Insulin Secretion in a Diet-Induced Insulin-Resistant State

    PubMed Central

    Kim, Kyuho; Oh, Chang-Myung; Ohara-Imaizumi, Mica; Park, Sangkyu; Namkung, Jun; Yadav, Vijay K.; Tamarina, Natalia A.; Roe, Michael W.; Philipson, Louis H.; Karsenty, Gerard; Nagamatsu, Shinya

    2015-01-01

    The physiological role of serotonin, or 5-hydroxytryptamine (5-HT), in pancreatic β-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases β-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the Gαq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in β-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of β-cell-specific Htr2b−/− (Htr2b βKO), Htr3a−/− (Htr3a knock-out [KO]), and β-cell-specific tryptophan hydroxylase 1 (Tph1)−/− (Tph1 βKO) mice on a high-fat diet (HFD). Htr2b βKO, Htr3a KO, and Tph1 βKO mice exhibited normal glucose tolerance on a standard chow diet. After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1 βKO mice developed glucose intolerance, but Htr2b βKO mice remained normoglycemic. Pancreas perfusion assays revealed defective first-phase insulin secretion in Htr3a KO mice. GSIS was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 βKO mice, and 5-HT treatment improved insulin secretion from Tph1 βKO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic islets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in β-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state. PMID:25426873

  16. Circulating retinol-binding protein-4, insulin sensitivity, insulin secretion, and insulin disposition index in obese and nonobese subjects.

    PubMed

    Broch, Montserrat; Vendrell, Joan; Ricart, Wifredo; Richart, Cristóbal; Fernández-Real, José-Manuel

    2007-07-01

    Recent investigations disclosed an upregulation of retinol-binding protein-4 (RBP4) in the adipose tissue of several insulin-resistant mouse models and increased serum RBP4 concentration in subjects with obesity and type 2 diabetes in association with insulin resistance. There is some experimental evidence that RBP4 also could been linked to insulin secretion. We aimed to evaluate insulin secretion, insulin sensitivity, insulin disposition index (minimal model analysis), and circulating RBP4 (enzyme-linked immunosorbent assay) in nondiabetic men with a wide range of obesity (n = 107). Serum RBP4 concentration was nonsignificantly different among lean, overweight, and obese subjects. Circulating RBP4 was not associated with age, BMI, waist-to-hip ratio, or metabolic parameters, including insulin sensitivity (r = -0.03, P = 0.6). On the contrary, circulating RBP4 was negatively associated with insulin secretion, especially in obese subjects (r = -0.48, P = 0.007), in whom RBP4 also was linked to insulin disposition index (r = -0.44, P = 0.01). On multiple regression analyses to predict insulin secretion (acute insulin response [AIR(g)]), insulin sensitivity was the only factor that contributed to 17% of AIR(g) variance in nonobese subjects. In obese subjects, however, RBP4 emerged as an independent factor that contributed independently to AIR(g) variance (23%). Our results suggest that oversecretion of RBP4 may negatively affect beta-cell function directly or by preventing the binding of transthyretin to its receptor. These mechanisms could be behind the association between increased circulating RBP4 and type 2 diabetes. RBP4 could be one signal from insulin-resistant tissues that impacts on beta-cell secretion.

  17. Thrombin stimulates insulin secretion via protease-activated receptor-3.

    PubMed

    Hänzelmann, Sonja; Wang, Jinling; Güney, Emre; Tang, Yunzhao; Zhang, Enming; Axelsson, Annika S; Nenonen, Hannah; Salehi, Albert S; Wollheim, Claes B; Zetterberg, Eva; Berntorp, Erik; Costa, Ivan G; Castelo, Robert; Rosengren, Anders H

    2015-01-01

    The disease mechanisms underlying type 2 diabetes (T2D) remain poorly defined. Here we aimed to explore the pathophysiology of T2D by analyzing gene co-expression networks in human islets. Using partial correlation networks we identified a group of co-expressed genes ('module') including F2RL2 that was associated with glycated hemoglobin. F2Rl2 is a G-protein-coupled receptor (GPCR) that encodes protease-activated receptor-3 (PAR3). PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a 'tethered ligand' to regulate cellular signaling. We have characterized the effect of PAR3 activation on insulin secretion by static insulin secretion measurements, capacitance measurements, studies of diabetic animal models and patient samples. We demonstrate that thrombin stimulates insulin secretion, an effect that was prevented by an antibody that blocks the thrombin cleavage site of PAR3. Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single β-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca(2+) release from intracellular stores. Moreover, we observed that the expression of tissue factor, which regulates thrombin generation, was increased in human islets from T2D donors and associated with enhanced β-cell exocytosis. Finally, we demonstrate that thrombin generation potential in patients with T2D was associated with increased fasting insulin and insulinogenic index. The findings provide a previously unrecognized link between hypercoagulability and hyperinsulinemia and suggest that reducing thrombin activity or blocking PAR3 cleavage could potentially counteract the exaggerated insulin secretion that drives insulin resistance and β-cell exhaustion in T2D.

  18. Insulin secretion in health and disease: nutrients dictate the pace.

    PubMed

    Regazzi, Romano; Rodriguez-Trejo, Adriana; Jacovetti, Cécile

    2016-02-01

    Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by entero-endocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes.

  19. Minireview: Dopaminergic Regulation of Insulin Secretion from the Pancreatic Islet

    PubMed Central

    Ustione, Alessandro

    2013-01-01

    Exogenous dopamine inhibits insulin secretion from pancreatic β-cells, but the lack of dopaminergic neurons in pancreatic islets has led to controversy regarding the importance of this effect. Recent data, however, suggest a plausible physiologic role for dopamine in the regulation of insulin secretion. We review the literature underlying our current understanding of dopaminergic signaling that can down-regulate glucose-stimulated insulin secretion from pancreatic islets. In this negative feedback loop, dopamine is synthesized in the β-cells from circulating l-dopa, serves as an autocrine signal that is cosecreted with insulin, and causes a tonic inhibition on glucose-stimulated insulin secretion. On the whole animal scale, l-dopa is produced by cells in the gastrointestinal tract, and its concentration in the blood plasma increases following a mixed meal. By reviewing the outcome of certain types of bariatric surgery that result in rapid amelioration of glucose tolerance, we hypothesize that dopamine serves as an “antiincretin” signal that counterbalances the stimulatory effect of glucagon-like peptide 1. PMID:23744894

  20. The importance of early insulin secretion and its impact on glycaemic regulation.

    PubMed

    Garber, A J

    2000-09-01

    Type 2 diabetes is characterised by a progressive deterioration of the prandial insulin response, in a situation of continuing insulin resistance. Early phase insulin release is attenuated and delayed and there is a consequent failure to suppress glucagon secretion and curtail hepatic glucose production and gluconeogenesis. Postprandial plasma glucose concentration rises to pathological levels and fails to return to normal before the patient consumes their next meal, creating a problem of continuous daytime hyperglycaemia. Although late insulin secretion is preserved it does not rectify the hyperglycaemia. The pathology of excessive prandial glucose excursions and continual daytime hyperglycaemia can be normalised, at least in part, if early-phase insulin availability is restored through pharmacologic intervention. Initially, the feasibility of this approach was demonstrated experimentally with the use of carefully controlled insulin infusions or insulin analogue injections. More recently, the availability of the rapid or early augmentor of insulin secretion--repaglinide--provides a means for restoring prandial glucose regulation with oral therapy. Placebo-controlled and oral hypoglycaemic agent (OHA) comparative studies of repaglinide have established its antidiabetic efficacy and flexible mealtime/dosing studies have confirmed the importance of the prandial approach to treatment. Prandial glucose regulation with repaglinide has also been demonstrated to provide synergies when used as combination therapy with insulin sensitising agents. As a strategy, prandial glucose regulation has a number of theoretical advantages over the use of fixed doses of conventional insulin secretagogues, and these have been borne out in clinical trials. As well as offering a more flexible approach to treatment, prandial repaglinide is associated with a reduced risk of severe hypoglycaemia.

  1. Prenatal Programming of Insulin Secretion in Intrauterine Growth Restriction

    PubMed Central

    Gatford, Kathryn L.; Simmons, Rebecca A.

    2014-01-01

    Intrauterine growth restriction (IUGR) impairs insulin secretion in humans and in animal models of IUGR. Several underlying mechanisms have been implicated, including decreased expression of molecular regulators of β-cell mass and function, in some cases shown to be due to epigenetic changes initiated by an adverse fetal environment. Alterations in cell cycle progression contribute to loss of β-cell mass, whereas decreased islet vascularity and mitochondrial dysfunction impair β-cell function in IUGR rodents. Animal models of IUGR sharing similar insulin secretion outcomes as the IUGR human are allowing underlying mechanisms to be identified. This review will focus on models of uteroplacental in sufficiency. PMID:23820120

  2. Prenatal programming of insulin secretion in intrauterine growth restriction.

    PubMed

    Gatford, Kathryn L; Simmons, Rebecca A

    2013-09-01

    Intrauterine growth restriction (IUGR) impairs insulin secretion in humans and in animal models of IUGR. Several underlying mechanisms have been implicated, including decreased expression of molecular regulators of β-cell mass and function, in some cases shown to be due to epigenetic changes initiated by an adverse fetal environment. Alterations in cell cycle progression contribute to loss of β-cell mass, whereas decreased islet vascularity and mitochondrial dysfunction impair β-cell function in IUGR rodents. Animal models of IUGR sharing similar insulin secretion outcomes as the IUGR human are allowing underlying mechanisms to be identified. This review will focus on models of uteroplacental insufficiency.

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

    SciTech Connect

    Permana, Paska A. . E-mail: Paska.Permana@med.va.gov; Menge, Christopher; Reaven, Peter D.

    2006-03-10

    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-{kappa}B) activity, and enhanced binding of U937 monocytes. All of these effects were prevented by co-incubation with pyrrolidinedithiocarbamate, an NF-{kappa}B 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.

  4. Quetiapine treatment in youth is associated with decreased insulin secretion.

    PubMed

    Ngai, Ying Fai; Sabatini, Paul; Nguyen, Duc; Davidson, Jana; Chanoine, Jean-Pierre; Devlin, Angela M; Lynn, Francis C; Panagiotopoulos, Constadina

    2014-06-01

    Second-generation antipsychotics (SGAs) are commonly prescribed to youth but are associated with metabolic effects including obesity and diabetes. The mechanisms underlying diabetes development are unclear. The purpose of this study was to compare glucose homeostasis, insulin sensitivity, insulin secretion, and overall β-cell function in risperidone-treated, quetiapine-treated, and SGA-naive youth with mental illness. We conducted a cross-sectional study in which youth aged 9 to 18 years underwent a 2-hour oral glucose tolerance test. Indices for insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), and β-cell function (insulin secretion-sensitivity index-2 [ISSI-2]) were calculated. A total of 18 SGA-naive, 20 risperidone-treated, and 16 quetiapine-treated youth participated. The 3 groups were similar in age, sex, ethnicity, body mass index standardized for age and sex, pubertal status, degree of psychiatric illness, psychiatric diagnoses, and other medications. The median treatment duration was 17 months (range, 3-91 months) for risperidone-treated youth and 10 months (range, 3-44 months) for quetiapine-treated youth. The quetiapine-treated group had lower insulinogenic index (P < 0.01) and lower ISSI-2 (P < 0.01) compared with that in the SGA-naive group. Only the body mass index standardized for age and sex was negatively associated with Matsuda index (β = -0.540, P < 0.001) in all youth. Quetiapine treatment was negatively associated with insulinogenic index (β = -0.426, P = 0.007) and ISSI-2 (β = -0.433, P = 0.008). Quetiapine reduced the insulin expression in isolated mouse islets suggesting a direct β-cell effect. Our results suggest that quetiapine treatment in youth is associated with impaired β-cell function, specifically lower insulin secretion. Prospective longitudinal studies are required to understand the progression of β-cell dysfunction after quetiapine initiation.

  5. Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia.

    PubMed

    Herzberg-Schäfer, S; Heni, M; Stefan, N; Häring, H-U; Fritsche, A

    2012-10-01

    One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the β-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.

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

    NASA Technical Reports Server (NTRS)

    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.

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

    NASA Technical Reports Server (NTRS)

    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.

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

    PubMed

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

    2002-10-01

    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.

  9. Effects of glucosamine infusion on insulin secretion and insulin action in humans.

    PubMed

    Monauni, T; Zenti, M G; Cretti, A; Daniels, M C; Targher, G; Caruso, B; Caputo, M; McClain, D; Del Prato, S; Giaccari, A; Muggeo, M; Bonora, E; Bonadonna, R C

    2000-06-01

    Glucose toxicity (i.e., glucose-induced reduction in insulin secretion and action) may be mediated by an increased flux through the hexosamine-phosphate pathway. Glucosamine (GlcN) is widely used to accelerate the hexosamine pathway flux, independently of glucose. We tested the hypothesis that GlcN can affect insulin secretion and/or action in humans. In 10 healthy subjects, we sequentially performed an intravenous glucose (plus [2-3H]glucose) tolerance test (IVGTT) and a euglycemic insulin clamp during either a saline infusion or a low (1.6 micromol x min(-1) x kg(-1)) or high (5 micromol x min(-1) x kg(-1) [n = 5]) GlcN infusion. Beta-cell secretion, insulin (SI*-IVGTT), and glucose (SG*) action on glucose utilization during the IVGTT were measured according to minimal models of insulin secretion and action. Infusion of GlcN did not affect readily releasable insulin levels, glucose-stimulated insulin secretion (GSIS), or the time constant of secretion, but it increased both the glucose threshold of GSIS (delta approximately 0.5-0.8 mmol/l, P < 0.03-0.01) and plasma fasting glucose levels (delta approximately 0.3-0.5 mmol/l, P < 0.05-0.02). GlcN did not change glucose utilization or intracellular metabolism (glucose oxidation and glucose storage were measured by indirect calorimetry) during the clamp. However, high levels of GlcN caused a decrease in SI*-IVGTT (delta approximately 30%, P < 0.02) and in SG* (delta approximately 40%, P < 0.05). Thus, in humans, acute GlcN infusion recapitulates some metabolic features of human diabetes. It remains to be determined whether acceleration of the hexosamine pathway can cause insulin resistance at euglycemia in humans.

  10. Key proteins involved in insulin vesicle exocytosis and secretion

    PubMed Central

    Xiong, Qian-Yin; Yu, Cui; Zhang, Yao; Ling, Liefeng; Wang, Lizhuo; Gao, Jia-Lin

    2017-01-01

    In vivo insulin secretion is predominantly affected by blood glucose concentration, blood concentration of amino acids, gastrointestinal hormones and free nerve functional status, in addition to other factors. Insulin is one of the most important hormones in the body, and its secretion is precisely controlled by nutrients, neurotransmitters and hormones. The insulin exocytosis process is similar to the neurotransmitter release mechanism. There are various types of proteins and lipids that participate in the insulin secretory vesicle fusion process, such as soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, Ras-related proteins and vacuolar-type H+-ATPase (V-ATPase). Notably, the SNARE protein is the molecular basis of exocytotic activity. In the current review, the role of the vesicle membrane proteins (synaptobrevins, vesicle associated membrane proteins and target membrane proteins) and auxiliary proteins (Rab proteins and Munc-18 proteins) in vesicle fusion activity were summarized. A summary of these key proteins involved in insulin granule secretion will facilitate understanding of the pathogenesis of diabetes. PMID:28357064

  11. Role of Vitamin D in Insulin Secretion and Insulin Sensitivity for Glucose Homeostasis

    PubMed Central

    Alvarez, Jessica A.; Ashraf, Ambika

    2010-01-01

    Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity. This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulin sensitivity. Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D (25(OH)D) is inversely associated with insulin resistance, although direct measurements of insulin sensitivity are required for confirmation. Reported associations with insulin secretion, however, are contradictory. Available prospective studies support a protective influence of high 25(OH)D concentrations on type 2 diabetes mellitus risk. There is a general lack of consistency in vitamin D intervention outcomes on insulin secretion and sensitivity, likely due to differences in subject populations, length of interventions, and forms of vitamin D supplementation. Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factor system may further influence glucose homeostasis. The ambiguity of optimal vitamin D dosing regimens and optimal therapeutic concentrations of serum 25(OH)D limit available intervention studies. Future studies, including cross-sectional and prospective, should be performed in populations at high risk for both vitamin D deficiency and type 2 diabetes mellitus. Well-designed, placebo-controlled, randomized intervention studies are required to establish a true protective influence of vitamin D on glucose homeostasis. PMID:20011094

  12. Role of vitamin d in insulin secretion and insulin sensitivity for glucose homeostasis.

    PubMed

    Alvarez, Jessica A; Ashraf, Ambika

    2010-01-01

    Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity. This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulin sensitivity. Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D (25(OH)D) is inversely associated with insulin resistance, although direct measurements of insulin sensitivity are required for confirmation. Reported associations with insulin secretion, however, are contradictory. Available prospective studies support a protective influence of high 25(OH)D concentrations on type 2 diabetes mellitus risk. There is a general lack of consistency in vitamin D intervention outcomes on insulin secretion and sensitivity, likely due to differences in subject populations, length of interventions, and forms of vitamin D supplementation. Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factor system may further influence glucose homeostasis. The ambiguity of optimal vitamin D dosing regimens and optimal therapeutic concentrations of serum 25(OH)D limit available intervention studies. Future studies, including cross-sectional and prospective, should be performed in populations at high risk for both vitamin D deficiency and type 2 diabetes mellitus. Well-designed, placebo-controlled, randomized intervention studies are required to establish a true protective influence of vitamin D on glucose homeostasis.

  13. A genetic strategy to measure circulating Drosophila insulin reveals genes regulating insulin production and secretion.

    PubMed

    Park, Sangbin; Alfa, Ronald W; Topper, Sydni M; Kim, Grace E S; Kockel, Lutz; Kim, Seung K

    2014-08-01

    Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (Ilp2) levels in Drosophila, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.

  14. Somatostatin-secreting Pheochromocytoma Mimicking Insulin-dependent Diabetes Mellitus

    PubMed Central

    Hirai, Hiroyuki; Midorikawa, Sanae; Suzuki, Shinichi; Sasano, Hironobu; Watanabe, Tsuyoshi; Satoh, Hiroaki

    2016-01-01

    We herein present the findings of a 42-year-old woman with either adrenal pheochromocytoma or intraadrenal paraganglioma that simultaneously secreted somatostatin, thus mimicking insulin-dependent diabetes mellitus. Pheochromocytoma was clinically diagnosed based on scintigraphy, elevated catecholamine levels, and finally a histopathological analysis of resected specimens. The patient had diabetic ketosis, requiring 40 U insulin for treatment. Following laparoscopic adrenalectomy, insulin therapy was discontinued and the urinary c-peptide levels changed from 5.5-9.0 to 81.3-87.0 μg/day. Histologically, somatostatin immunoreactivity was detected and the somatostatin levels were elevated in the serum-like fluid obtained from the tumor. Clinicians should be aware of the possible occurrence of simultaneous ectopic hormone secretion in patients with pheochromocytoma. PMID:27746437

  15. Somatostatin-secreting Pheochromocytoma Mimicking Insulin-dependent Diabetes Mellitus.

    PubMed

    Hirai, Hiroyuki; Midorikawa, Sanae; Suzuki, Shinichi; Sasano, Hironobu; Watanabe, Tsuyoshi; Satoh, Hiroaki

    We herein present the findings of a 42-year-old woman with either adrenal pheochromocytoma or intraadrenal paraganglioma that simultaneously secreted somatostatin, thus mimicking insulin-dependent diabetes mellitus. Pheochromocytoma was clinically diagnosed based on scintigraphy, elevated catecholamine levels, and finally a histopathological analysis of resected specimens. The patient had diabetic ketosis, requiring 40 U insulin for treatment. Following laparoscopic adrenalectomy, insulin therapy was discontinued and the urinary c-peptide levels changed from 5.5-9.0 to 81.3-87.0 μg/day. Histologically, somatostatin immunoreactivity was detected and the somatostatin levels were elevated in the serum-like fluid obtained from the tumor. Clinicians should be aware of the possible occurrence of simultaneous ectopic hormone secretion in patients with pheochromocytoma.

  16. Impaired insulin secretion increases the risk of Alzheimer disease.

    PubMed

    Rönnemaa, E; Zethelius, B; Sundelöf, J; Sundström, J; Degerman-Gunnarsson, M; Berne, C; Lannfelt, L; Kilander, L

    2008-09-30

    Subjects with diabetes are reported to have an increased risk of dementia and cognitive impairment. However, the underlying causes remain unknown. We investigated the longitudinal associations between midlife insulin secretion, glucose metabolism, and the subsequent development of Alzheimer disease (AD) and dementia. The population-based Uppsala Longitudinal Study of Adult Men started 1970 when the 2,322 participants were 50 years old. Investigation at baseline included determinations of acute insulin response and glucose tolerance using the IV glucose tolerance test and Homeostasis Model Assessment insulin resistance index. During a median follow up of 32 years, 102 participants were diagnosed with AD, 57 with vascular dementia, and 394 with any dementia or cognitive impairment. Associations were analyzed using Cox proportional hazard models. A low insulin response at baseline was associated with a higher cumulative risk of AD (hazard ratio for 1 SD decrease, 1.31; 95% CI, 1.10-1.56) also after adjustment for age, systolic blood pressure, body mass index, serum cholesterol, smoking, education level, and insulin resistance. This association was stronger in subjects without the APOE epsilon4 allele. Impaired glucose tolerance increased the risk of vascular dementia (hazard ratio for 1 SD decrease, 1.45; 95% CI, 1.05-2.00) but not AD. Impaired insulin secretion, glucose intolerance, and estimates of insulin resistance were all associated with higher risk of any dementia and cognitive impairment. In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.

  17. Advanced glycation end products (AGEs) are cross-sectionally associated with insulin secretion in healthy subjects.

    PubMed

    Forbes, Josephine M; Sourris, Karly C; de Courten, Maximilian P J; Dougherty, Sonia L; Chand, Vibhasha; Lyons, Jasmine G; Bertovic, David; Coughlan, Melinda T; Schlaich, Markus P; Soldatos, Georgia; Cooper, Mark E; Straznicky, Nora E; Kingwell, Bronwyn A; de Courten, Barbora

    2014-02-01

    It has been postulated that chronic exposure to high levels of advanced glycation end products (AGEs), in particular from dietary sources, can impair insulin secretion. In the present study, we investigated the cross-sectional relationship between AGEs and acute insulin secretion during an intravenous glucose tolerance test (IVGTT) and following a 75 g oral glucose tolerance test (OGTT) in healthy humans. We report the cross-sectional association between circulating AGE concentrations and insulin secretory function in healthy humans (17 F: 27 M, aged 30 ± 10 years) with a wide range of BMI (24.6-31.0 kg/m(2)). Higher circulating concentrations of AGEs were related to increased first phase insulin secretion during IVGTT (r = 0.43; p < 0.05) and lower 2-h glucose concentrations during OGTT (r = -0.31; p < 0.05). In addition, fasting (r = -0.36; p < 0.05) and 2-h glucose concentrations were negatively related to circulating levels of soluble receptor for AGE (RAGE) isoforms (r = -0.39; p < 0.01). In conclusion, in healthy humans, we show a cross-sectional association between advanced glycation end products and acute insulin secretion during glucose tolerance testing.

  18. Genome-Wide Interaction with Insulin Secretion Loci Reveals Novel Loci for Type 2 Diabetes in African Americans

    PubMed Central

    Keaton, Jacob M.; Hellwege, Jacklyn N.; Ng, Maggie C. Y.; Palmer, Nicholette D.; Pankow, James S.; Fornage, Myriam; Wilson, James G.; Correa, Adolfo; Rasmussen-Torvik, Laura J.; Rotter, Jerome I.; Chen, Yii-Der I.; Taylor, Kent D.; Rich, Stephen S.; Wagenknecht, Lynne E.; Freedman, Barry I.; Bowden, Donald W.

    2016-01-01

    Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction<5×10−6) interactions were observed at several loci including LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIRg GRS interactions were observed with SAMD4A (rs11627203) and UTRN (rs17074194). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci. PMID:27448167

  19. Dynamics of insulin secretion and the clinical implications for obesity and diabetes

    PubMed Central

    Seino, Susumu; Shibasaki, Tadao; Minami, Kohtaro

    2011-01-01

    Insulin secretion is a highly dynamic process regulated by various factors including nutrients, hormones, and neuronal inputs. The dynamics of insulin secretion can be studied at different levels: the single β cell, pancreatic islet, whole pancreas, and the intact organism. Studies have begun to analyze cellular and molecular mechanisms underlying dynamics of insulin secretion. This review focuses on our current understanding of the dynamics of insulin secretion in vitro and in vivo and discusses their clinical relevance. PMID:21633180

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

    PubMed

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

    2016-08-01

    Statins are beneficial in the treatment of cardiovascular disease (CVD), but these lipid-lowering drugs are associated with increased incidence of new on-set diabetes. The cellular mechanisms behind the development of diabetes by statins are elusive. Here we have treated mice on normal diet (ND) and high fat diet (HFD) with rosuvastatin. Under ND rosuvastatin lowered blood glucose through improved insulin sensitivity and increased glucose uptake in adipose tissue. In vitro rosuvastatin reduced insulin secretion and insulin content in islets. In the beta cell Ca(2+) signaling was impaired and the density of granules at the plasma membrane was increased by rosuvastatin treatment. HFD mice developed insulin resistance and increased insulin secretion prior to administration of rosuvastatin. Treatment with rosuvastatin decreased the compensatory insulin secretion and increased glucose uptake. In conclusion, our data shows dual effects on glucose homeostasis by rosuvastatin where insulin sensitivity is improved, but beta cell function is impaired. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Iron stores, blood donation, and insulin sensitivity and secretion.

    PubMed

    Fernández-Real, José Manuel; López-Bermejo, Abel; Ricart, Wifredo

    2005-07-01

    Epidemiologists have observed that blood donation is associated with decreased risk of type 2 diabetes and cardiovascular disease. We investigated the relationship between iron stores and insulin sensitivity, after controlling for known confounding factors, and compared insulin sensitivity between blood donors and individuals who had never donated blood (nondonors). In 181 men, insulin sensitivity and insulin secretion were evaluated through frequently sampled intravenous glucose tolerance tests with minimal model analysis. Men who donated blood between 6 months and 5 years before inclusion (n = 21) were carefully matched with nondonors (n = 66) for age, body mass index, waist-to-hip ratio, and cardiovascular risk profile, including blood lipids, blood pressure, and smoking status. Frequent blood donors (2-10 donations) had increased insulin sensitivity [3.42 (1.03) vs 2.45 (1.2) x 10(-4) x min(-1) x mIU/L; P = 0.04], decreased insulin secretion [186 (82) vs 401.7 (254) mIU/L x min; P <0.0001], and significantly lower iron stores [serum ferritin, 101.5 (74) vs 162 (100) microg/L; P = 0.017] than nondonors, but the 2 groups had similar blood hematocrits and blood hemoglobin concentrations. Blood donation is simultaneously associated with increased insulin sensitivity and decreased iron stores. Stored iron seems to impact negatively on insulin action even in healthy people, and not just in classic pathologic conditions associated with iron overload (hemochromatosis and hemosiderosis). According to these observations, it is imperative that a definition of excessive iron stores in healthy people be formulated.

  2. Signalling satiety and starvation to β-Cell insulin secretion.

    PubMed

    Holness, Mark J; Hegazy, Sharif; Sugden, Mary C

    2011-09-01

    The impact of bariatric surgery on insulin sensitivity and glucose tolerance has refocused interest in the role of gut-derived factors in the regulation of insulin secretion and action. The incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, including augmentation of glucose-stimulated insulin secretion (GSIS), actions that promote the cellular assimilation and storage of dietary glucose and lipid as liver and skeletal muscle glycogen and adipocyte triacylglycerol (TAG) respectively. Similarly, increased delivery of fatty acids (FA) acutely augments GSIS, and the resultant enhancement of GSIS facilitates FA storage as adipocyte TAG. Leptin secretion from white adipocytes curbs appetite to limit dietary nutrient intake and adipocyte TAG storage and, potentially, GSIS, thereby curtailing insulin-dependent TAG storage. On fasting, GSIS is curbed, an effect the mechanism of which is even now incompletely understood, but which may reflect augmented β-cell FA oxidation. The orexigen ghrelin, systemic concentrations of which increase with fasting, exerts enigmatic effects on GSIS, in that acylated ghrelin and unacylated ghrelin exert opposing effects on GSIS, whereas acylated ghrelin and unacylated ghrelin share protective effects on islet survival. This review will build on these emerging studies to evaluate the roles of the incretins, leptin, lipids and acylated and unacylated ghrelin in modulating islet function and survival during feasting and fasting.

  3. Apolipoprotein A-I interactions with insulin secretion and production.

    PubMed

    Rye, Kerry-Anne; Barter, Philip J; Cochran, Blake J

    2016-02-01

    Human population studies have established that an elevated plasma high-density lipoprotein cholesterol (HDL-C) level is associated with a decreased risk of developing cardiovascular disease. In addition to having several potentially cardioprotective functions, HDLs and apolipoprotein (apo)A-I, the main HDL apolipoprotein, also have antidiabetic properties. Interventions that elevate plasma HDL-C and apoA-I levels improve glycemic control in people with type 2 diabetes mellitus by enhancing pancreatic β-cell function and increasing insulin sensitivity. This review is concerned with recent advances in understanding the mechanisms by which HDLs and apoA-I improve pancreatic β-cell function. HDLs and apoA-I increase insulin synthesis and secretion in pancreatic β cells. The underlying mechanism of this effect is similar to what has been reported for intestinally derived incretins, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, which both increase β-cell insulin secretion under high glucose conditions. This involves the activation of a heterotrimeric G protein Gαs subunit on the β-cell surface that leads to induction of a transmembrane adenylyl cyclase, increased intracellular cyclic adenosine monophosphate and Ca levels, and activation of protein kinase A. Protein kinase A increases insulin synthesis by excluding FoxO1 from the β-cell nucleus and derepressing transcription of the insulin gene.

  4. Incretins, insulin secretion and Type 2 diabetes mellitus.

    PubMed

    Vilsbøll, T; Holst, J J

    2004-03-01

    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 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 to be able to near-normalize both fasting and postprandial glycaemic concentrations in the patients, perhaps because the treatment compensates for both the impaired secretion of GLP-1 and the impaired action of GIP. Several GLP-1 analogues are currently in clinical development and the reported results are, so far, encouraging.

  5. A Unifying Organ Model of Pancreatic Insulin Secretion

    PubMed Central

    De Gaetano, Andrea; Gaz, Claudio; Palumbo, Pasquale; Panunzi, Simona

    2015-01-01

    The secretion of insulin by the pancreas has been the object of much attention over the past several decades. Insulin is known to be secreted by pancreatic β-cells in response to hyperglycemia: its blood concentrations however exhibit both high-frequency (period approx. 10 minutes) and low-frequency oscillations (period approx. 1.5 hours). Furthermore, characteristic insulin secretory response to challenge maneuvers have been described, such as frequency entrainment upon sinusoidal glycemic stimulation; substantial insulin peaks following minimal glucose administration; progressively strengthened insulin secretion response after repeated administration of the same amount of glucose; insulin and glucose characteristic curves after Intra-Venous administration of glucose boli in healthy and pre-diabetic subjects as well as in Type 2 Diabetes Mellitus. Previous modeling of β-cell physiology has been mainly directed to the intracellular chain of events giving rise to single-cell or cell-cluster hormone release oscillations, but the large size, long period and complex morphology of the diverse responses to whole-body glucose stimuli has not yet been coherently explained. Starting with the seminal work of Grodsky it was hypothesized that the population of pancreatic β-cells, possibly functionally aggregated in islets of Langerhans, could be viewed as a set of independent, similar, but not identical controllers (firing units) with distributed functional parameters. The present work shows how a single model based on a population of independent islet controllers can reproduce very closely a diverse array of actually observed experimental results, with the same set of working parameters. The model’s success in reproducing a diverse array of experiments implies that, in order to understand the macroscopic behaviour of the endocrine pancreas in regulating glycemia, there is no need to hypothesize intrapancreatic pacemakers, influences between different islets of Langerhans

  6. Decreased first phase insulin response in children with congenital insensitivity to pain with anhidrosis.

    PubMed

    Schreiber, Ruth; Levy, Jacov; Loewenthal, Neta; Pinsk, Vered; Hershkovitz, Eli

    2005-09-01

    Nerve growth factor (NGF) and its receptor tyrosine kinase A (TrkA) participate in endocrine pancreas morphogenesis and insulin secretion in vitro. Mutations in the TrkA gene cause the syndrome of congenital insensitivity to pain with anhydrosis (CIPA). We hypothesized that CIPA may represent a natural model for impaired NGF effect on insulin secretion in humans. Glucose challenge tests were performed in seven children with CIPA. We calculated the first phase insulin response (FPIR), the second phase insulin response (SPIR) and glucose disposal rate. FPIR was impaired in four and borderline in two patients. SPIR and glucose disposal rate were within the normal range. Oral glucose tolerance test was normal in all patients. Low FPIR in. CIPA suggests for the first time that the NGF-TrkA pathway may play a role in insulin secretion in response to glucose challenge in humans. Additional studies on the clinical significance of NGF-TrkA effects on insulin secretion are required.

  7. Biomarkers in Fasting Serum to Estimate Glucose Tolerance, Insulin Sensitivity, and Insulin Secretion

    PubMed Central

    Goldfine, Allison B.; Gerwien, Robert W.; Kolberg, Janice A.; O’Shea, Sheila; Hamren, Sarah; Hein, Glenn P.; Xu, Xiaomei M.; Patti, Mary Elizabeth

    2014-01-01

    BACKGROUND Biomarkers for estimating reduced glucose tolerance, insulin sensitivity, or impaired insulin secretion would be clinically useful, since these physiologic measures are important in the pathogenesis of type 2 diabetes mellitus. METHODS We conducted a cross-sectional study in which 94 individuals, of whom 84 had 1 or more risk factors and 10 had no known risk factors for diabetes, underwent oral glucose tolerance testing. We measured 34 protein biomarkers associated with diabetes risk in 250-μL fasting serum samples. We applied multiple regression selection techniques to identify the most informative biomarkers and develop multivariate models to estimate glucose tolerance, insulin sensitivity, and insulin secretion. The ability of the glucose tolerance model to discriminate between diabetic individuals and those with impaired or normal glucose tolerance was evaluated by area under the ROC curve (AUC) analysis. RESULTS Of the at-risk participants, 25 (30%) were found to have impaired glucose tolerance, and 11 (13%) diabetes. Using molecular counting technology, we assessed multiple biomarkers with high accuracy in small volume samples. Multivariate biomarker models derived from fasting samples correlated strongly with 2-h postload glucose tolerance (R2 = 0.45, P < 0.0001), composite insulin sensitivity index (R2 = 0.91, P < 0.0001), and insulin secretion (R2 = 0.45, P < 0.0001). Additionally, the glucose tolerance model provided strong discrimination between diabetes vs impaired or normal glucose tolerance (AUC 0.89) and between diabetes and impaired glucose tolerance vs normal tolerance (AUC 0.78). CONCLUSIONS Biomarkers in fasting blood samples may be useful in estimating glucose tolerance, insulin sensitivity, and insulin secretion. PMID:21149503

  8. Effect of ovarian suppression with gonadotropin-releasing hormone agonist on glucose disposal and insulin secretion.

    PubMed

    Toth, Michael J; Cooper, Brian C; Pratley, Richard E; Mari, Andrea; Matthews, Dwight E; Casson, Peter R

    2008-06-01

    Several lines of evidence suggest that ovarian hormones influence glucose homeostasis, although their exact role in humans has not been clearly defined. In the present study, we sought to test the hypothesis that ovarian hormones regulate glucose homeostasis by examining the effect of pharmacologically induced ovarian hormone deficiency on glucose disposal and insulin secretion. Young, healthy women with regular menstrual patterns were studied during the follicular and luteal phases of their cycle at baseline and after 2 mo of treatment with gonadotropin-releasing hormone agonist (GnRHa; n = 7) or placebo (n = 6). Using hyperglycemic clamps, in combination with stable isotope-labeled (i.e., (13)C and (2)H) glucose tracers, we measured glucose disposal and insulin secretion. Additionally, we assessed body composition and regional fat distribution using radiologic imaging techniques as well as glucoregulatory hormones. Ovarian hormone suppression with GnRHa did not alter body composition, abdominal fat distribution, or thigh tissue composition. There was no effect of ovarian suppression on total, oxidative, or nonoxidative glucose disposal expressed relative to plasma insulin level. Similarly, no effect of ovarian hormone deficiency was observed on first- or second-phase insulin secretion or insulin clearance. Finally, ovarian hormone deficiency was associated with an increase in circulating adiponectin levels but no change in leptin concentration. Our findings suggest that a brief period of ovarian hormone deficiency in young, healthy, eugonadal women does not alter glucose disposal index or insulin secretion, supporting the conclusion that ovarian hormones play a minimal role in regulating glucose homeostasis. Our data do, however, support a role for ovarian hormones in the regulation of plasma adiponectin levels.

  9. Optical Control of Insulin Secretion Using an Incretin Switch.

    PubMed

    Broichhagen, Johannes; Podewin, Tom; Meyer-Berg, Helena; von Ohlen, Yorrick; Johnston, Natalie R; Jones, Ben J; Bloom, Stephen R; Rutter, Guy A; Hoffmann-Röder, Anja; Hodson, David J; Trauner, Dirk

    2015-12-14

    Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer-biased GLP-1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.

  10. Direct Stimulation of Islet Insulin Secretion by Glycolytic and Mitochondrial Metabolites in KCl-Depolarized Islets

    PubMed Central

    Deeney, Jude T.; Corkey, Barbara E.

    2016-01-01

    We have previously demonstrated that islet depolarization with 70 mM KCl opens Cx36 hemichannels and allows diffusion of small metabolites and cofactors through the β-cell plasma membrane. We have investigated in this islet “permeabilized” model whether glycolytic and citric acid cycle intermediates stimulate insulin secretion and how it correlates with ATP production (islet content plus extracellular nucleotide accumulation). Glycolytic intermediates (10 mM) stimulated insulin secretion and ATP production similarly. However, they showed differential sensitivities to respiratory chain or enzyme inhibitors. Pyruvate showed a lower secretory capacity and less ATP production than phosphoenolpyruvate, implicating an important role for glycolytic generation of ATP. ATP production by glucose-6-phosphate was not sensitive to a pyruvate kinase inhibitor that effectively suppressed the phosphoenolpyruvate-induced secretory response and islet ATP rise. Strong suppression of both insulin secretion and ATP production induced by glucose-6-phosphate was caused by 10 μM antimycin A, implicating an important role for the glycerophosphate shuttle in transferring reducing equivalents to the mitochondria. Five citric acid cycle intermediates were investigated for their secretory and ATP production capacity (succinate, fumarate, malate, isocitrate and α-ketoglutarate at 5 mM, together with ADP and/or NADP+ to feed the NADPH re-oxidation cycles). The magnitude of the secretory response was very similar among the different mitochondrial metabolites but α-ketoglutarate showed a more sustained second phase of secretion. Gabaculine (1 mM, a GABA-transaminase inhibitor) suppressed the second phase of secretion and the ATP-production stimulated by α-ketoglutarate, supporting a role for the GABA shuttle in the control of glucose-induced insulin secretion. None of the other citric acid intermediates essayed showed any suppression of both insulin secretion or ATP-production by the

  11. Melatonin modifies basal and stimulated insulin secretion via NADPH oxidase.

    PubMed

    Simões, Daniel; Riva, Patrícia; Peliciari-Garcia, Rodrigo Antonio; Cruzat, Vinicius Fernandes; Graciano, Maria Fernanda; Munhoz, Ana Claudia; Taneda, Marco; Cipolla-Neto, José; Carpinelli, Angelo Rafael

    2016-12-01

    Melatonin is a hormone synthesized in the pineal gland, which modulates several functions within the organism, including the synchronization of glucose metabolism and glucose-stimulated insulin secretion (GSIS). Melatonin can mediate different signaling pathways in pancreatic islets through two membrane receptors and via antioxidant or pro-oxidant enzymes modulation. NADPH oxidase (NOX) is a pro-oxidant enzyme responsible for the production of the reactive oxygen specie (ROS) superoxide, generated from molecular oxygen. In pancreatic islets, NOX-derived ROS can modulate glucose metabolism and regulate insulin secretion. Considering the roles of both melatonin and NOX in islets, the aim of this study was to evaluate the association of NOX and ROS production on glucose metabolism, basal and GSIS in pinealectomized rats (PINX) and in melatonin-treated isolated pancreatic islets. Our results showed that ROS content derived from NOX activity was increased in PINX at baseline (2.8 mM glucose), which was followed by a reduction in glucose metabolism and basal insulin secretion in this group. Under 16.7 mM glucose, an increase in both glucose metabolism and GSIS was observed in PINX islets, without changes in ROS content. In isolated pancreatic islets from control animals incubated with 2.8 mM glucose, melatonin treatment reduced ROS content, whereas in 16.7 mM glucose, melatonin reduced ROS and GSIS. In conclusion, our results demonstrate that both basal and stimulated insulin secretion can be regulated by melatonin through the maintenance of ROS homeostasis in pancreatic islets. © 2016 Society for Endocrinology.

  12. Insight into Insulin Secretion from Transcriptome and Genetic Analysis of Insulin-Producing Cells of Drosophila

    PubMed Central

    Cao, Jian; Ni, Julie; Ma, Wenxiu; Shiu, Vanessa; Milla, Luis A.; Park, Sangbin; Spletter, Maria L.; Tang, Sheng; Zhang, Jun; Wei, Xing; Kim, Seung K.; Scott, Matthew P.

    2014-01-01

    Insulin-producing cells (IPCs) in the Drosophila brain produce and release insulin-like peptides (ILPs) to the hemolymph. ILPs are crucial for growth and regulation of metabolic activity in flies, functions analogous to those of mammalian insulin and insulin-like growth factors (IGFs). To identify components functioning in IPCs to control ILP production, we employed genomic and candidate gene approaches. We used laser microdissection and messenger RNA sequencing to characterize the transcriptome of larval IPCs. IPCs highly express many genes homologous to genes active in insulin-producing β-cells of the mammalian pancreas. The genes in common encode ILPs and proteins that control insulin metabolism, storage, secretion, β-cell proliferation, and some not previously linked to insulin production or β-cell function. Among these novelties is unc-104, a kinesin 3 family gene, which is more highly expressed in IPCs compared to most other neurons. Knockdown of unc-104 in IPCs impaired ILP secretion and reduced peripheral insulin signaling. Unc-104 appears to transport ILPs along axons. As a complementary approach, we tested dominant-negative Rab genes to find Rab proteins required in IPCs for ILP production or secretion. Rab1 was identified as crucial for ILP trafficking in IPCs. Inhibition of Rab1 in IPCs increased circulating sugar levels, delayed development, and lowered weight and body size. Immunofluorescence labeling of Rab1 showed its tight association with ILP2 in the Golgi of IPCs. Unc-104 and Rab1 join other proteins required for ILP transport in IPCs. PMID:24558258

  13. Assessment of the Role of Metabolic Determinants on the Relationship between Insulin Sensitivity and Secretion

    PubMed Central

    Galgani, Jose E.; Gómez, Carmen; Mizgier, Maria L.; Gutierrez, Juan; Santos, Jose L.; Olmos, Pablo; Mari, Andrea

    2016-01-01

    Background Insulin secretion correlates inversely with insulin sensitivity, which may suggest the existence of a crosstalk between peripheral organs and pancreas. Such interaction might be mediated through glucose oxidation that may drive the release of circulating factors with action on insulin secretion. Aim To evaluate the association between whole-body carbohydrate oxidation and circulating factors with insulin secretion to consecutive oral glucose loading in non-diabetic individuals. Methods Carbohydrate oxidation was measured after an overnight fast and for 6 hours after two 3-h apart 75-g oral glucose tolerance tests (OGTT) in 53 participants (24/29 males/females; 34±9 y; 27±4 kg/m2). Insulin secretion was estimated by deconvolution of serum C-peptide concentration, β cell function by mathematical modelling and insulin sensitivity from an OGTT. Circulating lactate, free-fatty acids (FFA) and candidate chemokines were assessed before and after OGTT. The effect of recombinant RANTES (regulated on activation, normal T cell expressed and secreted) and IL8 (interleukin 8) on insulin secretion from isolated mice islets was also measured. Results Carbohydrate oxidation assessed over the 6-h period did not relate with insulin secretion (r = -0.11; p = 0.45) or β cell function indexes. Circulating lactate and FFA showed no association with 6-h insulin secretion. Circulating chemokines concentration increased upon oral glucose stimulation. Insulin secretion associated with plasma IL6 (r = 0.35; p<0.05), RANTES (r = 0.30; p<0.05) and IL8 (r = 0.41; p<0.05) determined at 60 min OGTT. IL8 was independently associated with in vivo insulin secretion; however, it did not affect in vitro insulin secretion. Conclusion Whole-body carbohydrate oxidation appears to have no influence on insulin secretion or putative circulating mediators. IL8 may be a potential factor influencing insulin secretion. PMID:28002466

  14. Assessment of the Role of Metabolic Determinants on the Relationship between Insulin Sensitivity and Secretion.

    PubMed

    Galgani, Jose E; Gómez, Carmen; Mizgier, Maria L; Gutierrez, Juan; Santos, Jose L; Olmos, Pablo; Mari, Andrea

    2016-01-01

    Insulin secretion correlates inversely with insulin sensitivity, which may suggest the existence of a crosstalk between peripheral organs and pancreas. Such interaction might be mediated through glucose oxidation that may drive the release of circulating factors with action on insulin secretion. To evaluate the association between whole-body carbohydrate oxidation and circulating factors with insulin secretion to consecutive oral glucose loading in non-diabetic individuals. Carbohydrate oxidation was measured after an overnight fast and for 6 hours after two 3-h apart 75-g oral glucose tolerance tests (OGTT) in 53 participants (24/29 males/females; 34±9 y; 27±4 kg/m2). Insulin secretion was estimated by deconvolution of serum C-peptide concentration, β cell function by mathematical modelling and insulin sensitivity from an OGTT. Circulating lactate, free-fatty acids (FFA) and candidate chemokines were assessed before and after OGTT. The effect of recombinant RANTES (regulated on activation, normal T cell expressed and secreted) and IL8 (interleukin 8) on insulin secretion from isolated mice islets was also measured. Carbohydrate oxidation assessed over the 6-h period did not relate with insulin secretion (r = -0.11; p = 0.45) or β cell function indexes. Circulating lactate and FFA showed no association with 6-h insulin secretion. Circulating chemokines concentration increased upon oral glucose stimulation. Insulin secretion associated with plasma IL6 (r = 0.35; p<0.05), RANTES (r = 0.30; p<0.05) and IL8 (r = 0.41; p<0.05) determined at 60 min OGTT. IL8 was independently associated with in vivo insulin secretion; however, it did not affect in vitro insulin secretion. Whole-body carbohydrate oxidation appears to have no influence on insulin secretion or putative circulating mediators. IL8 may be a potential factor influencing insulin secretion.

  15. C-Peptide-Based Assessment of Insulin Secretion in the Zucker Fatty Rat: A Modelistic Study

    PubMed Central

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

    2015-01-01

    A C-peptide-based assessment of β-cell function was performed here in the Zucker fatty rat, a suitable animal model of human metabolic syndrome. To this aim, a 90-min intravenous glucose tolerance test (IVGTT) was performed in seven Zucker fatty rats (ZFR), 7-to-9week-old, and seven age-matched Zucker lean rats (ZLR). The minimal model of C-peptide (CPMM), originally introduced for humans, was adapted to Zucker rats and then applied to interpret IVGTT data. For a comprehensive evaluation of glucose tolerance in ZFR, CPMM was applied in combination with the minimal model of glucose kinetics (GKMM). Our results showed that the present CPMM-based interpretation of data is able to: 1) provide a suitable fit of C-Peptide data; 2) achieve a satisfactory estimation of parameters of interest 3) quantify both insulin secretion by estimating the time course of pre-hepatic secretion rate, SR(t), and total insulin secretion, TIS, and pancreatic sensitivity by means of three specific indexes of β-cell responsiveness to glucose stimulus (first-phase, Ф1, second-phase, Ф2, and steady-state, Фss, never assessed in Zucker rats before; 4) detect the significant enhancement of insulin secretion in the ZFR, in face of a severe insulin-resistant state, previously observed only using a purely experimental approach. Thus, the methodology presented here represents a reliable tool to assess β-cell function in the Zucker rat, and opens new possibilities for the quantification of further processes involved in glucose homeostasis such as the hepatic insulin degradation. PMID:25938808

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

    PubMed

    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.

  17. Regulation of Insulin Secretion by Phosphatidylinositol-4,5-Bisphosphate

    PubMed Central

    Tomas, Alejandra; Yermen, Barbara; Regazzi, Romano; Pessin, Jeffrey E.; Halban, Philippe A.

    2014-01-01

    The role of PIP2 in pancreatic beta cell function was examined here using the beta cell line MIN6B1. Blocking PIP2 with PH-PLC-GFP or PIP5KIγ RNAi did not impact on glucose-stimulated secretion although susceptibility to apoptosis was increased. Over-expression of PIP5KIγ improved cell survival and inhibited secretion with accumulation of endocytic vacuoles containing F-actin, PIP2, transferrin receptor, caveolin 1, Arf6 and the insulin granule membrane protein phogrin but not insulin. Expression of constitutively active Arf6 Q67L also resulted in vacuole formation and inhibition of secretion, which was reversed by PH-PLC-GFP co-expression. PIP2 co-localized with gelsolin and F-actin, and gelsolin co-expression partially reversed the secretory defect of PIP5KIγ-over-expressing cells. RhoA/ROCK inhibition increased actin depolymerization and secretion, which was prevented by over-expressing PIP5KIγ, while blocking PIP2 reduced constitutively active RhoA V14-induced F-actin polymerization. In conclusion, although PIP2 plays a pro-survival role in MIN6B1 cells, excessive PIP2 production due to PIP5KIγ over-expression inhibits secretion due to both a defective Arf6/PIP5KIγ-dependent endocytic recycling of secretory membrane and secretory membrane components such as phogrin and the RhoA/ROCK/PIP5KIγ-dependent perturbation of F-actin cytoskeleton remodeling. PMID:19845918

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

    PubMed Central

    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

  19. Racial (black-white) differences in insulin secretion and clearance in adolescents: the Bogalusa heart study.

    PubMed

    Jiang, X; Srinivasan, S R; Radhakrishnamurthy, B; Dalferes, E R; Berenson, G S

    1996-03-01

    Earlier we found black-white contrast in insulin levels in adolescents. The purpose of this study is to assess whether this difference is attributable to alterations in insulin secretion and/or clearance. Fasting circulating insulin and C-peptide concentrations were examined in 1157 adolescents aged 11 to 18 years from a biracial community. Fasting plasma C-peptide, C-peptide to insulin ratio, and glucose to insulin ratio were used as indices of insulin secretion, hepatic insulin clearance, and insulin sensitivity, respectively. After adjusting several covariates (age, sexual maturation, and obesity), black adolescents had higher insulin levels (14.99 vs 12.66 microU/mL in girls). However, they had lower C-peptide levels than their white counterparts, indicating lower insulin secretion by pancreatic beta cells in black adolescents. Moreover, black adolescents had lower levels of C-peptide to insulin ratio than white adolescents (0.14 vs 0.17), suggesting reduced hepatic insulin clearance in black adolescents. In addition, significantly lower levels of glucose to insulin ratio in black girls suggest a reduced insulin sensitivity in this group. Further, differences in insulin levels between white and black girls disappeared after adjusting for differences in C-peptide to insulin ratio. These data suggest that elevated insulin levels observed in black adolescents, especially in black girls, may be attributed to their decreased hepatic insulin clearance, not hypersecretion of insulin.

  20. Glucagon regulates hepatic kisspeptin to impair insulin secretion.

    PubMed

    Song, Woo-Jin; Mondal, Prosenjit; Wolfe, Andrew; Alonso, Laura C; Stamateris, Rachel; Ong, Benny W T; Lim, Owen C; Yang, Kil S; Radovick, Sally; Novaira, Horacio J; Farber, Emily A; Farber, Charles R; Turner, Stephen D; Hussain, Mehboob A

    2014-04-01

    Early in the pathogenesis of type 2 diabetes mellitus (T2DM), dysregulated glucagon secretion from pancreatic α cells occurs prior to impaired glucose-stimulated insulin secretion (GSIS) from β cells. However, whether hyperglucagonemia is causally linked to β cell dysfunction remains unclear. Here we show that glucagon stimulates via cAMP-PKA-CREB signaling hepatic production of the neuropeptide kisspeptin1, which acts on β cells to suppress GSIS. Synthetic kisspeptin suppresses GSIS in vivo in mice and from isolated islets in a kisspeptin1 receptor-dependent manner. Kisspeptin1 is increased in livers and in serum from humans with T2DM and from mouse models of diabetes mellitus. Importantly, liver Kiss1 knockdown in hyperglucagonemic, glucose-intolerant, high-fat-diet fed, and Lepr(db/db) mice augments GSIS and improves glucose tolerance. These observations indicate a hormonal circuit between the liver and the endocrine pancreas in glycemia regulation and suggest in T2DM a sequential link between hyperglucagonemia via hepatic kisspeptin1 to impaired insulin secretion.

  1. Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets.

    PubMed Central

    Lambillotte, C; Gilon, P; Henquin, J C

    1997-01-01

    The direct effects of glucocorticoids on pancreatic beta cell function were studied with normal mouse islets. Dexamethasone inhibited insulin secretion from cultured islets in a concentration-dependent manner: maximum of approximately 75% at 250 nM and IC50 at approximately 20 nM dexamethasone. This inhibition was of slow onset (0, 20, and 40% after 1, 2, and 3 h) and only slowly reversible. It was prevented by a blocker of nuclear glucocorticoid receptors, by pertussis toxin, by a phorbol ester, and by dibutyryl cAMP, but was unaffected by an increase in the fuel content of the culture medium. Dexamethasone treatment did not affect islet cAMP levels but slightly reduced inositol phosphate formation. After 18 h of culture with or without 1 microM dexamethasone, the islets were perifused and stimulated by a rise in the glucose concentration from 3 to 15 mM. Both phases of insulin secretion were similarly decreased in dexamethasone-treated islets as compared with control islets. This inhibition could not be ascribed to a lowering of insulin stores (higher in dexamethasone-treated islets), to an alteration of glucose metabolism (glucose oxidation and NAD(P)H changes were unaffected), or to a lesser rise of cytoplasmic Ca2+ in beta cells (only the frequency of the oscillations was modified). Dexamethasone also inhibited insulin secretion induced by arginine, tolbutamide, or high K+. In this case also the inhibition was observed despite a normal rise of cytoplasmic Ca2+. In conclusion, dexamethasone inhibits insulin secretion through a genomic action in beta cells that leads to a decrease in the efficacy of cytoplasmic Ca2+ on the exocytotic process. PMID:9022074

  2. Insulin and growth hormone secretion in the nephrotic syndrome.

    PubMed

    Bridgman, J F; Summerskill, J; Buckler, J M; Hellman, B; Rosen, S M

    1975-01-01

    Carbohydrate metabolism was studied in a series of patients with the nephrotic syndrome and compared with a similar number of normal controls. The nephrotic syndrome was associated with a smaller secretion of insulin in response to intravenous glucose and tolbutamide than occurred in normals. In the syndrom fasting serum growth hormone (G.H.) concentrations were increased and did not show the characteristic suppression after glucose administration, and the disappearance rate of glucose (k value) was lower. well marked correlation existed between serum G.H. concentrations and the total urinary protein excreted. These abnormal findings returned to normal in a patient who underwent a repeat study when the nephrotic syndrome had resolved.

  3. Evidence for Early Defects in Insulin Sensitivity and Secretion Before the Onset of Glucose Dysregulation in Obese Youths

    PubMed Central

    Giannini, Cosimo; Weiss, Ram; Cali, Anna; Bonadonna, Riccardo; Santoro, Nicola; Pierpont, Bridget; Shaw, Melissa; Caprio, Sonia

    2012-01-01

    We sought to determine whether obese adolescents with high-“normal” 2-h post-oral glucose tolerance test glucose levels display defects in insulin secretion and sensitivity associated with future development of impaired glucose tolerance (IGT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and insulin secretion by applying mathematical modeling during the hyperglycemic clamp in 60 normal glucose tolerance (NGT) obese adolescents, divided into three groups based on the 2-h glucose values (<100, 100–119, 120–139 mg/dL), and in 21 IGT obese adolescents. Glucose tolerance was reevaluated after 2 years. Insulin sensitivity decreased significantly across 2-h glucose NGT categories, while the highest NGT category and IGT group were similar. First-phase insulin secretion decreased across NGT categories, while no difference was found between the highest NGT group and IGT subjects. Second-phase secretion was similar across all NGT and IGT groups. The disposition index (CDI) decreased across NGT categories, while no difference was observed between the highest NGT and IGT subjects. Age and CDI were the best predictors of 2-h glucose after two years. Across rising categories of normal 2-h glucose levels, NGT obese adolescents exhibit significant impairment of β-cell function relative to insulin sensitivity associated with the development of IGT. PMID:22315322

  4. Studies on the mechanism of salicylate-induced increase of insulin secretion in man.

    PubMed

    Giugliano, D; Cozzolino, D; Ceriello, A; Cerciello, T; Varano, R; Saccomanno, F; Torella, R

    1988-01-01

    Salicylate compounds are known to increase basal and stimulated insulin secretion in man. In our studies, infusion of lysine acetylsalicylate (72 mg/min) increased basal insulin levels and amplified insulin responses to glucose (5 g i.v.), arginine (5 g i.v.) and tolbutamide (1 g i.v.). Verapamil, an organic calcium antagonist, did not modify LAS-induced increase of basal insulin levels, but reduced the effect of LAS on glucose-induced insulin secretion. Calcitonin and somatostatin, two agents that inhibit basal and glucose-stimulated insulin secretion, inhibited the insulin response to glucose in presence of LAS infusion. The ability of salicylate compounds to augment insulin secretion might be due to multiple sites of action in the Beta-cells.

  5. The insulin secretion of a minced neonatal rat pancreas cultured in a pancreatic chamber, in response to various insulin secretagogues.

    PubMed

    Araki, Y; Yoshioka, K; Inoue, Y; Nakamura, Y; Nakamura, N; Nakano, K; Yoshida, T; Kondo, M

    1981-02-01

    The minced pancreas of the neonatal rat was cultured for 35 days in a pancreatic chamber which was constructed of a plastic tube and an ultrafiltration membrane. Insulin and amylase secreted from this pancreatic chamber into the culture medium were measured. During the experiment, the concentration of glucose in the culture medium was changed between 5.5 and 16.5 mM at 2-3 day intervals in order to determine the insulin secretory response of the pancreatic tissue. Insulin secretion was markedly increased in response to 16.5 mM glucose. The ratio of insulin secretion to amylase secretion in the culture medium increased with the advance of culture days although secretions of both insulin and amylase decreased individually. On the 7th culture day, short term incubations were performed to test with various insulin secretagogues; obvious insulin release into the incubation medium was observed. These results show that the pancreatic chamber also in vitro secretes insulin rapidly and significantly in response to various stimuli; that by longer culture of a neonatal rat pancreas in this device, insulin secretory cells without exocrine tissue would be obtained without using digestive enzymes; that application of a pancreatic chamber for a pancreatic transplantation may be feasible.

  6. Tear secretion and tear film function in insulin dependent diabetics

    PubMed Central

    Goebbels, M.

    2000-01-01

    BACKGROUND—Diabetic patients often complain of dry eye symptoms, such as burning and/or foreign body sensation. The aim of the present study was to investigate whether diabetes mellitus is correlated with tear film dysfunction and/or tear hyposecretion.
METHODS—In 86 consecutive insulin dependent diabetics with retinopathy and 84 non-diabetic controls (age and sex matched) we performed fluorophotometry of tear secretion, the Schirmer test, and impression cytology of the conjunctival epithelium and determined the tear film break up time.
RESULTS—When compared with the healthy control group diabetics showed decreased Schirmer test readings (−37%, p <0.001) and significantly more frequent and pronounced signs of conjunctival metaplasia. None of the other values differed between groups.
CONCLUSION—In insulin dependent diabetics, reflex tearing was demonstrated to be significantly decreased. In contrast, unstimulated basal tear flow and tear film break up time were found to be normal. However, a majority of insulin dependent diabetics shows distinct signs of conjunctival surface disease.

 PMID:10611093

  7. LIM-homeodomain transcription factor Isl-1 mediates kisspeptin's effect on insulin secretion in mice.

    PubMed

    Chen, Juan; Fu, Rui; Cui, Yan; Pan, Jirong; Li, Yushan; Zhang, Xiaoxin; Evans, Sylvia M; Cui, Sheng; Liu, Jiali

    2014-08-01

    Kisspeptin and the G protein-coupled receptor 54 (GPR54) are highly abundant in the pancreas. In addition, circulating kisspeptin directly influences insulin secretion through GPR54. However, the mechanisms by which kisspeptin affects insulin release are unclear. The LIM-homeodomain transcription factor, Isl-1, is expressed in all pancreatic islet cells and is involved in regulating both islet development and insulin secretion. We therefore investigated potential interactions between kisspeptin and Isl-1. Our results demonstrate that Isl-1 and GPR54 are coexpressed in mouse pancreatic islet β-cells and NIT cells. Both in vitro and in vivo results demonstrate that kisspeptin-54 (KISS-54) inhibits Isl-1 expression and insulin secretion and both the in vivo and in vitro effects of KISS-54 on insulin gene expression and secretion are abolished when an Isl-1-inducible knockout model is used. Moreover, our results demonstrate that the direct action of KISS-54 on insulin secretion is mediated by Isl-1. Our results further show that KISS-54 influences Isl-1 expression and insulin secretion through the protein kinase C-ERK1/2 pathway. Conversely, insulin has a feedback loop via the Janus kinase-phosphatidylinositol 3-kinase pathway regulating kisspeptin expression and secretion. These findings are important in understanding mechanisms of insulin secretion and metabolism in diabetes.

  8. Liver enzymes are associated with hepatic insulin resistance, insulin secretion, and glucagon concentration in healthy men and women.

    PubMed

    Bonnet, Fabrice; Ducluzeau, Pierre-Henri; Gastaldelli, Amalia; Laville, Martine; Anderwald, Christian H; Konrad, Thomas; Mari, Andrea; Balkau, Beverley

    2011-06-01

    The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration. We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals. In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001). In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes.

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

    PubMed

    Ran, J; Cheng, H; Li, F

    2000-01-01

    index (BMI) (P < 0.01), and MCR-I had significant negative correlation with AUCC (P < 0.01). There are obvious impaired first phase insulin secretion after glucose challenge in non-insulin-dependent diabetic subjects from MDP. Decrease in endogenous MCR-I might be an important factor to hyperinsulinemia and insulin resistance. Increased insulin secretion, decreased MCR-I and insulin sensitivity can be observed in abdominal obese subjects of control group.

  10. Mechanisms of insulin secretion in malnutrition: modulation by amino acids in rodent models.

    PubMed

    de Oliveira, Camila Aparecida Machado; Latorraca, Márcia Queiroz; de Mello, Maria Alice Rostom; Carneiro, Everardo Magalhães

    2011-04-01

    Protein restriction at early stages of life reduces β-cell volume, number of insulin-containing granules, insulin content and release by pancreatic islets in response to glucose and other secretagogues, abnormalities similar to those seen in type 2 diabetes. Amino acids are capable to directly modulate insulin secretion and/or contribute to the maintenance of β-cell function, resulting in an improvement of insulin release. Animal models of protein malnutrition have provided important insights into the adaptive mechanisms involved in insulin secretion in malnutrition. In this review, we discuss studies focusing on the modulation of insulin secretion by amino acids, specially leucine and taurine, in rodent models of protein malnutrition. Leucine supplementation increases insulin secretion by pancreatic islets in malnourished mice. This effect is at least in part due to increase in the expression of proteins involved in the secretion process, and the activation of the PI3K/PKB/mTOR pathway seems also to contribute. Mice supplemented with taurine have increased insulin content and secretion as well as increased expression of genes essential for β-cell functionality. The knowledge of the mechanisms through which amino acids act on pancreatic β-cells to stimulate insulin secretion is of interest for clinical medicine. It can reveal new targets for the development of drugs toward the treatment of endocrine diseases, in special type 2 diabetes.

  11. Simvastatin Impairs Insulin Secretion by Multiple Mechanisms in MIN6 Cells.

    PubMed

    Yaluri, Nagendra; Modi, Shalem; López Rodríguez, Maykel; Stančáková, Alena; Kuusisto, Johanna; Kokkola, Tarja; Laakso, Markku

    2015-01-01

    Statins are widely used in the treatment of hypercholesterolemia and are efficient in the prevention of cardiovascular disease. Molecular mechanisms explaining statin-induced impairment in insulin secretion remain largely unknown. In the current study, we show that simvastatin decreased glucose-stimulated insulin secretion in mouse pancreatic MIN6 β-cells by 59% and 79% (p<0.01) at glucose concentration of 5.5 mmol/l and 16.7 mmol/l, respectively, compared to control, whereas pravastatin did not impair insulin secretion. Simvastatin induced decrease in insulin secretion occurred through multiple targets. In addition to its established effects on ATP-sensitive potassium channels (p = 0.004) and voltage-gated calcium channels (p = 0.004), simvastatin suppressed insulin secretion stimulated by muscarinic M3 or GPR40 receptor agonists (Tak875 by 33%, p = 0.002; GW9508 by 77%, p = 0.01) at glucose level of 5.5 mmol/l, and inhibited calcium release from the endoplasmic reticulum. Impaired insulin secretion caused by simvastatin treatment were efficiently restored by GPR119 or GLP-1 receptor stimulation and by direct activation of cAMP-dependent signaling pathways with forskolin. The effects of simvastatin treatment on insulin secretion were not affected by the presence of hyperglycemia. Our observation of the opposite effects of simvastatin and pravastatin on glucose-stimulated insulin secretion is in agreement with previous reports showing that simvastatin, but not pravastatin, was associated with increased risk of incident diabetes.

  12. A functional circadian clock is required for proper insulin secretion by human pancreatic islet cells.

    PubMed

    Saini, C; Petrenko, V; Pulimeno, P; Giovannoni, L; Berney, T; Hebrok, M; Howald, C; Dermitzakis, E T; Dibner, C

    2016-04-01

    To determine the impact of a functional human islet clock on insulin secretion and gene transcription. Efficient circadian clock disruption was achieved in human pancreatic islet cells by small interfering RNA-mediated knockdown of CLOCK. Human islet secretory function was assessed in the presence or absence of a functional circadian clock by stimulated insulin secretion assays, and by continuous around-the-clock monitoring of basal insulin secretion. Large-scale transcription analysis was accomplished by RNA sequencing, followed by quantitative RT-PCR analysis of selected targets. Circadian clock disruption resulted in a significant decrease in both acute and chronic glucose-stimulated insulin secretion. Moreover, basal insulin secretion by human islet cells synchronized in vitro exhibited a circadian pattern, which was perturbed upon clock disruption. RNA sequencing analysis suggested alterations in 352 transcript levels upon circadian clock disruption. Among them, key regulators of the insulin secretion pathway (GNAQ, ATP1A1, ATP5G2, KCNJ11) and transcripts required for granule maturation and release (VAMP3, STX6, SLC30A8) were affected. Using our newly developed experimental approach for efficient clock disruption in human pancreatic islet cells, we show for the first time that a functional β-cell clock is required for proper basal and stimulated insulin secretion. Moreover, clock disruption has a profound impact on the human islet transcriptome, in particular, on the genes involved in insulin secretion. © 2015 John Wiley & Sons Ltd.

  13. The effect of fasting, diet, and actinomycin D on insulin secretion in the rat

    PubMed Central

    Grey, N. J.; Goldring, S.; Kipnis, D. M.

    1970-01-01

    The present studies were performed to elucidate the mechanisms responsible for the impairment of glucose-stimulated insulin secretion observed in fasting. Rats fasted for 48 hr displayed marked impairment in their insulin secretory response to both oral and intravenous glucose. Glucose-stimulated insulin secretion was restored within 24 hr by refeeding; actinomycin D given before refeeding blocked the expected return of normal glucose-stimulated insulin secretion despite adequate food intake. Fasted rats refed a diet devoid of carbohydrate failed to display a return of normal insulin secretory responsiveness to oral glucose in contrast to rats fed isocalorically a high carbohydrate diet. Differences in insulin secretion in fed, fasted, and fasted-refed rats could not be attributed to changes in pancreatic insulin content. There was no significant difference in the insulin secretory response to aminophylline of fed, fasted, or fasted-refed rats. The intermittent pulsing of fasted rats with hyperglycemic episodes by the injection of small amounts of glucose (500 mg) intraperitoneally every 8 hr ameliorated the impairment of glucose-stimulated insulin secretion characteristic of the fasting state. These results suggest that the impairment of glucose-stimulated insulin secretion during fasting and its restoration by refeeding are regulated by changes in a glucose-inducible enzyme system in the pancreatic beta cell. PMID:5441542

  14. Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice

    PubMed Central

    Gustavsson, Natalia; Lao, Ye; Maximov, Anton; Chuang, Jen-Chieh; Kostromina, Elena; Repa, Joyce J.; Li, Cai; Radda, George K.; Südhof, Thomas C.; Han, Weiping

    2008-01-01

    Vertebrates express at least 15 different synaptotagmins with the same domain structure but diverse localizations and tissue distributions. Synaptotagmin-1,-2, and -9 act as calcium sensors for the fast phrase of neurotransmitter release, and synaptotagmin-12 acts as a calcium-independent modulator of release. The exact functions of the remaining 11 synaptotagmins, however, have not been established. By analogy to the role of synaptotagmin-1, -2, and -9 in neurotransmission, these other synaptotagmins may serve as Ca2+ transducers regulating other Ca2+-dependent membrane processes, such as insulin secretion in pancreatic β-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic β-cells. To determine whether synaptotagmin-7 regulates Ca2+-dependent insulin secretion, we analyzed synaptotagmin-7 null mutant mice for glucose tolerance and insulin release. Here, we show that synaptotagmin-7 is required for the maintenance of systemic glucose tolerance and glucose-stimulated insulin secretion. Mutant mice have normal insulin sensitivity, insulin production, islet architecture and ultrastructural organization, and metabolic and calcium responses but exhibit impaired glucose-induced insulin secretion, indicating a calcium-sensing defect during insulin-containing secretory granule exocytosis. Taken together, our findings show that synaptotagmin-7 functions as a positive regulator of insulin secretion and may serve as a calcium sensor controlling insulin secretion in pancreatic β cells. PMID:18308938

  15. Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice.

    PubMed

    Gustavsson, Natalia; Lao, Ye; Maximov, Anton; Chuang, Jen-Chieh; Kostromina, Elena; Repa, Joyce J; Li, Cai; Radda, George K; Südhof, Thomas C; Han, Weiping

    2008-03-11

    Vertebrates express at least 15 different synaptotagmins with the same domain structure but diverse localizations and tissue distributions. Synaptotagmin-1,-2, and -9 act as calcium sensors for the fast phrase of neurotransmitter release, and synaptotagmin-12 acts as a calcium-independent modulator of release. The exact functions of the remaining 11 synaptotagmins, however, have not been established. By analogy to the role of synaptotagmin-1, -2, and -9 in neurotransmission, these other synaptotagmins may serve as Ca(2+) transducers regulating other Ca(2+)-dependent membrane processes, such as insulin secretion in pancreatic beta-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic beta-cells. To determine whether synaptotagmin-7 regulates Ca(2+)-dependent insulin secretion, we analyzed synaptotagmin-7 null mutant mice for glucose tolerance and insulin release. Here, we show that synaptotagmin-7 is required for the maintenance of systemic glucose tolerance and glucose-stimulated insulin secretion. Mutant mice have normal insulin sensitivity, insulin production, islet architecture and ultrastructural organization, and metabolic and calcium responses but exhibit impaired glucose-induced insulin secretion, indicating a calcium-sensing defect during insulin-containing secretory granule exocytosis. Taken together, our findings show that synaptotagmin-7 functions as a positive regulator of insulin secretion and may serve as a calcium sensor controlling insulin secretion in pancreatic beta cells.

  16. Insulin sensitivity and secretion in Arab Americans with glucose intolerance.

    PubMed

    Salinitri, Francine D; Pinelli, Nicole R; Martin, Emily T; Jaber, Linda A

    2013-12-01

    This study examined the pathophysiological abnormalities in Arab Americans with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of insulin secretion (HOMA-%β), and the Matsuda Insulin Sensitivity Index composite (ISIcomposite) were calculated from the fasting and stimulated glucose and insulin concentrations measured during the oral glucose tolerance test in a population-based, representative, cross-sectional sample of randomly selected Arab Americans. In total, 497 individuals (42±14 years old; 40% males; body mass index [BMI], 29±6 kg/m(2)) were studied. Multivariate linear regression models were performed to compare HOMA-IR, HOMA-%β, and ISIcomposite among individuals with normal glucose tolerance (NGT) (n=191) versus isolated IFG (n=136), isolated IGT (n=22), combined IFG/IGT (n=43), and diabetes (n=105). Compared with individuals with NGT (2.9±1.6), HOMA-IR progressively increased in individuals with isolated IFG (4.8±2.7, P<0.001), combined IFG/IGT (6.0±4.3, P<0.001), and diabetes (9.7±8.3, P<0.001) but not in those with isolated IGT (3.0±1.7, P=0.87). After adjustment for sex and BMI, these associations remained unchanged. Whole-body insulin sensitivity as measured by ISIcomposite was significantly lower in individuals with isolated IFG (3.9±2.3, P<0.001), isolated IGT (2.8±1.5, P<0.001), combined IFG/IGT (1.9±1.1, P<0.001), and diabetes (1.6±1.1, P<0.001) compared with those with NGT (6.1±3.5). HOMA-%β was significantly lower in diabetes (113.7±124.9, P<0.001) compared with NGT (161.3±92.0). After adjustment for age, sex, and BMI, isolated IFG (146.6±80.2) was also significantly associated with a decline in HOMA-%β relative to NGT (P=0.005). This study suggests that differences in the underlying metabolic defects leading to diabetes in Arab Americans with IFG and/or IGT exist and may require different strategies for the

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

    PubMed

    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.

  18. Weight-dependent differential contribution of insulin secretion and clearance to hyperinsulinemia of obesity.

    PubMed

    Erdmann, Johannes; Mayr, Martina; Oppel, Ulrich; Sypchenko, Oleg; Wagenpfeil, Stefan; Schusdziarra, Volker

    2009-01-08

    Obesity is associated with insulin resistance and the resulting hyperinsulinemia has been attributed to an increase of insulin secretion and a reduction of insulin clearance. The present study was intended to further characterize the relative contribution of secretion and clearance especially in the postprandial state. In relation to WHO body weight classes 291 subjects were divided in 5 subgroups Basal insulin concentrations rose stepwise and significantly with increasing BMI. This was paralleled by C-peptide concentrations and insulin secretion, while the reduction of insulin clearance was less stringent in relation to BMI. Basal glucose was unchanged in the BMI25 group and 8% higher in the obese groups (BMI 30, 35, 40) compared to normal weight (NW). Although postprandial insulin concentrations were significantly higher in the overweight and obese groups compared to NW the correlation was not as tight as in the basal state. Furthermore, the present data demonstrate for the first time that insulin secretion only increased in the overweight group without further augmentation in the obese groups. Further hyperinsulinemia of the latter was due to weight-dependent reduction of insulin clearance. The postprandial glucose response was 38-82% higher with increasing weight compared to NW. In summary basal hyperinsulinemia is mainly due to weight related increase of insulin secretion with moderate contribution of reduced insulin clearance. Postprandially, hyperinsulinemia of overweight is predominantly due to secretion while further postprandial hyperinsulinemia of obese subjects is mainly due to reduced clearance. Thus, postprandial insulin secretion cannot respond adequately to the challenge of weight-dependent insulin resistance already in non-diabetic obese subjects.

  19. Senescence marker protein-30/gluconolactonase deletion worsens glucose tolerance through impairment of acute insulin secretion.

    PubMed

    Hasegawa, Goji; Yamasaki, Masahiro; Kadono, Mayuko; Tanaka, Muhei; Asano, Mai; Senmaru, Takafumi; Kondo, Yoshitaka; Fukui, Michiaki; Obayashi, Hiroshi; Maruyama, Naoki; Nakamura, Naoto; Ishigami, Akihito

    2010-02-01

    Senescence marker protein-30 (SMP30) is an androgen-independent factor that decreases with age. We recently identified SMP30 as the lactone-hydrolyzing enzyme gluconolactonase (GNL), which is involved in vitamin C biosynthesis in animal species. To examine whether the age-related decrease in SMP30/GNL has effects on glucose homeostasis, we used SMP30/GNL knockout (KO) mice treated with L-ascorbic acid. In an ip glucose tolerance test at 15 wk of age, blood glucose levels in SMP30/GNL KO mice were significantly increased by 25% at 30 min after glucose administration compared with wild-type (WT) mice. Insulin levels in SMP30/GNL KO mice were significantly decreased by 37% at 30 min after glucose compared with WT mice. Interestingly, an insulin tolerance test showed a greater glucose-lowering effect in SMP30/GNL KO mice. High-fat diet feeding severely worsened glucose tolerance in both WT and SMP30/GNL KO mice. Morphometric analysis revealed no differences in the degree of high-fat diet-induced compensatory increase in beta-cell mass and proliferation. In the static incubation study of islets, insulin secretion in response to 20 mm glucose or KCl was significantly decreased in SMP30/GNL KO mice. On the other hand, islet ATP content at 20 mm in SMP30/GNL KO mice was similar to that in WT mice. Collectively, these data indicate that impairment of the early phase of insulin secretion due to dysfunction of the distal portion of the secretion pathway underlies glucose intolerance in SMP30/GNL KO mice. Decreased SMP30/GNL may contribute to the worsening of glucose tolerance that occurs in normal aging.

  20. D-chiro-inositol glycan stimulates insulin secretion in pancreatic β cells.

    PubMed

    Lazarenko, Roman; Geisler, Jessica; Bayliss, Douglas; Larner, Joseph; Li, Chien

    2014-04-25

    Insulin has been shown to act on pancreatic β cells to regulate its own secretion. Currently the mechanism underlying this effect is unclear. INS-2, a novel inositol glycan pseudo-disaccharide containing D-chiro-inositol and galactosamine, has been shown to function as an insulin mimetic and a putative insulin mediator. In the present study we found that INS-2 stimulates insulin secretion in MIN6 β cells and potentiates glucose stimulated insulin secretion in isolated mouse islets. Importantly, INS-2 failed to potentiate insulin secretion induced by tolbutamide, which stimulates insulin release by closing ATP sensitive potassium channels (KATP). Electrophysiological studies showed that INS-2 inhibited sulfonylurea-sensitive KATP conductance. The effect of INS-2 on inhibiting KATP channel is mediated by protein phosphatase 2C (PP2C), as knocking down PP2C expression in MIN6 cells by PP2C small hairpin RNA completely abolished the effect of INS-2 on KATP and consequently attenuated INS-2 induced insulin secretion. In conclusion, the present study identifies a novel mechanism involving PP2C in regulating KATP channel activity and consequently insulin secretion.

  1. Mitochondrial Glutamate Carrier GC1 as a Newly Identified Player in the Control of Glucose-stimulated Insulin Secretion*

    PubMed Central

    Casimir, Marina; Lasorsa, Francesco M.; Rubi, Blanca; Caille, Dorothée; Palmieri, Ferdinando; Meda, Paolo; Maechler, Pierre

    2009-01-01

    The SLC25 carrier family mediates solute transport across the inner mitochondrial membrane, a process that is still poorly characterized regarding both the mechanisms and proteins implicated. This study investigated mitochondrial glutamate carrier GC1 in insulin-secreting β-cells. GC1 was cloned from insulin-secreting cells, and sequence analysis revealed hydropathy profile of a six-transmembrane protein, characteristic of mitochondrial solute carriers. GC1 was found to be expressed at the mRNA and protein levels in INS-1E β-cells and pancreatic rat islets. Immunohistochemistry showed that GC1 was present in mitochondria, and ultrastructural analysis by electron microscopy revealed inner mitochondrial membrane localization of the transporter. Silencing of GC1 in INS-1E β-cells, mediated by adenoviral delivery of short hairpin RNA, reduced mitochondrial glutamate transport by 48% (p < 0.001). Insulin secretion at basal 2.5 mm glucose and stimulated either by intermediate 7.5 mm glucose or non-nutrient 30 mm KCl was not modified by GC1 silencing. Conversely, insulin secretion stimulated with optimal 15 mm glucose was reduced by 23% (p < 0.005) in GC1 knocked down cells compared with controls. Adjunct of cell-permeant glutamate (5 mm dimethyl glutamate) fully restored the secretory response at 15 mm glucose (p < 0.005). Kinetics of insulin secretion were investigated in perifused isolated rat islets. GC1 silencing in islets inhibited the secretory response induced by 16.7 mm glucose, both during first (−25%, p < 0.05) and second (−33%, p < 0.05) phases. This study demonstrates that insulin-secreting cells depend on GC1 for maximal glucose response, thereby assigning a physiological function to this newly identified mitochondrial glutamate carrier. PMID:19584051

  2. The good and bad effects of statins on insulin sensitivity and secretion.

    PubMed

    Muscogiuri, Giovanna; Sarno, Gerardo; Gastaldelli, Amalia; Savastano, Silvia; Ascione, Antonio; Colao, Annamaria; Orio, Francesco

    2014-01-01

    Statins are the main lipid-lowering treatment in both primary and secondary prevention populations. Whether statins deteriorates glycemic control, predisposing to the onset of diabetes mellitus has been a matter of recent concern. Statins may accelerate progression to diabetes via molecular mechanisms that impact insulin sensitivity and secretion. In this review, we debate the relative effect of statins in driving insulin resistance and the impairment of insulin secretion. Narrative overview of the literature synthesizing the findings of literature was retrieved from searches of computerized databases, hand searches, and authoritative texts employing the key words "Statins", "Randomized Clinical Trial", "Insulin sensitivity", "Insulin resistance", "Insulin Secretion", "Diabetes Mellitus" alone and/or in combination. The weight of clinical evidence suggests a worsening effect of statins on insulin resistance and secretion, anyway basic science studies did not find a clear molecular explanation, providing conflicting evidence regarding both the beneficial and the adverse effects of statin therapy on insulin sensitivity. Although most of the clinical studies suggest a worsening of insulin resistance and secretion, the cardiovascular benefits of statin therapy outweigh the risk of developing insulin resistance, thus the data suggest the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control.

  3. Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion

    PubMed Central

    Edgerton, Dale S.; Kraft, Guillaume; Smith, Marta; Farmer, Ben; Williams, Phillip E.; Coate, Katie C.; Printz, Richard L.; O’Brien, Richard M.; Cherrington, Alan D.

    2017-01-01

    Insulin can inhibit hepatic glucose production (HGP) by acting directly on the liver as well as indirectly through effects on adipose tissue, pancreas, and brain. While insulin’s indirect effects are indisputable, their physiologic role in the suppression of HGP seen in response to increased insulin secretion is not clear. Likewise, the mechanisms by which insulin suppresses lipolysis and pancreatic α cell secretion under physiologic circumstances are also debated. In this study, insulin was infused into the hepatic portal vein to mimic increased insulin secretion, and insulin’s indirect liver effects were blocked either individually or collectively. During physiologic hyperinsulinemia, plasma free fatty acid (FFA) and glucagon levels were clamped at basal values and brain insulin action was blocked, but insulin’s direct effects on the liver were left intact. Insulin was equally effective at suppressing HGP when its indirect effects were absent as when they were present. In addition, the inhibition of lipolysis, as well as glucagon and insulin secretion, did not require CNS insulin action or decreased plasma FFA. This indicates that the rapid suppression of HGP is attributable to insulin’s direct effect on the liver and that its indirect effects are redundant in the context of a physiologic increase in insulin secretion. PMID:28352665

  4. Differential-phase-shift quantum secret sharing.

    PubMed

    Inoue, K; Ohashi, T; Kukita, T; Watanebe, K; Hayashi, S; Honjo, T; Takesue, H

    2008-09-29

    A quantum secret sharing (QSS) protocol based on a differential-phase-shift scheme is proposed, which quantum mechanically provides a full secret key to one party and partial keys to two other parties. A weak coherent pulse train is utilized instead of individual photons as in conventional schemes. Compared with previous QSS protocols, the present one features a simple setup, is suitable for fiber transmission, and offers the possibility for a high key creation rate. An experiment is also carried out to demonstrate the operation.

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

    PubMed

    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.

  6. Nutrient-stimulated insulin secretion in mouse islets is critically dependent on intracellular pH

    PubMed Central

    Gunawardana, Subhadra C; Rocheleau, Jonathan V; Head, W Steven; Piston, David W

    2004-01-01

    Background Many mechanistic steps underlying nutrient-stimulated insulin secretion (NSIS) are poorly understood. The influence of intracellular pH (pHi) on insulin secretion is widely documented, and can be used as an investigative tool. This study demonstrates previously unknown effects of pHi-alteration on insulin secretion in mouse islets, which may be utilized to correct defects in insulin secretion. Methods Different components of insulin secretion in mouse islets were monitored in the presence and absence of forced changes in pHi. The parameters measured included time-dependent potentiation of insulin secretion by glucose, and direct insulin secretion by different mitochondrial and non-mitochondrial secretagogues. Islet pHi was altered using amiloride, removal of medium Cl-, and changing medium pH. Resulting changes in islet pHi were monitored by confocal microscopy using a pH-sensitive fluorescent indicator. To investigate the underlying mechanisms of the effects of pHi-alteration, cellular NAD(P)H levels were measured using two-photon excitation microscopy (TPEM). Data were analyzed using Student's t test. Results Time-dependent potentiation, a function normally absent in mouse islets, can be unmasked by a forced decrease in pHi. The optimal range of pHi for NSIS is 6.4–6.8. Bringing islet pHi to this range enhances insulin secretion by all mitochondrial fuels tested, reverses the inhibition of glucose-stimulated insulin secretion (GSIS) by mitochondrial inhibitors, and is associated with increased levels of cellular NAD(P)H. Conclusions Pharmacological alteration of pHi is a potential means to correct the secretory defect in non-insulin dependent diabetes mellitus (NIDDM), since forcing islet pHi to the optimal range enhances NSIS and induces secretory functions that are normally absent. PMID:15193158

  7. Investigation of morin-induced insulin secretion in cultured pancreatic cells.

    PubMed

    Lin, Mang Hung; Hsu, Chia-Chen; Lin, Jenshinn; Cheng, Juei Tang; Wu, Ming Chang

    2017-07-12

    Morin is a flavonoid contained in guava that is known to reduce hyperglycemia in diabetes. Insulin secretion has been demonstrated to increase following the administration of morin. The present study is designed to investigate the potential mechanism(s) of morin-induced insulin secretion in the MIN6 cell line. First, we identified that morin induced a dose-dependent increase in insulin secretion and intracellular calcium content in MIN6 cells. Morin potentiated glucose-stimulated insulin secretion (GSIS). Additionally, we used siRNA for the ablation of imidazoline receptor protein (NISCH) expression in MIN6 cells. Interestingly, the effects of increased insulin secretion by morin and canavanine were markedly reduced in Si-NISCH cells. Moreover, we used KU14R to block imidazoline I3 receptor (I-3R) that is known to enhance insulin release from the pancreatic β-cells. Without influence on the basal insulin secretion, KU14R dose-dependently inhibited the increased insulin secretion induced by morin or efaroxan in MIN6 cells. Additionally, effects of increased insulin secretion by morin or efaroxan were reduced by diazoxide at the dose sufficient to open KATP channels and attenuated by nifedipine at the dose used to inhibit L-type calcium channels. Otherwise, phospholipase C (PLC) is introduced to couple with imidazoline receptor (I-R). The PLC inhibitor dose-dependently inhibited the effects of morin in MIN6 cells. Similar blockade was also observed in protein kinase C (PKC) inhibitor-treated cells. Taken together, we found that morin increases insulin secretion via the activation of I-R in pancreatic cells. Therefore, morin would be useful to develop in the research and treatment of diabetic disorders. © 2017 John Wiley & Sons Australia, Ltd.

  8. CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion.

    PubMed

    Abels, Mia; Riva, Matteo; Bennet, Hedvig; Ahlqvist, Emma; Dyachok, Oleg; Nagaraj, Vini; Shcherbina, Liliya; Fred, Rikard G; Poon, Wenny; Sörhede-Winzell, Maria; Fadista, Joao; Lindqvist, Andreas; Kask, Lena; Sathanoori, Ramasri; Dekker-Nitert, Marloes; Kuhar, Michael J; Ahrén, Bo; Wollheim, Claes B; Hansson, Ola; Tengholm, Anders; Fex, Malin; Renström, Erik; Groop, Leif; Lyssenko, Valeriya; Wierup, Nils

    2016-09-01

    Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart (-/-) mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca(2+) oscillation patterns and exocytosis were studied in mouse islets. We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca(2+) signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis. We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.

  9. Brain Glucose Sensors Play a Significant Role in the Regulation of Pancreatic Glucose-Stimulated Insulin Secretion

    PubMed Central

    Osundiji, Mayowa A.; Lam, Daniel D.; Shaw, Jill; Yueh, Chen-Yu; Markkula, S. Pauliina; Hurst, Paul; Colliva, Carolina; Roda, Aldo; Heisler, Lora K.; Evans, Mark L.

    2012-01-01

    As patients decline from health to type 2 diabetes, glucose-stimulated insulin secretion (GSIS) typically becomes impaired. Although GSIS is driven predominantly by direct sensing of a rise in blood glucose by pancreatic β-cells, there is growing evidence that hypothalamic neurons control other aspects of peripheral glucose metabolism. Here we investigated the role of the brain in the modulation of GSIS. To examine the effects of increasing or decreasing hypothalamic glucose sensing on glucose tolerance and insulin secretion, glucose or inhibitors of glucokinase, respectively, were infused into the third ventricle during intravenous glucose tolerance tests (IVGTTs). Glucose-infused rats displayed improved glucose handling, particularly within the first few minutes of the IVGTT, with a significantly lower area under the excursion curve within the first 10 min (AUC0-10). This was explained by increased insulin secretion. In contrast, infusion of the glucokinase inhibitors glucosamine or mannoheptulose worsened glucose tolerance and decreased GSIS in the first few minutes of IVGTT. Our data suggest a role for brain glucose sensors in the regulation of GSIS, particularly during the early phase. We propose that pharmacological agents targeting hypothalamic glucose-sensing pathways may represent novel therapeutic strategies for enhancing early phase insulin secretion in type 2 diabetes. PMID:22210318

  10. Dopamine-Mediated Autocrine Inhibitory Circuit Regulating Human Insulin Secretion in Vitro

    PubMed Central

    Simpson, Norman; Maffei, Antonella; Freeby, Matthew; Burroughs, Steven; Freyberg, Zachary; Javitch, Jonathan; Leibel, Rudolph L.

    2012-01-01

    We describe a negative feedback autocrine regulatory circuit for glucose-stimulated insulin secretion in purified human islets in vitro. Using chronoamperometry and in vitro glucose-stimulated insulin secretion measurements, evidence is provided that dopamine (DA), which is loaded into insulin-containing secretory granules by vesicular monoamine transporter type 2 in human β-cells, is released in response to glucose stimulation. DA then acts as a negative regulator of insulin secretion via its action on D2R, which are also expressed on β-cells. We found that antagonism of receptors participating in islet DA signaling generally drive increased glucose-stimulated insulin secretion. These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity. PMID:22915827

  11. Effect of lipids on insulin, growth hormone and exocrine pancreatic secretion in man.

    PubMed

    Raptis, S; Dollinger, H C; von Berger, L; Kissing, J; Schröder, K E; Klör, U; Pfeiffer, E F

    1975-11-21

    Influences of fat on release of insulin, growth hormone and pancreatic enzyme secretion were studied in 35 metabolically healthy subjects. A fat solution containing 40 g of soy bean oil was administered, I.V., orally and intraduodenally. In all cases there was a similar increase of insulin but the rise in serum insulin after oral or intraduodenal fat administration was not related to the changes in plasma free fatty acids, free glycerol and triglyceride levels. Blood surgar responded according to insulin secretion. The route of fat administration may possibly influence growth hormone secretion. Following intraduodenal fat administration volume and bicarbonate contents of the duodenal juice rose slightly whereas trypsin and bilirubin content increased considerably. These results suggest that insulin secretion after oral or intraduodenal administration of fat is influenced by intestinal factors. Cholecystokinin-pancroezymin and gastric inhibitory polypeptide are qualified to serve as such factors.

  12. GPR54 peptide agonists stimulate insulin secretion from murine, porcine and human islets.

    PubMed

    Bowe, James E; Foot, Victoria L; Amiel, Stephanie A; Huang, Gao Cai; Lamb, Morgan W; Lakey, Jonathan; Jones, Peter M; Persaud, Shanta J

    2012-01-01

    This study was designed to determine the effects of 10 and 13 amino acid forms of kisspeptin on dynamic insulin secretion from mammalian islets since it is not clear from published data whether the shorter peptide is stimulatory while the longer peptide inhibits insulin release. Insulin secretion was measured by radioimmunoassay following perifusion of human, pig, rat and mouse isolated islets with kisspeptin-10 or kisspeptin-13 in the presence of 20 mM glucose. Both peptides stimulated rapid, reversible potentiation of glucose-stimulated insulin secretion from islets of all species tested. These data indicate that both kisspeptin-10 and kisspeptin-13, which is an extension of kisspeptin-10 by three amino acids, act directly at islet β-cells of various species to potentiate insulin secretion, and suggest that inhibitory effects reported in earlier studies may reflect differences in experimental protocols.

  13. Quantitative visualization of synchronized insulin secretion from 3D-cultured cells.

    PubMed

    Suzuki, Takahiro; Kanamori, Takao; Inouye, Satoshi

    2017-05-13

    Quantitative visualization of synchronized insulin secretion was performed in an isolated rat pancreatic islet and a spheroid of rat pancreatic beta cell line using a method of video-rate bioluminescence imaging. Video-rate images of insulin secretion from 3D-cultured cells were obtained by expressing the fusion protein of insulin and Gaussia luciferase (Insulin-GLase). A subclonal rat INS-1E cell line stably expressing Insulin-GLase, named iGL, was established and a cluster of iGL cells showed oscillatory insulin secretion that was completely synchronized in response to high glucose. Furthermore, we demonstrated the effect of an antidiabetic drug, glibenclamide, on synchronized insulin secretion from 2D- and 3D-cultured iGL cells. The amount of secreted Insulin-GLase from iGL cells was also determined by a luminometer. Thus, our bioluminescence imaging method could generally be used for investigating protein secretion from living 3D-cultured cells. In addition, iGL cell line would be valuable for evaluating antidiabetic drugs. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Gαo Represses Insulin Secretion by Reducing Vesicular Docking in Pancreatic β-Cells

    PubMed Central

    Zhao, Aizhen; Ohara-Imaizumi, Mica; Brissova, Marcella; Benninger, Richard K.P.; Xu, Yanwen; Hao, Yuhan; Abramowitz, Joel; Boulay, Guylain; Powers, Alvin C.; Piston, David; Jiang, Meisheng; Nagamatsu, Shinya; Birnbaumer, Lutz; Gu, Guoqiang

    2010-01-01

    OBJECTIVE Pertussis toxin uncoupling–based studies have shown that Gαi and Gαo can inhibit insulin secretion in pancreatic β-cells. Yet it is unclear whether Gαi and Gαo operate through identical mechanisms and how these G-protein–mediated signals inhibit insulin secretion in vivo. Our objective is to examine whether/how Gαo regulates islet development and insulin secretion in β-cells. RESEARCH DESIGN AND METHODS Immunoassays were used to analyze the Gαo expression in mouse pancreatic cells. Gαo was specifically inactivated in pancreatic progenitor cells by pancreatic cell–specific gene deletion. Hormone expression and insulin secretion in response to different stimuli were assayed in vivo and in vitro. Electron microscope and total internal reflection fluorescence–based assays were used to evaluate how Gαo regulates insulin vesicle docking and secretion in response to glucose stimulation. RESULTS Islet cells differentiate properly in Gαo−/− mutant mice. Gαo inactivation significantly enhances insulin secretion both in vivo and in isolation. Gαo nullizygous β-cells contain an increased number of insulin granules docked on the cell plasma membrane, although the total number of vesicles per β-cell remains unchanged. CONCLUSIONS Gαo is not required for endocrine islet cell differentiation, but it regulates the number of insulin vesicles docked on the β-cell membrane. PMID:20622165

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

    PubMed

    Wu, Bingbing; Wei, Shunhui; Petersen, Natalia; Ali, Yusuf; Wang, Xiaorui; Bacaj, Taulant; Rorsman, Patrik; Hong, Wanjin; Südhof, Thomas C; Han, Weiping

    2015-08-11

    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 ameliorated by glucagon-like peptide-1 (GLP-1) or by GLP-1 receptor agonists, which improve glucose homeostasis. However, the mechanism by which GLP-1 receptor agonists boost insulin secretion remains unclear. Here, we report that GLP-1 stimulates protein kinase A (PKA)-dependent phosphorylation of synaptotagmin-7 at serine-103, which enhances glucose- and Ca(2+)-stimulated insulin secretion and accounts for the improvement of glucose homeostasis by GLP-1. A phospho-mimetic synaptotagmin-7 mutant enhances Ca(2+)-triggered exocytosis, whereas a phospho-inactive synaptotagmin-7 mutant disrupts GLP-1 potentiation of insulin secretion. Our findings thus suggest that synaptotagmin-7 is directly activated by GLP-1 signaling and may serve as a drug target for boosting insulin secretion. Moreover, our data reveal, to our knowledge, the first physiological modulation of Ca(2+)-triggered exocytosis by direct phosphorylation of a synaptotagmin.

  16. Acute suppression of apo B secretion by insulin occurs independently of MTP.

    PubMed

    Sparks, Janet D; Chamberlain, Jeffrey M; O'Dell, Colleen; Khatun, Irani; Hussain, M Mahmood; Sparks, Charles E

    2011-03-11

    Secretion of apolipoprotein (apo) B-containing lipoproteins by the liver depends mainly upon apo B availability and microsomal triglyceride transfer protein (MTP) activity and is subject to insulin regulation. Hepatic MTP mRNA expression is negatively regulated by insulin which correlates with inhibition of apo B secretion suggesting that insulin might suppress apo B secretion through an MTP-dependent mechanism. To investigate this possibility, we examined the acute effect of insulin on hepatic MTP expression and activity levels in vivo utilizing apobec-1(-/-) mice. Insulin did not significantly alter hepatic MTP mRNA levels or lipid transfer activity 2h following injection, but suppressed expression of genes important in gluconeogenesis. To study the specific role of MTP, we expressed human MTP (hMTP) in primary rat hepatocytes using adenoviral gene transfer. Increased expression of hMTP resulted in a 47.6±17.9% increase in total apo B secreted. Incubation of hepatocytes with insulin suppressed apo B secretion by 50.1±10.8% in cells over-expressing hMTP and by 53.0±12.4% in control transfected hepatocytes. Results indicate that even under conditions of increased hepatic apo B secretion mediated by MTP, responsiveness of hepatocytes to insulin to suppress apo B secretion is maintained.

  17. A single-islet microplate assay to measure mouse and human islet insulin secretion.

    PubMed

    Truchan, Nathan A; Brar, Harpreet K; Gallagher, Shannon J; Neuman, Joshua C; Kimple, Michelle E

    2015-01-01

    One complication to comparing β-cell function among islet preparations, whether from genetically identical or diverse animals or human organ donors, is the number of islets required per assay. Islet numbers can be limiting, meaning that fewer conditions can be tested; other islet measurements must be excluded; or islets must be pooled from multiple animals/donors for each experiment. Furthermore, pooling islets negates the possibility of performing single-islet comparisons. Our aim was to validate a 96-well plate-based single islet insulin secretion assay that would be as robust as previously published methods to quantify glucose-stimulated insulin secretion from mouse and human islets. First, we tested our new assay using mouse islets, showing robust stimulation of insulin secretion 24 or 48 h after islet isolation. Next, we utilized the assay to quantify mouse islet function on an individual islet basis, measurements that would not be possible with the standard pooled islet assay methods. Next, we validated our new assay using human islets obtained from the Integrated Islet Distribution Program (IIDP). Human islets are known to have widely varying insulin secretion capacity, and using our new assay we reveal biologically relevant factors that are significantly correlated with human islet function, whether displayed as maximal insulin secretion response or fold-stimulation of insulin secretion. Overall, our results suggest this new microplate assay will be a useful tool for many laboratories, expert or not in islet techniques, to be able to precisely quantify islet insulin secretion from their models of interest.

  18. Brain glucagon-like peptide–1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

    PubMed Central

    Knauf, Claude; Cani, Patrice D.; Perrin, Christophe; Iglesias, Miguel A.; Maury, Jean François; Bernard, Elodie; Benhamed, Fadilha; Grémeaux, Thierry; Drucker, Daniel J.; Kahn, C. Ronald; Girard, Jean; Tanti, Jean François; Delzenne, Nathalie M.; Postic, Catherine; Burcelin, Rémy

    2005-01-01

    Intestinal glucagon-like peptide–1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9–39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state. PMID:16322793

  19. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage.

    PubMed

    Knauf, Claude; Cani, Patrice D; Perrin, Christophe; Iglesias, Miguel A; Maury, Jean François; Bernard, Elodie; Benhamed, Fadilha; Grémeaux, Thierry; Drucker, Daniel J; Kahn, C Ronald; Girard, Jean; Tanti, Jean François; Delzenne, Nathalie M; Postic, Catherine; Burcelin, Rémy

    2005-12-01

    Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

  20. Reduced insulin secretion and glucose intolerance are involved in the fasting susceptibility of common vampire bats.

    PubMed

    Freitas, Mariella B; Queiroz, Joicy F; Dias Gomes, Carolinne I; Collares-Buzato, Carla B; Barbosa, Helena C; Boschero, Antonio C; Gonçalves, Carlos A; Pinheiro, Eliana C

    2013-03-01

    Susceptibility during fasting has been reported for the common vampire bat (Desmodus rotundus), to the point of untimely deaths after only 2-3 nights of fasting. To investigate the underlying physiology of this critical metabolic condition, we analyzed serum insulin levels, pancreatic islets morphometry and immunocytochemistry (ICC), static insulin secretion in pancreas fragments, and insulin signaling mechanism in male vampire bats. A glucose tolerance test (ipGTT) was also performed. Serum insulin was found to be lower in fed vampires compared to other mammals, and was significantly reduced after 24h fasting. Morphometrical analyses revealed small irregular pancreatic islets with reduced percentage of β-cell mass compared to other bats. Static insulin secretion analysis showed that glucose-stimulated insulin secretion was impaired, as insulin levels did not reach significance under high glucose concentrations, whereas the response to the amino acid leucin was preserved. Results from ipGTT showed a failure on glucose clearance, indicating glucose intolerance due to diminished pancreatic insulin secretion and/or decreased β-cell response to glucose. In conclusion, data presented here indicate lower insulinemia and impaired insulin secretion in D. rotundus, which is consistent with the limited ability to store body energy reserves, previously reported in these animals. Whether these metabolic and hormonal features are associated with their blood diet remains to be determined. The peculiar food sharing through blood regurgitation, reported to this species, might be an adaptive mechanism overcoming this metabolic susceptibility.

  1. [Effects of chemical constituents of Crossostephium chinense on insulin secretion in rat islets in vitro].

    PubMed

    Zou, Lei; Wu, Qi; Yang, Xiuwei; Fu, Dexian

    2009-06-01

    To investigate the effects of the chemical constituents of the whole herbs of Crossostephium chinense on insulin secretion in rat islets. Islets were isolated from rat pancreata, cultured in vitro, and measured by color signals of dithizone stained digestion solution for detection of pancreatic islets. The morphological observation of islets was carried out by inverted microscope. The effects of test compounds, scopoletin (1), scopolin (2), tanacetin (3), quercetagetin-3,6,7-trimethylether (4) and 5-O-methyl-myo-inositol (5) isolated from the whole herbs of C. chinense, on the insulin secreting level from islets were compared with those of glybenclamide as a positive control substances, and the difference in insulin secreting level from islets between the presence and absence of test compounds was assayed. There was no difference in basal insulin secretion before and after 2 h incubation period of rat islets. The islets treated with quercetagetin-3,6,7-trimethylether have about 2-fold higher insulin secreting level (P < 0.01) compared a normal control group. The islets treated with 5-O-methyl-myo-inositol have about 1.5-fold higher insulin secreting level (P < 0.05) compared to a normal control group. Whereas the islets treated with scopoletin show about 1.9-fold lower basal insulin secreting level (P < 0.05) than a normal control group. In this paper the developed cultivation method of isolated pancreatic islets from rat can be used as a kind of islet-based drug screening model for diabetes mellitus in vitro. Quercetagetin-3,6,7-trimethylether and 5-O-methyl-myo-inositol could enhance rat islet insulin secretion and further in vivo studies are needed to clarify the nature of such an observation. However, scopletin suppress rat islet insulin secretion.

  2. Identifying the Targets of the Amplifying Pathway for Insulin Secretion in Pancreatic β-Cells by Kinetic Modeling of Granule Exocytosis

    PubMed Central

    Chen, Yi-der; Wang, Shaokun; Sherman, Arthur

    2008-01-01

    A kinetic model for insulin secretion in pancreatic β-cells is adapted from a model for fast exocytosis in chromaffin cells. The fusion of primed granules with the plasma membrane is assumed to occur only in the “microdomain” near voltage-sensitive L-type Ca2+-channels, where [Ca2+] can reach micromolar levels. In contrast, resupply and priming of granules are assumed to depend on the cytosolic [Ca2+]. Adding a two-compartment model to handle the temporal distribution of Ca2+ between the microdomain and the cytosol, we obtain a unified model that can generate both the fast granule fusion and the slow insulin secretion found experimentally in response to a step of membrane potential. The model can simulate the potentiation induced in islets by preincubation with glucose and the reduction in second-phase insulin secretion induced by blocking R-type Ca2+-channels (CaV2.3). The model indicates that increased second-phase insulin secretion induced by the amplifying signal is controlled by the “resupply” step of the exocytosis cascade. In contrast, enhancement of priming is a good candidate for amplification of first-phase secretion by glucose, cyclic adenosine 3′:5′-cyclic monophosphate, and protein kinase C. Finally, insulin secretion is enhanced when the amplifying signal oscillates in phase with the triggering Ca2+-signal. PMID:18515381

  3. Endocrine Determinants of Changes in Insulin Sensitivity and Insulin Secretion during a Weight Cycle in Healthy Men

    PubMed Central

    Karschin, Judith; Lagerpusch, Merit; Enderle, Janna; Eggeling, Ben; Müller, Manfred J.; Bosy-Westphal, Anja

    2015-01-01

    Objective Changes in insulin sensitivity (IS) and insulin secretion occur with perturbations in energy balance and glycemic load (GL) of the diet that may precede the development of insulin resistance and hyperinsulinemia. Determinants of changes in IS and insulin secretion with weight cycling in non-obese healthy subjects remain unclear. Methods In a 6wk controlled 2-stage randomized dietary intervention 32 healthy men (26±4y, BMI: 24±2kg/m2) followed 1wk of overfeeding (OF), 3wks of caloric restriction (CR) containing either 50% or 65% carbohydrate (CHO) and 2wks of refeeding (RF) with the same amount of CHO but either low or high glycaemic index at ±50% energy requirement. Measures of IS (basal: HOMA-index, postprandial: Matsuda-ISI), insulin secretion (early: Stumvoll-index, total: tAUC-insulin/tAUC-glucose) and potential endocrine determinants (ghrelin, leptin, adiponectin, thyroid hormone levels, 24h-urinary catecholamine excretion) were assessed. Results IS improved and insulin secretion decreased due to CR and normalized upon RF. Weight loss-induced improvements in basal and postprandial IS were associated with decreases in leptin and increases in ghrelin levels, respectively (r = 0.36 and r = 0.62, p<0.05). Weight regain-induced decrease in postprandial IS correlated with increases in adiponectin, fT3, TSH, GL of the diet and a decrease in ghrelin levels (r-values between -0.40 and 0.83, p<0.05) whereas increases in early and total insulin secretion were associated with a decrease in leptin/adiponectin-ratio (r = -0.52 and r = -0.46, p<0.05) and a decrease in fT4 (r = -0.38, p<0.05 for total insulin secretion only). After controlling for GL associations between RF-induced decrease in postprandial IS and increases in fT3 and TSH levels were no longer significant. Conclusion Weight cycling induced changes in IS and insulin secretion were associated with changes in all measured hormones, except for catecholamine excretion. While leptin, adiponectin and

  4. Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women.

    PubMed

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

    2013-07-15

    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 of insulin resistance based on fasting blood samples collected in a cross-sectional study of 1,075 US women (1997-1999) without diabetes, hypertension, or malignancy. Urinary 6-sulfatoxymelatonin level was standardized to urinary creatinine level; insulin resistance was defined as an insulin sensitivity index value (using the McAuley formula) less than 7.85. Logistic regression models included adjustment for age, body mass index, smoking, physical activity, alcohol intake, dietary glycemic index, family history of diabetes mellitus, blood pressure, plasma total cholesterol, uric acid, and estimated glomerular filtration rate. Higher nocturnal melatonin secretion was inversely associated with insulin levels and insulin resistance. In fully adjusted models, the odds ratio for insulin resistance was 0.45 (95% confidence interval: 0.28, 0.74) among women in the highest quartile of urinary 6-sulfatoxymelatonin:creatinine ratio compared with women in the lowest quartile. Nocturnal melatonin secretion is independently and inversely associated with insulin resistance.

  5. Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes

    PubMed Central

    Fu, Zhuo; Gilbert, Elizabeth R.; Liu, Dongmin

    2014-01-01

    Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how β-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in β-cell dysfunction, thereby triggering the pathogenesis of diabetes. PMID:22974359

  6. Co-occurrence of Risk Alleles in or Near Genes Modulating Insulin Secretion Predisposes Obese Youth to Prediabetes

    PubMed Central

    Giannini, Cosimo; Dalla Man, Chiara; Groop, Leif; Cobelli, Claudio; Zhao, Hongyu; Shaw, Melissa M.; Duran, Elvira; Pierpont, Bridget; Bale, Allen E.; Caprio, Sonia; Santoro, Nicola

    2014-01-01

    OBJECTIVE Paralleling the rise of pediatric obesity, the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) is increasing among youth. In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents. RESEARCH DESIGN AND METHODS We studied 714 obese subjects (290 boys and 424 girls; mean age 13.6 ± 3.1 years; mean z score BMI 2.2 ± 0.4) and evaluated the insulin secretion by using the oral minimal model and, in a subgroup of 37 subjects, the hyperglycemic clamp. Also, 203 subjects were followed up for a mean of 2.1 years. RESULTS We observed that the increase of risk alleles was associated with a progressive worsening of insulin secretion (P < 0.001) mainly due to an impairment of the dynamic phase of insulin secretion (P = 0.004); the higher the number of the risk alleles, the higher the chance of progression from normal glucose tolerance (NGT) to IGT/T2D (P = 0.022). Also, for those who were IGT at baseline, a higher risk score was associated with a lower odds to revert to NGT (P = 0.026). CONCLUSIONS Obese children and adolescents developing IGT/T2D have a higher genetic predisposition than those who do not show these diseases, and this predisposition is mainly related to gene variants modulating the early phase of insulin secretion. Although these data are very interesting, they need to be replicated in other cohorts. PMID:24062323

  7. Activation of islet 5-HT4 receptor regulates glycemic control through promoting insulin secretion.

    PubMed

    Chen, Hui; Hong, Feng; Chen, Ye; Li, Ji; Yao, Yuan-Sheng; Zhang, Yue; Zheng, Li-Fei; Zhu, Jin-Xia

    2016-10-15

    Mosapride, a gastrointestinal prokinetic drug, is an agonist of 5-hydroxytryptamine (5-HT) receptor 4 that also reduces blood glucose. Whether 5-HT4 receptor is distributed in pancreatic islets and whether mosapride can directly stimulate insulin secretion is unclear. In the present study, the protein expression and cellular location of 5-HT4 receptor in pancreas was detected through western blotting and immunofluorescence. The acute effects of 5-HT4 receptor agonists, mosapride and prucalopride, on insulin secretion were investigated in vivo and in vitro in normal and alloxan-induced diabetes rats. The results indicated that 5-HT4 receptor immunoreactivity was co-existed in the islets insulin-immunoreactive cells of rat, mouse, pig and human. However the immunoreactive cells of insulin and 5-HT4 receptor and the protein expression of 5-HT4 receptor were significantly decreased in the pancreas of alloxan-induced diabetes rats. In normal rats, mosapride and prucalopride decreased blood glucose and increased insulin secretion during glucose tolerance test, in association with an increase in glucose-stimulated insulin secretion, which was abolished by the 5-HT4 receptor antagonist GR113808. In diabetes rats, mosapride and prucalopride failed to improve blood glucose and insulin levels in the group of 180mg/kg alloxan, but increased glucose-stimulated insulin secretion in the group of 120mg/kg alloxan in vitro. We conclude that 5-HT4 receptor is distributed in the islet β cell. Activation of 5-HT4 receptor is able to stimulate insulin secretion directly, thereby reduce blood glucose. The study provides important experimental evidences for the 5-HT4 receptor regulating insulin secretion and acting as a potential drug target in diabetes treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease

    PubMed Central

    Koppe, Laetitia; Nyam, Elsa; Vivot, Kevin; Manning Fox, Jocelyn E.; Dai, Xiao-Qing; Nguyen, Bich N.; Attané, Camille; Moullé, Valentine S.; MacDonald, Patrick E.; Ghislain, Julien

    2016-01-01

    Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in CKD is caused by a direct effect of urea on pancreatic β cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea-exposed normal islets, we observed an increase in oxidative stress and protein O-GlcNAcylation. Protein O-GlcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea-exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GlcNAcylation. Inhibition of O-GlcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GlcNAcylation and impair glycolysis. PMID:27525435

  9. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease.

    PubMed

    Koppe, Laetitia; Nyam, Elsa; Vivot, Kevin; Manning Fox, Jocelyn E; Dai, Xiao-Qing; Nguyen, Bich N; Trudel, Dominique; Attané, Camille; Moullé, Valentine S; MacDonald, Patrick E; Ghislain, Julien; Poitout, Vincent

    2016-09-01

    Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in CKD is caused by a direct effect of urea on pancreatic β cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea-exposed normal islets, we observed an increase in oxidative stress and protein O-GlcNAcylation. Protein O-GlcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea-exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GlcNAcylation. Inhibition of O-GlcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GlcNAcylation and impair glycolysis.

  10. ADCY5 Couples Glucose to Insulin Secretion in Human Islets

    PubMed Central

    Mitchell, Ryan K.; Marselli, Lorella; Pullen, Timothy J.; Gimeno Brias, Silvia; Semplici, Francesca; Everett, Katy L.; Cooper, Dermot M.F.; Bugliani, Marco; Marchetti, Piero; Lavallard, Vanessa; Bosco, Domenico; Piemonti, Lorenzo; Johnson, Paul R.; Hughes, Stephen J.; Li, Daliang; Li, Wen-Hong; Shapiro, A.M. James

    2014-01-01

    Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, the mechanisms underlying the effects of these polymorphic variants at the level of pancreatic β-cells remain unclear. Here, we show firstly that ADCY5 mRNA expression in islets is lowered by the possession of risk alleles at rs11708067. Next, we demonstrate that ADCY5 is indispensable for coupling glucose, but not GLP-1, to insulin secretion in human islets. Assessed by in situ imaging of recombinant probes, ADCY5 silencing impaired glucose-induced cAMP increases and blocked glucose metabolism toward ATP at concentrations of the sugar >8 mmol/L. However, calcium transient generation and functional connectivity between individual human β-cells were sharply inhibited at all glucose concentrations tested, implying additional, metabolism-independent roles for ADCY5. In contrast, calcium rises were unaffected in ADCY5-depleted islets exposed to GLP-1. Alterations in β-cell ADCY5 expression and impaired glucose signaling thus provide a likely route through which ADCY5 gene polymorphisms influence fasting glucose levels and T2D risk, while exerting more minor effects on incretin action. PMID:24740569

  11. Role for the TRPV1 channel in insulin secretion from pancreatic beta cells.

    PubMed

    Diaz-Garcia, Carlos Manlio; Morales-Lázaro, Sara L; Sánchez-Soto, Carmen; Velasco, Myrian; Rosenbaum, Tamara; Hiriart, Marcia

    2014-06-01

    Transient receptor potential channels have been put forward as regulators of insulin secretion. A role for the TRPV1 ion channel in insulin secretion has been suggested in pancreatic beta cell lines. We explored whether TRPV1 is functionally expressed in RINm5F and primary beta cells from neonate and adult rats. We examined if capsaicin could activate cationic non-selective currents. Our results show that TRPV1 channels are not functional in insulin-secreting cells, since capsaicin did not produce current activation, not even under culture conditions known to induce the expression of other ion channels in these cells. Although TRPV1 channels seem to be irrelevant for the physiology of isolated beta cells, they may play a role in glucose homeostasis acting through the nerve fibers that regulate islet function. At the physiological level, we observed that Trpv1 (-/-) mice presented lower fasting insulin levels than their wild-type littermates, however, we did not find differences between these experimental groups nor in the glucose tolerance test or in the insulin secretion. However, we did find that the Trpv1 (-/-) mice exhibited a higher insulin sensitivity compared to their wild-type counterparts. Our results demonstrate that TRPV1 does not contribute to glucose-induced insulin secretion in beta cells as was previously thought, but it is possible that it may control insulin sensitivity.

  12. New type 2 diabetes risk genes provide new insights in insulin secretion mechanisms.

    PubMed

    Schäfer, Silke A; Machicao, Fausto; Fritsche, Andreas; Häring, Hans-Ulrich; Kantartzis, Konstantinos

    2011-08-01

    Type 2 diabetes results from the inability of beta cells to increase insulin secretion sufficiently to compensate for insulin resistance. Insulin resistance is thought to result mainly from environmental factors, such as obesity. However, there is compelling evidence that the decline of both insulin sensitivity and insulin secretion have also a genetic component. Recent genome-wide association studies identified several novel risk genes for type 2 diabetes. The vast majority of these genes affect beta cell function by molecular mechanisms that remain unknown in detail. Nevertheless, we and others could show that a group of genes affect glucose-stimulated insulin secretion, a group incretin-stimulated insulin secretion (incretin sensitivity or secretion) and a group proinsulin-to-insulin conversion. The most important so far type 2 diabetes risk gene, TCF7L2, interferes with all three mechanisms. In addition to advancing knowledge in the pathophysiology of type 2 diabetes, the discovery of novel genetic determinants of diabetes susceptibility may help understanding of gene-environment, gene-therapy and gene-gene interactions. It was also hoped that it could make determination of the individual risk for type 2 diabetes feasible. However, the allelic relative risks of most genetic variants discovered so far are relatively low. Thus, at present, clinical criteria assess the risk for type 2 diabetes with greater sensitivity and specificity than the combination of all known genetic variants.

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

    PubMed Central

    Cataldo, Luis R.; Gutierrez, Juan; Santos, José L.; Casas, Mariana; Contreras-Ferrat, Ariel E.; Moro, Cedric; Bouzakri, Karim

    2017-01-01

    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. PMID:28286777

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

    PubMed

    Mizgier, Maria L; Cataldo, Luis R; Gutierrez, Juan; Santos, José L; Casas, Mariana; Llanos, Paola; Contreras-Ferrat, Ariel E; Moro, Cedric; Bouzakri, Karim; Galgani, Jose E

    2017-01-01

    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.

  15. Interactions between imidazoline compounds and sulphonylureas in the regulation of insulin secretion

    PubMed Central

    Mourtada, Mirna; Brown, Colin A; Smith, Stephen A; Piercy, Valerie; Chan, Susan L F; Morgan, Noel G

    1997-01-01

    Imidazoline α2-antagonist drugs such as efaroxan have been shown to increase the insulin secretory response to sulphonylureas from rat pancreatic B-cells. We have investigated whether this reflects binding to an islet imidazoline receptor or whether α2-adrenoceptor antagonism is involved. Administration of (±)-efaroxan or glibenclamide to Wistar rats was associated with a transient increase in plasma insulin. When both drugs were administered together, the resultant increase in insulin levels was much greater than that obtained with either drug alone. Use of the resolved enantiomers of efaroxan revealed that the ability of the compound to enhance the insulin secretory response to glibenclamide resided only in the α2-selective-(+)-enantiomer; the imidazoline receptor-selective-(−)-enantiomer was ineffective. In vitro, (+)-efaroxan increased the insulin secretory response to glibenclamide in rat freshly isolated and cultured islets of Langerhans, whereas (−)-efaroxan was inactive. By contrast, (+)-efaroxan did not potentiate glucose-induced insulin secretion but (−)-efaroxan induced a marked increase in insulin secretion from islets incubated in the presence of 6 mM glucose. Incubation of rat islets under conditions designed to minimize the extent of α2-adrenoceptor signalling (by receptor blockade with phenoxybenzamine; receptor down-regulation or treatment with pertussis toxin) abolished the capacity of (+)-and (±)-efaroxan to enhance the insulin secretory response to glibenclamide. However, these manoeuvres did not alter the ability of (±)-efaroxan to potentiate glucose-induced insulin secretion. The results indicate that the enantiomers of efaroxan exert differential effects on insulin secretion which may result from binding to effector sites having opposite stereoselectivity. Binding of (−)-efaroxan (presumably to imidazoline receptors) results in potentiation of glucose-induced insulin secretion, whereas interaction of (+)-efaroxan with a

  16. Regulation of Endogenous (Male) Rodent GLP-1 Secretion and Human Islet Insulin Secretion by Antagonism of Somatostatin Receptor 5.

    PubMed

    Farb, Thomas B; Adeva, Marta; Beauchamp, Thomas J; Cabrera, Over; Coates, David A; DeShea Meredith, Tamika; Droz, Brian A; Efanov, Alexander; Ficorilli, James V; Gackenheimer, Susan L; Martinez-Grau, Maria A; Molero, Victoriano; Ruano, Gema; Statnick, Michael A; Suter, Todd M; Syed, Samreen K; Toledo, Miguel A; Willard, Francis S; Zhou, Xin; Bokvist, Krister B; Barrett, David G

    2017-09-11

    Incretin and insulin responses to nutrient loads are suppressed in persons with diabetes, resulting in decreased glycemic control. Whereas agents including sulfonylureas and Dipeptidyl peptidase-4 inhibitors (DPP4i) partially reverse these effects and provide therapeutic benefit, their modes of action limit efficacy. Because somatostatin (SST) has been shown to suppress both insulin and GLP-1 secretion through the Gi-coupled SST receptor 5 (SSTR5) isoform in vitro, antagonism of SSTR5 may improve glycemic control via intervention in both pathways. Here we show that a novel potent and selective SSTR5 antagonist reverses the blunting effects of SST on insulin secretion from isolated human islets, and demonstrate for the first time that SSTR5 antagonism affords increased levels of systemic GLP-1 in vivo. Knocking out Sstr5 in mice provided a similar increase in systemic GLP-1 levels, which were not increased further by treatment with the antagonist. Treatment of mice with the SSTR5 antagonist in combination with a DPP4i afforded increases in systemic GLP-1 levels that were more than additive, and resulted in greater glycemic control compared to either agent alone. In isolated human islets, the SSTR5 antagonist completely reversed the inhibitory effect of exogenous SST-14 on insulin secretion. Taken together, these data suggest that SSTR5 antagonism should increase circulating GLP-1 levels and stimulate insulin secretion (directly and via GLP-1) in humans, improving glycemic control in patients with diabetes. Copyright © 2017 Endocrine Society.

  17. Glucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion

    PubMed Central

    Sacco, Francesca; Humphrey, Sean J.; Cox, Jürgen; Mischnik, Marcel; Schulte, Anke; Klabunde, Thomas; Schäfer, Matthias; Mann, Matthias

    2016-01-01

    Insulin-secreting beta cells play an essential role in maintaining physiological blood glucose levels, and their dysfunction leads to the development of diabetes. To elucidate the signalling events regulating insulin secretion, we applied a recently developed phosphoproteomics workflow. We quantified the time-resolved phosphoproteome of murine pancreatic cells following their exposure to glucose and in combination with small molecule compounds that promote insulin secretion. The quantitative phosphoproteome of 30,000 sites clustered into three main groups in concordance with the modulation of the three key kinases: PKA, PKC and CK2A. A high-resolution time course revealed key novel regulatory sites, revealing the importance of methyltransferase DNMT3A phosphorylation in the glucose response. Remarkably a significant proportion of these novel regulatory sites is significantly downregulated in diabetic islets. Control of insulin secretion is embedded in an unexpectedly broad and complex range of cellular functions, which are perturbed by drugs in multiple ways. PMID:27841257

  18. Important role of heparan sulfate in postnatal islet growth and insulin secretion

    SciTech Connect

    Takahashi, Iwao; Noguchi, Naoya; Nata, Koji; Yamada, Shuhei; Kaneiwa, Tomoyuki; Mizumoto, Shuji; Ikeda, Takayuki; Sugihara, Kazushi; Asano, Masahide; Yoshikawa, Takeo; Yamauchi, Akiyo; Shervani, Nausheen Jamal; Uruno, Akira; Kato, Ichiro; Unno, Michiaki; Sugahara, Kazuyuki; Takasawa, Shin; and others

    2009-05-22

    Heparan sulfate (HS) binds with several signaling molecules and regulates ligand-receptor interactions, playing an essential role in embryonic development. Here we showed that HS was intensively expressed in pancreatic islet {beta}-cells after 1 week of age in mice. The enzymatic removal of HS in isolated islets resulted in attenuated glucose-induced insulin secretion with a concomitant reduction in gene expression of several key components in the insulin secretion machinery. We further depleted islet HS by inactivating the exostosin tumor-like 3 gene specifically in {beta}-cells. These mice exhibited abnormal islet morphology with reduced {beta}-cell proliferation after 1 week of age and glucose intolerance due to defective insulin secretion. These results demonstrate that islet HS is involved in the regulation of postnatal islet maturation and required to ensure normal insulin secretion.

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

    PubMed

    Jensen, Christine B; Storgaard, Heidi; Holst, Jens J; Dela, Flemming; Madsbad, Sten; Vaag, Allan A

    2003-06-01

    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 (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 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 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.

  20. Differential stimulation of insulin secretion by GLP-1 and Kisspeptin-10.

    PubMed

    Schwetz, Tara A; Reissaus, Christopher A; Piston, David W

    2014-01-01

    β-cells in the pancreatic islet respond to elevated plasma glucose by secreting insulin to maintain glucose homeostasis. In addition to glucose stimulation, insulin secretion is modulated by numerous G-protein coupled receptors (GPCRs). The GPCR ligands Kisspeptin-10 (KP) and glucagon-like peptide-1 (GLP-1) potentiate insulin secretion through Gq and Gs-coupled receptors, respectively. Despite many studies, the signaling mechanisms by which KP and GLP-1 potentiate insulin release are not thoroughly understood. We investigated the downstream signaling pathways of these ligands and their affects on cellular redox potential, intracellular calcium activity ([Ca(2+)]i), and insulin secretion from β-cells within intact murine islets. In contrast to previous studies performed on single β-cells, neither KP nor GLP-1 affect [Ca(2+)]i upon stimulation with glucose. KP significantly increases the cellular redox potential, while no effect is observed with GLP-1, suggesting that KP and GLP-1 potentiate insulin secretion through different mechanisms. Co-treatment with KP and the Gβγ-subunit inhibitor gallein inhibits insulin secretion similar to that observed with gallein alone, while co-treatment with gallein and GLP-1 does not differ from GLP-1 alone. In contrast, co-treatment with the Gβγ activator mSIRK and either KP or GLP-1 stimulates insulin release similar to mSIRK alone. Neither gallein nor mSIRK alter [Ca(2+)]i activity in the presence of KP or GLP-1. These data suggest that KP likely alters insulin secretion through a Gβγ-dependent process that stimulates glucose metabolism without altering Ca(2+) activity, while GLP-1 does so, at least partly, through a Gα-dependent pathway that is independent of both metabolism and Ca(2+).

  1. Differential Stimulation of Insulin Secretion by GLP-1 and Kisspeptin-10

    PubMed Central

    Schwetz, Tara A.; Reissaus, Christopher A.; Piston, David W.

    2014-01-01

    β-cells in the pancreatic islet respond to elevated plasma glucose by secreting insulin to maintain glucose homeostasis. In addition to glucose stimulation, insulin secretion is modulated by numerous G-protein coupled receptors (GPCRs). The GPCR ligands Kisspeptin-10 (KP) and glucagon-like peptide-1 (GLP-1) potentiate insulin secretion through Gq and Gs-coupled receptors, respectively. Despite many studies, the signaling mechanisms by which KP and GLP-1 potentiate insulin release are not thoroughly understood. We investigated the downstream signaling pathways of these ligands and their affects on cellular redox potential, intracellular calcium activity ([Ca2+]i), and insulin secretion from β-cells within intact murine islets. In contrast to previous studies performed on single β-cells, neither KP nor GLP-1 affect [Ca2+]i upon stimulation with glucose. KP significantly increases the cellular redox potential, while no effect is observed with GLP-1, suggesting that KP and GLP-1 potentiate insulin secretion through different mechanisms. Co-treatment with KP and the Gβγ-subunit inhibitor gallein inhibits insulin secretion similar to that observed with gallein alone, while co-treatment with gallein and GLP-1 does not differ from GLP-1 alone. In contrast, co-treatment with the Gβγ activator mSIRK and either KP or GLP-1 stimulates insulin release similar to mSIRK alone. Neither gallein nor mSIRK alter [Ca2+]i activity in the presence of KP or GLP-1. These data suggest that KP likely alters insulin secretion through a Gβγ-dependent process that stimulates glucose metabolism without altering Ca2+ activity, while GLP-1 does so, at least partly, through a Gα-dependent pathway that is independent of both metabolism and Ca2+. PMID:25401335

  2. Simvastatin Impairs Insulin Secretion by Multiple Mechanisms in MIN6 Cells

    PubMed Central

    López Rodríguez, Maykel; Stančáková, Alena; Kuusisto, Johanna; Kokkola, Tarja; Laakso, Markku

    2015-01-01

    Statins are widely used in the treatment of hypercholesterolemia and are efficient in the prevention of cardiovascular disease. Molecular mechanisms explaining statin-induced impairment in insulin secretion remain largely unknown. In the current study, we show that simvastatin decreased glucose-stimulated insulin secretion in mouse pancreatic MIN6 β-cells by 59% and 79% (p<0.01) at glucose concentration of 5.5 mmol/l and 16.7 mmol/l, respectively, compared to control, whereas pravastatin did not impair insulin secretion. Simvastatin induced decrease in insulin secretion occurred through multiple targets. In addition to its established effects on ATP-sensitive potassium channels (p = 0.004) and voltage-gated calcium channels (p = 0.004), simvastatin suppressed insulin secretion stimulated by muscarinic M3 or GPR40 receptor agonists (Tak875 by 33%, p = 0.002; GW9508 by 77%, p = 0.01) at glucose level of 5.5 mmol/l, and inhibited calcium release from the endoplasmic reticulum. Impaired insulin secretion caused by simvastatin treatment were efficiently restored by GPR119 or GLP-1 receptor stimulation and by direct activation of cAMP-dependent signaling pathways with forskolin. The effects of simvastatin treatment on insulin secretion were not affected by the presence of hyperglycemia. Our observation of the opposite effects of simvastatin and pravastatin on glucose-stimulated insulin secretion is in agreement with previous reports showing that simvastatin, but not pravastatin, was associated with increased risk of incident diabetes. PMID:26561346

  3. Increased adiposity and insulin correlates with the progressive suppression of pulsatile GH secretion during weight gain.

    PubMed

    Steyn, F J; Xie, T Y; Huang, L; Ngo, S T; Veldhuis, J D; Waters, M J; Chen, C

    2013-01-01

    Pathological changes associated with obesity are thought to contribute to GH deficiency. However, recent observations suggest that impaired GH secretion relative to excess calorie consumption contributes to progressive weight gain and thus may contribute to the development of obesity. To clarify this association between adiposity and GH secretion, we investigated the relationship between pulsatile GH secretion and body weight; epididymal fat mass; and circulating levels of leptin, insulin, non-esterified free fatty acids (NEFAs), and glucose. Data were obtained from male mice maintained on a standard or high-fat diet. We confirm the suppression of pulsatile GH secretion following dietary-induced weight gain. Correlation analyses reveal an inverse relationship between measures of pulsatile GH secretion, body weight, and epididymal fat mass. Moreover, we demonstrate an inverse relationship between measures of pulsatile GH secretion and circulating levels of leptin and insulin. The secretion of GH did not change relative to circulating levels of NEFAs or glucose. We conclude that impaired pulsatile GH secretion in the mouse occurs alongside progressive weight gain and thus precedes the development of obesity. Moreover, data illustrate key interactions between GH secretion and circulating levels of insulin and reflect the potential physiological role of GH in modulation of insulin-induced lipogenesis throughout positive energy balance.

  4. Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic β cells.

    PubMed

    Gao, Jingying; Zhong, Xiangqin; Ding, Yaqin; Bai, Tao; Wang, Hui; Wu, Hongbin; Liu, Yunfeng; Yang, Jing; Zhang, Yi

    2016-04-15

    Insulin secretion from pancreatic β cells is important to maintain glucose homeostasis and is regulated by electrical activities. Uncarboxylated osteocalcin, a bone-derived protein, has been reported to regulate glucose metabolism by increasing insulin secretion, stimulating β cell proliferation and improving insulin sensitivity. But the underlying mechanisms of uncarboxylated osteocalcin-modulated insulin secretion remain unclear. In the present study, we investigated the relationship of uncarboxylated osteocalcin-regulated insulin secretion and voltage-gated potassium (KV) channels, voltage-gated calcium channels in rat β cells. Insulin secretion was measured by radioimmunoassay. Channel currents and membrane action potentials were recorded using the conventional whole-cell patch-clamp technique. Calcium imaging system was used to analyze intracellular Ca(2+) concentration ([Ca(2+)]i). The data show that under 16.7mmol/l glucose conditions uncarboxylated osteocalcin alone increased insulin secretion and [Ca(2+)]i, but with no such effects on insulin secretion and [Ca(2+)]i in the presence of a KV channel blocker, tetraethylammonium chloride. In the patch-clamp experiments, uncarboxylated osteocalcin lengthened action potential duration and significantly inhibited KV currents, but had no influence on the characteristics of voltage-gated calcium channels. These results indicate that KV channels are involved in uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic β cells. By inhibiting KV channels, uncarboxylated osteocalcin prolongs action potential duration, increases intracellular Ca(2+) concentration and finally promotes insulin secretion. This finding provides new insight into the mechanisms of osteocalcin-modulated insulin secretion.

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

    PubMed

    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.

  6. Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells

    PubMed Central

    Bordone, Laura; Jhala, Ulupi S; Apfeld, Javier; McDonagh, Thomas; Lemieux, Madeleine; McBurney, Michael; Szilvasi, Akos; Easlon, Erin J; Lin, Su-Ju; Guarente, Leonard

    2006-01-01

    Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic β cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In β cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in β cells to affect insulin secretion. PMID:16366736

  7. Elevated Basal Insulin Secretion in Type 2 Diabetes Caused by Reduced Plasma Membrane Cholesterol

    PubMed Central

    Nagaraj, Vini; Kazim, Abdulla S.; Helgeson, Johan; Lewold, Clemens; Barik, Satadal; Buda, Pawel; Reinbothe, Thomas M.; Wennmalm, Stefan

    2016-01-01

    Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect in type 2 diabetic islets. Intriguingly, oxidation of cholesterol affected glucose-stimulated insulin secretion only modestly, whereas basal insulin release was elevated. This was accompanied by increased intracellular Ca2+ spike frequency and Ca2+ influx and explained by enhanced single Ca2+ channel activity. These results suggest that the reduced presence of membrane rafts could contribute to the elevated basal insulin secretion seen in type 2 diabetes. PMID:27533789

  8. Elevated Basal Insulin Secretion in Type 2 Diabetes Caused by Reduced Plasma Membrane Cholesterol.

    PubMed

    Nagaraj, Vini; Kazim, Abdulla S; Helgeson, Johan; Lewold, Clemens; Barik, Satadal; Buda, Pawel; Reinbothe, Thomas M; Wennmalm, Stefan; Zhang, Enming; Renström, Erik

    2016-10-01

    Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect in type 2 diabetic islets. Intriguingly, oxidation of cholesterol affected glucose-stimulated insulin secretion only modestly, whereas basal insulin release was elevated. This was accompanied by increased intracellular Ca(2+) spike frequency and Ca(2+) influx and explained by enhanced single Ca(2+) channel activity. These results suggest that the reduced presence of membrane rafts could contribute to the elevated basal insulin secretion seen in type 2 diabetes.

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

    PubMed

    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

  10. Mechanisms of p-methoxycinnamic acid-induced increase in insulin secretion.

    PubMed

    Adisakwattana, S; Hsu, W H; Yibchok-anun, S

    2011-10-01

    p-Methoxycinnamic acid (p-MCA) is a cinnamic acid derivative that shows various pharmacologic actions such as hepatoprotective and antihyperglycemic activities. The present study was to elucidate the mechanisms by which p-MCA increases [Ca²⁺]i and insulin secretion in INS-1 cells. p-MCA (100 μM) increased [Ca²⁺]i in INS-1 cells. The p-MCA-induced insulin secretion and rise in [Ca²⁺]i were markedly inhibited in the absence of extracellular Ca²⁺ or in the presence of an L-type Ca²⁺ channel blocker nimodipine. These results suggested that p-MCA increased Ca²⁺ influx via the L-type Ca²⁺ channels. Diazoxide, an ATP-sensitive K⁺ channel opener, did not alter p-MCA-induced insulin secretion, nor [Ca²⁺]i response. In addition, p-MCA enhanced glucose-, glibenclamide-induced insulin secretion whereas it also potentiated the increase in insulin secretion induced by arginine, and Bay K 8644, an L-type Ca²⁺ channel agonist. Taken together, our results suggest that p-MCA stimulated insulin secretion from pancreatic β-cells by increasing Ca²⁺ influx via the L-type Ca²⁺ channels, but not through the closure of ATP-sensitive K⁺ channels.

  11. Chronic activation of central AMPK attenuates glucose-stimulated insulin secretion and exacerbates hepatic insulin resistance in diabetic rats.

    PubMed

    Park, Sunmin; Kim, Da Sol; Kang, Suna; Shin, Bae Keun

    2014-09-01

    We investigated the effects of chronic AMP-activated kinase (AMPK) activation in the hypothalamus on energy and glucose metabolism in 90% pancreatectomized diabetic rats. Diabetic rats fed a high fat diet were divided into 3 groups and intracerebroventricular (ICV) administered with one of the following: 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, AMPK activator; 80 μg/day), AICAR+compound C (AMPK inhibitor; 6.2 μg/day), or an artificial cerebrospinal fluid (control) by means of osmotic pumps for 4 weeks. In the hypothalamus, central AICAR activated the phosphorylation of AMPK whereas adding compound C suppressed the activation. AICAR increased body weight and epididymal and retroperitoneal fat mass by increasing energy intake for the first 2 weeks and decreasing energy expenditure, whereas compound C reversed the AICAR effect on energy metabolism. Indirect calorimetry revealed that ICV-AICAR decreased carbohydrate oxidation, but not fat oxidation, compared to the control. During euglycemic hyperinsulinemic clamp, central AICAR increased hepatic glucose output at hyperinsulinemic states. ICV-AICAR increased expressions of hepatic genes involved in fatty acid synthesis and decreased expression of hepatic genes related to thermogenesis whereas compound C nullified the AICAR effect. Insulin secretion in the first and second phases decreased in AICAR-treated rats at hyperglycemic clamp, but compound C nullified the decrease. However, central AICAR did not alter β-cell mass via its proliferation or apoptosis. In conclusion, chronic hypothalamic AMPK activation impaired energy metabolism and glucose homeostasis by increasing food intake, increasing hepatic glucose output and decreasing insulin secretion in diabetic rats. The impairment of energy and glucose homeostasis by AMPK activation was nullified by an AMPK inhibitor. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Indices of insulin secretion during a liquid mixed-meal test in obese youth with diabetes

    USDA-ARS?s Scientific Manuscript database

    To compare indices of insulin secretion, insulin sensitivity (IS),and oral disposition index (oDI) during the liquid mixed-meal test in obese youth with clinically diagnosed type 2 diabetes mellitus (T2DM) and negative autoantibodies (Ab-) versus those with T2DM and positive autoantibodies (Ab+) to ...

  13. Intra- and Inter-Islet Synchronization of Metabolically Driven Insulin Secretion

    PubMed Central

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

    2005-01-01

    Insulin secretion from pancreatic β-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 profile it is necessary that the insulin secretion from individual β-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,” which responds to the level of insulin secretion by adjusting the blood glucose concentration in an appropriate way. Since all islets are exposed to the blood, the distributed islet-liver system can synchronize the individual islet insulin oscillations. Thus, we demonstrate how intra-islet and inter-islet synchronization of insulin oscillations may be achieved. PMID:15834002

  14. Influence of Insulin in the Ventromedial Hypothalamus on Pancreatic Glucagon Secretion In Vivo

    PubMed Central

    Paranjape, Sachin A.; Chan, Owen; Zhu, Wanling; Horblitt, Adam M.; McNay, Ewan C.; Cresswell, James A.; Bogan, Jonathan S.; McCrimmon, Rory J.; Sherwin, Robert S.

    2010-01-01

    OBJECTIVE Insulin released by the β-cell is thought to act locally to regulate glucagon secretion. The possibility that insulin might also act centrally to modulate islet glucagon secretion has received little attention. RESEARCH DESIGN AND METHODS Initially the counterregulatory response to identical hypoglycemia was compared during intravenous insulin and phloridzin infusion in awake chronically catheterized nondiabetic rats. To explore whether the disparate glucagon responses seen were in part due to changes in ventromedial hypothalamus (VMH) exposure to insulin, bilateral guide cannulas were inserted to the level of the VMH and 8 days later rats received a VMH microinjection of either 1) anti-insulin affibody, 2) control affibody, 3) artificial extracellular fluid, 4) insulin (50 μU), 5) insulin receptor antagonist (S961), or 6) anti-insulin affibody plus a γ-aminobutyric acid A (GABAA) receptor agonist muscimol, prior to a hypoglycemic clamp or under baseline conditions. RESULTS As expected, insulin-induced hypoglycemia produced a threefold increase in plasma glucagon. However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression. In contrast, epinephrine responses were not altered. The phloridzin-hypoglycemia induced glucagon increase was attenuated (40%) by VMH insulin microinjection. Conversely, local VMH blockade of insulin amplified glucagon twofold to threefold during insulin-induced hypoglycemia. Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABAA receptor agonist. CONCLUSIONS Together, these data suggest that insulin's inhibitory effect on α-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions. PMID:20299468

  15. Stress-impaired transcription factor expression and insulin secretion in transplanted human islets

    PubMed Central

    Dai, Chunhua; Kayton, Nora S.; Shostak, Alena; Poffenberger, Greg; Cyphert, Holly A.; Aramandla, Radhika; Thompson, Courtney; Papagiannis, Ioannis G.; Shiota, Masakazu; Stafford, John M.; Greiner, Dale L.; Herrera, Pedro L.; Shultz, Leonard D.; Stein, Roland; Powers, Alvin C.

    2016-01-01

    Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and progressive β cell dysfunction. Excess glucose and lipid impair β cell function in islet cell lines, cultured rodent and human islets, and in vivo rodent models. Here, we examined the mechanistic consequences of glucotoxic and lipotoxic conditions on human islets in vivo and developed and/or used 3 complementary models that allowed comparison of the effects of hyperglycemic and/or insulin-resistant metabolic stress conditions on human and mouse islets, which responded quite differently to these challenges. Hyperglycemia and/or insulin resistance impaired insulin secretion only from human islets in vivo. In human grafts, chronic insulin resistance decreased antioxidant enzyme expression and increased superoxide and amyloid formation. In human islet grafts, expression of transcription factors NKX6.1 and MAFB was decreased by chronic insulin resistance, but only MAFB decreased under chronic hyperglycemia. Knockdown of NKX6.1 or MAFB expression in a human β cell line recapitulated the insulin secretion defect seen in vivo. Contrary to rodent islet studies, neither insulin resistance nor hyperglycemia led to human β cell proliferation or apoptosis. These results demonstrate profound differences in how excess glucose or lipid influence mouse and human insulin secretion and β cell activity and show that reduced expression of key islet-enriched transcription factors is an important mediator of glucotoxicity and lipotoxicity. PMID:27064285

  16. The mechanisms of insulin secretion and calcium signaling in pancreatic β-cells exposed to fluoroquinolones.

    PubMed

    Bito, Motoki; Tomita, Takashi; Komori, Mika; Taogoshi, Takanori; Kimura, Yasuhiro; Kihira, Kenji

    2013-01-01

    Fluoroquinolones reportedly induce hypoglycemia through stimulation of insulin secretion from pancreatic β-cells via inhibition of K(ATP) channels and activation of L-type voltage-dependent Ca(2+) channels. In physiological condition, the cytosolic Ca(2+) concentration ([Ca(2+)](c)) is also regulated by release of Ca(2+) from intracellular Ca(2+) stores. In this study, we investigated the mechanism of insulin secretion induced by fluoroquinolones, with respect to intracellular Ca(2+) stores. Even where the absence of supplemental extracellular Ca(2+), insulin secretion and [Ca(2+)](c) were increased by gatifloxacin, levofloxacin or tolbutamide. Insulin secretion and the rise of [Ca(2+)](c) induced by fluoroquinolones were reduced by depleting of Ca(2+) in endoplasmic reticumum (ER) by thapsigargin, and inhibiting ryanodine receptor of ER by dantrolene. Inhibition of inositol 1,4,5-triphosphate receptor of ER by xestospongin C suppressed insulin secretion induced by fluoroquinolones, whereas it did not affect [Ca(2+)](c). Destruction of acidic Ca(2+) stores such as lysosome and lysosome-related organelles by glycyl-L-phenylalanine-2-nephthylamide (GPN) did not affect insulin secretion and the rise of [Ca(2+)](c) induced by fluoroquinolones. The increase in insulin and [Ca(2+)](c) induced by tolbutamide were reduced by thapsigargin, dantrolene, and GPN but not by xestospongin C. In conclusion, fluoroquinolones induces Ca(2+) release from ER mediated by the ryanodine receptor, and the reaction might involve in insulin secretion. Sulfonylureas induce Ca(2+) release from GPN-sensitive acidic Ca(2+) stores, but fluoroquinolones did not.

  17. Adiponectin increases glucose-induced insulin secretion through the activation of lipid oxidation.

    PubMed

    Patané, G; Caporarello, N; Marchetti, P; Parrino, C; Sudano, D; Marselli, L; Vigneri, R; Frittitta, L

    2013-12-01

    The expression of adiponectin receptors has been demonstrated in human and rat pancreatic beta cells, where globular (g) adiponectin rescues rat beta cells from cytokine and fatty acid-induced apoptosis. The aim of our study was to evaluate whether adiponectin has a direct effect on insulin secretion and the metabolic pathways involved. Purified human pancreatic islets and rat beta cells (INS-1E) were exposed (1 h) to g-adiponectin, and glucose-induced insulin secretion was measured. A significant increase in glucose-induced insulin secretion was observed in the presence of g-adiponectin (1 nmol/l) with respect to control cells in both human pancreatic islets (n = 5, p < 0.05) and INS-1E cells (n = 5, p < 0.001). The effect of globular adiponectin on insulin secretion was independent of AMP-dependent protein kinase (AMPK) activation or glucose oxidation. In contrast, g-adiponectin significantly increased oleate oxidation (n = 5, p < 0.05), and the effect of g-adiponectin (p < 0.001) on insulin secretion by INS-1E was significantly reduced in the presence of etomoxir (1 μmol/l), an inhibitor of fatty acid beta oxidation. g-Adiponectin potentiates glucose-induced insulin secretion in both human pancreatic islets and rat beta cells via an AMPK independent pathway. Increased fatty acid oxidation rather than augmented glucose oxidation is the mechanism responsible. Overall, our data indicate that, in addition to its anti-apoptotic action, g-adiponectin has another direct effect on beta cells by potentiating insulin secretion. Adiponectin, therefore, in addition to its well-known effect on insulin sensitivity, has important effects at the pancreatic level.

  18. Aldosterone decreases glucose-stimulated insulin secretion in vivo in mice and in murine islets

    PubMed Central

    Luo, P.; Kreger, M. T.; Brissova, M.; Dai, C.; Whitfield, T. T.; Kim, H. S.; Wasserman, D. H.; Powers, A. C.; Brown, N. J.

    2011-01-01

    Aims/hypothesis Aldosterone concentrations increase in obesity and predict the onset of diabetes. We investigated the effects of aldosterone on glucose homeostasis and insulin secretion in vivo and in vitro. Methods We assessed insulin sensitivity and insulin secretion in aldosterone synthase-deficient (As [also known as Cyp11b2]−/−)and wild-type mice using euglycaemic-hyperinsulinaemic and hyperglycaemic clamps, respectively. We also conducted studies during high sodium intake to normalise renin activity and potassium concentration in As−/− mice. We subsequently assessed the effect of aldosterone on insulin secretion in vitro in the presence or absence of mineralocorticoid receptor antagonists in isolated C57BL/6J islets and in the MIN6 beta cell line. Results Fasting glucose concentrations were reduced in As−/−mice compared with wild-type. During hyperglycaemic clamps, insulin and C-peptide concentrations increased to a greater extent in As−/− than in wild-type mice. This was not attributable to differences in potassium or angiotensin II, as glucose-stimulated insulin secretion was enhanced in As−/− mice even during high sodium intake. There was no difference in insulin sensitivity between As−/− and wild-type mice in euglycaemic-hyperinsulinaemic clamp studies. In islet and MIN6 beta cell studies, aldosterone inhibited glucose and isobutylmethylxanthine-stimulated insulin secretion, an effect that was not blocked by mineralocorticoid receptor antagonism, but was prevented by the superoxide dismutase mimetic tempol. Conclusions/interpretation We demonstrated that aldosterone deficiency or excess modulates insulin secretion in vivo and in vitro via reactive oxygen species and in a manner that is independent of mineralocorticoid receptors. These findings provide insight into the mechanism of glucose intolerance in conditions of relative aldosterone excess. PMID:21519965

  19. Inhibitory effect of kisspeptins on insulin secretion from isolated mouse islets.

    PubMed

    Vikman, J; Ahrén, B

    2009-11-01

    Islet hormone secretion is regulated by a variety of factors, and many of these signal through G protein-coupled receptors (GPCRs). A novel islet GPCR is GPR54, which couples to the Gq isoform of G proteins, which in turn signal through the phospholipase C pathway. Ligands for GPR54 are kisspeptins, which are peptides encoded in the KISS1 gene and also expressed in islet beta-cells. The KISS1 gene encodes a hydrophobic 145-amino acid protein that is cleaved into a 54-amino acid protein, kisspeptin-54 or KP54. Shorter kisspeptins also exist, such as kisspeptin-10 (KP10) and kisspeptin-13 (KP13). The involvement of GPR54 and kisspeptins in the regulation of islet function is not known. To address this problem, we incubated isolated mouse islets in the presence of KP13 and KP54 for 60 min and measured insulin secretion. We found that both KP13 and KP54 at 10 nM, 100 nM and 1microM inhibited insulin secretion in the presence of 2.8 mM glucose. However, by increasing the glucose concentration, this inhibitory action of the kisspeptins vanished. Thus, at 11.1 mM glucose, KP13 and KP54 inhibited insulin secretion only at high doses, and at 16.7 mM they no longer inhibited insulin secretion in any of the doses. We conclude that kisspeptins inhibit insulin secretion at glucose concentrations below 11.1 mM. This suggests that kisspeptins are regulating insulin secretion at physiological concentrations of glucose. The mechanisms by which kisspeptins regulate islet function and insulin secretion are unknown and will be further investigated.

  20. Measuring phospholipase D activity in insulin-secreting pancreatic beta-cells and insulin-responsive muscle cells and adipocytes.

    PubMed

    Cazzolli, Rosanna; Huang, Ping; Teng, Shuzhi; Hughes, William E

    2009-01-01

    Phospholipase D (PLD) is an enzyme producing phosphatidic acid and choline through hydrolysis of phosphatidylcholine. The enzyme has been identified as a member of a variety of signal transduction cascades and as a key regulator of numerous intracellular vesicle trafficking processes. A role for PLD in regulating glucose homeostasis is emerging as the enzyme has recently been identified in events regulating exocytosis of insulin from pancreatic beta-cells and also in insulin-stimulated glucose uptake through controlling GLUT4 vesicle exocytosis in muscle and adipose tissue. We present methodologies for assessing cellular PLD activity in secretagogue-stimulated insulin-secreting pancreatic beta-cells and also insulin-stimulated adipocyte and muscle cells, two of the principal insulin-responsive cell types controlling blood glucose levels.

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

    PubMed Central

    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 < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol. In conclusion: 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

  2. ENPP1 Affects Insulin Action and Secretion: Evidences from In Vitro Studies

    PubMed Central

    Di Paola, Rosa; Caporarello, Nunzia; Marucci, Antonella; Dimatteo, Claudia; Iadicicco, Claudia; Del Guerra, Silvia; Prudente, Sabrina; Sudano, Dora; Miele, Claudia; Parrino, Cristina; Piro, Salvatore; Beguinot, Francesco; Marchetti, Piero

    2011-01-01

    The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance

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

    PubMed

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

    2017-05-03

    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 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  4. Defective insulin secretion in pancreatic β cells lacking type 1 IGF receptor

    PubMed Central

    Xuan, Shouhong; Kitamura, Tadahiro; Nakae, Jun; Politi, Katerina; Kido, Yoshiaki; Fisher, Peter E.; Morroni, Manrico; Cinti, Saverio; White, Morris F.; Herrera, Pedro L.; Accili, Domenico; Efstratiadis, Argiris

    2002-01-01

    Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase of β cell mass and impaired glucose-dependent insulin release. β cell proliferation and secretion are thought to be regulated by signaling through receptor tyrosine kinases. In this regard, we sought to examine the potential proliferative and/or antiapoptotic role of IGFs in β cells by tissue-specific conditional mutagenesis ablating type 1 IGF receptor (IGF1R) signaling. Unexpectedly, lack of functional IGF1R did not affect β cell mass, but resulted in age-dependent impairment of glucose tolerance, associated with a decrease of glucose- and arginine-dependent insulin release. These observations reveal a requirement of IGF1R-mediated signaling for insulin secretion. PMID:12370279

  5. Mechanisms of amino acid-stimulated insulin secretion in congenital hyperinsulinism.

    PubMed

    Zhang, Tingting; Li, Changhong

    2013-01-01

    The role of amino acids in the regulation of insulin secretion in pancreatic beta-cells is highlighted in three forms of congenital hyperinsulinism (HI), namely gain-of-function mutations of glutamate dehydrogenase (GDH), loss-of-function mutations of ATP-dependent potassium channels, and a deficiency of short-chain 3-hydroxyacyl-CoA dehydrogenase. Studies on disease mouse models of HI suggest that amino acid oxidation and signaling effects are the major mechanisms of amino acid-stimulated insulin secretion. Amino acid oxidation via GDH produces ATP and triggers insulin secretion. The signaling effect of amino acids amplifies insulin release after beta-cell depolarization and elevation of cytosolic calcium.

  6. mTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome

    PubMed Central

    Rovira, Jordi; Ramírez-Bajo, María Jose; Banon-Maneus, Elisenda; Moya-Rull, Daniel; Ventura-Aguiar, Pedro; Hierro-Garcia, Natalia; Lazo-Rodriguez, Marta; Revuelta, Ignacio; Torres, Armando; Oppenheimer, Federico; Campistol, Josep M.; Diekmann, Fritz

    2016-01-01

    Background Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β-cell toxicity. Methods Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression. Results After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated. Conclusions In conditions that require adaptive β-cell proliferation, SRL might reveal harmful effects by blocking β-cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy. PMID:27500257

  7. Mechanisms of enhanced insulin secretion and sensitivity with n-3 unsaturated fatty acids.

    PubMed

    Bhaswant, Maharshi; Poudyal, Hemant; Brown, Lindsay

    2015-06-01

    The widespread acceptance that increased dietary n-3 polyunsaturated fatty acids (PUFAs), especially α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), improve health is based on extensive studies in animals, isolated cells and humans. Visceral adiposity is part of the metabolic syndrome, together with insulin resistance, dyslipidemia, hypertension and inflammation. Alleviation of metabolic syndrome requires normalization of insulin release and responses. This review assesses our current knowledge of the mechanisms that allow n-3 PUFAs to improve insulin secretion and sensitivity. EPA has been more extensively studied than either ALA or DHA. The complex actions of EPA include increased G-protein-receptor-mediated release of glucagon-like peptide 1 (GLP-1) from enteroendocrine L-cells in the intestine, up-regulation of the apelin pathway and down-regulation of other control pathways to promote insulin secretion by the pancreatic β-cells, together with suppression of inflammatory responses to adipokines, inhibition of peroxisome proliferator-activated receptor α actions and prevention of decreased insulin-like growth factor-1 secretion to improve peripheral insulin responses. The receptors involved and the mechanisms of action probably differ for ALA and DHA, with antiobesity effects predominating for ALA and anti-inflammatory effects for DHA. Modifying both GLP-1 release and the actions of adipokines by n-3 PUFAs could lead to additive improvements in both insulin secretion and sensitivity.

  8. Functional Reconstitution of the Insulin-Secreting Porosome Complex in Live Cells.

    PubMed

    Naik, Akshata R; Kulkarni, Sanjana P; Lewis, Kenneth T; Taatjes, Douglas J; Jena, Bhanu P

    2016-01-01

    Supramolecular cup-shaped lipoprotein structures called porosomes embedded in the cell plasma membrane mediate fractional release of intravesicular contents from cells during secretion. The presence of porosomes, have been documented in many cell types including neurons, acinar cells of the exocrine pancreas, GH-secreting cells of the pituitary, and insulin-secreting pancreatic β-cells. Functional reconstitution of porosomes into artificial lipid membranes, have also been accomplished. Earlier studies on mouse insulin-secreting Min6 cells report 100-nm porosome complexes composed of nearly 30 proteins. In the current study, porosomes have been functionally reconstituted for the first time in live cells. Isolated Min6 porosomes reconstituted into live Min6 cells demonstrate augmented levels of porosome proteins and a consequent increase in the potency and efficacy of glucose-stimulated insulin release. Elevated glucose-stimulated insulin secretion 48 hours after reconstitution, reflects on the remarkable stability and viability of reconstituted porosomes, documenting the functional reconstitution of native porosomes in live cells. These results, establish a new paradigm in porosome-mediated insulin secretion in β-cells.

  9. Nitric Oxide Overproduction Reduces Insulin Secretion from Isolated Islets in Fetal Hypothyroid Rats.

    PubMed

    Rouintan, Z; Farrokhfall, K; Karbalaei, N; Ghasemi, A

    2016-02-01

    Thyroid hormones have developmental effects during fetal life. Fetal hypothyroidism leads to glucose intolerance and reduced insulin secretion capacity. Activity of nitric oxide synthases follows a heterogeneous pattern in hypothyroidism. Overactivity of constitutive nitric oxide synthase (NOS), inhibits glucose-stimulated insulin release. The aim of this study was to examine if reduction in insulin secretion in fetal hypothyroidism is due to overproduction of nitric oxide. Pregnant Wistar rats were divided into 2 groups; the experimental group consumed water containing 0.02% of 6-propyl-2-thiouracil till delivery, while the control group consumed tap water. After delivery serum thyroid hormones were measured. Intravenous glucose tolerance test was performed in 6-month old offspring (n=8). After 3 weeks recovery, pancreatic islets were isolated and insulin secretion, inducible and constitutive nitric oxide synthase activity were measured (n=4). Compared to controls, during intravenous glucose tolerance test, fetal hypothyroid rats had high plasma glucose concentration (p=0.003) and low plasma insulin levels (p=0.012) at 5-20 min and their insulin secretion from isolated islets at basal glucose concentration and in the presence of l-arginine was lower. The nitric oxide synthase inhibitor, NG-nitro-l-arginine methyl ester significantly improved insulin secretion in fetal hypothyroid rats at basal glucose concentration and in the presence of l-arginine. The results showed higher NOS activities in fetal hypothyroid rats (constitutive 17.60±1.09 vs. 47.34±4.44 and inducible 4.09±0.96 vs. 19.97±1.14 pmol/min/mg proteins, p=0.002). In conclusion, NO overproduction through NOS participates in decreased insulin secretion in fetal hypothyroid rats.

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

    PubMed

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

    2015-04-01

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

  11. Reactive Oxygen Species Stimulate Insulin Secretion in Rat Pancreatic Islets: Studies Using Mono-Oleoyl-Glycerol

    PubMed Central

    Kane, Ada; Shirihai, Orian; Corkey, Barbara E.; Deeney, Jude T.

    2012-01-01

    Chronic exposure (24–72 hrs) of pancreatic islets to elevated glucose and fatty acid leads to glucolipoxicity characterized by basal insulin hypersecretion and impaired glucose-stimulated insulin secretion (GSIS). Our aim was to determine the mechanism for basal hypersecretion of insulin. We used mono-oleoyl-glycerol (MOG) as a tool to rapidly increase lipids in isolated rat pancreatic ß-cells and in the clonal pancreatic ß-cell line INS-1 832/13. MOG (25–400 µM) stimulated basal insulin secretion from ß-cells in a concentration dependent manner without increasing intracellular Ca2+ or O2 consumption. Like GSIS, MOG increased NAD(P)H and reactive oxygen species (ROS). The mitochondrial reductant ß-hydroxybutyrate (ß-OHB) also increased the redox state and ROS production, while ROS scavengers abrogated secretion. Diazoxide (0.4 mM) did not prevent the stimulatory effect of MOG, confirming that the effect was independent of the KATP-dependent pathway of secretion. MOG was metabolized to glycerol and long-chain acyl-CoA (LC-CoA), whereas, acute oleate did not similarly increase LC-CoA. Inhibition of diacylglycerol kinase (DGK) did not mimic the effect of MOG on insulin secretion, indicating that MOG did not act primarily by inhibiting DGK. Inhibition of acyl-CoA synthetase (ACS) reduced the stimulatory effect of MOG on basal insulin secretion by 30% indicating a role for LC-CoA. These data suggest that basal insulin secretion is stimulated by increased ROS production, due to an increase in the mitochondrial redox state independent of the established components of GSIS. PMID:22272304

  12. Sodium arsenite impairs insulin secretion and transcription in pancreatic {beta}-cells

    SciTech Connect

    Diaz-Villasenor, Andrea; Sanchez-Soto, M. Carmen; Cebrian, Mariano E.; Ostrosky-Wegman, Patricia; Hiriart, Marcia . E-mail: mhiriart@ifc.unam.mx

    2006-07-01

    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 {beta}-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 {beta}-cells. Cells were treated with 0.5, 1, 2, 5 and 10 {mu}M sodium arsenite and incubated for 72 and 144 h. The highest dose tested (10 {mu}M) decreased {beta}-cell viability, by 33% and 83%, respectively. Insulin secretion and mRNA expression were evaluated in the presence of 1 and 5 {mu}M sodium arsenite. Basal insulin secretion, in 5.6 mM glucose, was not significantly affected by 1 or 5 {mu}M treatment for 72 h, but basal secretion was reduced when cells were exposed to 5 {mu}M 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 {mu}M sodium arsenite during 72 h. Our data suggest that arsenic may contribute to the development of diabetes mellitus by impairing pancreatic {beta}-cell functions, particularly insulin synthesis and secretion.

  13. Cooperation between cAMP signalling and sulfonylurea in insulin secretion.

    PubMed

    Shibasaki, T; Takahashi, T; Takahashi, H; Seino, S

    2014-09-01

    Although glucose is physiologically the most important regulator of insulin secretion, glucose-induced insulin secretion is modulated by hormonal and neural inputs to pancreatic β-cells. Most of the hormones and neurotransmitters evoke intracellular signals such as cAMP, Ca²⁺ , and phospholipid-derived molecules by activating G protein-coupled receptors (GPCRs). In particular, cAMP is a key second messenger that amplifies insulin secretion in a glucose concentration-dependent manner. The action of cAMP on insulin secretion is mediated by both protein kinase A (PKA)-dependent and Epac2A-dependent mechanisms. Many of the proteins expressed in β-cells are phosphorylated by PKA in vitro, but only a few proteins in which PKA phosphorylation directly affects insulin secretion have been identified. On the other hand, Epac2A activates the Ras-like small G protein Rap in a cAMP-dependent manner. Epac2A is also directly activated by various sulfonylureas, except for gliclazide. 8-pCPT-2'-O-Me-cAMP, an Epac-selective cAMP analogue, and glibenclamide, a sulfonylurea, synergistically activate Epac2A and Rap1, whereas adrenaline, which suppresses cAMP production in pancreatic β-cells, blocks activation of Epac2A and Rap1 by glibenclamide. Thus, cAMP signalling and sulfonylurea cooperatively activate Epac2A and Rap1. This interaction could account, at least in part, for the synergistic effects of incretin-related drugs and sulfonylureas in insulin secretion. Accordingly, clarification of the mechanism of Epac2A activation may provide therapeutic strategies to improve insulin secretion in diabetes.

  14. Case report: a glucose responsive insulinoma--implication for the diagnosis of insulin secreting tumors.

    PubMed

    Sjoberg, R J; Kidd, G S

    1992-09-01

    Normal insulin secretagogues, including glucose, usually have little influence on insulin secretion from insulinomas. Therefore, insulinomas typically cause fasting hypoglycemia with relative hyperinsulinemia. This report describes a patient with hyperinsulinemia due to an islet cell adenoma with microadenomatosis, which, upon provocative in vivo testing, was found to be profoundly responsive to hypoglycemic and hyperglycemic stimuli. A 72 hr fast followed by brisk exercise resulted in a gradual reduction of serum glucose and insulin concentrations, but did not provoke symptomatic hypoglycemia. Oral glucose tolerance testing resulted in a prompt 10-fold increase in serum insulin accompanied by a mildly symptomatic and gradual fall in serum glucose to 30 mg/dl 90 minutes after glucose ingestion. An intravenous glucose challenge caused an acute increase in serum insulin to more than 1200 microU/ml with a resulting serum glucose of 11 mg/dl 25 minutes later, associated with loss of consciousness. Although a prolonged fast has proven to be the best diagnostic test for insulin secreting tumors, many other provocative tests that use normal insulin secretagogues have been somewhat useful in this regard. The patient in this report supports the concept that insulinomas vary widely in their response to a number of normal physiologic regulators of insulin secretion, including the serum glucose concentration. A variety of provocative tests may be needed to fully evaluate the rare patient in whom there is a strong clinical suspicion of insulinoma but who has a nondiagnostic prolonged fast.

  15. Ghrelin but not obestatin regulates insulin secretion from INS1 beta cell line via UCP2-dependent mechanism.

    PubMed

    Chmielewska, J; Szczepankiewicz, D; Skrzypski, M; Kregielska, D; Strowski, M Z; Nowak, K W

    2010-01-01

    The mitochondrial UCP2 mediates glucose-stimulated insulin secretion by decreasing intracellular ATP/ADP ratio. Insulin secretion is a tightly regulated process. Ghrelin, as well as obestatin, were intensively studied to determine their ability to modify insulin secretion. Ghrelin is considered to be an inhibitor of insulin release from pancreatic islets, however little is known about the effects of obestatin. In our study we demonstrate the stimulating effects of both peptides on insulin secretion in INS1 cells. Furthermore, we investigate the potential role of UCP2 in mediating the effects of both peptides on insulin secretion. UCP2 mRNA expression was down-regulated by ghrelin in the presence of 26.4 mM glucose, however it was unchanged after obestatin treatment. Our results confirm that UCP2 could be involved in the stimulating effect of ghrelin on insulin release from INS1 cells.

  16. Evidence for early defects in insulin sensitivity and secretion before the onset of glucose dysregulation in obese youths: a longitudinal study.

    PubMed

    Giannini, Cosimo; Weiss, Ram; Cali, Anna; Bonadonna, Riccardo; Santoro, Nicola; Pierpont, Bridget; Shaw, Melissa; Caprio, Sonia

    2012-03-01

    We sought to determine whether obese adolescents with high-"normal" 2-h post-oral glucose tolerance test glucose levels display defects in insulin secretion and sensitivity associated with future development of impaired glucose tolerance (IGT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and insulin secretion by applying mathematical modeling during the hyperglycemic clamp in 60 normal glucose tolerance (NGT) obese adolescents, divided into three groups based on the 2-h glucose values (<100, 100-119, 120-139 mg/dL), and in 21 IGT obese adolescents. Glucose tolerance was reevaluated after 2 years. Insulin sensitivity decreased significantly across 2-h glucose NGT categories, while the highest NGT category and IGT group were similar. First-phase insulin secretion decreased across NGT categories, while no difference was found between the highest NGT group and IGT subjects. Second-phase secretion was similar across all NGT and IGT groups. The disposition index ((C)DI) decreased across NGT categories, while no difference was observed between the highest NGT and IGT subjects. Age and (C)DI were the best predictors of 2-h glucose after two years. Across rising categories of normal 2-h glucose levels, NGT obese adolescents exhibit significant impairment of β-cell function relative to insulin sensitivity associated with the development of IGT.

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

    PubMed Central

    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

    2015-01-01

    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 Ca2+ 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 Ca2+ from thapsigargin-sensitive Ca2+ 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. PMID:26571400

  18. Angiopoietin-like peptide 4 regulates insulin secretion and islet morphology.

    PubMed

    Kim, Hyun-Kyong; Kwon, Obin; Park, Kyeong-Han; Lee, Kyung Jin; Youn, Byung-Soo; Kim, Seung-Whan; Kim, Min-Seon

    2017-02-07

    Insulin secretion from pancreatic islet β-cells is primarily regulated by the blood glucose level, and also modulated by a number of biological factors produced inside the islets or released from remote organs. Previous studies have shown that angiopoietin-like protein 4 (Angptl4) controls glucose and lipid metabolism through its actions in the liver, adipose tissue, and skeletal muscles. In this present study, we investigated the possible role of Angptl4 in the regulation of insulin secretion from pancreatic islets. Angptl4 was found to be highly expressed in the α-cells but not β-cells of rodent islets. Moreover, treatment of rodent islets with Angptl4 peptide potentiated glucose-stimulated insulin secretion through a protein kinase A-dependent mechanism. Consistently, Angptl4 knockout mice showed impaired glucose tolerance. In the cultured islets from Angptl4 knockout mice, glucose-stimulated insulin secretion was significantly lower than in islets from wild type mice. Angptl4 peptide replacement partially reversed this reduction. Moreover, Angptl4 knockout mice had dysmorphic islets with abnormally distributed α-cells. In contrast, the β-cell mass and distribution were not significantly altered in these knockout mice. Our current data collectively suggest that Angptl4 may play a critical role in the regulation of insulin secretion and islet morphogenesis.

  19. Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea.

    PubMed

    Seino, S

    2012-08-01

    Clarification of the molecular mechanisms of insulin secretion is crucial for understanding the pathogenesis and pathophysiology of diabetes and for development of novel therapeutic strategies for the disease. Insulin secretion is regulated by various intracellular signals generated by nutrients and hormonal and neural inputs. In addition, a variety of glucose-lowering drugs including sulfonylureas, glinide-derivatives, and incretin-related drugs such as dipeptidyl peptidase IV (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists are used for glycaemic control by targeting beta cell signalling for improved insulin secretion. There has been a remarkable increase in our understanding of the basis of beta cell signalling over the past two decades following the application of molecular biology, gene technology, electrophysiology and bioimaging to beta cell research. This review discusses cell signalling in insulin secretion, focusing on the molecular targets of ATP, cAMP and sulfonylurea, an essential metabolic signal in glucose-induced insulin secretion (GIIS), a critical signal in the potentiation of GIIS, and the commonly used glucose-lowering drug, respectively.

  20. Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion.

    PubMed

    MacDonald, Michael J; Fahien, Leonard A; Brown, Laura J; Hasan, Noaman M; Buss, Julian D; Kendrick, Mindy A

    2005-01-01

    The importance of mitochondrial biosynthesis in stimulus secretion coupling in the insulin-producing beta-cell probably equals that of ATP production. In glucose-induced insulin secretion, the rate of pyruvate carboxylation is very high and correlates more strongly with the glucose concentration the beta-cell is exposed to (and thus with insulin release) than does pyruvate decarboxylation, which produces acetyl-CoA for metabolism in the citric acid cycle to produce ATP. The carboxylation pathway can increase the levels of citric acid cycle intermediates, and this indicates that anaplerosis, the net synthesis of cycle intermediates, is important for insulin secretion. Increased cycle intermediates will alter mitochondrial processes, and, therefore, the synthesized intermediates must be exported from mitochondria to the cytosol (cataplerosis). This further suggests that these intermediates have roles in signaling insulin secretion. Although evidence is quite good that all physiological fuel secretagogues stimulate insulin secretion via anaplerosis, evidence is just emerging about the possible extramitochondrial roles of exported citric acid cycle intermediates. This article speculates on their potential roles as signaling molecules themselves and as exporters of equivalents of NADPH, acetyl-CoA and malonyl-CoA, as well as alpha-ketoglutarate as a substrate for hydroxylases. We also discuss the "succinate mechanism," which hypothesizes that insulin secretagogues produce both NADPH and mevalonate. Finally, we discuss the role of mitochondria in causing oscillations in beta-cell citrate levels. These parallel oscillations in ATP and NAD(P)H. Oscillations in beta-cell plasma membrane electrical potential, ATP/ADP and NAD(P)/NAD(P)H ratios, and glycolytic flux are known to correlate with pulsatile insulin release. Citrate oscillations might synchronize oscillations of individual mitochondria with one another and mitochondrial oscillations with oscillations in glycolysis

  1. Adipose Triglyceride Lipase Is Implicated in Fuel- and Non-fuel-stimulated Insulin Secretion*

    PubMed Central

    Peyot, Marie-Line; Guay, Claudiane; Latour, Martin G.; Lamontagne, Julien; Lussier, Roxane; Pineda, Marco; Ruderman, Neil B.; Haemmerle, Guenter; Zechner, Rudolf; Joly, Érik; Madiraju, S. R. Murthy; Poitout, Vincent; Prentki, Marc

    2009-01-01

    Reduced lipolysis in hormone-sensitive lipase-deficient mice is associated with impaired glucose-stimulated insulin secretion (GSIS), suggesting that endogenous β-cell lipid stores provide signaling molecules for insulin release. Measurements of lipolysis and triglyceride (TG) lipase activity in islets from HSL−/− mice indicated the presence of other TG lipase(s) in the β-cell. Using real time-quantitative PCR, adipose triglyceride lipase (ATGL) was found to be the most abundant TG lipase in rat islets and INS832/13 cells. To assess its role in insulin secretion, ATGL expression was decreased in INS832/13 cells (ATGL-knockdown (KD)) by small hairpin RNA. ATGL-KD increased the esterification of free fatty acid (FFA) into TG. ATGL-KD cells showed decreased glucose- or Gln + Leu-induced insulin release, as well as reduced response to KCl or palmitate at high, but not low, glucose. The KATP-independent/amplification pathway of GSIS was considerably reduced in ATGL-KD cells. ATGL−/− mice were hypoinsulinemic and hypoglycemic and showed decreased plasma TG and FFAs. A hyperglycemic clamp revealed increased insulin sensitivity and decreased GSIS and arginine-induced insulin secretion in ATGL−/− mice. Accordingly, isolated islets from ATGL−/− mice showed reduced insulin secretion in response to glucose, glucose + palmitate, and KCl. Islet TG content and FFA esterification into TG were increased by 2-fold in ATGL−/− islets, but glucose usage and oxidation were unaltered. The results demonstrate the importance of ATGL and intracellular lipid signaling for fuel- and non-fuel-induced insulin secretion. PMID:19389712

  2. Adipose triglyceride lipase is implicated in fuel- and non-fuel-stimulated insulin secretion.

    PubMed

    Peyot, Marie-Line; Guay, Claudiane; Latour, Martin G; Lamontagne, Julien; Lussier, Roxane; Pineda, Marco; Ruderman, Neil B; Haemmerle, Guenter; Zechner, Rudolf; Joly, Erik; Madiraju, S R Murthy; Poitout, Vincent; Prentki, Marc

    2009-06-19

    Reduced lipolysis in hormone-sensitive lipase-deficient mice is associated with impaired glucose-stimulated insulin secretion (GSIS), suggesting that endogenous beta-cell lipid stores provide signaling molecules for insulin release. Measurements of lipolysis and triglyceride (TG) lipase activity in islets from HSL(-/-) mice indicated the presence of other TG lipase(s) in the beta-cell. Using real time-quantitative PCR, adipose triglyceride lipase (ATGL) was found to be the most abundant TG lipase in rat islets and INS832/13 cells. To assess its role in insulin secretion, ATGL expression was decreased in INS832/13 cells (ATGL-knockdown (KD)) by small hairpin RNA. ATGL-KD increased the esterification of free fatty acid (FFA) into TG. ATGL-KD cells showed decreased glucose- or Gln + Leu-induced insulin release, as well as reduced response to KCl or palmitate at high, but not low, glucose. The K(ATP)-independent/amplification pathway of GSIS was considerably reduced in ATGL-KD cells. ATGL(-/-) mice were hypoinsulinemic and hypoglycemic and showed decreased plasma TG and FFAs. A hyperglycemic clamp revealed increased insulin sensitivity and decreased GSIS and arginine-induced insulin secretion in ATGL(-/-) mice. Accordingly, isolated islets from ATGL(-/-) mice showed reduced insulin secretion in response to glucose, glucose + palmitate, and KCl. Islet TG content and FFA esterification into TG were increased by 2-fold in ATGL(-/-) islets, but glucose usage and oxidation were unaltered. The results demonstrate the importance of ATGL and intracellular lipid signaling for fuel- and non-fuel-induced insulin secretion.

  3. Constitutively active heat shock factor 1 enhances glucose-driven insulin secretion.

    PubMed

    Uchiyama, Tsuyoshi; Tomono, Shoichi; Utsugi, Toshihiro; Ohyama, Yoshio; Nakamura, Tetsuya; Tomura, Hideaki; Kawazu, Shoji; Okajima, Fumikazu; Kurabayashi, Masahiko

    2011-06-01

    Weak pancreatic β-cell function is a cause of type 2 diabetes mellitus. Glucokinase regulates insulin secretion via phosphorylation of glucose. The present study focused on a system for the self-protection of pancreatic cell by expressing heat shock factor (HSF) and heat shock protein (HSP) to improve insulin secretion without inducing hypoglycemia. We previously generated a constitutively active form of human HSF1 (CA-hHSF1). An adenovirus expressing CA-hHSF1 using the cytomegalovirus promoter was generated to infect mouse insulinoma cells (MIN6 cells). An adenovirus expressing CA-hHSF1 using a human insulin promoter (Ins-CA-hHSF1) was also generated to infect rats. We investigated whether CA-hHSF1 induces insulin secretion in MIN6 cells and whether Ins-CA-hHSF1 can improve blood glucose and serum insulin levels in healthy Wister rats and type 2 diabetes mellitus model rats. CA-hHSF1 expression increased insulin secretion 1.27-fold compared with the overexpression of wild-type hHSF1 in MIN6 cells via induction of HSP90 expression and subsequent activation of glucokinase. This mechanism is associated with activation of both glucokinase and neuronal nitric oxide synthase. Ins-CA-hHSF1 improved blood glucose levels in neonatal streptozotocin-induced diabetic rats. Furthermore, Ins-CA-hHSF1 reduced oral glucose tolerance testing results in healthy Wister rats because of an insulin spike at 15 minutes; however, it did not induce hypoglycemia. CA-hHSF1 induced insulin secretion both in vitro and in vivo. These findings suggest that gene therapy with Ins-CA-hHSF1 will be able to be used to treat patients with type 2 diabetes mellitus and impaired glucose tolerance without causing hypoglycemia at fasting. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Increased levels of circulating islet amyloid polypeptide in patients with chronic renal failure have no effect on insulin secretion.

    PubMed Central

    Ludvik, B; Clodi, M; Kautzky-Willer, A; Schuller, M; Graf, H; Hartter, E; Pacini, G; Prager, R

    1994-01-01

    To elucidate the metabolism of islet amyloid polypeptide (IAPP) with respect to a possible renal elimination we investigated IAPP levels in 20 lean, nondiabetic patients with renal failure maintained on chronic hemodialysis (HD) and in 20 healthy controls. The basal levels of IAPP were significantly higher in uremic patients than in controls (15.1 +/- 3.2 vs. 3.2 +/- 0.2 pM, P < 0.001) suggesting renal excretion of IAPP. To investigate the impact of chronically elevated levels of endogenous IAPP on insulin secretion and insulin sensitivity, a frequently sampled intravenous glucose tolerance test (FSIGT) was performed in a subset of patients on hemodialysis and in age-matched healthy controls (C) and obese patients with normal (NGT) and with impaired glucose tolerance (IGT). Insulin sensitivity index (SI) was 8.7 +/- 1.5 in C (P < 0.05 vs. NGT, P < 0.01 vs. IGT), 5.4 +/- 0.9 in HD (P < 0.05 vs. IGT), 3.1 +/- 1.0 in NGT, and 2.0 +/- 0.5 in IGT. First phase insulin secretion was increased in patients on HD compared with those of several control groups. The results of this study therefore indicate a renal route of metabolism of IAPP. Increased endogenous circulating IAPP levels over a long period of time do not lead to a decrease in insulin release in patients on HD and do not cause the insulin resistance commonly seen in obesity and diabetes. Increased levels of circulating IAPP therefore are not likely to be a pathogenetic factor in the development of non-insulin-dependent diabetes mellitus (NIDDM). PMID:7962550

  5. Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells.

    PubMed

    Ferdaoussi, Mourad; Dai, Xiaoqing; Jensen, Mette V; Wang, Runsheng; Peterson, Brett S; Huang, Chao; Ilkayeva, Olga; Smith, Nancy; Miller, Nathanael; Hajmrle, Catherine; Spigelman, Aliya F; Wright, Robert C; Plummer, Gregory; Suzuki, Kunimasa; Mackay, James P; van de Bunt, Martijn; Gloyn, Anna L; Ryan, Terence E; Norquay, Lisa D; Brosnan, M Julia; Trimmer, Jeff K; Rolph, Timothy P; Kibbey, Richard G; Manning Fox, Jocelyn E; Colmers, William F; Shirihai, Orian S; Neufer, P Darrell; Yeh, Edward T H; Newgard, Christopher B; MacDonald, Patrick E

    2015-10-01

    Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolarizing β cells, and opening voltage-dependent Ca2+ channels to elicit insulin exocytosis. However, one or more additional pathway(s) amplify the secretory response, likely at the distal exocytotic site. The mitochondrial export of isocitrate and engagement with cytosolic isocitrate dehydrogenase (ICDc) may be one key pathway, but the mechanism linking this to insulin secretion and its role in T2D have not been defined. Here, we show that the ICDc-dependent generation of NADPH and subsequent glutathione (GSH) reduction contribute to the amplification of insulin exocytosis via sentrin/SUMO-specific protease-1 (SENP1). In human T2D and an in vitro model of human islet dysfunction, the glucose-dependent amplification of exocytosis was impaired and could be rescued by introduction of signaling intermediates from this pathway. Moreover, islet-specific Senp1 deletion in mice caused impaired glucose tolerance by reducing the amplification of insulin exocytosis. Together, our results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues β cell function in T2D.

  6. Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells

    PubMed Central

    Ferdaoussi, Mourad; Dai, Xiaoqing; Jensen, Mette V.; Wang, Runsheng; Peterson, Brett S.; Huang, Chao; Ilkayeva, Olga; Smith, Nancy; Miller, Nathanael; Hajmrle, Catherine; Spigelman, Aliya F.; Wright, Robert C.; Plummer, Gregory; Suzuki, Kunimasa; Mackay, James P.; van de Bunt, Martijn; Gloyn, Anna L.; Ryan, Terence E.; Norquay, Lisa D.; Brosnan, M. Julia; Trimmer, Jeff K.; Rolph, Timothy P.; Kibbey, Richard G.; Manning Fox, Jocelyn E.; Colmers, William F.; Shirihai, Orian S.; Neufer, P. Darrell; Yeh, Edward T.H.; Newgard, Christopher B.; MacDonald, Patrick E.

    2015-01-01

    Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolarizing β cells, and opening voltage-dependent Ca2+ channels to elicit insulin exocytosis. However, one or more additional pathway(s) amplify the secretory response, likely at the distal exocytotic site. The mitochondrial export of isocitrate and engagement with cytosolic isocitrate dehydrogenase (ICDc) may be one key pathway, but the mechanism linking this to insulin secretion and its role in T2D have not been defined. Here, we show that the ICDc-dependent generation of NADPH and subsequent glutathione (GSH) reduction contribute to the amplification of insulin exocytosis via sentrin/SUMO-specific protease-1 (SENP1). In human T2D and an in vitro model of human islet dysfunction, the glucose-dependent amplification of exocytosis was impaired and could be rescued by introduction of signaling intermediates from this pathway. Moreover, islet-specific Senp1 deletion in mice caused impaired glucose tolerance by reducing the amplification of insulin exocytosis. Together, our results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues β cell function in T2D. PMID:26389676

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

    PubMed

    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.

  8. Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals

    PubMed Central

    Ortega, Emilio; Koska, Juraj; Pannacciulli, Nicola; Bunt, Joy C; Krakoff, Jonathan

    2008-01-01

    Background Thyroid hormones (TH) may influence glucose metabolism. Hyperthyroid subjects have higher insulin secretion rates when compared with euthyroid individuals. Objective To evaluate the association between TH concentrations and insulin secretion in euthyroid, healthy Pima Indian adults (n=55, 29±7 years, females/males 36/19) with normal glucose tolerance (NGT) admitted to a Clinical Research Unit. Methods TSH, free thyroxine (FT4), 3,5,3′-L-tri-iodothyronine (FT3), and fasting plasma insulin (FPI) concentrations were measured in fasting plasma samples, percentage of body fat (%BF) by dual energy x-ray absorptiometry (DXA), acute insulin response (AIR), and incremental area under the curve (AUC) of insulin in response to a 25 g intravenous glucose tolerance test (IVGTT) and 75 g oral glucose tolerance test (OGTT) respectively and insulin action (M) during an euglycemic clamp. Results FT3 concentrations were associated with FPI, AIR, and insulin AUC both before (r=0.33, P=0.01; r=0.29, P=0.03; and r=0.35, P=0.008 respectively) and after adjustment for age, sex, %BF, glucose (fasting concentrations or glucose AUC), and M (β=0.09, P=0.01; β=0.16, P=0.03; and β=0.24, P=0.0007 respectively). No associations were found for TSH or FT4. Conclusion FT3 was associated with several measurements of insulin secretion in euthyroid individuals with NGT. T3 concentrations may play a role in the regulation of insulin secretion. PMID:18230829

  9. Inhibition of the malate-aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion.

    PubMed

    Stamenkovic, Jelena A; Andersson, Lotta E; Adriaenssens, Alice E; Bagge, Annika; Sharoyko, Vladimir V; Gribble, Fiona; Reimann, Frank; Wollheim, Claes B; Mulder, Hindrik; Spégel, Peter

    2015-05-15

    Altered secretion of insulin as well as glucagon has been implicated in the pathogenesis of Type 2 diabetes (T2D), but the mechanisms controlling glucagon secretion from α-cells largely remain unresolved. Therefore, we studied the regulation of glucagon secretion from αTC1-6 (αTC1 clone 6) cells and compared it with insulin release from INS-1 832/13 cells. We found that INS-1 832/13 and αTC1-6 cells respectively secreted insulin and glucagon concentration-dependently in response to glucose. In contrast, tight coupling of glycolytic and mitochondrial metabolism was observed only in INS-1 832/13 cells. Although glycolytic metabolism was similar in the two cell lines, TCA (tricarboxylic acid) cycle metabolism, respiration and ATP levels were less glucose-responsive in αTC1-6 cells. Inhibition of the malate-aspartate shuttle, using phenyl succinate (PhS), abolished glucose-provoked ATP production and hormone secretion from αTC1-6 but not INS-1 832/13 cells. Blocking the malate-aspartate shuttle increased levels of glycerol 3-phosphate only in INS-1 832/13 cells. Accordingly, relative expression of constituents in the glycerol phosphate shuttle compared with malate-aspartate shuttle was lower in αTC1-6 cells. Our data suggest that the glycerol phosphate shuttle augments the malate-aspartate shuttle in INS-1 832/13 but not αTC1-6 cells. These results were confirmed in mouse islets, where PhS abrogated secretion of glucagon but not insulin. Furthermore, expression of the rate-limiting enzyme of the glycerol phosphate shuttle was higher in sorted primary β- than in α-cells. Thus, suppressed glycerol phosphate shuttle activity in the α-cell may prevent a high rate of glycolysis and consequently glucagon secretion in response to glucose. Accordingly, pyruvate- and lactate-elicited glucagon secretion remains unaffected since their signalling is independent of mitochondrial shuttles.

  10. Decreased irisin secretion contributes to muscle insulin resistance in high-fat diet mice.

    PubMed

    Yang, Zaigang; Chen, Xu; Chen, Yujuan; Zhao, Qian

    2015-01-01

    Recent studies have revealed the relationship between irisin and insulin signaling, while positive associations of muscle FNDC5 with insulin resistance is observed. However, the functional mechanism of irisin on muscle insulin resistance is still obscure. This study aims to investigate the effect of irisin on muscle insulin action. Diabetic mouse model was established by high fat diet (HFD) induced obesity in C57BL/6 mice. Body indexes and serum levels of triglyceride (TG), blood glucose and insulin were record. Oral glucose tolerance test (OGTT) was performed before being killed. Circulating irisin level was also detected, while FNDC5/irisin expression was determined by RT-PCR and western blot analysis in both muscle and adipose tissues. Insulin action was further evaluated by the phosphorylation of AKT and Erk, and palmitic acid treated muscle cells were introduced for mimicking diabetic status in vitro. Obvious obese feathers associated with type 2 diabetes were observed in HFD feeding mice, with decreased circulating irisin level and FNDC5/irisin secretion in adipose tissues. Although FNDC5/irisin expression showed little change in skeletal muscle, the insulin action was inhibited significantly. Moreover, palmitic acid treated muscle cells showed similar inhibition of insulin action, and FNDC5/irisin expression change. Besides, insulin action could be reversed by irisin addition in muscle cells. HFD induced obese mice showed decreased irisin secretion from adipose tissues, which might contribute to muscle insulin resistance. Furthermore, irisin addition could recover insulin action in palmitic acid treated muscle cells, indicating the importance of irisin for preserving insulin signaling.

  11. Restoration of insulin secretion in pancreatic islets of protein-deficient rats by reduced expression of insulin receptor substrate (IRS)-1 and IRS-2.

    PubMed

    Araujo, E P; Amaral, M E C; Filiputti, E; De Souza, C T; Laurito, T L; Augusto, V D; Saad, M J A; Boschero, A C; Velloso, L A; Carneiro, E M

    2004-04-01

    Autocrine and paracrine insulin signaling may participate in the fine control of insulin secretion. In the present study, tissue distribution and protein amounts of the insulin receptor and its major substrates, insulin receptor substrate (IRS)-1 and IRS-2, were evaluated in a model of impaired glucose-induced insulin secretion, the protein-deficient rat. Immunoblot and RT-PCR studies showed that the insulin receptor and IRS-2 expression are increased, whilst IRS-1 protein and mRNA contents are decreased in pancreatic islets of protein-deficient rats. Immunohistochemical studies revealed that the insulin receptor and IRS-1 and -2 are present in the great majority of islet cells; however, the greatest staining was localized at the periphery, suggesting a co-localization with non-insulin-secreting cells. Exogenous insulin stimulation of isolated islets promoted higher insulin receptor and IRS-1 and -2 tyrosine phosphorylation in islets from protein-deficient rats, as compared with controls. Moreover, insulin-induced IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activity are increased in islets of protein-deficient rats. The reduction of IRS-1 and IRS-2 protein expression in islets isolated from protein-deficient rats by the use of antisense IRS-1 or IRS-2 phosphorthioate-modified oligonucleotides partially restored glucose-induced insulin secretion. Thus, the impairment of insulin cell signaling through members of the IRS family of proteins in isolated rat pancreatic islets improves glucose-induced insulin secretion. The present data reinforced the role of insulin paracrine and autocrine signaling in the control of its own secretion.

  12. Heterozygous SOD2 Deletion Impairs Glucose-Stimulated Insulin Secretion, but Not Insulin Action, in High-Fat–Fed Mice

    PubMed Central

    Dai, Chunhua; Lustig, Mary E.; Bonner, Jeffrey S.; Mayes, Wesley H.; Mokshagundam, Shilpa; James, Freyja D.; Thompson, Courtney S.; Lin, Chien-Te; Perry, Christopher G.R.; Anderson, Ethan J.; Neufer, P. Darrell; Wasserman, David H.; Powers, Alvin C.

    2014-01-01

    Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2+/+) and heterozygous knockout mice (sod2+/−) were fed a chow or high-fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were performed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2+/− and sod2+/+ but was markedly decreased in HF-fed sod2+/−. Remarkably, this impairment was not paralleled by reduced HG glucose infusion rate (GIR). Decreased GSIS in HF-fed sod2+/− was associated with increased ROS, such as superoxide ion. Surprisingly, insulin action determined by HI clamps did not differ between sod2+/− and sod2+/+ of either diet. Since insulin action was unaffected, we hypothesized that the unchanged HG GIR in HF-fed sod2+/− was due to increased glucose effectiveness. Increased GLUT-1, hexokinase II, and phospho-AMPK protein in muscle of HF-fed sod2+/− support this hypothesis. We conclude that heterozygous SOD2 deletion in mice, a model that mimics SOD2 changes observed in diabetic humans, impairs GSIS in HF-fed mice without affecting insulin action. PMID:24947366

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

    SciTech Connect

    Douillet, Christelle; Currier, Jenna; Saunders, Jesse; Bodnar, Wanda M.; Matoušek, Tomáš; Stýblo, Miroslav

    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

  14. The role of pancreatic insulin secretion in neonatal glucoregulation. I. Healthy term and preterm infants.

    PubMed Central

    Hawdon, J M; Aynsley-Green, A; Alberti, K G; Ward Platt, M P

    1993-01-01

    The glucoregulatory role of insulin in adult subjects is undisputed. However, less is known about the secretion of insulin and its actions in the neonatal period, either for healthy subjects, or for those at risk of disordered blood glucose homoeostasis. The relationships between blood glucose and plasma immunoreactive insulin concentrations were therefore examined in 52 healthy children (aged 1 month-10 years), 67 appropriate birth weight for gestational age (AGA) term infants, and 39 AGA preterm neonates. In children and AGA neonates, plasma immunoreactive insulin concentration was positively related to blood glucose concentration. However, although both groups of neonates had significantly lower blood glucose concentrations than children, plasma immunoreactive insulin concentrations were significantly higher in both term and preterm neonates, when compared with children. The variation in plasma immunoreactive insulin concentrations was greater for neonates than for children. These data suggest, that compared with older subjects, plasma immunoreactive insulin concentrations are high in newborn babies and that neonatal pancreatic insulin secretion is less closely linked to circulating blood glucose concentrations. There are important implications for the interpretation of studies in hypoglycaemic and hyperglycaemic neonates. PMID:8466262

  15. Association between Higher Serum Cortisol Levels and Decreased Insulin Secretion in a General Population

    PubMed Central

    Kamba, Aya; Daimon, Makoto; Murakami, Hiroshi; Otaka, Hideyuki; Matsuki, Kota; Sato, Eri; Tanabe, Jutaro; Takayasu, Shinobu; Matsuhashi, Yuki; Yanagimachi, Miyuki; Terui, Ken; Kageyama, Kazunori; Tokuda, Itoyo; Takahashi, Ippei; Nakaji, Shigeyuki

    2016-01-01

    Glucocorticoids (GCs) are well known to induce insulin resistance. However, the effect of GCs on insulin secretion has not been well characterized under physiological conditions in human. We here evaluated the effect of GCs on insulin secretion/ß-cell function precisely in a physiological condition. A population-based study of 1,071 Japanese individuals enrolled in the 2014 Iwaki study (390 men, 681 women; aged 54.1 ± 15.1 years), those excluded individuals taking medication for diabetes or steroid treatment, were enrolled in the present study. Association between serum cortisol levels and insulin resistance/secretion assessed by homeostasis model assessment using fasting blood glucose and insulin levels (HOMA-R and HOMA-ß, respectively) were examined. Univariate linear regression analyses showed correlation of serum cortisol levels with HOMA-ß (ß = -0.134, p <0.001) but not with HOMA-R (ß = 0.042, p = 0.172). Adjustments for age, gender, and the multiple clinical characteristics correlated with HOMA indices showed similar results (HOMA-ß: ß = -0.062, p = 0.025; HOMA-R: ß = -0.023, p = 0.394). The correlation between serum cortisol levels and HOMA-ß remained significant after adjustment for HOMA- R (ß = -0.057, p = 0.034). When subjects were tertiled based on serum cortisol levels, the highest tertile was at greater risk of decreased insulin secretion (defined as lower one third of HOMA-ß (≤70)) than the lowest tertile, after adjustment for multiple factors including HOMA- R (odds ratio 1.26, 95% confidence interval 1.03–1.54). In conclusion, higher serum cortisol levels are significantly associated with decreased insulin secretion in the physiological cortisol range in a Japanese population. PMID:27861636

  16. Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass.

    PubMed

    Uc, Aliye; Olivier, Alicia K; Griffin, Michelle A; Meyerholz, David K; Yao, Jianrong; Abu-El-Haija, Maisam; Buchanan, Katherine M; Vanegas Calderón, Oriana G; Abu-El-Haija, Marwa; Pezzulo, Alejandro A; Reznikov, Leah R; Hoegger, Mark J; Rector, Michael V; Ostedgaard, Lynda S; Taft, Peter J; Gansemer, Nick D; Ludwig, Paula S; Hornick, Emma E; Stoltz, David A; Ode, Katie L; Welsh, Michael J; Engelhardt, John F; Norris, Andrew W

    2015-01-01

    Diabetes is a common and significant co-morbidity in cystic fibrosis (CF). The pathogenesis of cystic fibrosis related diabetes (CFRD) is incompletely understood. Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis. We determined the structure of the endocrine pancreas in fetal, newborn and older CF and non-CF pigs and assessed endocrine pancreas function by intravenous glucose tolerance test (IV-GTT). In fetal pigs, pancreatic insulin and glucagon density was similar between CF and non-CF. In newborn and older pigs, the insulin and glucagon density was unchanged between CF and non-CF per total pancreatic area, but increased per remnant lobular tissue in CF reflecting exocrine pancreatic loss. Although fasting glucose levels were not different between CF and non-CF newborns, CF newborns demonstrated impaired glucose tolerance and increased glucose area under the curve during IV-GTT. Second phase insulin secretion responsiveness was impaired in CF newborn pigs and significantly lower than that observed in non-CF newborns. Older CF pigs had elevated random blood glucose levels compared with non-CF. In summary, glycaemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycaemia developed over time. Functional changes in CF pig pancreas were not associated with a decline in islet cell mass. Our results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.

  17. Selective Serotonin Reuptake Inhibitors (SSRIs) Inhibit Insulin Secretion and Action in Pancreatic β Cells*

    PubMed Central

    Isaac, Roi; Boura-Halfon, Sigalit; Gurevitch, Diana; Shainskaya, Alla; Levkovitz, Yechiel; Zick, Yehiel

    2013-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are antidepressants used for the treatment of mood and anxiety disorders. Here, we demonstrate that incubation (2 h) of murine islets or Min6 β cell line with the SSRIs paroxetine, fluoxetine, or sertraline inhibited insulin-induced Tyr phosphorylation of insulin receptor substrate (IRS)-2 protein and the activation of its downstream targets Akt and the ribosomal protein S6 kinase-1 (S6K1). Inhibition was dose-dependent with half-maximal effects at ∼15–20 μm. It correlated with a rapid dephosphorylation and activation of the IRS kinase GSK3β. Introduction of GSK3β siRNAs eliminated the inhibitory effects of the SSRIs. Inhibition of IRS-2 action by 30 μm SSRI was associated with a marked inhibition of glucose-stimulated insulin secretion from murine and human pancreatic islets. Secretion induced by basic secretagogues (KCl and Arg) was not affected by these drugs. Prolonged treatment (16 h) of Min6 cells with sertraline resulted in the induction of inducible nitric oxide synthase; activation of endoplasmic reticulum stress, and the initiation of the unfolded protein response, manifested by enhanced transcription of ATF4 and C/EBP homologous protein. This triggered an apoptotic process, manifested by enhanced caspase 3/7 activity, which resulted in β cell death. These findings implicate SSRIs as inhibitors of IRS protein function and insulin action through the activation of GSK3β. They further suggest that SSRIs inhibit insulin secretion; induce the unfolded protein response; activate an apoptotic process, and trigger β cell death. Given that SSRIs promote insulin resistance while inhibiting insulin secretion, these drugs might accelerate the transition from an insulin-resistant state to overt diabetes. PMID:23275337

  18. Pseudoislet formation enhances gene expression, insulin secretion and cytoprotective mechanisms of clonal human insulin-secreting 1.1B4 cells.

    PubMed

    Green, Alastair D; Vasu, Srividya; McClenaghan, Neville H; Flatt, Peter R

    2015-10-01

    We have studied the effects of cell communication on human beta cell function and resistance to cytotoxicity using the novel human insulin-secreting cell line 1.1B4 configured as monolayers and pseudoislets. Incubation with the incretin gut hormones GLP-1 and GIP caused dose-dependent stimulation of insulin secretion from 1.1B4 cell monolayers and pseudoislets. The secretory responses were 1.5-2.7-fold greater than monolayers. Cell viability (MTT), DNA damage (comet assay) and apoptosis (acridine orange/ethidium bromide staining) were investigated following 2-h exposure of 1.1B4 monolayers and pseudoislets to ninhydrin, H2O2, streptozotocin, glucose, palmitate or cocktails of proinflammatory cytokines. All agents tested decreased viability and increased DNA damage and apoptosis in both 1.1B4 monolayers and pseudoislets. However, pseudoislets exhibited significantly greater resistance to cytotoxicity (1.5-2.7-fold increases in LD50) and lower levels of DNA damage (1.3-3.4-fold differences in percentage tail DNA and olive tail moment) and apoptosis (1.3-1.5-fold difference) compared to monolayers. Measurement of gene expression by reverse-transcription, real-time PCR showed that genes involved with insulin secretion (INS, PDX1, PCSK1, PCSK2, GLP1R and GIPR), cell-cell communication (GJD2, GJA1 and CDH1) and antioxidant defence (SOD1, SOD2, GPX1 and CAT) were significantly upregulated in pseudoislets compared to monolayers, whilst the expression of proapoptotic genes (NOS2, MAPK8, MAPK10 and NFKB1) showed no significant differences. In summary, these data indicate cell-communication associated with three-dimensional islet architecture is important both for effective insulin secretion and for protection of human beta cells against cytotoxicity.

  19. Optogenetic control of insulin secretion by pancreatic β-cells in vitro and in vivo.

    PubMed

    Kushibiki, T; Okawa, S; Hirasawa, T; Ishihara, M

    2015-07-01

    The present study assessed the ability of optogenetics techniques to provide a better understanding of the control of insulin secretion, particularly regarding pancreatic β-cell function in homeostasis and pathological conditions such as diabetes mellitus (DM). We used optogenetics to investigate whether insulin secretion and blood glucose homeostasis could be controlled by regulating intracellular calcium ion concentrations ([Ca(2+)]i) in a mouse pancreatic β-cell line (MIN6) transfected with the optogenetic protein channelrhodopsin-2 (ChR2). The ChR2-transfected MIN6 (ChR2-MIN6) cells secreted insulin following irradiation with a laser (470 nm). The increase in [Ca(2+)]i was accompanied by elevated levels of messenger RNAs that encode calcium/calmodulin-dependent protein kinase II delta and adenylate cyclase 1. ChR2-MIN6 cells suspended in matrigel were inoculated into streptozotocin-induced diabetic mice that were then subjected to a glucose tolerance test. Laser irradiation of these mice caused a significant decrease in blood glucose, and the irradiated implanted cells expressed insulin. These findings demonstrate the power of optogenetics to precisely and efficiently controlled insulin secretion by pancreatic β-cells 'on demand', in contrast to techniques using growth factors or chemical inducers. Optogenetic technology shows great promise for understanding the mechanisms of glucose homeostasis and for developing treatments for metabolic diseases such as DM.

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

    PubMed Central

    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

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

    PubMed

    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.

  2. Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice.

    PubMed

    Ahlkvist, Linda; Omar, Bilal; Valeur, Anders; Fosgerau, Keld; Ahrén, Bo

    2016-03-01

    Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized; however, the effect of long-term GCGR activation on β-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2 weeks) infused with the stable glucagon analog ZP-GA-1 and challenged with oral glucose and intravenous glucose±glucagon-like peptide 1 (GLP1). Islets were isolated to evaluate the insulin secretory response to glucose±GLP1 and their pancreas were collected for immunohistochemical analysis. Two weeks of ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP1. Also, we observed increased β-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of β-cell function during development of type 2 diabetes.

  3. Kin of IRRE-like Protein 2 Is a Phosphorylated Glycoprotein That Regulates Basal Insulin Secretion*

    PubMed Central

    Yesildag, Burcak; Bock, Thomas; Herrmanns, Karolin; Wollscheid, Bernd; Stoffel, Markus

    2015-01-01

    Direct interactions among pancreatic β-cells via cell surface proteins inhibit basal and enhance stimulated insulin secretion. Here, we functionally and biochemically characterized Kirrel2, an immunoglobulin superfamily protein with β-cell-specific expression in the pancreas. Our results show that Kirrel2 is a phosphorylated glycoprotein that co-localizes and interacts with the adherens junction proteins E-cadherin and β-catenin in MIN6 cells. We further demonstrate that the phosphosites Tyr595–596 are functionally relevant for the regulation of Kirrel2 stability and localization. Analysis of the extracellular and intracellular domains of Kirrel2 revealed that it is cleaved and shed from MIN6 cells and that the remaining membrane spanning cytoplasmic domain is processed by γ-secretase complex. Kirrel2 knockdown with RNA interference in MIN6 cells and ablation of Kirrel2 from mice with genetic deletion resulted in increased basal insulin secretion from β-cells, with no immediate influence on stimulated insulin secretion, total insulin content, or whole body glucose metabolism. Our results show that in pancreatic β-cells Kirrel2 localizes to adherens junctions, is regulated by multiple post-translational events, including glycosylation, extracellular cleavage, and phosphorylation, and engages in the regulation of basal insulin secretion. PMID:26324709

  4. Effects of insulin, recombinant bovine somatotropin, and their interaction on insulin-like growth factor-I secretion and milk protein production in dairy cows.

    PubMed

    Molento, C F M; Block, E; Cue, R I; Petitclerc, D

    2002-04-01

    This trial was designed to test the effects of insulin, recombinant bovine somatotropin (rbST), and their interaction on milk protein and selected blood parameters in dairy cows. Eight Holstein cows (86 +/- 10 d in milk) were divided in two groups and used in two replicates of a Latin square design with four animals, four periods, and four treatments: 1) intravenous infusion of saline, 2) infusion of saline and subcutaneous administration of 40 mg of rbST per day, 3) intravenous infusion of 12 mg of insulin per day coupled with glucose infusion, and 4) rbST administration combined with insulin and glucose infusion. The glucose infusion rate was adjusted to maintain euglycemia. Each experimental period lasted 14 d: treatments were administered during the first 6 d, and no treatment was administered during the following 8-d resting phase. The average daily amount of glucose infusion needed to avoid hypoglycemia was 2.8 kg/cow when only insulin was infused as opposed to 2.2 kg/cow when both insulin and rbST were administered, indicating that either rbST causes a peripheral resistance to insulin or rbST increased liver gluconeogenesis or both. Data from the last 3 d of infusion were analyzed by using the SAS system for mixed models. Percent protein of milk tended to be lower (2.84 vs. 2.79%) and milk urea content was lower (16.6 vs. 14.8 mg/dl) during rbST administration, regardless of insulin infusion. Insulin infusion increased percent protein (2.78 vs. 2.85%) and percent casein (2.36 vs. 2.46%) and decreased milk urea content (17.1 vs. 14.3 mg/dl) regardless of rbST administration. For milk yield, protein yield, casein yield, lactose percent, and lactose yield, there were significant interactions between insulin and rbST administration. For example, casein yield averaged 1.17, 1.12, 1.20, and 1.28 kg/d for saline, insulin, rbST, and insulin combined with rbST, respectively. Similarly, there was a significant interaction between insulin and rbST on IGF-I levels

  5. Glucagon-like peptide 1 and fatty acids amplify pulsatile insulin secretion from perifused rat islets.

    PubMed Central

    Cunningham, Barbara A; Richard, Ann-Marie T; Dillon, Joseph S; Daley, Jennifer T; Civelek, Vildan N; Deeney, Jude T; Yaney, Gordon C; Corkey, Barbara E; Tornheim, Keith

    2003-01-01

    Glucose-induced insulin secretion from isolated, perifused rat islets is pulsatile with a period of about 5-10 min, similar to the insulin oscillations that are seen in healthy humans but which are impaired in Type II diabetes. We evaluated the pattern of enhancement by the potent incretin, glucagon-like peptide 1 (GLP-1). GLP-1 increased the amplitude of pulses and the magnitude of insulin secretion from the perifused islets, without affecting the average time interval between pulses. Forskolin and the phosphodiesterase inhibitor isobutylmethylxanthine had the same effect, suggesting that the effect was due to elevated cAMP levels. The possibility that cAMP might enhance the amplitude of pulses by reducing phosphofructo-2-kinase (PFK-2) activity was eliminated when the liver isoform of PFK-2 was shown to be absent from beta-cells. The possibility that cAMP enhanced pulsatile secretion, at least in part, by stimulating lipolysis was supported by the observations that added oleate had a similar effect on secretion, and that the incretin effect of GLP-1 was inhibited by the lipase inhibitor orlistat. These data show that the physiological incretin GLP-1 preserves and enhances normal pulsatile insulin secretion, which may be essential in proposed therapeutic uses of GLP-1 or its analogues. PMID:12356335

  6. Effects of I(Ks) channel inhibitors in insulin-secreting INS-1 cells.

    PubMed

    Ullrich, Susanne; Su, Jiping; Ranta, Felicia; Wittekindt, Oliver H; Ris, Frederic; Rösler, Martin; Gerlach, Uwe; Heitzmann, Dirk; Warth, Richard; Lang, Florian

    2005-12-01

    Potassium channels regulate insulin secretion. The closure of K(ATP) channels leads to membrane depolarisation, which triggers Ca(2+) influx and stimulates insulin secretion. The subsequent activation of K(+) channels terminates secretion. We examined whether KCNQ1 channels are expressed in pancreatic beta-cells and analysed their functional role. Using RT/PCR cellular mRNA of KCNQ1 but not of KCNE1 channels was detected in INS-1 cells. Effects of two sulfonamide analogues, 293B and HMR1556, inhibitors of KCNQ1 channels, were examined on voltage-activated outwardly rectifying K(+) currents using the patch-clamp method. It was found that 293B inhibited 60% of whole-cell outward currents induced by voltage pulses from -70 to +50 mV with a concentration for half-maximal inhibition (IC(50)) of 37 microM. The other sulfonamide analogue HMR1556 inhibited 48% of the outward current with an IC(50) of 7 microM. The chromanol 293B had no effect on tolbutamide-sensitive K(ATP) channels. Action potentials induced by current injections were broadened and after-repolarisation was attenuated by 293B. Insulin secretion in the presence but not in the absence of tolbutamide was significantly increased by 293B. These results suggest that 293B- and HMR1556-sensitive channels, probably in concert with other voltage-activated K(+) channels, influence action potential duration and frequency and thus insulin secretion.

  7. Cadherin engagement improves insulin secretion of single human β-cells.

    PubMed

    Parnaud, Geraldine; Lavallard, Vanessa; Bedat, Benoît; Matthey-Doret, David; Morel, Philippe; Berney, Thierry; Bosco, Domenico

    2015-03-01

    The aim of this study was to assess whether cadherin-mediated adhesion of human islet cells was affected by insulin secretagogues and explore the role of cadherins in the secretory activity of β-cells. Experiments were carried out with single islet cells adherent to chimeric proteins made of functional E-, N-, or P-cadherin ectodomains fused to the Fc fragment of immunoglobulin (E-cad/Fc, N-cad/Fc, and P-cad/Fc) and immobilized on an inert substrate. We observed that cadherin expression in islet cells was not affected by insulin secretagogues. Adhesion tests showed that islet cells attached to N-cad/Fc and E-cad/Fc acquired, in a time- and secretagogue-dependent manner, a spreading form that was inhibited by blocking cadherin antibodies. By reverse hemolytic plaque assay, we showed that glucose-stimulated insulin secretion of single β-cells was increased by N-cad/Fc and E-cad/Fc adhesion compared with control. In the presence of E-cad/Fc and after glucose stimulation, we showed that total insulin secretion was six times higher in spreading β-cells compared with round β-cells. Furthermore, cadherin-mediated adhesion induced an asymmetric distribution of cortical actin in β-cells. Our results demonstrate that adhesion of β-cells to E- and N-cadherins is regulated by insulin secretagogues and that E- and N-cadherin engagement promotes stimulated insulin secretion.

  8. Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells

    PubMed Central

    Sugawara, Taichi; Kano, Fumi; Murata, Masayuki

    2014-01-01

    Rab2A, a small GTPase localizing to the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), regulates COPI-dependent vesicular transport from the ERGIC. Rab2A knockdown inhibited glucose-stimulated insulin secretion and concomitantly enlarged the ERGIC in insulin-secreting cells. Large aggregates of polyubiquitinated proinsulin accumulated in the cytoplasmic vicinity of a unique large spheroidal ERGIC, designated the LUb-ERGIC. Well-known components of ER-associated degradation (ERAD) also accumulated at the LUb-ERGIC, creating a suitable site for ERAD-mediated protein quality control. Moreover, chronically high glucose levels, which induced the enlargement of the LUb-ERGIC and ubiquitinated protein aggregates, impaired Rab2A activity by promoting dissociation from its effector, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in response to poly (ADP-ribosyl)ation of GAPDH. The inactivation of Rab2A relieved glucose-induced ER stress and inhibited ER stress-induced apoptosis. Collectively, these results suggest that Rab2A is a pivotal switch that controls whether insulin should be secreted or degraded at the LUb-ERGIC and Rab2A inactivation ensures alleviation of ER stress and cell survival under chronic glucotoxicity. PMID:25377857

  9. Influence of Maternal Obesity on Insulin Sensitivity and Secretion in Offspring

    PubMed Central

    Mingrone, Geltrude; Manco, Melania; Valera Mora, Maria Elena; Guidone, Caterina; Iaconelli, Amerigo; Gniuli, Donatella; Leccesi, Laura; Chiellini, Chiara; Ghirlanda, Giovanni

    2008-01-01

    OBJECTIVE—The purpose of this study was to clarify the effects of maternal obesity on insulin sensitivity and secretion in offspring. RESEARCH DESIGN AND METHODS—Fifty-one offspring of both sexes of obese (Ob group) and 15 offspring of normal-weight (control group) mothers were studied. Plasma glucose, insulin, and C-peptide were measured during an oral glucose tolerance test (OGTT). Insulin sensitivity was calculated using the oral glucose insulin sensitivity index, and insulin secretion and β-cell glucose sensitivity were computed by a mathematical model. Fasting leptin and adiponectin were also measured. Body composition was assessed by dual-X-ray absorptiometry. RESULTS—No birth weight statistical difference was observed in the two groups. Of the Ob group, 69% were obese and 19% were overweight. The Ob group were more insulin resistant than the control group (398.58 ± 79.32 vs. 513.81 ± 70.70 ml−1 · min−1 · m−2 in women, P < 0.0001; 416.42 ± 76.17 vs. 484.242 ± 45.76 ml−1 · min−1 · m−2 in men, P < 0.05). Insulin secretion after OGTT was higher in Ob group than in control group men (63.94 ± 21.20 vs. 35.71 ± 10.02 nmol · m−2, P < 0.01) but did not differ significantly in women. β-Cell glucose sensitivity was not statistically different between groups. A multivariate analysis of variance showed that maternal obesity and offspring sex concurred together with BMI and β-cell glucose sensitivity to determine the differences in insulin sensitivity and secretion observed in offspring. CONCLUSIONS—Obese mothers can give birth to normal birth weight babies who later develop obesity and insulin resistance. The maternal genetic/epigenetic transmission shows a clear sexual dimorphism, with male offspring having a higher value of insulin sensitivity (although not statistically significant) associated with significantly higher insulin secretion than female offspring. PMID:18535193

  10. Endogenous somatostatin-28 modulates postprandial insulin secretion. Immunoneutralization studies in baboons.

    PubMed Central

    Ensinck, J W; Vogel, R E; Laschansky, E C; Koerker, D J; Prigeon, R L; Kahn, S E; D'Alessio, D A

    1997-01-01

    Somatostatin-28 (S-28), secreted into the circulation from enterocytes after food, and S-14, released mainly from gastric and pancreatic D cells and enteric neurons, inhibit peripheral cellular functions. We hypothesized that S-28 is a humoral regulator of pancreatic B cell function during nutrient absorption. Consistent with this postulate, we observed in baboons a two to threefold increase in portal and peripheral levels of S-28 after meals, with minimal changes in S-14. We attempted to demonstrate a hormonal effect of these peptides by measuring their concentrations before and after infusing a somatostatin-specific monoclonal antibody (mAb) into baboons and comparing glucose, insulin, and glucagon-like peptide-1 levels before and for 4 h after intragastric nutrients during a control study and on 2 d after mAb administration (days 1 and 2). Basal growth hormone (GH) and glucagon levels and parameters of insulin and glucose kinetics were also measured. During immunoneutralization, we found that (a) postprandial insulin levels were elevated on days 1 and 2; (b) GH levels rose immediately and were sustained for 28 h, while glucagon fell; (c) basal insulin levels were unchanged on day 1 but were increased two to threefold on day 2, coincident with decreased insulin sensitivity; and (d) plasma glucose concentrations were similar to control values. We attribute the eventual rise in fasting levels of insulin to its enhanced secretion in compensation for the heightened insulin resistance from increased GH action. Based on the elevated postmeal insulin levels after mAb administration, we conclude that S-28 participates in the enteroinsular axis as a decretin to regulate postprandial insulin secretion. PMID:9410907

  11. The effects of caerulein on insulin secretion in anaesthetized dogs.

    PubMed

    Bertaccini, G; De Caro, G; Melchiorri, P

    1970-09-01

    1. Insulin concentration changes in pancreatico-duodenal venous plasma were studied in anaesthetized dogs injected with caerulein.2. Rises in insulin concentration were elicited by rapid intravenous injection of caerulein, as well as by intravenous infusion. Threshold doses were 10 ng/kg and 0.5-1 (ng/kg)/min respectively.3. At the highest dose used (500 ng/kg by rapid intravenous injection and (25 ng/kg)/min by intravenous infusion) the increase in immuno-reactive insulin release was approximately 7 to 9 times the base levels.4. Adrenalectomy potentiated the effects of intravenous infusion of caerulein.5. On a molar basis, caerulein was 2-3 times as active as pancreozymin.6. It is concluded that caerulein is a potent stimulant of pancreatic islets in the dog and that it may be considered as a model peptide, capable of being substituted for pancreozymin in any experiment.7. The mechanism of the insulin stimulating effect of caerulein is discussed. The possibility of a direct "beta-cytotropic" effect of the peptide is suggested.

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

    SciTech Connect

    Yu, Yunli; Wang, Xinting; Liu, Can; Yao, Dan; Hu, Mengyue; Li, Jia; Hu, Nan; Liu, Li; Liu, Xiaodong

    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

  13. Does adrenergic activity suppress insulin secretion during surgery? A clinical experiment with halothane anesthesia.

    PubMed Central

    Aärimaa, M; Syvälahti, E; Ovaska, J

    1978-01-01

    Peroperative inhibition of insulin release is widely attributed to increased alpha-adrenergic activity. To test this hypothesis serum insulin and glucose concentrations were measured at short intervals in 11 patients who underwent major surgery. Five patients were anesthetized with halothane and six with general anesthesia without halothane. The results were similar in both patient groups; halothane had no effect on insulin. This suggests that suppression of insulin under operations is probably not due to activation of the alpha-adrenergic receptors of the pancreatic beta-cells. The authors propose that suppression of insulin secretion during surgery may be caused by adrenaline, which, in competing for the glucose receptors, insensitizes the pancreatic beta-cells. PMID:202205

  14. Nicotinamide induces differentiation of embryonic stem cells into insulin-secreting cells

    SciTech Connect

    Vaca, Pilar; Berna, Genoveva; Araujo, Raquel; Carneiro, Everardo M.; Bedoya, Francisco J.; Soria, Bernat; Martin, Franz

    2008-03-10

    The poly(ADP-ribose) polymerase (PARP) inhibitor, nicotinamide, induces differentiation and maturation of fetal pancreatic cells. In addition, we have previously reported evidence that nicotinamide increases the insulin content of cells differentiated from embryonic stem (ES) cells, but the possibility of nicotinamide acting as a differentiating agent on its own has never been completely explored. Islet cell differentiation was studied by: (i) X-gal staining after neomycin selection; (ii) BrdU studies; (iii) single and double immunohistochemistry for insulin, C-peptide and Glut-2; (iv) insulin and C-peptide content and secretion assays; and (v) transplantation of differentiated cells, under the kidney capsule, into streptozotocin (STZ)-diabetic mice. Here we show that undifferentiated mouse ES cells treated with nicotinamide: (i) showed an 80% decrease in cell proliferation; (ii) co-expressed insulin, C-peptide and Glut-2; (iii) had values of insulin and C-peptide corresponding to 10% of normal mouse islets; (iv) released insulin and C-peptide in response to stimulatory glucose concentrations; and (v) after transplantation into diabetic mice, normalized blood glucose levels over 7 weeks. Our data indicate that nicotinamide decreases ES cell proliferation and induces differentiation into insulin-secreting cells. Both aspects are very important when thinking about cell therapy for the treatment of diabetes based on ES cells.

  15. Effects of glucose and insulin on secretion of amyloid-β by human adipose tissue cells.

    PubMed

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

    2016-07-01

    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-β (Aβ) precursor protein and associated β- and γ-secretases are expressed in adipose tissue. Aβ precursor protein is up-regulated with obesity and correlated to insulin resistance. Aβ may be secreted by adipose tissue, its production may be regulated through metabolic pathways, and Aβ may exert effects on adipose tissue insulin receptor signaling. Human stromal-vascular cells and differentiated adipocytes were cultured with different combinations of glucose and insulin and then assayed for Aβ in conditioned media. Aβ was measured in vivo using adipose tissue microdialysis. Aβ secretion was increased by glucose and insulin in vitro. Adipose tissue microdialysates contained Aβ. Adipocytes treated with Aβ had decreased expression of insulin receptor substrate-2 and reduced Akt-1 phosphorylation. Aβ was made by adipose tissue cells in vitro at concentrations similar to in vivo measurements. Regulation of Aβ production by glucose and insulin and effects of Aβ on the insulin receptor pathway suggest similar cellular mechanisms may exist between neuronal dysfunction in Alzheimer disease and adipose dysfunction in type 2 diabetes. © 2016 The Authors Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).

  16. Loss of regular oscillatory insulin secretion in islet cell antibody positive non-diabetic subjects.

    PubMed

    Bingley, P J; Matthews, D R; Williams, A J; Bottazzo, G F; Gale, E A

    1992-01-01

    Basal insulin secretion was compared in nine islet-cell antibody positive, non-diabetic first-degree relatives of children with Type 1 (insulin-dependent) diabetes mellitus and nine normal control subjects matched for age, sex and weight. Acute insulin responses to a 25 g intravenous glucose tolerance test were similar in the two groups (243 (198-229) vs 329 (285-380) mU.l-1 x 10 min-1, mean (+/- SE), p = 0.25). Fasting plasma insulin was assayed in venous samples taken at one min intervals for 2 h. Time series analysis was used to demonstrate oscillatory patterns in plasma insulin. Autocorrelation showed that regular oscillatory activity was generally absent in the islet-cell antibody-positive group, whereas a regular 13 min cycle was shown in control subjects (p less than 0.0001). Fourier transformation did, however, show a 13 min spectral peak in the islet-cell antibody positive group, consistent with intermittent pulsatility. We conclude that overall oscillatory patterns of basal insulin secretion are altered in islet-cell antibody positive subjects even when the acute insulin response is within the normal range.

  17. Lack of TRPM2 Impaired Insulin Secretion and Glucose Metabolisms in Mice

    PubMed Central

    Uchida, Kunitoshi; Dezaki, Katsuya; Damdindorj, Boldbaatar; Inada, Hitoshi; Shiuchi, Tetsuya; Mori, Yasuo; Yada, Toshihiko; Minokoshi, Yasuhiko; Tominaga, Makoto

    2011-01-01

    OBJECTIVE TRPM2 is a Ca2+-permeable nonselective cation channel activated by adenosine dinucleotides. We previously demonstrated that TRPM2 is activated by coapplication of heat and intracellular cyclic adenosine 5′-diphosphoribose, which has been suggested to be involved in intracellular Ca2+ increase in immunocytes and pancreatic β-cells. To clarify the involvement of TRPM2 in insulin secretion, we analyzed TRPM2 knockout (TRPM2-KO) mice. RESEARCH DESIGN AND METHODS Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed in TRPM2-KO and wild-type mice. We also measured cytosolic free Ca2+ in single pancreatic cells using fura-2 microfluorometry and insulin secretion from pancreatic islets. RESULTS Basal blood glucose levels were higher in TRPM2-KO mice than in wild-type mice without any difference in plasma insulin levels. The OGTT and IPGTT demonstrated that blood glucose levels in TRPM2-KO mice were higher than those in wild-type mice, which was associated with an impairment in insulin secretion. In isolated β-cells, smaller intracellular Ca2+ increase was observed in response to high concentrations of glucose and incretin hormone in TRPM2-KO cells than in wild-type cells. Moreover, insulin secretion from the islets of TRPM2-KO mice in response to glucose and incretin hormone treatment was impaired, whereas the response to tolbutamide, an ATP-sensitive potassium channel inhibitor, was not different between the two groups. CONCLUSIONS These results indicate that TRPM2 is involved in insulin secretion stimulated by glucose and that further potentiated by incretins. Thus, TRPM2 may be a new target for diabetes therapy. PMID:20921208

  18. Pregnancy restores insulin secretion from pancreatic islets in cafeteria diet-induced obese rats.

    PubMed

    Vanzela, E C; Ribeiro, R A; de Oliveira, C A Machado; Rodrigues, F B; Bonfleur, M L; Carneiro, E M; Souza, K L A; Boschero, A C

    2010-02-01

    Insulin resistance during pregnancy is counteracted by enhanced insulin secretion. This condition is aggravated by obesity, which increases the risk of gestational diabetes. Therefore, pancreatic islet functionality was investigated in control nonpregnant (C) and pregnant (CP), and cafeteria diet-fed nonpregnant (Caf), and pregnant (CafP) obese rats. Isolated islets were used for measurements of insulin secretion (RIA), NAD(P)H production (MTS), glucose oxidation ((14)CO(2) production), intracellular Ca(2+) levels (fura-2 AM), and gene expression (real-time PCR). Impaired glucose tolerance was clearly established in Caf and CafP rats at the 14th wk on a diet. Insulin secretion induced by direct depolarizing agents such as KCl and tolbutamide and increasing concentrations of glucose was significantly reduced in Caf, compared with C islets. This reduction was not observed in islets from CP and CafP rats. Accordingly, the glucose oxidation and production of reduced equivalents were increased in CafP islets. The glucose-induced Ca(2+) increase was significantly lower in Caf and higher in CafP, compared with all other groups. CP and CafP islets demonstrated an increased Ca(2+) oscillation frequency, compared with both C and Caf islets, and the amplitude of oscillations was augmented in CafP, compared with Caf islets. In addition, Ca(v)alpha1.2 and SERCA2a mRNA levels were reduced in Caf islets. Ca(v)alpha1.2, but not SERCA2a, mRNA was normalized in CafP islets. In conclusion, cafeteria diet-induced obesity impairs insulin secretion. This alteration is related to the impairment of Ca(2+) handling in pancreatic islets, in especial Ca(2+) influx, a defect that is reversed during pregnancy allowing normalization of insulin secretion.

  19. Human insulin B24 (Phe----Ser). Secretion and metabolic clearance of the abnormal insulin in man and in a dog model.

    PubMed Central

    Shoelson, S E; Polonsky, K S; Zeidler, A; Rubenstein, A H; Tager, H S

    1984-01-01

    We have already demonstrated that a hyperinsulinemic, diabetic subject secreted an abnormal insulin in which serine replaced phenylalanine B24 (Shoelson S., M. Fickova, M. Haneda, A. Nahum, G. Musso, E. T. Kaiser, A. H. Rubenstein, and H. Tager. 1983. Proc. Natl. Acad. Sci. USA. 80:7390-7394). High performance liquid chromatography analysis now shows that the circulating insulin in several other family members also consists of a mixture of the abnormal human insulin B24 (Phe----Ser) and normal human insulin in a ratio of approximately 9.5:1 during fasting. Although all affected subjects show fasting hyperinsulinemia, only the propositus and her father are overtly diabetic. Analysis of the serum insulin from two nondiabetic siblings revealed that normal insulin increased from approximately 2 to 15% of total serum insulin after the ingestion of glucose and that the proportion of the normal hormone plateaued or fell while the level of total insulin continued to rise. Animal studies involving the graded intraportal infusion of equimolar amounts of semisynthetic human [SerB24]-insulin and normal human insulin in pancreatectomized dogs (to simulate the secretion of insulin due to oral glucose in man) also showed both a rise in the fraction of normal insulin that reached the periphery and the attainment of a brief steady state in this fraction while total insulin levels continued to rise. Separate experiments documented a decreased hepatic extraction, a decreased metabolic clearance rate, and an increased plasma half-life of human [SerB24]-insulin within the same parameters as those determined for normal human insulin. These results form a basis for considering (a) the differential clearance of low activity abnormal insulins and normal insulin from the circulation in vivo, and (b) the causes of hyperinsulinemia in both diabetic and nondiabetic individuals who secrete abnormal human insulins. PMID:6371057

  20. Disturbances of basal and postprandial insulin secretion and clearance in obese patients with type 2 diabetes mellitus.

    PubMed

    Erdmann, J; Pöhnl, K; Mayr, M; Sypchenko, O; Naumann, A; Wagenpfeil, S; Schusdziarra, V

    2012-01-01

    Hyperinsulinemia of nondiabetic overweight and obese subjects is associated with weight-dependent increased insulin secretion and decreased insulin clearance. The present analysis examines whether similar effects can be observed in overweight and obese patients with type 2 diabetes mellitus (DM2). Additionally basal and postprandial insulin secretion and clearance were analyzed in relation to duration of disease. In a random sample of 348 DM2 patients basal plasma insulin concentrations were significantly higher in most BMI groups compared to matched nondiabetic (ND) controls. The weight-dependent increase of basal insulin in DM2 was primarily the result of reduced clearance rather than augmented secretion. Postprandial insulin concentrations were lower in DM2 patients and did not show any BMI-related increase. The weight-dependent reduction of postprandial insulin clearance was absent in DM2. At the time of diagnosis basal insulin concentration was higher and secretion was comparable to ND subjects and this did not change with duration of diabetes. The early postprandial insulin response was still comparable between DM2 and ND subjects at the time of diagnosis but deteriorated with longer duration of disease. The later postprandial response at diagnosis (AUC 90-180) was characterized by significantly greater insulin secretion and concentration while later on the 3-fold higher secretion was paralleled by comparable peripheral plasma concentrations due to a significantly greater postprandial insulin clearance in DM2. In conclusion, the present data indicate that apart from disturbances of insulin secretion substantial changes of insulin clearance contribute to inadequate peripheral insulin concentrations in obese DM2 patients.

  1. Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion.

    PubMed

    Ahlkvist, L; Brown, K; Ahrén, B

    2013-06-01

    We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.

  2. A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity

    PubMed Central

    Oláhová, Monika; Veal, Elizabeth A

    2015-01-01

    Peroxiredoxins (Prx) are abundant thiol peroxidases with a conserved anti-ageing role. In contrast to most animals, the nematode worm, Caenorhabditis elegans, encodes a single cytosolic 2-Cys Prx, PRDX-2, rendering it an excellent model for examining how peroxiredoxins affect animal physiology and ageing. Our previous work revealed that, although PRDX-2 protects against the toxicity of peroxides, enigmatically, prdx-2-mutant animals are hyper-resistant to other forms of oxidative stress. Here, we have investigated the basis for this increased resistance. Mammalian FOXO and Nrf2 transcription factors directly promote the expression of a range of detoxification enzymes. We show that the FOXO orthologue, DAF-16, and the Nrf2 orthologue, SKN-1, are required for the increased stress resistance of prdx-2-mutant worms. Our data suggest that PRDX-2 is required for normal levels of insulin secretion and hence the inhibition of DAF-16 and SKN-1 by insulin/IGF-1-like signalling (IIS) under nutrient-rich conditions. Intriguingly, loss of PRDX-2 increases DAF-16 and SKN-1 activities sufficiently to increase arsenite resistance without initiating other IIS-inhibited processes. Together, these data suggest that loss of peroxiredoxin function may increase stress resistance by reducing insulin secretion, but that further changes in insulin signalling are required for the reprogramming of development and fat metabolism. In addition, we reveal that the temperature-dependent prolongevity function of PRDX-2 is required for the extended lifespan associated with several pathways, including further reductions in IIS. PMID:25808059

  3. Prenatal stress due to a natural disaster predicts insulin secretion in adolescence.

    PubMed

    Dancause, Kelsey N; Veru, Franz; Andersen, Ross E; Laplante, David P; King, Suzanne

    2013-09-01

    Prenatal stress might increase cardiometabolic disease risk. We measured prenatal stress due to an ice storm in 1998, and measured glucose tolerance among a subsample of 32 exposed adolescents in 2011. Severity of stress was positively associated with insulin secretion, suggesting that prenatal stress independently predicts metabolic outcomes in adolescence.

  4. p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion.

    PubMed

    Helman, Aharon; Klochendler, Agnes; Azazmeh, Narmen; Gabai, Yael; Horwitz, Elad; Anzi, Shira; Swisa, Avital; Condiotti, Reba; Granit, Roy Z; Nevo, Yuval; Fixler, Yaakov; Shreibman, Dorin; Zamir, Amit; Tornovsky-Babeay, Sharona; Dai, Chunhua; Glaser, Benjamin; Powers, Alvin C; Shapiro, A M James; Magnuson, Mark A; Dor, Yuval; Ben-Porath, Ittai

    2016-04-01

    Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity. We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16(Ink4a) and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

  5. Antrodia camphorata Increases Insulin Secretion and Protects from Apoptosis in MIN6 Cells

    PubMed Central

    Vong, Chi Teng; Tseng, Hisa Hui Ling; Kwan, Yiu Wa; Lee, Simon Ming-Yuen; Hoi, Maggie Pui Man

    2016-01-01

    Antrodia camphorata is a Taiwanese-specific fungus which has been used clinically to treat hypertension, immune- and liver-related diseases and cancer; however, it has never been studied in type 2 diabetes mellitus (T2DM). Hyperglycemia in T2DM causes endoplasmic reticulum (ER) stress, leading to β-cell dysfunction. During chronic ER stress, misfolded proteins accumulate and initiate β-cell apoptosis. Moreover, β-cell dysfunction leads to defect in insulin secretion, which is the key process in the development and progression of T2DM. Therefore, the aim of the present study was to examine the effects of A. camphorata on insulin secretion and ER stress-induced apoptosis in a mouse β-cell line, MIN6, and their underlying mechanisms. We demonstrated that the ethanolic extract of A. camphorata increased glucose-induced insulin secretion dose-dependently through peroxisome proliferator-activated receptor-γ (PPAR-γ) pathway, and upregulated genes that were involved in insulin secretion, including PPAR-γ, glucose transporter-2 and glucokinase. Furthermore, A. camphorata slightly increased cell proliferation, as well as protected from ER stress-induced apoptosis in MIN6 cells. In conclusion, this study provided evidences that A. camphorata might have anti-diabetic effects and could be a novel drug for T2DM. PMID:27047382

  6. Antrodia camphorata Increases Insulin Secretion and Protects from Apoptosis in MIN6 Cells.

    PubMed

    Vong, Chi Teng; Tseng, Hisa Hui Ling; Kwan, Yiu Wa; Lee, Simon Ming-Yuen; Hoi, Maggie Pui Man

    2016-01-01

    Antrodia camphorata is a Taiwanese-specific fungus which has been used clinically to treat hypertension, immune- and liver-related diseases and cancer; however, it has never been studied in type 2 diabetes mellitus (T2DM). Hyperglycemia in T2DM causes endoplasmic reticulum (ER) stress, leading to β-cell dysfunction. During chronic ER stress, misfolded proteins accumulate and initiate β-cell apoptosis. Moreover, β-cell dysfunction leads to defect in insulin secretion, which is the key process in the development and progression of T2DM. Therefore, the aim of the present study was to examine the effects of A. camphorata on insulin secretion and ER stress-induced apoptosis in a mouse β-cell line, MIN6, and their underlying mechanisms. We demonstrated that the ethanolic extract of A. camphorata increased glucose-induced insulin secretion dose-dependently through peroxisome proliferator-activated receptor-γ (PPAR-γ) pathway, and upregulated genes that were involved in insulin secretion, including PPAR-γ, glucose transporter-2 and glucokinase. Furthermore, A. camphorata slightly increased cell proliferation, as well as protected from ER stress-induced apoptosis in MIN6 cells. In conclusion, this study provided evidences that A. camphorata might have anti-diabetic effects and could be a novel drug for T2DM.

  7. Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice.

    PubMed

    González-Mariscal, Isabel; Krzysik-Walker, Susan M; Kim, Wook; Rouse, Michael; Egan, Josephine M

    2016-03-05

    The cannabinoid 1 receptor (CB1) is an important regulator of energy metabolism. Reports of in vivo and in vitro studies give conflicting results regarding its role in insulin secretion, possibly due to circulatory factors, such as incretins. We hypothesized that this receptor may be a regulator of the entero-insular axis. We found that despite lower food consumption and lower body weight postprandial GLP-1 plasma concentrations were increased in CB1(-/-) mice compared to CB1(+/+) mice administered a standard diet or high fat/sugar diet. Upon exogenous GLP-1 treatment, CB1(-/-) mice had increased glucose-stimulated insulin secretion. In mouse insulinoma cells, cannabinoids reduced GLP-1R-mediated intracellular cAMP accumulation and subsequent insulin secretion. Importantly, such effects were also evident in human islets, and were prevented by pharmacologic blockade of CB1. Collectively, these findings suggest a novel mechanism in which endocannabinoids are negative modulators of incretin-mediated insulin secretion. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Ion channels and regulation of insulin secretion in human β-cells

    PubMed Central

    Fridlyand, Leonid E.; Jacobson, David A.; Philipson, L.H.

    2013-01-01

    In mammals an increase in glucose leads to block of ATP dependent potassium channels in pancreatic β cells leading to membrane depolarization. This leads to the repetitive firing of action potentials that increases calcium influx and triggers insulin granule exocytosis. Several important differences between species in this process suggest that a dedicated human-oriented approach is advantageous as extrapolating from rodent data may be misleading in several respects. We examined depolarization-induced spike activity in pancreatic human islet-attached β-cells employing whole-cell patch-clamp methods. We also reviewed the literature concerning regulation of insulin secretion by channel activity and constructed a data-based computer model of human β cell function. The model couples the Hodgkin-Huxley-type ionic equations to the equations describing intracellular Ca2+ homeostasis and insulin release. On the basis of this model we employed computational simulations to better understand the behavior of action potentials, calcium handling and insulin secretion in human β cells under a wide range of experimental conditions. This computational system approach provides a framework to analyze the mechanisms of human β cell insulin secretion. PMID:23624892

  9. Class IA phosphatidylinositol 3-kinase in pancreatic β cells controls insulin secretion by multiple mechanisms.

    PubMed

    Kaneko, Kazuma; Ueki, Kohjiro; Takahashi, Noriko; Hashimoto, Shinji; Okamoto, Masayuki; Awazawa, Motoharu; Okazaki, Yukiko; Ohsugi, Mitsuru; Inabe, Kazunori; Umehara, Toshihiro; Yoshida, Masashi; Kakei, Masafumi; Kitamura, Tadahiro; Luo, Ji; Kulkarni, Rohit N; Kahn, C Ronald; Kasai, Haruo; Cantley, Lewis C; Kadowaki, Takashi

    2010-12-01

    Type 2 diabetes is characterized by insulin resistance and pancreatic β cell dysfunction, the latter possibly caused by a defect in insulin signaling in β cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in β cells and the pik3r2 gene systemically (βDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. β cells of βDKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca(2+) influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of βDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in β cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes.

  10. Nuclear PLCs affect insulin secretion by targeting PPARγ in pancreatic β cells.

    PubMed

    Fiume, Roberta; Ramazzotti, Giulia; Faenza, Irene; Piazzi, Manuela; Bavelloni, Alberto; Billi, Anna Maria; Cocco, Lucio

    2012-01-01

    Type 2 diabetes is a heterogeneous disorder caused by concomitant impairment of insulin secretion by pancreatic β cells and of insulin action in peripheral target tissues. Studies with inhibitors and agonists established a role for PLC in the regulation of insulin secretion but did not distinguish between effects due to nuclear or cytoplasmic PLC signaling pathways that act in a distinct fashion. We report that in MIN6 β cells, PLCβ1 localized in both nucleus and cytoplasm, PLCδ4 in the nucleus, and PLCγ1 in the cytoplasm. By silencing each isoform, we observed that they all affected glucose-induced insulin release both at basal and high glucose concentrations. To elucidate the molecular basis of PLC regulation, we focused on peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor transcription factor that regulates genes critical to β-cell maintenance and functions. Silencing of PLCβ1 and PLCδ4 resulted in a decrease in the PPARγ mRNA level. By means of a PPARγ-promoter-luciferase assay, the decrease could be attributed to a PLC action on the PPARγ-promoter region. The effect was specifically observed on silencing of the nuclear and not the cytoplasmic PLC. These findings highlight a novel pathway by which nuclear PLCs affect insulin secretion and identify PPARγ as a novel molecular target of nuclear PLCs.

  11. Non-traditional roles of complement in type 2 diabetes: Metabolism, insulin secretion and homeostasis.

    PubMed

    King, Ben C; Blom, Anna M

    2017-04-01

    Type 2 Diabetes (T2D) is a disease of increasing importance and represents a growing burden on global healthcare and human health. In T2D, loss of effectiveness of insulin signaling in peripheral tissues cannot be compensated for by adequate insulin secretion, leading to hyperglycemia and resultant complications. In recent years, inflammation has been identified as a central component of T2D, both in inducing peripheral insulin resistance as well as in the pancreatic islet, where it contributes to loss of insulin secretion and death of insulin-secreting beta cells. In this review we will focus on non-traditional roles of complement proteins which have been identified in T2D-associated inflammation, beta cell secretory function, and in maintaining homeostasis of the pancreatic islet. Improved understanding of both traditional and novel roles of complement proteins in T2D may lead to new therapeutic approaches for this global disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    PubMed

    Jensen, Christine B; Storgaard, Heidi; Dela, Flemming; Holst, Jens Juul; Madsbad, Sten; Vaag, Allan A

    2002-04-01

    Several studies have linked low birth weight (LBW) and type 2 diabetes. We investigated hepatic and peripheral insulin action including intracellular glucose metabolism in 40 19-year-old men (20 LBW, 20 matched control subjects), using the hyperinsulinemic-euglycemic clamp technique at two physiological insulin levels (10 and 40 mU/m(2) per min), indirect calorimetry, and [3-(3)H]glucose. Insulin secretion was examined during an oral and intravenous glucose tolerance test. Fasting p-glucose was higher in the LBW group (5.6 +/- 0.1 vs. 5.4 +/- 0.1; P < 0.05). Basal plasma glycerol concentrations 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 glycolysis precedes overt insulin resistance in LBW men. A lower insulin secretion may contribute to impaired glucose tolerance and ultimately lead to diabetes.

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

    PubMed

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

    2009-02-01

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

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

    PubMed

    Godini, Aliashraf; Ghasemi, Asghar; Zahediasl, Saleh

    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 (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 apparatus of the

  15. In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion.

    PubMed

    Maechler, Pierre; Carobbio, Stefania; Rubi, Blanca

    2006-01-01

    Pancreatic beta-cells are unique neuroendocrine cells displaying the peculiar feature of responding to nutrients, principally glucose, as primary stimulus. This requires translation of a metabolic substrate into intracellular messengers recognized by the exocytotic machinery. Central to this signal transduction mechanism, mitochondria integrate and generate metabolic signals, thereby coupling glucose recognition to insulin secretion. In response to a glucose rise, nucleotides and metabolites are generated by mitochondria and participate, together with cytosolic calcium, to the stimulation of insulin exocytosis. This review describes the mitochondrion-dependent pathways of regulated insulin secretion. In particular, importance of cataplerotic and anaplerotic processes is discussed, with special attention to the mitochondrial enzyme glutamate dehydrogenase. Mitochondrial defects, such as mutations and reactive oxygen species production, are presented in the context of beta-cell failure in the course of type 2 diabetes.

  16. Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size Regulation

    PubMed Central

    Koyama, Takashi; Mirth, Christen K.

    2016-01-01

    In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR) signaling, and produces an unidentified humoral factor(s) to regulate insulin-like peptide (ILP) synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs) specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size. PMID:26928023

  17. Human umbilical cord-derived mesenchymal stem cells can secrete insulin in vitro and in vivo.

    PubMed

    Boroujeni, Zahra Niki; Aleyasin, Ahmad

    2014-01-01

    Diabetes mellitus is characterized by autoimmune destruction of pancreatic beta cells, leading to decreased insulin production. Differentiation of mesenchymal stem cells (MSCs) into insulin-producing cells offers novel ways of diabetes treatment. MSCs can be isolated from the human umbilical cord tissue and differentiate into insulin-secreting cells. Human umbilical cord-derived stem cells (hUDSCs) were obtained after birth, selected by plastic adhesion, and characterized by flow cytometric analysis. hUDSCs were transduced with nonintegrated lentivirus harboring PDX1 (nonintegrated LV-PDX1) and was cultured in differentiation medium in 21 days. Pancreatic duodenum homeobox protein-1 (PDX1) is a transcription factor in pancreatic development. Significant expressions of PDX1, neurogenin3 (Ngn3), glucagon, glucose transporter2 (Glut2), and somatostatin were detected by quantitative RT-PCR (P < 0.05). PDX1 and insulin proteins were shown by immunocytochemistry analysis. Insulin secretion of hUDSCs(PDX1+) in the high-glucose medium was 1.8 μU/mL. They were used for treatment of diabetic rats and could decrease the blood glucose level from 400 mg/dL to a normal level in 4 days. In conclusion, our results demonstrated that hUDSCs are able to differentiate into insulin-producing cells by transduction with nonintegrated LV-PDX1. These hUDSCs(PDX1+) have the potential to be used as a viable resource in cell-based gene therapy of type 1 diabetes.

  18. Decreased basal insulin secretion from pancreatic islets of pups in a rat model of maternal obesity.

    PubMed

    Zambrano, Elena; Sosa-Larios, Tonantzin; Calzada, Lizbeth; Ibáñez, Carlos A; Mendoza-Rodríguez, Carmen A; Morales, Angélica; Morimoto, Sumiko

    2016-10-01

    Maternal obesity (MO) is a deleterious condition that enhances susceptibility of adult offspring to metabolic diseases such as type 2 diabetes. The objective is to study the effect of MO on in vitro insulin secretion and pancreatic cellular population in offspring. We hypothesize that a harmful antenatal metabolic environment due to MO diminishes the basal glucose-responsive secretory function of pancreatic beta cells in offspring. Mothers were fed a control (C) or high-fat diet from weaning through pregnancy (120 days) and lactation. At postnatal days (PNDs) 36 and 110, pups were killed, peripheral blood was collected and pancreatic islets were isolated. Basal insulin secretion was measured in vitro in islets for 60 min. It was found that blood insulin, glucose and homeostasis model assessment (HOMA) index were unaffected by maternal diet and age in females. However, male MO offspring at PND 110 showed hyperinsulinemia and insulin resistance compared with C. Body weight was not modified by MO, but fat content was higher in MO pups compared with C pups. Triglycerides and leptin concentrations were higher in MO than in C offspring in all groups except in females at PND 36. Pancreatic islet cytoarchitecture was unaffected by MO. At PND 36, islets of male and female C and MO offspring responded similarly to glucose, but at PND 110, male and female MO offspring islets showed a 50% decrease in insulin secretion. It was concluded that MO impairs basal insulin secretion of offspring with a greater impact on males than females, and this effect mainly manifests in adulthood.

  19. Insulin Secretion Improves in Cystic Fibrosis Following Ivacaftor Correction of CFTR: A Small Pilot Study

    PubMed Central

    Bellin, Melena D.; Laguna, Theresa; Leschyshyn, Janice; Regelmann, Warren; Dunitz, Jordan; Billings, JoAnne; Moran, Antoinette

    2013-01-01

    Objective To determine whether the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector, ivacaftor. Methods This open-label pilot study was conducted in CF patients with the G551D mutation given new prescriptions for ivacaftor. At baseline and 4 weeks after daily ivacaftor therapy, intravenous (IVGTT) and oral glucose (OGTT) tolerance tests were performed. Results Five patients age 6–52 were studied. After 1 month on ivacaftor, the insulin response to oral glucose improved by 66–178% in all subjects except one with long-standing diabetes. OGTT glucose levels were not lower in the two individuals with diabetes or the two with normal glucose tolerance (NGT), but the glucose tolerance category in the subject with impaired glucose tolerance (IGT) improved to NGT after treatment. In response to intravenous glucose, the only patient whose acute insulin secretion did not improve had newly diagnosed, untreated CFRD. The others improved by 51–346%. Acute insulin secretion was partially restored in two subjects with no measurable acute insulin response at baseline, including the one with IGT and the one with long-standing diabetes. Conclusions This small pilot study suggests there is a direct role of CFTR in human insulin secretion. Larger, long-term longitudinal studies are necessary to determine whether early initiation of CFTR correction, particularly in young children with CF who have not yet lost considerable beta-cell mass, will delay or prevent development of diabetes in this high risk population. PMID:23952705

  20. Sex effect on insulin secretion and mitochondrial function in pancreatic beta cells of elderly Wistar rats.

    PubMed

    Li, Tianyi; Jiao, Wenjun; Li, Weifang; Li, Hua

    2016-08-01

    Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes in the elderly people. Previous studies have reported the sex differences in risk for type 2 diabetes, especially in the elderly people, whereas reasons for these sex differences remain poorly understood. This study aims to evaluate the effect of sex on glucose-stimulated insulin secretion and mitochondrial function in pancreatic beta cells of Wistar rats. 3-month-old and 18-month-old Wistar rats of both sexes were used. Insulin secretion of islets was analyzed by glucose-stimulated insulin secretion and islet perifusion assays; ATP content and oxygen consumption rate of islets were determined to evaluate the mitochondrial function. Insulin secretion of islets under high glucose conditions declined significantly with age in both sexes. Glucose-stimulated insulin secretion of elderly female groups was markedly higher than that of male groups under high glucose conditions. Importantly, islets from elderly female groups showed higher mitochondrial function compared with male counterparts, evidenced by higher ATP content and oxygen consumption rate under high glucose conditions. It was also noted that mitochondrial biogenesis of islets from elderly female rats was significant higher compared with male rats. There were notable increases in expression of genes involved in mitochondrial biogenesis in islets from elderly female rats compared with male rats. This study demonstrates a sex dimorphism in the age-associated impairment of pancreatic beta cell function in elderly rats, while the potential mechanism may be related to the sexual differences in mitochondrial biogenesis and function.

  1. Interleukin-6 Enhances Glucose-Stimulated Insulin Secretion From Pancreatic β-Cells

    PubMed Central

    Suzuki, Toshinobu; Imai, Junta; Yamada, Tetsuya; Ishigaki, Yasushi; Kaneko, Keizo; Uno, Kenji; Hasegawa, Yutaka; Ishihara, Hisamitsu; Oka, Yoshitomo; Katagiri, Hideki

    2011-01-01

    OBJECTIVE Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic β-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic β-cell functions both in vivo and in vitro. RESEARCH DESIGN AND METHODS First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine β-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells. RESULTS Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-β1, but not with a protein kinase A inhibitor, H-89, inhibited IL-6–induced enhancement of GSIS. An inositol triphosphate (IP3) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6. CONCLUSIONS The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic β-cells and enhances GSIS. The PLC-IP3–dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS. PMID:21270264

  2. The Drosophila cytokine Unpaired 2 regulates physiological homeostasis by remotely controlling Insulin secretion

    PubMed Central

    Rajan, Akhila; Perrimon, Norbert

    2012-01-01

    In Drosophila the fat body (FB), a functional analog of the vertebrate adipose tissue, is the 'nutrient sensor' that conveys the nutrient status to the insulin producing cells (IPCs) in the fly brain to release insulin-like peptides (Dilps). Dilp secretion in turn regulates energy balance and promotes systemic growth. We identify Unpaired2 (Upd2), a protein with similarities to type I cytokines, as a secreted factor produced by the FB in the ‘fed’ state. When upd2 function is perturbed specifically in the FB, it results in a systemic reduction in growth and alters energy metabolism. Upd2 activates JAK/STAT signaling in a population of GABAergic neurons that project onto the IPCs. This activation relieves the inhibitory tone of the GABAergic neurons on the IPCs, resulting in the secretion of Dilps. Strikingly, we find that human Leptin, can rescue the upd2 mutant phenotypes, suggesting that Upd2 is the functional homolog of Leptin. PMID:23021220

  3. Influence of Basal Insulin and Glucagon Secretion on Potassium and Sodium Metabolism

    PubMed Central

    Defronzo, Ralph A.; Sherwin, Robert S.; Dillingham, Mark; Hendler, Rosa; Tamborlane, William V.; Felig, Philip

    1978-01-01

    To examine the role of basal insulin and glucagon secretion in potassium and sodium homeostasis, somatostatin, a potent inhibitor of insulin and glucagon secretion, was infused for 5 h into healthy human subjects, maturity-onset diabetes, juvenile-onset diabetics, and normal dogs. Infusion of somatostatin resulted in an increase in serum potassium (0.5-0.6 meq/liter) in normal subjects and maturity-onset diabetics, but not in juvenile-onset diabetics despite equivalent reductions in plasma glucagon in all three groups. A similar rise in serum potassium was observed in normal conscious dogs given somatostatin and was reversed by insulin replacement. Urinary excretion of potassium was unaffected by somatostatin. In dogs given intravenous potassium chloride in doses (0.375 meq/kg per h) which do not alter basal insulin levels, the rise in serum potassium (0.6 meq/liter in controls) increased 100% when somatostatin was administered together with the KCl infusion. Addition of replacement doses of insulin to the somatostatin infusion resulted in increments in serum potassium which were comparable to infusion of KCl alone. Urinary potassium excretion rose after KCl administration and was unchanged by the addition of somatostatin. Serum sodium concentration was unaffected by somatostatin administration in both the human and dog studies. However, urinary sodium excretion displayed a biphasic response falling by 20-60% within the first 2 h of somatostatin administration and then rising to values 50-80% above basal levels at 3-4 h. Inulin and p-aminohippurate clearances were unaffected by somatostatin. It is concluded that (a) potassium homeostasis is influenced by basal insulin levels in the absence of which serum potassium concentration rises and potassium tolerance declines; (b) this effect of insulin is mediated via extrarenal mechanisms of potassium disposal; (c) somatostatin has a biphasic effect on urinary sodium secretion, the mechanism of which remains to be

  4. Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice.

    PubMed

    Kang, Li; Dai, Chunhua; Lustig, Mary E; Bonner, Jeffrey S; Mayes, Wesley H; Mokshagundam, Shilpa; James, Freyja D; Thompson, Courtney S; Lin, Chien-Te; Perry, Christopher G R; Anderson, Ethan J; Neufer, P Darrell; Wasserman, David H; Powers, Alvin C

    2014-11-01

    Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2(+/+)) and heterozygous knockout mice (sod2(+/-)) were fed a chow or high-fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were performed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2(+/-) and sod2(+/+) but was markedly decreased in HF-fed sod2(+/-). Remarkably, this impairment was not paralleled by reduced HG glucose infusion rate (GIR). Decreased GSIS in HF-fed sod2(+/-) was associated with increased ROS, such as superoxide ion. Surprisingly, insulin action determined by HI clamps did not differ between sod2(+/-) and sod2(+/+) of either diet. Since insulin action was unaffected, we hypothesized that the unchanged HG GIR in HF-fed sod2(+/-) was due to increased glucose effectiveness. Increased GLUT-1, hexokinase II, and phospho-AMPK protein in muscle of HF-fed sod2(+/-) support this hypothesis. We conclude that heterozygous SOD2 deletion in mice, a model that mimics SOD2 changes observed in diabetic humans, impairs GSIS in HF-fed mice without affecting insulin action. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  5. Threshold secret sharing scheme based on phase-shifting interferometry.

    PubMed

    Deng, Xiaopeng; Shi, Zhengang; Wen, Wei

    2016-11-01

    We propose a new method for secret image sharing with the (3,N) threshold scheme based on phase-shifting interferometry. The secret image, which is multiplied with an encryption key in advance, is first encrypted by using Fourier transformation. Then, the encoded image is shared into N shadow images based on the recording principle of phase-shifting interferometry. Based on the reconstruction principle of phase-shifting interferometry, any three or more shadow images can retrieve the secret image, while any two or fewer shadow images cannot obtain any information of the secret image. Thus, a (3,N) threshold secret sharing scheme can be implemented. Compared with our previously reported method, the algorithm of this paper is suited for not only a binary image but also a gray-scale image. Moreover, the proposed algorithm can obtain a larger threshold value t. Simulation results are presented to demonstrate the feasibility of the proposed method.

  6. Palmitic acid acutely inhibits acetylcholine- but not GLP-1-stimulated insulin secretion in mouse pancreatic islets

    PubMed Central

    Qin, Wei; Vinogradov, Sergei A.; Wilson, David F.; Matschinsky, Franz M.

    2010-01-01

    Fatty acids, acetylcholine, and GLP-1 enhance insulin secretion in a glucose-dependent manner. However, the interplay between glucose, fatty acids, and the neuroendocrine regulators of insulin secretion is not well understood. Therefore, we studied the acute effects of PA (alone or in combination with glucose, acetylcholine, or GLP-1) on isolated cultured mouse islets. Two different sets of experiments were designed. In one, a fixed concentration of 0.5 mM of PA bound to 0.15 mM BSA was used; in the other, a PA ramp from 0 to 0.5 mM was applied at a fixed albumin concentration of 0.15 mM so that the molar PA/BSA ratio changed within the physiological range. At a fixed concentration of 0.5 mM, PA markedly inhibited acetylcholine-stimulated insulin release, the rise of intracellular Ca2+, and enhancement of cAMP production but did not influence the effects of GLP-1 on these parameters of islet cell function. 2-ADB, an IP3 receptor inhibitor, reduced the effect of acetylcholine on insulin secretion and reversed the effect of PA on acetylcholine-stimulated insulin release. Islet perfusion for 35–40 min with 0.5 mM PA significantly reduced the calcium storage capacity of ER measured by the thapsigargin-induced Ca2+ release. Oxygen consumption due to low but not high glucose was reduced by PA. When a PA ramp from 0 to 0.5 mM was applied in the presence of 8 mM glucose, PA at concentrations as low as 50 μM significantly augmented glucose-stimulated insulin release and markedly reduced acetylcholine's effects on hormone secretion. We thus demonstrate that PA acutely reduces the total oxygen consumption response to glucose, glucose-dependent acetylcholine stimulation of insulin release, Ca2+, and cAMP metabolism, whereas GLP-1's actions on these parameters remain unaffected or potentiated. We speculate that acute emptying of the ER calcium by PA results in decreased glucose stimulation of respiration and acetylcholine potentiation of insulin secretion. PMID:20606076

  7. Essential role of chicken ovalbumin upstream promoter-transcription factor II in insulin secretion and insulin sensitivity revealed by conditional gene knockout.

    PubMed

    Bardoux, Pascale; Zhang, Pili; Flamez, Daisy; Perilhou, Anaïs; Lavin, Tiphaine Aguirre; Tanti, Jean-François; Hellemans, Karine; Gomas, Emmanuel; Godard, Cécile; Andreelli, Fabrizio; Buccheri, Maria Antonietta; Kahn, Axel; Le Marchand-Brustel, Yannick; Burcelin, Rémy; Schuit, Frans; Vasseur-Cognet, Mireille

    2005-05-01

    Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been implicated in the control of blood glucose by its potent effect on expression and signaling of various nuclear receptors. To understand the role of COUP-TFII in glucose homeostasis, conditional COUP-TFII-deficient mice were generated and crossed with mice expressing Cre under the control of rat insulin II gene promoter, resulting in deletion of COUP-TFII in pancreatic beta-cells. Homozygous mutants died before birth for yet undetermined reasons. Heterozygous mice appeared healthy at birth and showed normal growth and fertility. When challenged intraperitoneally, the animals had glucose intolerance associated with reduced glucose-stimulated insulin secretion. Moreover, these heterozygous mice presented a mild increase in fasting and random-fed circulating insulin levels. In accordance, islets isolated from these animals exhibited higher insulin secretion in low glucose conditions and markedly decreased glucose-stimulated insulin secretion. Their pancreata presented normal microscopic architecture and insulin content up to 16 weeks of study. Altered insulin secretion was associated with peripheral insulin resistance in whole animals. It can be concluded that COUP-TFII is a new, important regulator of glucose homeostasis and insulin sensitivity.

  8. Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitus

    PubMed Central

    Sidharta, Patricia N; Rave, Klaus; Heinemann, Lutz; Chiossi, Eleonora; Krähenbühl, Stephan; Dingemanse, Jasper

    2009-01-01

    AIMS To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study. METHODS After 4 weeks' oral treatment with 125 mg palosuran or placebo b.i.d., effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake. RESULTS Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of −1.8 µU ml−1, 95% confidence interval (CI) −7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean Cmax and AUCτ (95% CI) and median tmax (range) in this patient population were 180 ng ml−1 (125, 260), 581 ng·h ml−1 (422, 800) and 3.0 h (0.67, 4.3), respectively. CONCLUSIONS The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes. PMID:19843053

  9. Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitus.

    PubMed

    Sidharta, Patricia N; Rave, Klaus; Heinemann, Lutz; Chiossi, Eleonora; Krähenbühl, Stephan; Dingemanse, Jasper

    2009-10-01

    To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study. After 4 weeks' oral treatment with 125 mg palosuran or placebo b.i.d.,effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake. Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of -1.8 microU ml(-1), 95% confidence interval (CI) -7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean C(max) and AUC(tau) (95% CI) and median t(max) (range) in this patient population were 180 ng ml(-1) (125, 260), 581 ng.h ml(-1) (422, 800) and 3.0 h (0.67, 4.3), respectively. The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes.

  10. Effects of free fatty acids on insulin secretion in obesity.

    PubMed

    Zraika, S; Dunlop, M; Proietto, J; Andrikopoulos, S

    2002-05-01

    The prevalence of obesity in Western society has reached epidemic proportions and its aetiological role in the development of type 2 diabetes has made finding an effective treatment for the condition of crucial importance. Of the many consequences of obesity, derangements in glucose metabolism present one of the greatest problems to health. While the role of obesity in causing insulin resistance has received much attention, the effect of obesity on beta-cell failure and the consequent development of type 2 diabetes requires re-emphasis. In this review, the current understanding of the effects of elevated free-fatty acids on beta-cell function will be examined, including a discussion of potential mechanisms. In particular, dysregulation of biochemical pathways and alterations in key enzymes, proteins and hormones will be considered as grounds for the progression to a diabetic phenotype.

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

    PubMed Central

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

    2015-01-01

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

  12. Potentiation of Calcium Influx and Insulin Secretion in Pancreatic Beta Cell by the Specific TREK-1 Blocker Spadin

    PubMed Central

    Hivelin, Céline; Béraud-Dufour, Sophie; Devader, Christelle; Moreno, Sébastien; Moha ou Maati, Hamid; Djillani, Alaeddine; Heurteaux, Catherine; Borsotto, Marc

    2016-01-01

    Inhibition of the potassium channels TREK-1 by spadin (SPA) is currently thought to be a promising therapeutic target for the treatment of depression. Since these channels are expressed in pancreatic β-cells, we investigated their role in the control of insulin secretion and glucose homeostasis. In this study, we confirmed the expression of TREK-1 channels in the insulin secreting MIN6-B1 β-cell line and in mouse islets. We found that their blockade by SPA potentiated insulin secretion induced by potassium chloride dependent membrane depolarization. Inhibition of TREK-1 by SPA induced a decrease of the resting membrane potential (ΔVm ~ 12 mV) and increased the cytosolic calcium concentration. In mice, administration of SPA enhanced the plasma insulin level stimulated by glucose, confirming its secretagogue effect observed in vitro. Taken together, this work identifies SPA as a novel potential pharmacological agent able to control insulin secretion and glucose homeostasis. PMID:28105440

  13. Glutamate Acts as a Key Signal Linking Glucose Metabolism to Incretin/cAMP Action to Amplify Insulin Secretion

    PubMed Central

    Gheni, Ghupurjan; Ogura, Masahito; Iwasaki, Masahiro; Yokoi, Norihide; Minami, Kohtaro; Nakayama, Yasumune; Harada, Kazuo; Hastoy, Benoit; Wu, Xichen; Takahashi, Harumi; Kimura, Kazushi; Matsubara, Toshiya; Hoshikawa, Ritsuko; Hatano, Naoya; Sugawara, Kenji; Shibasaki, Tadao; Inagaki, Nobuya; Bamba, Takeshi; Mizoguchi, Akira; Fukusaki, Eiichiro; Rorsman, Patrik; Seino, Susumu

    2014-01-01

    Summary Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion. PMID:25373904

  14. Increased expression of the diabetes gene SOX4 reduces insulin secretion by impaired fusion pore expansion

    PubMed Central

    Collins, Stephan C.; Do, Hyun Woong; Hastoy, Benoit; Hugill, Alison; Adam, Julie; Chibalina, Margarita V.; Galvanovskis, Juris; Godazgar, Mahdieh; Lee, Sheena; Goldsworthy, Michelle; Salehi, Albert; Tarasov, Andrei I.; Rosengren, Anders H.; Cox, Roger; Rorsman, Patrik

    2016-01-01

    The transcription factor Sox4 has been proposed to underlie the increased type-2 diabetes risk linked to an intronic SNP in CDKAL1. In a mouse model expressing a mutant form of Sox4, glucose-induced insulin secretion is reduced by 40% despite normal intracellular Ca2+ signalling and depolarization-evoked exocytosis. This paradox is explained by a 4-fold increase in kiss-and-run exocytosis (as determined by single-granule exocytosis measurements), in which the fusion pore connecting the granule lumen to the exterior only expands to a diameter of 2 nm that does not allow the exit of insulin. Microarray analysis indicated that this correlated with an increased expression of the exocytosis-regulating protein Stxbp6. In a large collection of human islet preparations (n=63), STXBP6 expression and GIIS correlated positively and negatively with SOX4 expression, respectively. Overexpression of SOX4 in the human insulin-secreting cell EndoC-βH2 interfered with granule emptying and inhibited hormone release, the latter effect was reversed by silencing of STXBP6. These data suggest that increased SOX4 expression inhibits insulin secretion and increased diabetes risk by upregulation of STXBP6 and an increase in kiss-and-run exocytosis at the expense of full fusion. We propose that pharmacological interventions promoting fusion pore expansion may be effective in diabetes therapy. PMID:26993066

  15. Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells.

    PubMed

    Velasco, Myrian; Díaz-García, Carlos Manlio; Larqué, Carlos; Hiriart, Marcia

    2016-09-01

    Pancreatic beta cells, unique cells that secrete insulin in response to an increase in glucose levels, play a significant role in glucose homeostasis. Glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells has been extensively explored. In this mechanism, glucose enters the cells and subsequently the metabolic cycle. During this process, the ATP/ADP ratio increases, leading to ATP-sensitive potassium (KATP) channel closure, which initiates depolarization that is also dependent on the activity of TRP nonselective ion channels. Depolarization leads to the opening of voltage-gated Na(+) channels (Nav) and subsequently voltage-dependent Ca(2+) channels (Cav). The increase in intracellular Ca(2+) triggers the exocytosis of insulin-containing vesicles. Thus, electrical activity of pancreatic beta cells plays a central role in GSIS. Moreover, many growth factors, incretins, neurotransmitters, and hormones can modulate GSIS, and the channels that participate in GSIS are highly regulated. In this review, we focus on the principal ionic channels (KATP, Nav, and Cav channels) involved in GSIS and how classic and new proteins, hormones, and drugs regulate it. Moreover, we also discuss advances on how metabolic disorders such as metabolic syndrome and diabetes mellitus change channel activity leading to changes in insulin secretion.

  16. PPARalpha suppresses insulin secretion and induces UCP2 in insulinoma cells.

    PubMed

    Tordjman, Karen; Standley, Kara N; Bernal-Mizrachi, Carlos; Leone, Teresa C; Coleman, Trey; Kelly, Daniel P; Semenkovich, Clay F

    2002-06-01

    Fatty acids may promote type 2 diabetes by altering insulin secretion from pancreatic beta cells, a process known as lipotoxicity. The underlying mechanisms are poorly understood. To test the hypothesis that peroxisome proliferator-activated receptor alpha (PPARalpha) has a direct effect on islet function, we treated INS-1 cells, an insulinoma cell line, with a PPARalpha adenovirus (AdPPARalpha) as well as the PPARalpha agonist clofibric acid. AdPPARalpha-infected INS-1 cells showed PPARalpha agonist- and fatty acid-dependent transactivation of a PPARalpha reporter gene. Treatment with either AdPPARalpha or clofibric acid increased both catalase activity (a marker of peroxisomal proliferation) and palmitate oxidation. AdPPARalpha induced carnitine-palmitoyl transferase-I (CPT-I) mRNA, but had no effect on insulin gene expression. AdPPARalpha treatment increased cellular triglyceride content but clofibric acid did not. Both AdPPARalpha and clofibric acid decreased basal and glucose-stimulated insulin secretion. Despite increasing fatty acid oxidation, AdPPARalpha did not increase cellular ATP content suggesting the stimulation of uncoupled respiration. Consistent with these observations, UCP2 expression doubled in PPARalpha-treated cells. Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir. These data suggest that PPARalpha-stimulated fatty acid oxidation can impair beta cell function.

  17. Endogenous beta-cell CART regulates insulin secretion and transcription of beta-cell genes.

    PubMed

    Shcherbina, L; Edlund, A; Esguerra, J L S; Abels, M; Zhou, Y; Ottosson-Laakso, E; Wollheim, C B; Hansson, O; Eliasson, L; Wierup, N

    2017-05-15

    Impaired beta-cell function is key to the development of type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART) is an islet peptide with insulinotropic and glucagonostatic properties. Here we studied the role of endogenous CART in beta-cell function. CART silencing in INS-1 (832/13) beta-cells reduced insulin secretion and production, ATP levels and beta-cell exocytosis. This was substantiated by reduced expression of several exocytosis genes, as well as reduced expression of genes important for insulin secretion and processing. In addition, CART silencing reduced the expression of a network of transcription factors essential for beta-cell function. Moreover, in RNAseq data from human islet donors, CARTPT expression levels correlated with insulin, exocytosis genes and key beta-cell transcription factors. Thus, endogenous beta-cell CART regulates insulin expression and secretion in INS-1 (832/13) cells, via actions on the exocytotic machinery and a network of beta-cell transcription factors. We conclude that CART is important for maintaining the beta-cell phenotype. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Sox17 Regulates Insulin Secretion in the Normal and Pathologic Mouse β Cell

    PubMed Central

    Jonatan, Diva; Spence, Jason R.; Method, Anna M.; Kofron, Matthew; Sinagoga, Katie; Haataja, Leena; Arvan, Peter; Deutsch, Gail H.; Wells, James M.

    2014-01-01

    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. PMID:25144761

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

    PubMed

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

    2011-11-15

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

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

    PubMed Central

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

    2011-01-01

    Abstract Cell–cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca2+]i) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca2+]i ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell–cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36−/−), and these results were compared to those obtained using fully isolated β-cells. KATP loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36−/− islets, elevations in [Ca2+]i persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36−/− islets was minimally altered. [Ca2+]i was further elevated under basal conditions, but insulin release still suppressed in KATP loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell–cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca2+]i signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion. PMID:21930600

  1. Reevaluation of Fatty Acid Receptor 1 as a Drug Target for the Stimulation of Insulin Secretion in Humans

    PubMed Central

    Wagner, Robert; Kaiser, Gabriele; Gerst, Felicia; Christiansen, Elisabeth; Due-Hansen, Maria E.; Grundmann, Manuel; Machicao, Fausto; Peter, Andreas; Kostenis, Evi; Ulven, Trond; Fritsche, Andreas; Häring, Hans-Ulrich; Ullrich, Susanne

    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 undergoing investigation for the treatment of type 2 diabetes. Surprisingly, genome-wide association studies did not discover diabetes risk variants in FFAR1. We reevaluated the role of FFAR1 in insulin secretion using a specific agonist, FFAR1-knockout mice and human islets. Nondiabetic individuals were metabolically phenotyped and genotyped. In vitro experiments indicated that palmitate and a specific FFAR1 agonist, TUG-469, stimulate glucose-induced insulin secretion through FFAR1. The proapoptotic effect of chronic exposure of β-cells to palmitate was independent of FFAR1. TUG-469 was protective, whereas inhibition of FFAR1 promoted apoptosis. In accordance with the proapoptotic effect of palmitate, in vivo cross-sectional observations demonstrated a negative association between fasting free fatty acids (NEFAs) and insulin secretion. Because NEFAs stimulate secretion through FFAR1, we examined the interaction of genetic variation in FFAR1 with NEFA and insulin secretion. The inverse association of NEFA and secretion was modulated by rs1573611 and became steeper for carriers of the minor allele. In conclusion, FFAR1 agonists support β-cell function, but variation in FFAR1 influences NEFA effects on insulin secretion and therefore could affect therapeutic efficacy of FFAR1 agonists. PMID:23378609

  2. Metabolic signaling of insulin secretion by pancreatic β-cell and its derangement in type 2 diabetes.

    PubMed

    Zou, C-Y; Gong, Y; Liang, J

    2014-01-01

    Pancreatic beta-cell is responsible for insulin secretion in response to the availability of nutrients. Type 2 diabetes mellitus (T2D) is the result of pancreatic b-cell failure to supply sufficient amount of insulin accompanied with decreased sensitivity of the body tissues to respond to insulin. The insulin secretion apparatus of beta-cell is uniquely equipped with multiple metabolic and signaling steps that are under rigorous control. The metabolic machinery of beta-cell is designed to sense the fluctuations in blood glucose level and supply insulin accordingly to the needs of body. Besides glucose, amino acids including glutamine and leucine and also fatty acids are known to either stimulate the beta-cell directly or potentiate the glucose stimulated insulin secretion (GSIS) response. Glucose metabolism dependent GSIS is linked with the production of ATP that is needed for K+ATP channel inhibition and influx of calcium, necessary for insulin granule exocytosis. Besides glucose metabolism, amino acid metabolism and lipid metabolism derived metabolites mediate the optimal glucose response of beta-cells to secrete insulin. Metabolites derived from nutrient secretagogues that directly or indirectly participate in the enhancement of GSIS are considered as metabolic coupling factors. In this review, we will discuss the regulation of insulin secretion by b-cell keeping the recent developments in metabolic signaling in focus. The relevant metabolic pathways in pancreatic beta-cell and their role in the control of fuel-stimulated insulin secretion will be reviewed to arrive at a consensus picture with respect to the metabolic signaling of insulin secretion.

  3. Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

    PubMed Central

    Kim, Jung Dae; Toda, Chitoku; D’Agostino, Giuseppe; Zeiss, Caroline J.; DiLeone, Ralph J.; Elsworth, John D.; Kibbey, Richard G.; Chan, Owen; Harvey, Brandon K.; Richie, Christopher T.; Savolainen, Mari; Myöhänen, Timo; Jeong, Jin Kwon; Diano, Sabrina

    2014-01-01

    Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prepgt/gt) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, S17092, impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prepgt/gt and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prepgt/gt and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prepgt/gt mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus–PREP reversed the glucose-intolerant phenotype of the Prepgt/gt mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function. PMID:25071172

  4. Nuclear SREBP-1a causes loss of pancreatic {beta}-cells and impaired insulin secretion

    SciTech Connect

    Iwasaki, Yuko; Iwasaki, Hitoshi; Yatoh, Shigeru; Ishikawa, Mayumi; Kato, Toyonori; Matsuzaka, Takashi; Nakagawa, Yoshimi; Yahagi, Naoya; Kobayashi, Kazuto; Takahashi, Akimitsu; Suzuki, Hiroaki; Yamada, Nobuhiro; Shimano, Hitoshi

    2009-01-16

    Transgenic mice expressing nuclear sterol regulatory element-binding protein-1a under the control of the insulin promoter were generated to determine the role of SREBP-1a in pancreatic {beta}-cells. Only low expressors could be established, which exhibited mild hyperglycemia, impaired glucose tolerance, and reduced plasma insulin levels compared to C57BL/6 controls. The islets isolated from the transgenic mice were fewer and smaller, and had decreased insulin content and unaltered glucagon staining. Both glucose- and potassium-stimulated insulin secretions were decreased. The transgenic islets consistently expressed genes for fatty acids and cholesterol synthesis, resulting in accumulation of triglycerides but not cholesterol. PDX-1, {beta}{epsilon}{tau}{alpha}2, MafA, and IRS-2 were suppressed, partially explaining the loss and dysfunction of {beta}-cell mass. The transgenic mice on a high fat/high sucrose diet still exhibited impaired insulin secretion and continuous {beta}-cell growth defect. Therefore, nuclear SREBP-1a, even at a low level, strongly disrupts {beta}-cell mass and function.

  5. Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques.

    PubMed

    Cummings, Bethany P; Bremer, Andrew A; Kieffer, Timothy J; D'Alessio, David; Havel, Peter J

    2013-02-01

    Dexamethasone has well-described effects to induce insulin resistance and increase insulin secretion. Herein, we examined potential contributors to the effect of dexamethasone to increase insulin secretion in rhesus macaques. Six male rhesus macaques received daily injections of either saline or dexamethasone (0.25 mg/kg i.m. for 7 days) in random order with 3 weeks between treatments. At the end of the treatment period, animals were fasted overnight and underwent a feeding study the next day, during which blood samples were taken before and for 60 min after a meal in order to assess islet hormone and incretin secretion. Dexamethasone induced marked increases in fasting plasma insulin, glucagon, leptin, and adiponectin concentrations (P<0.05). Surprisingly, the glycemic response after meal ingestion was decreased twofold during dexamethasone treatment (P<0.05). Dexamethasone-treated animals exhibited a significant increase in both insulin and glucose-dependent insulinotropic polypeptide (GIP) secretion during the feeding study (P<0.05). However, glucagon-like peptide-1 secretion was significantly lower in dexamethasone-treated animals compared with controls (P<0.01). Fasting and meal-stimulated pancreatic polypeptide concentrations (an index of the parasympathetic input to the islet) did not differ between saline and dexamethasone treatments. However, the proinsulin:insulin ratio was decreased throughout the feeding study with dexamethasone treatment suggesting an improvement of β-cell function (P<0.05). In conclusion, the maintenance of euglycemia and reduction of postprandial glycemia with short-term dexamethasone treatment appears to be due to the marked elevations of fasting and meal-stimulated insulin secretion. Furthermore, increases in postprandial GIP secretion with dexamethasone treatment appear to contribute to the effect of dexamethasone treatment to increase insulin secretion.

  6. The Effects of Secretin, Pancreozymin, and Gastrin on Insulin and Glucagon Secretion in Anesthetized Dogs *

    PubMed Central

    Unger, Roger H.; Ketterer, Hermann; Dupré, John; Eisentraut, Anna M.

    1967-01-01

    The effects upon islet hormone secretion of highly purified preparations of secretin and of pancreozymin-cholecystokinin and of a crude gastrin-containing extract of hog antrum have been studied in acutely operated dogs. All three preparations were shown to cause a striking increase in insulin concentration in the pancreaticoduodenal venous plasma after their rapid endoportal injection in anesthetized dogs. With each hormone preparation, the peak in insulin secretion occurred 1 minute after injection, and a rapid decline was observed immediately thereafter. Whereas secretin and gastrin failed to alter significantly the pancreaticoduodenal venous glucagon or arterial glucose concentration, pancreozymin caused a dramatic rise in pancreaticoduodenal venous glucagon concentration, which reached a peak 3 minutes after injection, and hyperglycemia was noted to occur soon thereafter. Endoportal infusion of secretin and pancreozymin for 20 minutes caused responses that were sustained but qualitatively identical to the responses noted after rapid injection of the hormones. The beta-cytotropic effect of secretin was abolished by the infusion of epinephrine. These results could not be attributed to the small degree of contamination of the enteric hormone preparations with insulin or glucagon, and it would appear that secretin, pancreozymin, and probably gastrin have insulin-releasing activity and that pancreozymin has, in addition, glucagon-releasing activity. The demonstration that these three hormones possess insulin-releasing activity suggests that there is in the gastrointestinal tract a chain of betacytotropic hormones from antrum to ileum that is capable of augmenting insulin secretion as required for disposal of substrate loads. It is suggested that the existence of this “entero-insular axis” prevents high substrate concentrations that would otherwise follow ingestion of large meals were the insular response entirely a function of arterial substrate concentration

  7. Sweet taste receptors regulate basal insulin secretion and contribute to compensatory insulin hypersecretion during the development of diabetes in male mice.

    PubMed

    Kyriazis, George A; Smith, Kathleen R; Tyrberg, Björn; Hussain, Tania; Pratley, Richard E

    2014-06-01

    β-Cells rapidly secrete insulin in response to acute increases in plasma glucose but, upon further continuous exposure to glucose, insulin secretion progressively decreases. Although the mechanisms are unclear, this mode of regulation suggests the presence of a time-dependent glucosensory system that temporarily attenuates insulin secretion. Interestingly, early-stage β-cell dysfunction is often characterized by basal (ie, fasting) insulin hypersecretion, suggesting a disruption of these related mechanisms. Because sweet taste receptors (STRs) on β-cells are implicated in the regulation of insulin secretion and glucose is a bona fide STR ligand, we tested whether STRs mediate this sensory mechanism and participate in the regulation of basal insulin secretion. We used mice lacking STR signaling (T1R2(-/-) knockout) and pharmacologic inhibition of STRs in human islets. Mouse and human islets deprived of STR signaling hypersecrete insulin at short-term fasting glucose concentrations. Accordingly, 5-hour fasted T1R2(-/-) mice have increased plasma insulin and lower glucose. Exposure of isolated wild-type islets to elevated glucose levels reduced STR expression, whereas islets from diabetic (db/db) or diet-induced obese mouse models show similar down-regulation. This transcriptional reprogramming in response to hyperglycemia correlates with reduced STR function in these mouse models, leading to insulin hypersecretion. These findings reveal a novel mechanism by which insulin secretion is physiologically regulated by STRs and also suggest that, during the development of diabetes, STR function is compromised by hyperglycemia leading to hyperinsulinemia. These observations further suggest that STRs might be a promising therapeutic target to prevent and treat type 2 diabetes.

  8. Sweet Taste Receptors Regulate Basal Insulin Secretion and Contribute to Compensatory Insulin Hypersecretion During the Development of Diabetes in Male Mice

    PubMed Central

    Smith, Kathleen R.; Tyrberg, Björn; Hussain, Tania; Pratley, Richard E.

    2014-01-01

    β-Cells rapidly secrete insulin in response to acute increases in plasma glucose but, upon further continuous exposure to glucose, insulin secretion progressively decreases. Although the mechanisms are unclear, this mode of regulation suggests the presence of a time-dependent glucosensory system that temporarily attenuates insulin secretion. Interestingly, early-stage β-cell dysfunction is often characterized by basal (ie, fasting) insulin hypersecretion, suggesting a disruption of these related mechanisms. Because sweet taste receptors (STRs) on β-cells are implicated in the regulation of insulin secretion and glucose is a bona fide STR ligand, we tested whether STRs mediate this sensory mechanism and participate in the regulation of basal insulin secretion. We used mice lacking STR signaling (T1R2−/− knockout) and pharmacologic inhibition of STRs in human islets. Mouse and human islets deprived of STR signaling hypersecrete insulin at short-term fasting glucose concentrations. Accordingly, 5-hour fasted T1R2−/− mice have increased plasma insulin and lower glucose. Exposure of isolated wild-type islets to elevated glucose levels reduced STR expression, whereas islets from diabetic (db/db) or diet-induced obese mouse models show similar down-regulation. This transcriptional reprogramming in response to hyperglycemia correlates with reduced STR function in these mouse models, leading to insulin hypersecretion. These findings reveal a novel mechanism by which insulin secretion is physiologically regulated by STRs and also suggest that, during the development of diabetes, STR function is compromised by hyperglycemia leading to hyperinsulinemia. These observations further suggest that STRs might be a promising therapeutic target to prevent and treat type 2 diabetes. PMID:24712876

  9. Increased Very Low Density Lipoprotein Secretion, Hepatic Steatosis, and Insulin Resistance

    PubMed Central

    Choi, Sung Hee; Ginsberg, Henry N

    2011-01-01

    Insulin resistance (IR) not only affects regulation of carbohydrate metabolism, but all aspects of lipid and lipoprotein metabolism. IR is associated with increased secretion of very low density lipoproteins (VLDL) and increased plasma triglycerides, as well as hepatic steatosis, despite the increased VLDL secretion. Here, we link IR with increased VLDL secretion and hepatic steatosis at both the physiologic and molecular levels. Increased VLDL secretion, together with the downstream effects on high density lipoprotein cholesterol and low density lipoprotein size is pro-atherogenic. Hepatic steatosis is a risk for steatohepatitis and cirrhosis. Understanding the complex inter-relationship between IR and these abnormalities of liver lipid homeostasis may provide insights relevant to new therapies for these increasing clinical problems. PMID:21616678

  10. 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.

    PubMed

    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.

  11. Cholesterol reduction ameliorates glucose-induced calcium handling and insulin secretion in islets from low-density lipoprotein receptor knockout mice.

    PubMed

    Souza, J C; Vanzela, E C; Ribeiro, R A; Rezende, L F; de Oliveira, C A; Carneiro, E M; Oliveira, H C F; Boschero, A C

    2013-04-01

    Changes in cellular cholesterol level may contribute to beta cell dysfunction. Islets from low density lipoprotein receptor knockout (LDLR(-/-)) mice have higher cholesterol content and secrete less insulin than wild-type (WT) mice. Here, we investigated the association between cholesterol content, insulin secretion and Ca(2+) handling in these islets. Isolated islets from both LDLR(-/-) and WT mice were used for measurements of insulin secretion (radioimmunoassay), cholesterol content (fluorimetric assay), cytosolic Ca(2+) level (fura-2AM) and SNARE protein expression (VAMP-2, SNAP-25 and syntaxin-1A). Cholesterol was depleted by incubating the islets with increasing concentrations (0-10mmol/l) of methyl-beta-cyclodextrin (MβCD). The first and second phases of glucose-stimulated insulin secretion (GSIS) were lower in LDLR(-/-) than in WT islets, paralleled by an impairment of Ca(2+) handling in the former. SNAP-25 and VAMP-2, but not syntaxin-1A, were reduced in LDLR(-/-) compared with WT islets. Removal of excess cholesterol from LDLR(-/-) islets normalized glucose- and tolbutamide-induced insulin release. Glucose-stimulated Ca(2+) handling was also normalized in cholesterol-depleted LDLR(-/-) islets. Cholesterol removal from WT islets by 0.1 and 1.0mmol/l MβCD impaired both GSIS and Ca(2+) handling. In addition, at 10mmol/l MβCD WT islet showed a loss of membrane integrity and higher DNA fragmentation. Abnormally high (LDLR(-/-) islets) or low cholesterol content (WT islets treated with MβCD) alters both GSIS and Ca(2+) handling. Normalization of cholesterol improves Ca(2+) handling and insulin secretion in LDLR(-/-) islets. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Genetic variants in MTNR1B affecting insulin secretion.

    PubMed

    Müssig, Karsten; Staiger, Harald; Machicao, Fausto; Häring, Hans-Ulrich; Fritsche, Andreas

    2010-09-01

    The incidence of type 2 diabetes mellitus has markedly increased worldwide over the past decades. Pancreatic beta-cell dysfunction as well as central and peripheral insulin resistance appears to be elementary features in the pathophysiology of type 2 diabetes mellitus. Major environmental conditions predisposing to the development of type 2 diabetes are excessive food intake and sedentary life-style on the background of a genetic predisposition. Recent genome-wide association studies identified several novel type 2 diabetes risk genes, with impaired pancreatic beta-cell function as the underlying mechanism of increased diabetes risk in the majority of genes. Many of the novel type 2 diabetes risk genes, including MTNR1B which encodes one of the two known human melatonin receptors, were unexpected at first glance. However, previous animal as well as human studies already pointed to a significant impact of the melatonin system on the regulation of glucose homeostasis, in addition to its well known role in modulation of sleep and circadian rhythms. This brief review aims to give an overview of how alterations in the melatonin system could contribute to an increased diabetes risk, paying special attention to the role of melatonin receptors in pancreatic beta-cell function.

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

    PubMed

    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.

  14. Effects of sleep restriction on glucose control and insulin secretion during diet-induced weight loss

    PubMed Central

    Nedeltcheva, A. V.; Imperial, J. G.; Penev, P. D.

    2012-01-01

    Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight-loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24-hour blood glucose control during diet-induced weight loss, 10 overweight and obese adults (3F/7M; mean [SD] age 41 [5] y; BMI 27.4 [2.0] kg/m2) completed two 14-day treatments with hypocaloric diet and 8.5 or 5.5-h nighttime sleep opportunity in random order 7 [3] months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free-fatty acids (FFA), and 24-hour blood glucose, insulin, C-peptide, and counter-regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 [0.3] BMI units) during each treatment. Bedtime restriction reduced sleep by 131 [30] min/day. Recurrent sleep curtailment decreased 24-hour serum insulin concentrations (i.e. enhanced 24-hour insulin economy) without changes in oral glucose tolerance and 24-hour glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA which suppressed normally following glucose ingestion, and lower total and LDL cholesterol concentrations. Sleep-loss-related changes in counter-regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24-hour insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep-restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability. PMID:22513492

  15. Linoleic acid decreases leptin and adiponectin secretion from primary rat adipocytes in the presence of insulin.

    PubMed

    Pérez-Matute, P; Martínez, J A; Marti, A; Moreno-Aliaga, M J

    2007-10-01

    Obesity rates have dramatically increased over the last few decades and, at the same time, major changes in the type of fatty acid intake have occurred. Linoleic acid, an n-6 polyunsaturated fatty acid, is an essential fatty acid occurring in high amounts in several western diets. A potential role of this fatty acid on obesity has been suggested. Controversial effects of linoleic acid on insulin sensitivity have also been reported. Thus, the aim of this study was to examine the direct effects of linoleic acid on leptin and adiponectin production, two adipokines known to influence weight gain and insulin sensitivity. Because insulin-stimulated glucose metabolism is an important regulator of leptin production, the effects of linoleic acid on adipocyte metabolism were also examined. For this purpose, isolated rat adipocytes were incubated with linoleic acid (1-200 microM) in the absence or presence of insulin. Linoleic acid (1-200 microM) significantly decreased insulin-stimulated leptin secretion and expression (P < 0.05), however, no changes in basal leptin production were observed. Linoleic acid also induced a significant decrease (approximately 20%) in adiponectin secretion (P < 0.05), but only in the presence of insulin and at the highest concentration tested (200 microM). This fatty acid did not modify either glucose uptake or lactate production and the percentage of glucose metabolized to lactate was not changed either. Together, these results suggest that linoleic acid seems to interfere with other insulin signalling pathway different from those controlling glucose uptake and metabolism, but involved in the regulation of leptin and adiponectin production.

  16. Common Variants in the Type 2 Diabetes KCNQ1 Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp

    PubMed Central

    van Vliet-Ostaptchouk, Jana V.; van Haeften, Timon W.; Landman, Gijs W. D.; Reiling, Erwin; Kleefstra, Nanne; Bilo, Henk J. G.; Klungel, Olaf H.; de Boer, Anthonius; van Diemen, Cleo C.; Wijmenga, Cisca; Boezen, H. Marike; Dekker, Jacqueline M.; van 't Riet, Esther; Nijpels, Giel; Welschen, Laura M. C.; Zavrelova, Hata; Bruin, Elinda J.; Elbers, Clara C.; Bauer, Florianne; Onland-Moret, N. Charlotte; van der Schouw, Yvonne T.; Grobbee, Diederick E.; Spijkerman, Annemieke M. W.; van der A, Daphne L.; Simonis-Bik, Annemarie M.; Eekhoff, Elisabeth M. W.; Diamant, Michaela; Kramer, Mark H. H.; Boomsma, Dorret I.; de Geus, Eco J.; Willemsen, Gonneke; Slagboom, P. Eline

    2012-01-01

    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. PMID:22403629

  17. Essential role of mitochondrial Ca2+ uniporter in the generation of mitochondrial pH gradient and metabolism-secretion coupling in insulin-releasing cells.

    PubMed

    Quan, Xianglan; Nguyen, Tuyet Thi; Choi, Seong-Kyung; Xu, Shanhua; Das, Ranjan; Cha, Seung-Kuy; Kim, Nari; Han, Jin; Wiederkehr, Andreas; Wollheim, Claes B; Park, Kyu-Sang

    2015-02-13

    In pancreatic β-cells, ATP acts as a signaling molecule initiating plasma membrane electrical activity linked to Ca(2+) influx, which triggers insulin exocytosis. The mitochondrial Ca(2+) uniporter (MCU) mediates Ca(2+) uptake into the organelle, where energy metabolism is further stimulated for sustained second phase insulin secretion. Here, we have studied the contribution of the MCU to the regulation of oxidative phosphorylation and metabolism-secretion coupling in intact and permeabilized clonal β-cells as well as rat pancreatic islets. Knockdown of MCU with siRNA transfection blunted matrix Ca(2+) rises, decreased nutrient-stimulated ATP production as well as insulin secretion. Furthermore, MCU knockdown lowered the expression of respiratory chain complexes, mitochondrial metabolic activity, and oxygen consumption. The pH gradient formed across the inner mitochondrial membrane following nutrient stimulation was markedly lowered in MCU-silenced cells. In contrast, nutrient-induced hyperpolarization of the electrical gradient was not altered. In permeabilized cells, knockdown of MCU ablated matrix acidification in response to extramitochondrial Ca(2+). Suppression of the putative Ca(2+)/H(+) antiporter leucine zipper-EF hand-containing transmembrane protein 1 (LETM1) also abolished Ca(2+)-induced matrix acidification. These results demonstrate that MCU-mediated Ca(2+) uptake is essential to establish a nutrient-induced mitochondrial pH gradient which is critical for sustained ATP synthesis and metabolism-secretion coupling in insulin-releasing cells.

  18. Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults: a randomized placebo-controlled trial.

    PubMed

    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

  19. Dopamine synthesis and D3 receptor activation in pancreatic β-cells regulates insulin secretion and intracellular [Ca(2+)] oscillations.

    PubMed

    Ustione, Alessandro; Piston, David W

    2012-11-01

    Pancreatic islets are critical for glucose homeostasis via the regulated secretion of insulin and other hormones. We propose a novel mechanism that regulates insulin secretion from β-cells within mouse pancreatic islets: a dopaminergic negative feedback acting on insulin secretion. We show that islets are a site of dopamine synthesis and accumulation outside the central nervous system. We show that both dopamine and its precursor l-dopa inhibit glucose-stimulated insulin secretion, and this inhibition correlates with a reduction in frequency of the intracellular [Ca(2+)] oscillations. We further show that the effects of dopamine are abolished by a specific antagonist of the dopamine receptor D3. Because the dopamine transporter and dopamine receptors are expressed in the islets, we propose that cosecretion of dopamine with insulin activates receptors on the β-cell surface. D3 receptor activation results in changes in intracellular [Ca(2+)] dynamics, which, in turn, lead to lowered insulin secretion. Because blocking dopaminergic negative feedback increases insulin secretion, expanding the knowledge of this pathway in β-cells might offer a potential new target for the treatment of type 2 diabetes.

  20. Dopamine Synthesis and D3 Receptor Activation in Pancreatic β-Cells Regulates Insulin Secretion and Intracellular [Ca2+] Oscillations

    PubMed Central

    Ustione, Alessandro

    2012-01-01

    Pancreatic islets are critical for glucose homeostasis via the regulated secretion of insulin and other hormones. We propose a novel mechanism that regulates insulin secretion from β-cells within mouse pancreatic islets: a dopaminergic negative feedback acting on insulin secretion. We show that islets are a site of dopamine synthesis and accumulation outside the central nervous system. We show that both dopamine and its precursor l-dopa inhibit glucose-stimulated insulin secretion, and this inhibition correlates with a reduction in frequency of the intracellular [Ca2+] oscillations. We further show that the effects of dopamine are abolished by a specific antagonist of the dopamine receptor D3. Because the dopamine transporter and dopamine receptors are expressed in the islets, we propose that cosecretion of dopamine with insulin activates receptors on the β-cell surface. D3 receptor activation results in changes in intracellular [Ca2+] dynamics, which, in turn, lead to lowered insulin secretion. Because blocking dopaminergic negative feedback increases insulin secretion, expanding the knowledge of this pathway in β-cells might offer a potential new target for the treatment of type 2 diabetes. PMID:22918877

  1. Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion.

    PubMed

    Giordanetto, Fabrizio; Revell, Jefferson D; Knerr, Laurent; Hostettler, Marie; Paunovic, Amalia; Priest, Claire; Janefeldt, Annika; Gill, Adrian

    2013-12-12

    Agonists of vasoactive intestinal peptide receptor 2 (VPAC2) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC2. However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging. Here, we investigated two peptide cyclization strategies, lactamisation and olefin-metathesis stapling, and their effects on VPAC2 agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC2 agonist potency, glucose-dependent insulin secretion activity, and increased helical content were discovered; however, neither cyclization strategy appeared to effect proteolytic stability or cell permeability of the resulting peptides.

  2. The mitochondrial 2-oxoglutarate carrier is part of a metabolic pathway that mediates glucose- and glutamine-stimulated insulin secretion.

    PubMed

    Odegaard, Matthew L; Joseph, Jamie W; Jensen, Mette V; Lu, Danhong; Ilkayeva, Olga; Ronnebaum, Sarah M; Becker, Thomas C; Newgard, Christopher B

    2010-05-28

    Glucose-stimulated insulin secretion from pancreatic islet beta-cells is dependent in part on pyruvate cycling through the pyruvate/isocitrate pathway, which generates cytosolic alpha-ketoglutarate, also known as 2-oxoglutarate (2OG). Here, we have investigated if mitochondrial transport of 2OG through the 2-oxoglutarate carrier (OGC) participates in control of nutrient-stimulated insulin secretion. Suppression of OGC in clonal pancreatic beta-cells (832/13 cells) and isolated rat islets by adenovirus-mediated delivery of small interfering RNA significantly decreased glucose-stimulated insulin secretion. OGC suppression also reduced insulin secretion in response to glutamine plus the glutamate dehydrogenase activator 2-amino-2-norbornane carboxylic acid. Nutrient-stimulated increases in glucose usage, glucose oxidation, glutamine oxidation, or ATP:ADP ratio were not affected by OGC knockdown, whereas suppression of OGC resulted in a significant decrease in the NADPH:NADP(+) ratio during stimulation with glucose but not glutamine + 2-amino-2-norbornane carboxylic acid. Finally, OGC suppression reduced insulin secretion in response to a membrane-permeant 2OG analog, dimethyl-2OG. These data reveal that the OGC is part of a mechanism of fuel-stimulated insulin secretion that is common to glucose, amino acid, and organic acid secretagogues, involving flux through the pyruvate/isocitrate cycling pathway. Although the components of this pathway must remain intact for appropriate stimulus-secretion coupling, production of NADPH does not appear to be the universal second messenger signal generated by these reactions.

  3. Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

    PubMed Central

    Lehto, M; Tuomi, T; Mahtani, M M; Widén, E; Forsblom, C; Sarelin, L; Gullström, M; Isomaa, B; Lehtovirta, M; Hyrkkö, A; Kanninen, T; Orho, M; Manley, S; Turner, R C; Brettin, T; Kirby, A; Thomas, J; Duyk, G; Lander, E; Taskinen, M R; Groop, L

    1997-01-01

    Maturity-onset diabetes of the young (MODY) type 3 is a dominantly inherited form of diabetes, which is often misdiagnosed as non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM). Phenotypic analysis of members from four large Finnish MODY3 kindreds (linked to chromosome 12q with a maximum lod score of 15) revealed a severe impairment in insulin secretion, which was present also in those normoglycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with IDDM by lack of glutamic acid decarboxylase antibodies (GAD-Ab). Taken together with our recent findings of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM (NIDDM2), the data suggest that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response, that subsequently progresses to diabetes and underlines the importance of subphenotypic classification in studies of diabetes. PMID:9045858

  4. Inhibition of connexin 36 hemichannels by glucose contributes to the stimulation of insulin secretion.

    PubMed

    Pizarro-Delgado, Javier; Fasciani, Ilaria; Temperan, Ana; Romero, María; González-Nieto, Daniel; Alonso-Magdalena, Paloma; Nualart-Marti, Anna; Estil'les, Elisabet; Paul, David L; Martín-del-Río, Rafael; Montanya, Eduard; Solsona, Carles; Nadal, Angel; Barrio, Luis Carlos; Tamarit-Rodríguez, J

    2014-06-15

    The existence of functional connexin36 (Cx36) hemichannels in β-cells was investigated in pancreatic islets of rat and wild-type (Cx36(+/+)), monoallelic (Cx36(+/-)), and biallelic (Cx36(-/-)) knockout mice. Hemichannel opening by KCl depolarization was studied by measuring ATP release and changes of intracellular ATP (ADP). Cx36(+/+) islets lost ATP after depolarization with 70 mM KCl at 5 mM glucose; ATP loss was prevented by 8 and 20 mM glucose or 50 μM mefloquine (connexin inhibitor). ATP content was higher in Cx36(-/-) than Cx36(+/+) islets and was not decreased by KCl depolarization; Cx36(+/-) islets showed values between that of control and homozygous islets. Five minimolar extracellular ATP increased ATP content and ATP/ADP ratio and induced a biphasic insulin secretion in depolarized Cx36(+/+) and Cx36(+/-) but not Cx36(-/-) islets. Cx36 hemichannels expressed in oocytes opened upon depolarization of membrane potential, and their activation was inhibited by mefloquine and glucose (IC₅₀ ∼8 mM). It is postulated that glucose-induced inhibition of Cx36 hemichannels in islet β-cells might avoid depolarization-induced ATP loss, allowing an optimum increase of the ATP/ADP ratio by sugar metabolism and a biphasic stimulation of insulin secretion. Gradual suppression of glucose-induced insulin release in Cx36(+/-) and Cx36(-/-) islets confirms that Cx36 gap junction channels are necessary for a full secretory stimulation and might account for the glucose intolerance observed in mice with defective Cx36 expression. Mefloquine targeting of Cx36 on both gap junctions and hemichannels also suppresses glucose-stimulated secretion. By contrast, glucose stimulation of insulin secretion requires Cx36 hemichannels' closure but keeping gap junction channels opened.

  5. Sulfonylurea Receptor 1 Mutations That Cause Opposite Insulin Secretion Defects with Chemical Chaperone Exposure*S⃞

    PubMed Central

    Pratt, Emily B.; Yan, Fei-Fei; Gay, Joel W.; Stanley, Charles A.; Shyng, Show-Ling

    2009-01-01

    The β-cell ATP-sensitive potassium (KATP) channel composed of sulfonylurea receptor SUR1 and potassium channel Kir6.2 serves a key role in insulin secretion regulation by linking glucose metabolism to cell excitability. Mutations in SUR1 or Kir6.2 that decrease channel function are typically associated with congenital hyperinsulinism, whereas those that increase channel function are associated with neonatal diabetes. Here we report that two hyperinsulinism-associated SUR1 missense mutations, R74W and E128K, surprisingly reduce channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes. Under normal conditions, both mutant channels showed poor surface expression due to retention in the endoplasmic reticulum, accounting for the loss of channel function phenotype in the congenital hyperinsulinism patients. This trafficking defect, however, could be corrected by treating cells with the oral hypoglycemic drugs sulfonylureas, which we have shown previously to act as small molecule chemical chaperones for KATP channels. The R74W and E128K mutants thus rescued to the cell surface paradoxically exhibited ATP sensitivity 6- and 12-fold lower than wild-type channels, respectively. Further analyses revealed a nucleotide-independent decrease in mutant channel intrinsic open probability, suggesting the mutations may reduce ATP sensitivity by causing functional uncoupling between SUR1 and Kir6.2. In insulin-secreting cells, rescue of both mutant channels to the cell surface led to hyperpolarized membrane potentials and reduced insulin secretion upon glucose stimulation. Our results show that sulfonylureas, as chemical chaperones, can dictate manifestation of the two opposite insulin secretion defects by altering the expression levels of the disease mutants. PMID:19151370

  6. Sulfonylurea receptor 1 mutations that cause opposite insulin secretion defects with chemical chaperone exposure.

    PubMed

    Pratt, Emily B; Yan, Fei-Fei; Gay, Joel W; Stanley, Charles A; Shyng, Show-Ling

    2009-03-20

    The beta-cell ATP-sensitive potassium (K(ATP)) channel composed of sulfonylurea receptor SUR1 and potassium channel Kir6.2 serves a key role in insulin secretion regulation by linking glucose metabolism to cell excitability. Mutations in SUR1 or Kir6.2 that decrease channel function are typically associated with congenital hyperinsulinism, whereas those that increase channel function are associated with neonatal diabetes. Here we report that two hyperinsulinism-associated SUR1 missense mutations, R74W and E128K, surprisingly reduce channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes. Under normal conditions, both mutant channels showed poor surface expression due to retention in the endoplasmic reticulum, accounting for the loss of channel function phenotype in the congenital hyperinsulinism patients. This trafficking defect, however, could be corrected by treating cells with the oral hypoglycemic drugs sulfonylureas, which we have shown previously to act as small molecule chemical chaperones for K(ATP) channels. The R74W and E128K mutants thus rescued to the cell surface paradoxically exhibited ATP sensitivity 6- and 12-fold lower than wild-type channels, respectively. Further analyses revealed a nucleotide-independent decrease in mutant channel intrinsic open probability, suggesting the mutations may reduce ATP sensitivity by causing functional uncoupling between SUR1 and Kir6.2. In insulin-secreting cells, rescue of both mutant channels to the cell surface led to hyperpolarized membrane potentials and reduced insulin secretion upon glucose stimulation. Our results show that sulfonylureas, as chemical chaperones, can dictate manifestation of the two opposite insulin secretion defects by altering the expression levels of the disease mutants.

  7. TCF7L2 Regulates Late Events in Insulin Secretion From Pancreatic Islet β-Cells

    PubMed Central

    da Silva Xavier, Gabriela; Loder, Merewyn K.; McDonald, Angela; Tarasov, Andrei I.; Carzaniga, Raffaella; Kronenberger, Katrin; Barg, Sebastian; Rutter, Guy A.

    2009-01-01

    OBJECTIVE Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature β-cell function and suggest a potential mechanism for its actions. RESEARCH DESIGN AND METHODS TCF7L2 expression in rodent islets and β-cell lines was altered using RNAi or adenoviral transduction. β-Cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology. RESULTS Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca2+ concentration ([Ca2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+]i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18–1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion. CONCLUSION—TCF7L2 is involved in maintaining expression of β-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles. PMID:19168596

  8. TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells.

    PubMed

    da Silva Xavier, Gabriela; Loder, Merewyn K; McDonald, Angela; Tarasov, Andrei I; Carzaniga, Raffaella; Kronenberger, Katrin; Barg, Sebastian; Rutter, Guy A

    2009-04-01

    Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature beta-cell function and suggest a potential mechanism for its actions. TCF7L2 expression in rodent islets and beta-cell lines was altered using RNAi or adenoviral transduction. Beta-cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology. Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca2+ concentration ([Ca2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+]i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18-1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion. TCF7L2 is involved in maintaining expression of beta-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles.

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

    PubMed

    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.

  10. Effects of fatty acids and ketone bodies on basal insulin secretion in type 2 diabetes.

    PubMed

    Boden, G; Chen, X

    1999-03-01

    The objective of this study was to assess the role of free fatty acids (FFAs) as insulin secretagogues in patients with type 2 diabetes. To this end, basal insulin secretion rates (ISR) in response to acute increases in plasma FFAs were evaluated in patients with type 2 diabetes and in age- and weight-matched nondiabetic control subjects during 1) intravenous infusion of lipid plus heparin (L/H), which stimulated intravascular lipolysis, and 2) the FFA rebound, which followed lowering of plasma FFAs with nicotinic acid (NA) and was a consequence of increased lipolysis from the subject's own adipose tissue. At comparable euglycemia, diabetic patients had similar ISR but higher plasma beta-hydroxybutyrate (beta-OHB) levels during L/H infusion and higher plasma FFA and beta-OHB levels during the FFA rebound than nondiabetic control subjects. Correlating ISR with plasma FFA plus beta-OHB levels showed that in response to the same changes in FFA plus beta-OHB levels, diabetic patients secreted approximately 30% less insulin than nondiabetic control subjects. In addition, twice as much insulin was secreted during L/H infusion as during the FFA rebound in response to the same FFA/beta-OHB stimulation by both diabetic patients and control subjects. Glycerol, which was present in the infused lipid (272 mmol/l) did not affect ISR. We concluded that 1) assessment of FFA effects on ISR requires consideration of effects on ISR by ketone bodies; 2) ISR responses to FFA/beta-OHB were defective in patients with type 2 diabetes (partial beta-cell lipid blindness), but this defect was compensated by elevated plasma levels of FFAs and ketone bodies; and 3) approximately two times more insulin was released per unit change in plasma FFA plus beta-OHB during L/H infusion than during the FFA rebound after NA. The reason for this remains to be explored.

  11. Dietary fatty acids and insulin secretion: a population-based study.

    PubMed

    Rojo-Martínez, G; Esteva, I; Ruiz de Adana, M S; García-Almeida, J M; Tinahones, F; Cardona, F; Morcillo, S; García-Escobar, E; García-Fuentes, E; Soriguer, F

    2006-10-01

    Few epidemiological studies have examined the relationship of dietary fatty acids, especially MUFA, with the interrelation between insulin secretion and insulin resistance. We assessed the relation of dietary fatty acids with insulin secretion in a free-living population. This cross-sectional, population-based study was undertaken in Pizarra, a small town in Spain. Anthropometrical data were collected for 1226 persons selected randomly from the municipal census, 538 of whom (randomly chosen) were given a prospective, quantitative, 7-day nutritional questionnaire. The fatty acid composition of the serum phospholipids was used as a biological marker of the type of fat consumed. Beta-cell function (betaCFI) and insulin-resistance index (IRI) were estimated by the Homeostasis Model Assessment. To determine which factors influence the variability of the betaCFI, we analyzed the variance of the betaCFI according to sex, the presence of carbohydrate metabolism disorders and the different components of the diet, adjusting the models for age, body mass index (BMI) and IRI. The dietary MUFA and polyunsaturated fatty acids (PUFA) contributed to the variability of the betaCFI, whereas only the proportion of serum phospholipid MUFA, but neither the saturated fatty acids nor the PUFA accounted for part of the variability of the betaCFI in a multiple regression analysis. The results of this population-based study corroborate the results of other clinical and experimental studies suggesting a favorable relationship of MUFA with beta-cell insulin secretion. Fondo de Investigación Sanitaria, Junta de Andalucía and the Asociación Maimónides.

  12. Novel therapy for insulin-dependent diabetes mellitus: infusion of in vitro-generated insulin-secreting cells.

    PubMed

    Dave, S D; Vanikar, A V; Trivedi, H L; Thakkar, U G; Gopal, S C; Chandra, T

    2015-02-01

    Insulin-dependent diabetes mellitus (IDDM) is a metabolic disease usually resulting from autoimmune-mediated β-cell destruction requiring lifetime exogenous insulin replacement. Mesenchymal stem cells (MSC) hold promising therapy. We present our experience of treating IDDM with co-infusion of in vitro autologous adipose tissue-derived MSC-differentiated insulin-secreting cells (ISC) with hematopoietic stem cells (HSC). This was an Institutional Review Board approved prospective non-randomized open-labeled clinical trial after informed consent from ten patients. ISC were differentiated from autologous adipose tissue-derived MSC and were infused with bone marrow-derived HSC in portal, thymic circulation by mini-laparotomy and in subcutaneous circulation. Patients were monitored for blood sugar levels, serum C-peptide levels, glycosylated hemoglobin (Hb1Ac) and glutamic acid decarboxylase (GAD) antibodies. Insulin administration was made on sliding scale with an objective of maintaining FBS < 150 mg/dL and PPBS around 200 mg/dL. Mean 3.34 mL cell inoculums with 5.25 × 10(4) cells/μL were infused. No untoward effects were observed. Over a mean follow-up of 31.71 months, mean serum C-peptide of 0.22 ng/mL before infusion had sustained rise of 0.92 ng/mL with decreased exogenous insulin requirement from 63.9 international units (IU)/day to 38.6 IU/day. Improvement in mean Hb1Ac was observed from 10.99 to 6.72%. Mean GAD antibodies were positive in all patients with mean of 331.10 IU/mL, which decreased to mean of 123 IU/mL. Co-infusion of autologous ISC with HSC represents a viable novel therapeutic option for IDDM.

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

    PubMed

    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.

  14. Lipid transport by TMEM24 at ER-plasma membrane contacts regulates pulsatile insulin secretion.

    PubMed

    Lees, Joshua A; Messa, Mirko; Sun, Elizabeth Wen; Wheeler, Heather; Torta, Federico; Wenk, Markus R; De Camilli, Pietro; Reinisch, Karin M

    2017-02-17

    Insulin is released by β cells in pulses regulated by calcium and phosphoinositide signaling. Here, we describe how transmembrane protein 24 (TMEM24) helps coordinate these signaling events. We showed that TMEM24 is an endoplasmic reticulum (ER)-anchored membrane protein whose reversible localization to ER-plasma membrane (PM) contacts is governed by phosphorylation and dephosphorylation in response to oscillations in cytosolic calcium. A lipid-binding module in TMEM24 transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol between bilayers, allowing replenishment of PI(4,5)P2 hydrolyzed during signaling. In the absence of TMEM24, calcium oscillations are abolished, leading to a defect in triggered insulin release. Our findings implicate direct lipid transport between the ER and the PM in the control of insulin secretion, a process impaired in patients with type II diabetes.

  15. Engineering of pseudoislets: effect on insulin secretion activity by cell number, cell population, and microchannel networks.

    PubMed

    Kojima, N; Takeuchi, S; Sakai, Y

    2014-05-01

    Engineered pseudoislets reconstituted from a suspension of pancreatic α and β cells have the potential to relieve the shortage of donor islets for transplantation in the treatment of type 1 diabetes. However, the methods to fabricate pseudoislets are not well developed. In this study, we attempted to generate pseudoislets, which show a higher potential for glucose-induced insulin secretion, by altering total cell number, adjusting the cell ratio of pancreatic α and β cells, and fabricating microchannel networks with the use of alginate hydrogel beads. To effectively aggregate α and β cells and hydrogel beads, we used a previously established rapid aggregation method. When pseudoislets were reconstituted with 8,000 cells in a 1:8 α/β-cell ratio, we observed that the glucose-induced insulin secretion was enhanced by 3.1 times compared with the pseudoislets formed with β cells only. In addition, embedding of microchannel networks increased the insulin secretion rate by 4.4 times compared with the pseudoislets without the microstructures. These findings demonstrated that active modification was effective in reconstituting higher functional pseudoislets, which may be useful for islet transplantation.

  16. Interaction of Munc18 and Syntaxin in the regulation of insulin secretion

    SciTech Connect

    Dong, Yongming; Wan, Qunfang; Yang, Xiaofei; Bai, Li; Xu, Pingyong . E-mail: pyxu@moon.ibp.ac.cn

    2007-08-31

    Syntaxin1A and Munc18-1 play essential roles in exocytosis. However, the molecular mechanism and the functional roles of their interaction in insulin secretion remain to be explored. Using membrane capacitance measurement, we examine effect of overexpressing Munc18-1 on exocytosis in pancreatic {beta} cells. The results show that Munc18-1 negatively regulates vesicle fusion. To probe the interaction between Munc18-1 and Syntaxin1A, Munc18-1-Tdimer2 and EGFP-Syntaxin1A were co-transfected into INS-1 cells. FRET measurement confirmed that Munc18-1 interacted with wild type Syntaxin 1A, but not the constitutively open form (DM) of Syntaxin1A. Overexpressing DM in primary pancreatic {beta} cells augmented insulin secretion, and this effect can overcome the inhibitory effect of Munc18-1 overexpression. We propose that Munc18-1 inhibitis the SNARE complex assembly by stabilizing Syntaxin1A in a closed conformation in vesicle priming process, therefore negatively regulates insulin secretion.

  17. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion

    PubMed Central

    van der Meulen, Talitha; Donaldson, Cynthia J.; Cáceres, Elena; Hunter, Anna E.; Cowing–Zitron, Christopher; Pound, Lynley D.; Adams, Michael W.; Zembrzycki, Andreas; Grove, Kevin L.; Huising, Mark O.

    2015-01-01

    The peptide hormone Urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co–released with insulin and potentiates glucose–stimulated somatostatin secretion via cognate receptor on delta cells. Further, we found that islets lacking endogenous Ucn3 demonstrate fewer delta cells, reduced somatostatin content, impaired somatostatin secretion and exaggerated insulin release, and that these defects are rectified by synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque diabetes models and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease. PMID:26076035

  18. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion.

    PubMed

    van der Meulen, Talitha; Donaldson, Cynthia J; Cáceres, Elena; Hunter, Anna E; Cowing-Zitron, Christopher; Pound, Lynley D; Adams, Michael W; Zembrzycki, Andreas; Grove, Kevin L; Huising, Mark O

    2015-07-01

    The peptide hormone urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co-released with insulin and potentiates glucose-stimulated somatostatin secretion via cognate receptors on delta cells. Further, we found that islets lacking endogenous Ucn3 have fewer delta cells, reduced somatostatin content, impaired somatostatin secretion, and exaggerated insulin release, and that these defects are rectified by treatment with synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque models of diabetes and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control, whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease.

  19. Reversal of diabetes following transplantation of an insulin-secreting human liver cell line: Melligen cells

    PubMed Central

    Lawandi, Janet; Tao, Chang; Ren, Binhai; Williams, Paul; Ling, Dora; Swan, M Anne; Nassif, Najah T; Torpy, Fraser R; O’Brien, Bronwyn A; Simpson, Ann M

    2015-01-01

    As an alternative to the transplantation of islets, a human liver cell line has been genetically engineered to reverse type 1 diabetes (TID). The initial liver cell line (Huh7ins) commenced secretion of insulin in response to a glucose concentration of 2.5 mmol/l. After transfection of the Huh7ins cells with human islet glucokinase, the resultant Melligen cells secreted insulin in response to glucose within the physiological range; commencing at 4.25 mmol/l. Melligen cells exhibited increased glucokinase enzymatic activity in response to physiological glucose concentrations, as compared with Huh7ins cells. When transplanted into diabetic immunoincompetent mice, Melligen cells restored normoglycemia. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that both cell lines expressed a range of β-cell transcription factors and pancreatic hormones. Exposure of Melligen and Huh7ins cells to proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) affected neither their viability nor their ability to secrete insulin to glucose. Gene expression (microarray and qRT-PCR) analyses indicated the survival of Melligen cells in the presence of known β-cell cytotoxins was associated with the expression of NF-κB and antiapoptotic genes (such as BIRC3). This study describes the successful generation of an artificial β-cell line, which, if encapsulated to avoid allograft rejection, may offer a clinically applicable cure for T1D. PMID:26029722

  20. Direct Substrate Delivery into Mitochondrial-Fission Deficient Pancreatic Islets Rescues Insulin Secretion.

    PubMed

    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

    2017-02-07

    In pancreatic beta cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion (GSIS). Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we here demonstrate that mitochondrial fission is necessary for GSIS 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-fuelled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient beta cells, demonstrating that defective mitochondrial dynamics solely impact substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights in how mitochondrial dysfunction may cause pancreatic beta 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.

  1. The effects of sevoflurane anesthesia on insulin secretion and glucose metabolism in pigs.

    PubMed

    Saho, S; Kadota, Y; Sameshima, T; Miyao, J; Tsurumaru, T; Yoshimura, N

    1997-06-01

    We investigated the effects of two different concentrations of sevoflurane, 0.4 minimum alveolar anesthetic concentration (MAC) and 1.0 MAC, on insulin secretion before, during, and after sevoflurane anesthesia using three successive intravenous glucose tolerance tests (IVGTT) in pigs with indwelling catheters. We also investigated changes in the levels of plasma glucose, catecholamines (epinephrine [E], norepinephrine [NE]), and cortisol (Cor). The pigs were grouped as awake, 0.4 MAC, or 1.0 MAC. Sevoflurane decreased the ratio of insulin/glucose (INS/GLU) in the basal condition (P < 0.05 awake versus 1.0 MAC) and during IVGTT (P < 0.01 awake versus 1.0 MAC and 0.4 MAC). These decreases were quickly reversible (control levels were regained within 2 h of the end of anesthesia), were probably dose-related, appeared not to be mediated by E, NE, or Cor. In addition, the INS/GLU ratio 2.5-4 h after the end of anesthesia was significantly higher in the anesthetized groups than in the awake group. We conclude that sevoflurane anesthesia has a rapidly reversible inhibitory effect on basal and glucose-stimulated insulin secretion, as do other inhaled anesthetics, and might induce insulin resistance.

  2. A novel Gymnema sylvestre extract stimulates insulin secretion from human islets in vivo and in vitro.

    PubMed

    Al-Romaiyan, A; Liu, B; Asare-Anane, H; Maity, C R; Chatterjee, S K; Koley, N; Biswas, T; Chatterji, A K; Huang, G-C; Amiel, S A; Persaud, S J; Jones, P M

    2010-09-01

    Many plant-based products have been suggested as potential antidiabetic agents, but few have been shown to be effective in treating the symptoms of Type 2 diabetes mellitus (T2DM) in human studies, and little is known of their mechanisms of action. Extracts of Gymnema sylvestre (GS) have been used for the treatment of T2DM in India for centuries. The effects of a novel high molecular weight GS extract, Om Santal Adivasi, (OSA(R)) on plasma insulin, C-peptide and glucose in a small cohort of patients with T2DM are reported here. Oral administration of OSA(R) (1 g/day, 60 days) induced significant increases in circulating insulin and C-peptide, which were associated with significant reductions in fasting and post-prandial blood glucose. In vitro measurements using isolated human islets of Langerhans demonstrated direct stimulatory effects of OSA(R) on insulin secretion from human ß-cells, consistent with an in vivo mode of action through enhancing insulin secretion. These in vivo and in vitro observations suggest that OSA(R) may provide a potential alternative therapy for the hyperglycemia associated with T2DM.

  3. Stimulatory effect of apigenin-6-C-beta-L-fucopyranoside on insulin secretion and glycogen synthesis.

    PubMed

    Cazarolli, Luisa Helena; Folador, Poliane; Moresco, Henrique Hunger; Brighente, Inês Maria Costa; Pizzolatti, Moacir Geraldo; Silva, Fátima Regina M Barreto

    2009-11-01

    In vivo and in vitro treatments were carried out to investigate the effects of apigenin-6-C-beta-L-fucopyranoside (1), isolated from Averrhoa carambola L. (Oxalidaceae), on serum glucose and insulin levels in hyperglycemic rats as well as its effect on glycogen synthesis in normal rat soleus muscle. Apigenin-6-C-beta-L-fucopyranoside showed an acute effect on blood glucose lowering in hyperglycemic rats and stimulated glucose-induced insulin secretion. A stimulatory effect of 1 on glycogen synthesis was observed when muscles were incubated with this flavonoid and also its effect was completely nullified by pre-treatment with insulin signal transduction inhibitors. Taking this into account, the MAPK-PP1 and PI3K-GSK3 pathways are involved in the apigenin-6-C-beta-L-fucopyranoside-induced increase in glycogen synthesis in muscle. This study provides evidence for dual effects of apigenin-6-C-beta-L-fucopyranoside as an antihyperglycemic (insulin secretion) as well as an insulinomimetic (glycogen synthesis) agent.

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

    PubMed

    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.

  5. Theophylline prevents the inhibitory effect of prostaglandin E2 on glucose-induced insulin secretion in man.

    PubMed

    Giugliano, D; Cozzolino, D; Salvatore, T; Giunta, R; Torella, R

    1988-06-01

    This study was undertaken to assess the mechanism by which prostaglandins of the E series inhibit glucose-induced insulin secretion in man. Acute insulin response (mean change 3-10 min) to iv glucose (0.33 g/kg) was decreased by 40% during the infusion of prostaglandin E2 (10 micrograms/min) and glucose disappearance rates were reduced (P less than 0.05). Insulin response to arginine (5 g iv) and tolbutamide (1 g iv) were not affected by the same rate of prostaglandin E2 infusion. The inhibitory effect of prostaglandin E2 on glucose-induced insulin secretion was prevented by theophylline (100 mg as a loading dose followed by a 5 mg/min infusion), a drug that increases the intracellular cAMP concentrations by inhibiting phosphodiesterase activity. Our data suggest the involvement of the adenylate cyclase system in the inhibitory action of prostaglandin E2 on glucose-induced insulin secretion in man.

  6. Pathophysiology of diabetes mellitus type 2: beyond the duo "insulin resistance-secretion deficit".

    PubMed

    Carrera Boada, C A; Martínez-Moreno, J M

    2013-03-01

    T2DM involves at least two primary pathogenic mechanisms: (a) a progressive decline in pancreatic islet cell function resulting in reduced insulin secretion and (b) peripheral insulin resistance resulting in a decrease in the metabolic responses to insulin. This dynamic interaction between insulin secretion and insulin resistance is essential to the maintenance of normal glucose tolerance (NGT). The transition from the normal control of glucose metabolism to type 2 diabetes mellitus occurs through the intermediate states of altered metabolism that worsen over time. The first state of the disease is known as prediabetes, and consists of a set of metabolic disorder characterized by a great hyperglycemia, enough to increase of retinopathies, nephropathies and neuropathies incidence. If we advance in the T2DM temporal sequence we found a remarkable change in the pancreatic cells population that form the Langerhans islets, mainly caused by amylin fibers accumulation over these cells from polypeptide hormone called amyloid polypeptide or IAPP. The IAPP hypersecretion and amylin fibers deposition attached to the endoplasmic reticulum stress caused by excessive workload due to biosynthesis overproduction of insulin and IAPP result in ?-cell apoptosis. In addition to these alterations, we must also consider the changes observed in incretins profiles like GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide 1) directly related to glucose homeostasis maintenance. Risk factors that predispose to a healthy individual to develop T2DM are several, but the most important is the obesity. The body mass index (BMI) has been used in numerous epidemiological studies as a powerful indicator of T2DM risk. Lipotoxicity caused by circulating free fatty acids increased, changes in lipoprotein profiles, body fat distribution and glucotoxicity caused by cells over-stimulation are other risk factors to consider in T2DM developing.

  7. Endogenous gut-derived bacterial endotoxin tonically primes pancreatic secretion of insulin in normal rats.

    PubMed

    Cornell, R P

    1985-12-01

    This laboratory has proposed that endogenous gut-derived bacterial endotoxin primes the pancreatic secretion of insulin in normal rats. Endogenous lipopolysaccharide (LPS) is continually absorbed from the gut into intestinal capillaries, and low-grade portal venous endotoxemia is the status quo. Under physiologic conditions, Kupffer cells of the liver totally phagocytize and degrade endotoxin from the portal circulation. Evidence from this and other laboratories indicates that administration of exogenous LPS to humans and rats enhances pancreatic secretion of both insulin and glucagon. Conversely, findings of the present study demonstrate that restriction of endogenous LPS in fasted rats depresses the basal and arginine-stimulated concentrations of plasma insulin. Techniques used to restrict gut-derived LPS availability included chronic daily gavage with neomycin and cefazolin for gut sterilization and with cholestyramine or lactulose to reduce endotoxin within the gut. In addition, induction of endotoxin tolerance was produced by progressively higher doses of LPS intraperitoneally (i.p.), and polymyxin B was administered subcutaneously (s.c.) daily to neutralize the lipid A portion of circulating LPS. Finally, isolator-reared, defined flora rats, which were gram-negative-bacteria-deficient, and, therefore, LPS-deficient, were compared with conventional counterparts. Basal plasma insulin but not glucagon levels were consistently and significantly reduced in endogenous LPS-restricted animals. Glucose-stimulated plasma insulin was decreased only after parenteral treatment by tolerance induction and polymyxin B administration. Both plasma insulin and glucagon were depressed in response to arginine challenge in most LPS-restricted rats.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells.

    PubMed

    Dai, Feihan F; Bhattacharjee, Alpana; Liu, Ying; Batchuluun, Battsetseg; Zhang, Ming; Wang, Xinye Serena; Huang, Xinyi; Luu, Lemieux; Zhu, Dan; Gaisano, Herbert; Wheeler, Michael B

    2015-10-09

    GLP1 activates its receptor, GLP1R, to enhance insulin secretion. The activation and transduction of GLP1R requires complex interactions with a host of accessory proteins, most of which remain largely unknown. In this study, we used membrane-based split ubiquitin yeast two-hybrid assays to identify novel GLP1R interactors in both mouse and human islets. Among these, ATP6ap2 (ATPase H(+)-transporting lysosomal accessory protein 2) was identified in both mouse and human islet screens. ATP6ap2 was shown to be abundant in islets including both alpha and beta cells. When GLP1R and ATP6ap2 were co-expressed in beta cells, GLP1R was shown to directly interact with ATP6ap2, as assessed by co-immunoprecipitation. In INS-1 cells, overexpression of ATP6ap2 did not affect insulin secretion; however, siRNA knockdown decreased both glucose-stimulated and GLP1-induced insulin secretion. Decreases in GLP1-induced insulin secretion were accompanied by attenuated GLP1 stimulated cAMP accumulation. Because ATP6ap2 is a subunit required for V-ATPase assembly of insulin granules, it has been reported to be involved in granule acidification. In accordance with this, we observed impaired insulin granule acidification upon ATP6ap2 knockdown but paradoxically increased proinsulin secretion. Importantly, as a GLP1R interactor, ATP6ap2 was required for GLP1-induced Ca(2+) influx, in part explaining decreased insulin secretion in ATP6ap2 knockdown cells. Taken together, our findings identify a group of proteins that interact with the GLP1R. We further show that one interactor, ATP6ap2, plays a novel dual role in beta cells, modulating both GLP1R signaling and insulin processing to affect insulin secretion.

  9. Identification of morin as an agonist of imidazoline I-3 receptor for insulin secretion in diabetic rats.

    PubMed

    Lin, Mang Hung; Hsu, Chia-Chen; Lin, Jenshinn; Cheng, Juei-Tang; Wu, Ming Chang

    2017-07-08

    Morin is a flavonoid contained in guava that is known to reduce hyperglycemia in diabetics. Morin has been demonstrated to increase plasma insulin. However, the mechanism(s) remains unknown. The present study is designed to investigate the effect of morin on the imidazoline receptor (I-R) that regulates insulin secretion. We used Chinese hamster ovary (CHO) cells transfected with an I-R expression construct (NISCH-CHO-K1 cells) to identify the direct effect of morin on the I-R. Moreover, the imidazoline I3 receptor (I-3R) is known to be present in pancreatic β cells and involved in insulin secretion. Therefore, we applied a specific antagonist (KU14R) to block I-3R in diabetic rats. Additionally, the effect of morin on insulin secretion was characterized in isolated pancreatic islets. Morin decreased blood glucose levels by increasing plasma insulin levels in diabetic rats. In CHO cells expressing an I-R, morin increased calcium influx in a dose-dependent manner. Additionally, KU14R dose-dependently inhibited the morin-induced effects, including hypoglycemia and the increase in insulin secretion and plasma C-peptide levels, in diabetic rats. Furthermore, morin enhanced insulin secretion from isolated pancreatic islets, and this effect was also dose-dependently inhibited by KU14R. Phospholipase C (PLC) is known to couple with the I-R, and a PLC inhibitor dose-dependently attenuated the insulin secretion induced by morin in isolated pancreatic islets. Taken together, these data suggest that morin can activate I-3R to enhance insulin secretion. Therefore, it would be useful to develop morin into a treatment for diabetic disorders.

  10. Enhanced glycemic responsiveness to epinephrine in insulin-dependent diabetes mellitus is the result of the inability to secrete insulin. Augmented insulin secretion normally limits the glycemic, but not the lipolytic or ketogenic, response to epinephrine in humans.

    PubMed Central

    Berk, M A; Clutter, W E; Skor, D; Shah, S D; Gingerich, R P; Parvin, C A; Cryer, P E

    1985-01-01

    To determine if the enhanced glycemic response to epinephrine in patients with insulin-dependent diabetes mellitus (IDDM) is the result of increased adrenergic sensitivity per se, increased glucagon secretion, decreased insulin secretion, or a combination of these, plasma epinephrine concentration-response curves were determined in insulin-infused (initially euglycemic) patients with IDDM and nondiabetic subjects on two occasions: once when insulin and glucagon were free to change (control study), and again when insulin and glucagon were held constant (islet clamp study). During the control study, plasma C-peptide doubled, and glucagon did not change in the nondiabetic subjects, whereas plasma C-peptide did not change but glucagon increased in the patients. The patients with IDDM exhibited threefold greater increments in plasma glucose, largely the result of greater increments in glucose production. This enhanced glycemic response was apparent with 30-min increments in epinephrine to plasma concentrations as low as 100-200 pg/ml, levels that occur commonly under physiologic conditions. During the islet clamp study (somatostatin infusion with insulin and glucagon replacement at fixed rates), the heightened glycemic response was unaltered in the patients with IDDM, but the nondiabetic subjects exhibited an enhanced glycemic response to epinephrine indistinguishable from that of patients with IDDM. In contrast, the FFA, glycerol, and beta-hydroxybutyrate responses were unaltered. Thus, we conclude the following: Short, physiologic increments in plasma epinephrine cause greater increments in plasma glucose in patients with IDDM than in nondiabetic subjects, a finding likely to be relevant to glycemic control during the daily lives of such patients as well as during the stress of intercurrent illness. Enhanced glycemic responsiveness of patients with IDDM to epinephrine is not the result of increased sensitivity of adrenergic receptor-effector mechanisms per se nor of

  11. Enhanced glycemic responsiveness to epinephrine in insulin-dependent diabetes mellitus is the result of the inability to secrete insulin. Augmented insulin secretion normally limits the glycemic, but not the lipolytic or ketogenic, response to epinephrine in humans.

    PubMed

    Berk, M A; Clutter, W E; Skor, D; Shah, S D; Gingerich, R P; Parvin, C A; Cryer, P E

    1985-06-01

    To determine if the enhanced glycemic response to epinephrine in patients with insulin-dependent diabetes mellitus (IDDM) is the result of increased adrenergic sensitivity per se, increased glucagon secretion, decreased insulin secretion, or a combination of these, plasma epinephrine concentration-response curves were determined in insulin-infused (initially euglycemic) patients with IDDM and nondiabetic subjects on two occasions: once when insulin and glucagon were free to change (control study), and again when insulin and glucagon were held constant (islet clamp study). During the control study, plasma C-peptide doubled, and glucagon did not change in the nondiabetic subjects, whereas plasma C-peptide did not change but glucagon increased in the patients. The patients with IDDM exhibited threefold greater increments in plasma glucose, largely the result of greater increments in glucose production. This enhanced glycemic response was apparent with 30-min increments in epinephrine to plasma concentrations as low as 100-200 pg/ml, levels that occur commonly under physiologic conditions. During the islet clamp study (somatostatin infusion with insulin and glucagon replacement at fixed rates), the heightened glycemic response was unaltered in the patients with IDDM, but the nondiabetic subjects exhibited an enhanced glycemic response to epinephrine indistinguishable from that of patients with IDDM. In contrast, the FFA, glycerol, and beta-hydroxybutyrate responses were unaltered. Thus, we conclude the following: Short, physiologic increments in plasma epinephrine cause greater increments in plasma glucose in patients with IDDM than in nondiabetic subjects, a finding likely to be relevant to glycemic control during the daily lives of such patients as well as during the stress of intercurrent illness. Enhanced glycemic responsiveness of patients with IDDM to epinephrine is not the result of increased sensitivity of adrenergic receptor-effector mechanisms per se nor of

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

    PubMed Central

    Nam, Jeongsu

    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 (p<0.05). In diabetic rats, those levels in the CATO group seemed to be lower during the 30~180 min, but only glucose level at 30 min showed significant difference compared to that in the control group. Moreover, CATO delayed the peak time of the glucose rise in both normal and diabetic rats in the glucose curves. On the other hand, when CATO was administered orally to the diabetic rats for 5 days, 12 hr fasting serum glucose level was decreased in the diabetic rats (p<0.05). Degree of a decrease in 12 hr fasting serum insulin levels was significantly less in the diabetic CATO rats as compared to diabetic control rats. On the last day of feeding, β cells of the pancreas were stimulated by 200 mg/dL glucose through a 40 min-pancreas perfusion. Amounts of the insulin secreted from the pancreas during the first phase (11~20 min) and the second phase (21~40 min) in the CATO fed diabetic rats were significantly greater than those in the diabetic control group (p<0.05). These findings indicated that constituents of Cassia 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. PMID:20016725

  13. Pancreatic fat content assessed by (1) H magnetic resonance spectroscopy is correlated with insulin resistance, but not with insulin secretion, in Japanese individuals with normal glucose tolerance.

    PubMed

    Komada, Hisako; Sakaguchi, Kazuhiko; Hirota, Yushi; Sou, Anna; Nakamura, Tomoaki; Kyotani, Katsusuke; Kawamitsu, Hideaki; Sugimura, Kazuro; Okuno, Yoko; Ogawa, Wataru

    2017-08-02

    Whereas some clinical studies have shown that excessive fat accumulation in the pancreas is associated with impairment of insulin secretion, others have not found such an association. (1) H magnetic resonance spectroscopy allows quantitative fat analysis in various tissues including the pancreas. The pathological relevance of pancreatic fat content (PFC) in Japanese individuals remains unclear, however. We analyzed PFC in 30 Japanese individuals with normal glucose tolerance by (1) H magnetic resonance spectroscopy, and then investigated the relationships between PFC and indexes of insulin secretion and insulin sensitivity-resistance determined by an oral glucose tolerance test. We also measured hepatic fat content and intramyocellular lipid content by (1) H magnetic resonance spectroscopy, as well as visceral fat area and subcutaneous fat area by magnetic resonance imaging, and we examined the relationships between these fat content measures and oral glucose tolerance test-derived parameters. PFC was correlated with indexes of insulin sensitivity-resistance, but not with those of insulin secretion. Hepatic fat content and visceral fat area were correlated with similar sets of parameters as was PFC, whereas subcutaneous fat area was correlated with parameters of insulin secretion, and intramyocellular lipid content was not correlated with any of the measured parameters. The correlation between PFC and homeostasis model assessment of insulin resistance remained significant after adjustment for age, body mass index and sex. Among fat content measures, PFC was most highly correlated with hepatic fat content and visceral fat area. PFC was correlated with indexes of insulin resistance, but not with those of insulin secretion in non-obese Japanese individuals with normal glucose tolerance. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  14. Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase β-cell mass in fetal sheep.

    PubMed

    Gadhia, Monika M; Maliszewski, Anne M; O'Meara, Meghan C; Thorn, Stephanie R; Lavezzi, Jinny R; Limesand, Sean W; Hay, William W; Brown, Laura D; Rozance, Paul J

    2013-02-15

    Amino acids and glucose acutely stimulate fetal insulin secretion. In isolated adult pancreatic islets, amino acids potentiate glucose-stimulated insulin secretion (GSIS), but whether amino acids have this same effect in the fetus is unknown. Therefore, we tested the effects of increased fetal amino acid supply on GSIS and morphology of the pancreas. We hypothesized that increasing fetal amino acid supply would potentiate GSIS. Singleton fetal sheep received a direct intravenous infusion of an amino acid mixture (AA) or saline (CON) for 10-14 days during late gestation to target a 25-50% increase in fetal branched-chain amino acids (BCAA). Early-phase GSIS increased 150% in the AA group (P < 0.01), and this difference was sustained for the duration of the hyperglycemic clamp (105 min) (P < 0.05). Glucose-potentiated arginine-stimulated insulin secretion (ASIS), pancreatic insulin content, and pancreatic glucagon content were similar between groups. β-Cell mass and area were unchanged between groups. Baseline and arginine-stimulated glucagon concentrations were increased in the AA group (P < 0.05). Pancreatic α-cell mass and area were unchanged. Fetal and pancreatic weights were similar. We conclude that a sustained increase of amino acid supply to the normally growing late-gestation fetus potentiated fetal GSIS but did not affect the morphology or insulin content of the pancreas. We speculate that increased β-cell responsiveness (insulin secretion) following increased amino acid supply may be due to increased generation of secondary messengers in the β-cell. This may be enhanced by the paracrine action of glucagon on the β-cell.

  15. Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase β-cell mass in fetal sheep

    PubMed Central

    Gadhia, Monika M.; Maliszewski, Anne M.; O'Meara, Meghan C.; Thorn, Stephanie R.; Lavezzi, Jinny R.; Limesand, Sean W.; Hay, William W.; Brown, Laura D.

    2013-01-01

    Amino acids and glucose acutely stimulate fetal insulin secretion. In isolated adult pancreatic islets, amino acids potentiate glucose-stimulated insulin secretion (GSIS), but whether amino acids have this same effect in the fetus is unknown. Therefore, we tested the effects of increased fetal amino acid supply on GSIS and morphology of the pancreas. We hypothesized that increasing fetal amino acid supply would potentiate GSIS. Singleton fetal sheep received a direct intravenous infusion of an amino acid mixture (AA) or saline (CON) for 10–14 days during late gestation to target a 25–50% increase in fetal branched-chain amino acids (BCAA). Early-phase GSIS increased 150% in the AA group (P < 0.01), and this difference was sustained for the duration of the hyperglycemic clamp (105 min) (P < 0.05). Glucose-potentiated arginine-stimulated insulin secretion (ASIS), pancreatic insulin content, and pancreatic glucagon content were similar between groups. β-Cell mass and area were unchanged between groups. Baseline and arginine-stimulated glucagon concentrations were increased in the AA group (P < 0.05). Pancreatic α-cell mass and area were unchanged. Fetal and pancreatic weights were similar. We conclude that a sustained increase of amino acid supply to the normally growing late-gestation fetus potentiated fetal GSIS but did not affect the morphology or insulin content of the pancreas. We speculate that increased β-cell responsiveness (insulin secretion) following increased amino acid supply may be due to increased generation of secondary messengers in the β-cell. This may be enhanced by the paracrine action of glucagon on the β-cell. PMID:23211516

  16. Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes.

    PubMed

    Duan, Franklin F; Liu, Joy H; March, John C

    2015-05-01

    The inactive full-length form of GLP-1(1-37) stimulates conversion of both rat and human intestinal epithelial cells into insulin-secreting cells. We investigated whether oral administration of human commensal bacteria engineered to secrete GLP-1(1-37) could ameliorate hyperglycemia in a rat model of diabetes by reprogramming intestinal cells into glucose-responsive insulin-secreting cells. Diabetic rats were fed daily with human lactobacilli engineered to secrete GLP-1(1-37). Diabetic rats fed GLP-1-secreting bacteria showed significant increases in insulin levels and, additionally, were significantly more glucose tolerant than those fed the parent bacterial strain. These rats developed insulin-producing cells within the upper intestine in numbers sufficient to replace ∼25-33% of the insulin capacity of nondiabetic healthy rats. Intestinal tissues in rats with reprogrammed cells expressed MafA, PDX-1, and FoxA2. HNF-6 expression was observed only in crypt epithelia expressing insulin and not in epithelia located higher on the villous axis. Staining for other cell markers in rats treated with GLP-1(1-37)-secreting bacteria suggested that normal function was not inhibited by the close physical proximity of reprogrammed cells. These results provide evidence of the potential for a safe and effective nonabsorbed oral treatment for diabetes and support the concept of engineered commensal bacterial signaling to mediate enteric cell function in vivo.

  17. Engineered Commensal Bacteria Reprogram Intestinal Cells Into Glucose-Responsive Insulin-Secreting Cells for the Treatment of Diabetes

    PubMed Central

    Duan, Franklin F.; Liu, Joy H.

    2015-01-01

    The inactive full-length form of GLP-1(1-37) stimulates conversion of both rat and human intestinal epithelial cells into insulin-secreting cells. We investigated whether oral administration of human commensal bacteria engineered to secrete GLP-1(1-37) could ameliorate hyperglycemia in a rat model of diabetes by reprogramming intestinal cells into glucose-responsive insulin-secreting cells. Diabetic rats were fed daily with human lactobacilli engineered to secrete GLP-1(1-37). Diabetic rats fed GLP-1–secreting bacteria showed significant increases in insulin levels and, additionally, were significantly more glucose tolerant than those fed the parent bacterial strain. These rats developed insulin-producing cells within the upper intestine in numbers sufficient to replace ∼25–33% of the insulin capacity of nondiabetic healthy rats. Intestinal tissues in rats with reprogrammed cells expressed MafA, PDX-1, and FoxA2. HNF-6 expression was observed only in crypt epithelia expressing insulin and not in epithelia located higher on the villous axis. Staining for other cell markers in rats treated with GLP-1(1-37)–secreting bacteria suggested that normal function was not inhibited by the close physical proximity of reprogrammed cells. These results provide evidence of the potential for a safe and effective nonabsorbed oral treatment for diabetes and support the concept of engineered commensal bacterial signaling to mediate enteric cell function in vivo. PMID:25626737

  18. Protein Inhibitor of Activated STAT Y (PIASy) Regulates Insulin Secretion by Interacting with LIM Homeodomain Transcription Factor Isl1

    PubMed Central

    Yan, Chengzhi; Yu, Chulin; Zhang, Di; Cui, Yan; Zhou, Jinlian; Cui, Sheng

    2016-01-01

    It is known that the LIM homeodomain transcription factor Isl1 is highly expressed in all pancreatic endocrine cells and functions in regulating pancreatic development and insulin secretion. The Isl1 mutation has been found to be associated with type 2 diabetes, but the mechanism responsible for Isl1 regulation of insulin synthesis and secretion still needs to be elucidated. In the present study, the protein inhibitor of activated STAT Y (PIASy) was identified as a novel Isl1-interacting protein with a yeast two-hybrid system, and its interaction with Isl1 was further confirmed by a co-immunoprecipitation experiment. PIASy and Isl1 colocalize in human and mouse pancreas and NIT beta cells. Furthermore, PIASy and Isl1 upregulate insulin gene expression and insulin secretion in a dose-dependent manner by activating the insulin promoter. PIASy and Isl1 mRNA expression levels were also increased in type 2 diabetic db/db mice. In addition, our results demonstrate that PIASy and Isl1 cooperate to activate the insulin promoter through the Isl1 homeodomain and PIASy ring domain. These data suggest that that PIASy regulates insulin synthesis and secretion by interacting with Isl1 and provide new insight into insulin regulation, although the detailed molecular mechanism needs to be clarified in future studies. PMID:28000708

  19. Insulin secretion and sensitivity in healthy adults with low vitamin D are not affected by high-dose ergocalciferol administration: a randomized controlled trial12

    PubMed Central

    Mitchell, Deborah M; Leder, Benjamin Z; Cagliero, Enrico; Mendoza, Natalia; Henao, Maria P; Hayden, Douglas L; Finkelstein, Joel S; Burnett-Bowie, Sherri-Ann M

    2015-01-01

    Background: Epidemiologic data suggest that low serum 25-hydroxyvitamin D [25(OH)D] increases insulin resistance and the risk of type 2 diabetes. Few interventional trials have assessed the effect of vitamin D on insulin metabolism, and published results are discordant. Objective: The goal of this study was to perform a detailed assessment of the effect of ergocalciferol administration on glucose and insulin metabolism in healthy people with low total 25(OH)Dtotal. Design: This was a 12-wk, double-blinded, randomized controlled trial. We enrolled 90 healthy volunteers aged 18–45 y with serum 25(OH)D ≤20 ng/mL (by immunoassay) and administered 50,000 IU ergocalciferol/wk or placebo for 12 wk. Primary endpoints were change in first-phase insulin response and insulin sensitivity as measured by intravenous glucose tolerance test. Secondary endpoints included change in homeostasis model assessment of insulin resistance; fasting glucose, insulin, and lipids; body mass index (BMI); and blood pressure. Results: On-study 25(OH)Dtotal was assessed by liquid chromatography–tandem mass spectrometry. In the treated group, 25(OH)Dtotal rose from 18 ± 7 to 43 ± 12 ng/mL (P < 0.001) with no change in the placebo group. Despite this increase, at 12 wk, there were no between-group differences in either insulin response or insulin sensitivity; nor were there differences in any measured secondary endpoints. There was no evidence of effect modification by sex, race, glucose tolerance status, baseline 25(OH)Dtotal, or BMI. Conclusion: In healthy persons with low 25(OH)Dtotal, ergocalciferol administration for 12 wk normalizes 25(OH)Dtotal but does not improve insulin secretion, insulin sensitivity, or other markers of metabolic health. This trial was registered at clinicaltrials.gov as NCT00491322. PMID:26156733

  20. Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents

    PubMed Central

    Yasuda, Shin-ichiro; Tsuchida, Takuma; Oguma, Takahiro; Marley, Anna; Wennberg-Huldt, Charlotte; Hovdal, Daniel; Fukuda, Hajime; Yoneyama, Yukimi; Sasaki, Kazuyo; Johansson, Anders; Lundqvist, Sara; Brengdahl, Johan; Isaacs, Richard J.; Brown, Daniel; Geschwindner, Stefan; Benthem, Lambertus; Priest, Claire; Turnbull, Andrew

    2015-01-01

    Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents. PMID:26720709

  1. Hormones and Obesity: Changes in Insulin and Growth Hormone Secretion Following Surgically Induced Weight Loss

    PubMed Central

    Crockford, P. M.; Salmon, P. A.

    1970-01-01

    Ten obese patients were subjected to insulin tolerance tests (0.2 unit per kg. regular insulin intravenously) and/or treadmill exercise tolerance testing (2.6 m.p.h. at 11° angulation) before and after surgically induced weight reduction. Immunoreactive growth hormone (IRGH) responses returned to normal with weight reduction in all but one—a grossly obese woman studied relatively early in the postoperative period when still far from the ideal body weight. Five of these patients and two additional subjects had intravenous glucose tolerance tests (0.5 g. per kg.) before and after weight reduction. In all, there was a significant diminution in immunoreactive insulin (IRI) values, accompained by little or no change in the glucose disappearance rate (KG) and a significant improvement in insulin effectiveness as indicated by the calculated “insulinogenic index”. It was concluded that the abnormalities in IRGH and IRI secretion, as well as the insulin resistance in obesity, are probably secondary and not of primary importance in the etiology of this disorder. PMID:5430052

  2. Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice.

    PubMed

    Carrat, Gaelle R; Hu, Ming; Nguyen-Tu, Marie-Sophie; Chabosseau, Pauline; Gaulton, Kyle J; van de Bunt, Martijn; Siddiq, Afshan; Falchi, Mario; Thurner, Matthias; Canouil, Mickaël; Pattou, Francois; Leclerc, Isabelle; Pullen, Timothy J; Cane, Matthew C; Prabhala, Priyanka; Greenwald, William; Schulte, Anke; Marchetti, Piero; Ibberson, Mark; MacDonald, Patrick E; Manning Fox, Jocelyn E; Gloyn, Anna L; Froguel, Philippe; Solimena, Michele; McCarthy, Mark I; Rutter, Guy A

    2017-02-02

    Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca(2+) dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  3. Novel I1-Imidazoline Agonist S43126 Augment Insulin Secretion in Min6 Cells

    PubMed Central

    Tesfai, Jerusalem; Crane, Louis; Baziard-Mouysset, Genevieve; Edwards, Lincoln P.

    2016-01-01

    The I1-imidazoline receptor is a novel drug target for hypertension and insulin resistance which are major disorders associated with Type II diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126 on calcium fluxes and insulin secretion from Min6 β-cells. We also examined the effects of S43126 on the induction of IRAS, and phosphorylation of components in the I1-imidazoline signaling pathways, namely ERK and PKB. Min6 β-cells were treated with varying doses of S43126 [10−8M to 10−5M] for various time (5–60mins). S43126 at higher dose [10−5M] stimulated insulin secretion under elevated glucose concentration compared to basal. In addition, insulin secretion and Ca2+ influx mediated by S43126 [10−5M] were decreased following co-treatment with efaroxan (I1-antagonist) and nifedipine (L-type voltage-gated Ca2+-channel blocker) at various times (5–60mins). Furthermore, S43126 at [10−5M] increased Ca2+ oscillation, [Ca2+] and 45Ca2+ uptake in a time and dose-dependent manner. Moreover, Western blot analysis of treated samples showed that S43126 caused an increased protein expression of IRAS as well as phosphorylation of both ERK1/2 and PKB in a concentration-dependent manner. We conclude that S43126 exerts its insulinotropic effect in a glucose dependent manner by a mechanism involving L-type calcium channels and imidazoline I1-receptors. PMID:27429837

  4. Peptidomic analysis of skin secretions from the bullfrog Lithobates catesbeianus (Ranidae) identifies multiple peptides with potent insulin-releasing activity.

    PubMed

    Mechkarska, Milena; Ojo, Opeolu O; Meetani, Mohammed A; Coquet, Laurent; Jouenne, Thierry; Abdel-Wahab, Yasser H A; Flatt, Peter R; King, Jay D; Conlon, J Michael

    2011-02-01

    Using a combination of reversed-phase HPLC and electrospray mass spectrometry, peptidomic analysis of norepinephrine-stimulated skin secretions of the American bullfrog Lithobates catesbeianus Shaw, 1802 led to the identification and characterization of five newly described peptides (ranatuerin-1CBb, ranatuerin-2CBc, and -CBd, palustrin-2CBa, and temporin-CBf) together with seven peptides previously isolated on the basis of their antimicrobial activity (ranatuerin-1CBa, ranatuerin-2CBa, brevinin-1CBa, and -1CBb, temporin-CBa, -CBb, and -CBd). The abilities of the most abundant of the purified peptides to stimulate the release of insulin from the rat BRIN-BD11 clonal β cell line were evaluated. Ranatuerin-2CBd (GFLDIIKNLGKTFAGHMLDKIRCTIGTCPPSP) was the most potent peptide producing a significant stimulation of insulin release (119% of basal rate, P<0.01) from BRIN-BD11 cells at a concentration of 30nM, with a maximum response (236% of basal rate, P<0.001) at a concentration of 3μM. Ranatuerin-2CBd did not stimulate release of the cytosolic enzyme, lactate dehydrogenase at concentrations up to 3μM, indicating that the integrity of the plasma membrane had been preserved. Brevinin-1CBb (FLPFIARLAAKVFPSIICSVTKKC) produced the maximum stimulation of insulin release (285% of basal rate, P<0.001 at 3μM) but the peptide was cytotoxic at this concentration.

  5. Insulin resistance, secretion and breakdown are increased 9 months following severe burn injury

    PubMed Central

    Cree, Melanie G.; Fram, Ricki Y.; Barr, David; Chinkes, David; Wolfe, Robert R.; Herndon, David N.

    2012-01-01

    Insulin resistance in the acute burn period has been well described, however, it is unknown if alterations in glucose metabolism persist beyond discharge from the acute injury. To measure the duration of insulin resistance following recovery from the acute burn injury, we performed a prospective cross-sectional study with a standard two hour oral glucose tolerance test in 46 severely burned children at 6, 9 or 12 months following initial injury. Glucose uptake and insulin secretion were assessed following the glucose load. Results were compared to those previously published in healthy children. At 6 months post-burn, the 2 hour glucose concentration was significantly (P<0.001) greater than controls, and the area under the curve (AUC) of glucose was significantly higher compared to 12 months and to healthy children (P=0.027 and P<0.001, respectively). The 9 month AUC glucose was higher than controls (P<0.01). The 6 month 2 hour insulin in was significantly higher than controls, as was the AUC of insulin in all time points post-burn. The AUC of C-peptide was significantly greater at 6 months post-injury compared to 9 and 12 months (P<0.01 for both). Increased 2 hour and AUC glucose and insulin indicate that glucose metabolism is still altered at 6 and 9 months post-injury, and coincides with previously documented defects in bone and muscle metabolism at these time points. Insulin breakdown is also still increased in this population. Further study of this population is warranted to determine if specific treatment is needed. PMID:18672331

  6. Raldh3 expression in diabetic islets reciprocally regulates secretion of insulin and glucagon from pancreatic islets.

    PubMed

    Shimamura, Mitsuru; Karasawa, Hiroshi; Sakakibara, Sachiko; Shinagawa, Akira

    2010-10-08

    We have previously reported that obesity-induced diabetes developed in high-fat diet (HFD)-fed BDF1 mice. This is caused by insufficient insulin response to an excess glucose load. In this study, we have shown that the enhanced expression of retinaldehyde dehydrogenase 3 (Raldh3) causes functional disorders of pancreatic islets in diabetic mouse models. In the pancreatic islets of HFD-induced diabetic BDF1 mice and spontaneously diabetic C57BL/KsJ(db/db) mice, gene expression analysis with oligonucleotide microarray revealed a significant increase in Raldh3 expression. Exposure to a culture medium containing a higher glucose concentration (25 mM) significantly increased Raldh3 expression in murine MIN6 and alphaTC1 clone 9 cells, which derived from the α and β-cells of pancreatic islets, respectively. Overexpression of Raldh3 reduced the insulin secretion in MIN6 cells, and surprisingly, increased the glucagon secretion in alphaTC1 clone 9 cells. Furthermore, the knockdown of Raldh3 expression with siRNA decreased the glucagon secretion in alphaTC1 clone 9 cells. Raldh3 catalyzes the conversion of 13-cis retinal to 13-cis retinoic acid and we revealed that 13-cis retinoic acid significantly reduces cell viability in MIN6 and alphaTC1 clone 9 cells, but not in cells of H4IIEC3, 3T3-L1, and COS-1 cell lines. These findings suggest that an increasing expression of Raldh3 deregulates the balanced mechanisms of insulin and glucagon secretion in the pancreatic islets and may induce β-cell dysfunction leading to the development of type 2 diabetes. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2.

    PubMed

    Cheng, Haiying; Straub, Susanne G; Sharp, Geoffrey W G

    2003-08-01

    The major physiological inhibitors of insulin secretion, norepinephrine, somatostatin, galanin, and prostaglandin E2, act via specific receptors that activate pertussis toxin (PTX)-sensitive G proteins. Four inhibitory mechanisms are known: 1) activation of ATP-sensitive K channels and repolarization of the beta-cell; 2) inhibition of L-type Ca2+ channels; 3) decreased activity of adenylyl cyclase; and 4) inhibition of exocytosis at a "distal" site in stimulus-secretion coupling. We have examined the underlying mechanisms of inhibition at this distal site. In rat pancreatic islets, 2-bromopalmitate, cerulenin, and polyunsaturated fatty acids, all of which suppress protein acyltransferase activity, blocked the distal inhibitory effects of norepinephrine in a concentration-dependent manner. In contrast, control compounds such as palmitate, 16-hydroxypalmitate, and etomoxir, which do not block protein acylation, had no effect. Furthermore, 2-bromopalmitate also blocked the distal inhibitory actions of somatostatin, galanin, and prostaglandin E2. Importantly, neither 2-bromopalmitate nor cerulenin affected the action of norepinephrine to decrease cAMP production. We also examined the effects of norepinephrine, 2-bromopalmitate, and cerulenin on palmitate metabolism. Palmitate oxidation and its incorporation into lipids seemed not to contribute to the effects of 2-bromopalmitate and cerulenin on norepinephrine action. These data suggest that protein acylation mediates the distal inhibitory effect on insulin secretion. We propose that the inhibitors of insulin secretion, acting via PTX-sensitive G proteins, activate a specific protein acyltransferase, causing the acylation of a protein or proteins critical to exocytosis. This particular acylation and subsequent disruption of the essential and precise interactions involved in core complex formation would block exocytosis.

  8. Overexpression of the ped/pea-15 gene causes diabetes by impairing glucose-stimulated insulin secretion in addition to insulin action.

    PubMed

    Vigliotta, Giovanni; Miele, Claudia; Santopietro, Stefania; Portella, Giuseppe; Perfetti, Anna; Maitan, Maria Alessandra; Cassese, Angela; Oriente, Francesco; Trencia, Alessandra; Fiory, Francesca; Romano, Chiara; Tiveron, Cecilia; Tatangelo, Laura; Troncone, Giancarlo; Formisano, Pietro; Beguinot, Francesco

    2004-06-01

    Overexpression of the ped/pea-15 gene is a common feature of type 2 diabetes. In the present work, we show that transgenic mice ubiquitously overexpressing ped/pea-15 exhibited mildly elevated random-fed blood glucose levels and decreased glucose tolerance. Treatment with a 60% fat diet led ped/pea-15 transgenic mice to develop diabetes. Consistent with insulin resistance in these mice, insulin administration reduced glucose levels by only 35% after 45 min, compared to 70% in control mice. In vivo, insulin-stimulated glucose uptake was decreased by almost 50% in fat and muscle tissues of the ped/pea-15 transgenic mice, accompanied by protein kinase Calpha activation and block of insulin induction of protein kinase Czeta. These changes persisted in isolated adipocytes from the transgenic mice and were rescued by the protein kinase C inhibitor bisindolylmaleimide. In addition to insulin resistance, ped/pea-15 transgenic mice showed a 70% reduction in insulin response to glucose loading. Stable overexpression of ped/pea-15 in the glucose-responsive MIN6 beta-cell line also caused protein kinase Calpha activation and a marked decline in glucose-stimulated insulin secretion. Antisense block of endogenous ped/pea-15 increased glucose sensitivity by 2.5-fold in these cells. Thus, in vivo, overexpression of ped/pea-15 may lead to diabetes by impairing insulin secretion in addition to insulin action.

  9. Exercise at anaerobic threshold intensity and insulin secretion by isolated pancreatic islets of rats

    PubMed Central

    de Oliveira, Camila Aparecida Machado; Paiva, Mauricio Ferreira; Mota, Clécia Alencar Soares; Ribeiro, Carla; de Almeida Leme, José Alexandre Curiacos; Luciano, Eliete

    2010-01-01

    To evaluate the effect of acute exercise and exercise training at the anaerobic threshold (AT) intensity on aerobic conditioning and insulin secretion by pancreatic islets, adult male Wistar rats were submitted to the lactate minimum test (LMT) for AT determination. Half of the animals were submitted to swimming exercise training (trained), 1 h/day, 5 days/week during 8 weeks, with an overload equivalent to the AT. The other half was kept sedentary. At the end of the experimental period, the rats were submitted to an oral glucose tolerance test and to another LMT. Then, the animals were sacrificed at rest or immediately after 20 minutes of swimming exercise at the AT intensity for pancreatic islets isolation. At the end of the experiment mean workload (% bw) at AT was higher and blood lactate concentration (mmol/L) was lower in the trained than in the control group. Rats trained at the AT intensity showed no alteration in the areas under blood glucose and insulin during OGTT test. Islet insulin content of trained rats was higher than in the sedentary rats while islet glucose uptake did not differ among the groups. The static insulin secretion in response to the high glucose concentration (16.7 mM) of the sedentary group at rest was lower than the sedentary group submitted to the acute exercise and the inverse was observed in relation to the trained groups. Physical training at the AT intensity improved the aerobic condition and altered insulin secretory pattern by pancreatic islets. PMID:21099318

  10. Neuronal Calcium Sensor Synaptotagmin-9 Is Not Involved in the Regulation of Glucose Homeostasis or Insulin Secretion

    PubMed Central

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

    2010-01-01

    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. PMID:21085706

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

    PubMed

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

    2010-11-09

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

  12. Starch with high amylose and low in vitro digestibility increases short-chain fatty acid absorption, reduces peak insulin secretion, and modulates incretin secretion in pigs.

    PubMed

    Regmi, Prajwal R; van Kempen, Theo A T G; Matte, J Jacques; Zijlstra, Ruurd T

    2011-03-01

    Diets containing different starch types affect peripheral glucose and insulin responses. However, the role of starch chemistry in kinetics of nutrient absorption and insulin and incretin secretion is poorly understood. Four portal vein-catheterized pigs (35.0 ± 0.2 kg body weight) consumed 4 diets containing 70% purified starch [0-63.2% amylose content and 0.22 (slowly) to 1.06%/min (rapidly) maximum rate of in vitro digestion] for 7-d periods in a 4 × 4 Latin square. On d 7, blood was collected for 12 h postprandial with simultaneous blood flow measurement for determining the net portal appearance (NPA) of nutrients and hormones. The NPA of glucose, insulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) during 0-4 h postprandial were lower (P < 0.05) and those of butyrate and total SCFA were higher (P < 0.05) when pigs consumed the diet containing slowly digestible compared with rapidly digestible starch. The peak NPA of insulin occurred prior to that of glucose when pigs consumed diets containing rapidly digestible starch. The kinetics of insulin secretion had a linear positive relation with kinetics of NPA of glucose (R(2) = 0.50; P < 0.01). In conclusion, starch with high amylose and low in vitro digestibility decreases the kinetics of glucose absorption and insulin and GIP secretion and increases SCFA absorption and glucagon-like peptide-1 secretion. In conclusion, starch with high amylose content and a lower rate and extent of in vitro digestion decreased glucose absorption and insulin secretion and increased SCFA absorption.

  13. Rosuvastatin Treatment Affects Both Basal and Glucose-Induced Insulin Secretion in INS-1 832/13 Cells

    PubMed Central

    Salunkhe, Vishal A.; Elvstam, Olof; Eliasson, Lena; Wendt, Anna

    2016-01-01

    Rosuvastatin is a member of the statin family. Like the other statins it is prescribed to lower cholesterol levels and thereby reduce the risk of cardiovascular events. Rosuvastatin lowers the cholesterol levels by inhibiting the key enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) in the cholesterol producing mevalonate pathway. It has been recognized that apart from their beneficial lipid lowering effects, statins also exhibit diabetogenic properties. The molecular mechanisms behind these remain unresolved. To investigate the effects of rosuvastatin on insulin secretion, we treated INS-1 832/13 cells with varying doses (20 nM to 20 μM) of rosuvastatin for 48 h. At concentrations of 2 μM and above basal insulin secretion was significantly increased. Using diazoxide we could determine that rosuvastatin did not increase basal insulin secretion by corrupting the KATP channels. Glucose-induced insulin secretion on the other hand seemed to be affected differently at different rosuvastatin concentrations. Rosuvastatin treatment (20 μM) for 24–48 h inhibited voltage-gated Ca2+ channels, which lead to reduced depolarization-induced exocytosis of insulin-containing granules. At lower concentrations of rosuvastatin (≤ 2 μM) the stimulus-secretion coupling pathway was intact downstream of the KATP channels as assessed by the patch clamp technique. However, a reduction in glucose-induced insulin secretion could be observed with rosuvastatin concentrations as low as 200 nM. The inhibitory effects of rosuvastatin on glucose-induced insulin secretion could be reversed with mevalonate, but not squalene, indicating that rosuvastatin affects insulin secretion through its effects on the mevalonate pathway, but not through the reduction of cholesterol biosynthesis. Taken together, these data suggest that rosuvastatin has the potential to increase basal insulin secretion and reduce glucose-induced insulin secretion. The latter is possibly an unavoidable

  14. Encapsulation of pancreatic islets within nano-thin functional polyethylene glycol coatings for enhanced insulin secretion.

    PubMed

    Kizilel, Seda; Scavone, Andrew; Liu, Xiang; Nothias, Jean-Manuel; Ostrega, Diane; Witkowski, Piotr; Millis, Michael

    2010-07-01

    Covalent attachment of polymers to cells and tissues could be used to solve a variety of problems associated with cellular therapies. Insulin-dependent diabetes mellitus is a disease resulting from the autoimmune destruction of the beta cells of the islets of Langerhans in the pancreas. Transplantation of islets into diabetic patients is an attractive form of treatment, provided that the islets could be protected from the host's immune system to prevent graft rejection, and smaller numbers of islets transplanted in smaller volumes could be sufficient to reverse diabetes. Therefore, a need exists to develop islet encapsulation strategies that minimize transplant volume. In this study, we demonstrate the formation of nano-thin, poly(ethylene glycol) (PEG)-rich functional conformal coatings on individual islets via layer-by-layer assembly technique. The surface of the islets is modified with biotin-PEG-N-hydroxysuccinimide (NHS), and the islets are further covered by streptavidin (SA) and biotin-PEG-peptide conjugates using the layer-by-layer method. An insulinotropic ligand, glucagon-like peptide-1 (GLP-1), is conjugated to biotin-PEG-NHS. The insulinotropic effect of GLP-1 is investigated through layer-by-layer encapsulation of islets using the biotin-PEG-GLP-1 conjugate. The effect of islet surface modification using the biotin-PEG-GLP-1 conjugate on insulin secretion in response to glucose challenge is compared via static incubation and dynamic perifusion assays. The results show that islets coated with the functional PEG conjugate are capable of secreting more insulin in response to high glucose levels compared to control islets. Finally, the presence of SA is confirmed by indirect fluorescent staining with SA-Cy3, and the presence of PEG-peptide on the surface of the islets after treatment with biotin-PEG-GLP-1 is confirmed by indirect fluorescent staining with biotin-PEG-fluorescein isothiocyanate (FITC) and separately with an anti-GLP-1 antibody. This work

  15. [Impaired insulin secretion in isolated islets of Goto-Kakizaki rats, an animal model of non obese type 2 diabetes, is a primary event].

    PubMed

    Seiça, Raquel M; Suzuki, K I; Santos, Rosa M; Do Rosário, Luis M

    2004-01-01

    The development of type 2 diabetes is associated with the impairment of insulin secretion. To evaluate the evolution of the secretory response, a chronological study comparing normal Wistar (W) vs Goto-Kakizaki (GK) rats, an animal model of non obese type 2 diabetes, was done. Glucose and arginine were tested in collagenase isolated islets of Langerhans with perfusion and ELISA immunoassay techniques. Fasting glycaemia and insulinemia and glucose tolerance were also evaluated. We have seen, in W rats, a mild glucose intolerance in the first two weeks of age. GK rats were always glucose intolerant with hyperglycaemia and hyperinsulinemia at fasten after one month old. Wistar islets had a characteristic biphasic response to glucose after the first two weeks of age. GK islets were always glucose irresponsive. Arginine induced an increase in insulin secretion in both animal models, independent of age, although GK rats had always a smaller response when compared to W rats. We concluded that 1) in W rats, a biphasic insulin secretion in response to glucose is observed after the first two weeks of age, simultaneously with glycaemia stabilization 2) in GK rats, both first and second phases of glucose-induced insulin release are significantly reduced and a smaller reduction in response to arginine is observed. This beta-cell disfunction is a primary event in this model of type 2 diabetes, preceding fasting hyperglycaemia and hyperinsulinemia.

  16. Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice.

    PubMed

    da Silva Xavier, G; Mondragon, A; Sun, G; Chen, L; McGinty, J A; French, P M; Rutter, G A

    2012-10-01

    Individuals carrying type 2 diabetes risk alleles in TCF7L2 display decreased beta cell levels of T cell factor 7 like-2 (TCF7L2) immunoreactivity, and impaired insulin secretion and beta cell sensitivity to glucagon-like peptide 1 (GLP-1). Here, we sought to determine whether selective deletion of Tcf7l2 in mouse pancreas impairs insulin release and glucose homeostasis. Pancreas-specific Tcf7l2-null (pTcf7l2) mice were generated by crossing mice carrying conditional knockout alleles of Tcf7l2 (Tcf7l2-flox) with mice expressing Cre recombinase under the control of the Pdx1 promoter (Pdx1.Cre). Gene expression was assessed by real-time quantitative PCR and beta cell mass by optical projection tomography. Glucose tolerance, insulin secretion from isolated islets, and plasma insulin, glucagon and GLP-1 content were assessed by standard protocols. From 12 weeks of age, pTcf7l2 mice displayed decreased oral glucose tolerance vs control littermates; from 20 weeks they had glucose intolerance upon administration of glucose by the intraperitoneal route. pTcf7l2 islets displayed impaired insulin secretion in response to 17 (vs 3.0) mmol/l glucose (54.6 ± 4.6%, p < 0.01) or to 17 mmol/l glucose plus 100 nmol/l GLP-1 (44.3 ± 4.9%, p < 0.01) compared with control islets. Glp1r (42 ± 0.08%, p < 0.01) and Ins2 (15.4 ± 4.6%, p < 0.01) expression was significantly lower in pTcf7l2 islets than in controls. Maintained on a high-fat (but not on a normal) diet, pTcf7l2 mice displayed decreased expansion of pancreatic beta cell volume vs control littermates. No differences were observed in plasma insulin, proinsulin, glucagon or GLP-1 concentrations. Selective deletion of Tcf7l2 in the pancreas replicates key aspects of the altered glucose homeostasis in human carriers of TCF7L2 risk alleles, indicating the direct role of this factor in controlling beta cell function.

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

    PubMed

    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% O2, 10% O2, 7.5% O2, and 5% O2) 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 O2 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).

  18. A volume-activated anion conductance in insulin-secreting cells.

    PubMed

    Best, L; Sheader, E A; Brown, P D

    1996-01-01

    The whole-cell patch-clamp recording technique was used to measure volume-activated currents in K+-free solutions in RINm5F and HIT-T15 insulinoma cells and in dispersed rat islet cells. Cell swelling, induced by intracellular hypertonicity or extracellular hypotonicity, caused activation of an outwardly rectifying conductance which could be subsequently inactivated by hypertonic extracellular solutions. The conductance required adenosine 5'-triphosphate (ATP) in the pipette solution but was Ca2+ independent. Na+ and Cl- substitution studies suggested that the swelling-activated current is Cl- selective with a halide permeability sequence of Br > Cl > I. The conductance was reversibly inhibited by the anion channel inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Further evidence for a volume-activated anion conductance was provided by studies of volume regulation in insulin-secreting cells. When RINm5F cells were exposed to a hypotonic medium, the initial cell swelling was followed by a regulatory volume decrease (RVD). This RVD response was also inhibited by DIDS and by NPPB. These data therefore provide evidence for a volume-activated anion conductance in insulin-secreting cells which could be involved in the RVD following osmotic stress. A possible role for the conductance in hypotonically induced insulin release is also discussed.

  19. Insulin-secreting β cells require a post-genomic concept

    PubMed Central

    Jiang, Fang-Xu; Morahan, Grant

    2016-01-01

    Pancreatic insulin-secreting β cells are essential in maintaining normal glucose homeostasis accomplished by highly specialized transcription of insulin gene, of which occupies up to 40% their transcriptome. Deficiency of these cells causes diabetes mellitus, a global public health problem. Although tremendous endeavors have been made to generate insulin-secreting cells from human pluripotent stem cells (i.e., primitive cells capable of giving rise to all cell types in the body), a regenerative therapy to diabetes has not yet been established. Furthermore, the nomenclature of β cells has become inconsistent, confusing and controversial due to the lack of standardized positive controls of developmental stage-matched in vivo cells. In order to minimize this negative impact and facilitate critical research in this field, a post-genomic concept of pancreatic β cells might be helpful. In this review article, we will briefly describe how β cells were discovered and islet lineage is developed that may help understand the cause of nomenclatural controversy, suggest a post-genomic definition and finally provide a conclusive remark on future research of this pivotal cell. PMID:27226815

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

    PubMed

    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. Regulation of insulin secretion and reactive oxygen species production by free fatty acids in pancreatic islets.

    PubMed

    Graciano, Maria Fernanda Rodrigues; Valle, Maíra M R; Kowluru, Anjan; Curi, Rui; Carpinelli, Angelo R

    2011-01-01

    Free fatty acids regulate insulin secretion through metabolic and intracellular signaling mechanisms such as induction of malonyl-CoA/long-chain CoA pathway, production of lipids, GPRs (G protein-coupled receptors) activation and the modulation of calcium currents. Fatty acids (FA) are also important inducers of ROS (reactive oxygen species) production in β-cells. Production of ROS for short periods is associated with an increase in GSIS (glucose-stimulated insulin secretion), but excessive or sustained production of ROS is negatively correlated with the insulin secretory process. Several mechanisms for FA modulation of ROS production by pancreatic β-cells have been proposed, such as the control of mitochondrial complexes and electron transport, induction of uncoupling proteins, NADPH oxidase activation, interaction with the renin-angiotensin system, and modulation of the antioxidant defense system. The major sites of superoxide production within mitochondria derive from complexes I and III. The amphiphilic nature of FA favors their incorporation into mitochondrial membranes, altering the membrane fluidity and facilitating the electron leak. The extra-mitochondrial ROS production induced by FA through the NADPH oxidase complex is also an important source of these species in β-cells.

  2. Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus.

    PubMed

    Andrews, Sasha E; Brown, Laura D; Thorn, Stephanie R; Limesand, Sean W; Davis, Melissa; Hay, William W; Rozance, Paul J

    2015-01-01

    Insulin may stimulate its own insulin secretion and is a potent growth factor for the pancreatic β-cell. Complications of pregnancy, such as diabetes and intrauterine growth restriction, are associated with changes in fetal insulin concentrations, secretion, and β-cell mass. However, glucose concentrations are also abnormal in these conditions. The direct effect of chronic fetal hyperinsulinemia with euglycemia on fetal insulin secretion and β-cell mass has not been tested. We hypothesized that chronic fetal hyperinsulinemia with euglycemia would increase glucose-stimulated insulin secretion (GSIS) and β-cell mass in the ovine fetus. Singleton ovine fetuses were infused with iv insulin to produce high physiological insulin concentrations, or saline for 7-10 days. The hyperinsulinemic animals also received a direct glucose infusion to maintain euglycemia. GSIS, measured at 133 ± 1 days of gestation, was significantly attenuated in the hyperinsulinemic fetuses (P < .05). There was no change in β-cell mass. The hyperinsulinemic fetuses also had decreased oxygen (P < .05) and higher norepinephrine (1160 ± 438 vs 522 ± 106 pg/mL; P < .005). Acute pharmacologic adrenergic blockade restored GSIS in the hyperinsulinemic-euglycemic fetuses, demonstrating that increased adrenergic signaling mediates decreased GSIS in these fetuses.

  3. Metabolic memory of ß-cells controls insulin secretion and is mediated by CaMKIIa

    PubMed Central

    Santos, Gustavo Jorge dos; Ferreira, Sandra Mara; Ortis, Fernanda; Rezende, Luiz Fernando; Li, Chengyang; Naji, Ali; Carneiro, Everardo Magalhães; Kaestner, Klaus H.; Boschero, Antonio Carlos

    2014-01-01

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) functions both in regulation of insulin secretion and neurotransmitter release through common downstream mediators. Therefore, we hypothesized that pancreatic ß-cells acquire and store the information contained in calcium pulses as a form of “metabolic memory”, just as neurons store cognitive information. To test this hypothesis, we developed a novel paradigm of pulsed exposure of ß-cells to intervals of high glucose, followed by a 24-h consolidation period to eliminate any acute metabolic effects. Strikingly, ß-cells exposed to this high-glucose pulse paradigm exhibited significantly stronger insulin secretion. This metabolic memory was entirely dependent on CaMKII. Metabolic memory was reflected on the protein level by increased expression of proteins involved in glucose sensing and Ca2+-dependent vesicle secretion, and by elevated levels of the key ß-cell transcription factor MAFA. In summary, like neurons, human and mouse ß-cells are able to acquire and retrieve information. PMID:24944908

  4. Metabolic memory of ß-cells controls insulin secretion and is mediated by CaMKII.

    PubMed

    Santos, Gustavo Jorge Dos; Ferreira, Sandra Mara; Ortis, Fernanda; Rezende, Luiz Fernando; Li, Chengyang; Naji, Ali; Carneiro, Everardo Magalhães; Kaestner, Klaus H; Boschero, Antonio Carlos

    2014-07-01

    Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) functions both in regulation of insulin secretion and neurotransmitter release through common downstream mediators. Therefore, we hypothesized that pancreatic ß-cells acquire and store the information contained in calcium pulses as a form of "metabolic memory", just as neurons store cognitive information. To test this hypothesis, we developed a novel paradigm of pulsed exposure of ß-cells to intervals of high glucose, followed by a 24-h consolidation period to eliminate any acute metabolic effects. Strikingly, ß-cells exposed to this high-glucose pulse paradigm exhibited significantly stronger insulin secretion. This metabolic memory was entirely dependent on CaMKII. Metabolic memory was reflected on the protein level by increased expression of proteins involved in glucose sensing and Ca(2+)-dependent vesicle secretion, and by elevated levels of the key ß-cell transcription factor MAFA. In summary, like neurons, human and mouse ß-cells are able to acquire and retrieve information.

  5. α 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic β-cells.

    PubMed

    Kalis, Martins; Kumar, Rajesh; Janciauskiene, Sabina; Salehi, Albert; Cilio, Corrado M

    2010-01-01

    α1-antitrypsin (AAT) is a serine protease inhibitor, which recently has been shown to prevent type 1 diabetes (T1D) development, to prolong islet allograft survival and to inhibit β-cell apoptosis in vivo. It has also been reported that T1D patients have significantly lower plasma concentrations of AAT suggesting the potential role of AAT in the pathogenesis of T1D. We have investigated whether plasma-purified AAT can affect β-cell function in vitro. INS-1E cells or primary rat pancreatic islets were used to study the effect of AAT on insulin secretion after glucose, glucagon-like peptide-1 (GLP-1) and forskolin stimulation and on cytokine-mediated apoptosis. The secreted insulin and total cyclic AMP (cAMP) were determined using radioimmunoassay and apoptosis was evaluated by propidium iodide staining followed by FACS analysis. We found that AAT increases insulin secretion in a glucose-dependent manner, potentiates the effect of GLP-1 and forskolin and neutralizes the inhibitory effect of clonidine on insulin secretion. The effect of AAT on insulin secretion was accompanied by an increase in cAMP levels. In addition, AAT protected INS-1E cells from cytokine-induced apoptosis. Our findings show that AAT stimulates insulin secretion and protects β-cells against cytokine-induced apoptosis, and these effects of AAT seem to be mediated through the cAMP pathway. In view of these novel findings we suggest that AAT may represent a novel anti-inflammatory compound to protect β-cells under the immunological attack in T1D but also therapeutic strategy to potentiate insulin secretion in type 2 diabetes (T2D).

  6. Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose.

    PubMed

    Terauchi, Y; Sakura, H; Yasuda, K; Iwamoto, K; Takahashi, N; Ito, K; Kasai, H; Suzuki, H; Ueda, O; Kamada, N

    1995-12-22

    Mice carrying a null mutation in the glucokinase (GK) gene in pancreatic beta-cells, but not in the liver, were generated by disrupting the beta-cell-specific exon. Heterozygous mutant mice showed early-onset mild diabetes due to impaired insulin-secretory response to glucose. Homozygotes showed severe diabetes shortly after birth and died within a week. GK-deficient islets isolated from homozygotes showed defective insulin secretion in response to glucose, while they responded to other secretagogues: almost normally to arginine and to some extent to sulfonylureas. These data provide the first direct proof that GK serves as a glucose sensor molecule for insulin secretion and plays a pivotal role in glucose homeostasis. GK-deficient mice serve as an animal model of the insulin-secretory defect in human non-insulin-dependent diabetes mellitus.

  7. Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

    PubMed

    Rutter, Guy A; Chabosseau, Pauline; Bellomo, Elisa A; Maret, Wolfgang; Mitchell, Ryan K; Hodson, David J; Solomou, Antonia; Hu, Ming

    2016-02-01

    Zinc is an important micronutrient, essential in the diet to avoid a variety of conditions associated with malnutrition such as diarrhoea and alopecia. Lowered circulating levels of zinc are also found in diabetes mellitus, a condition which affects one in twelve of the adult population and whose treatments consume approximately 10 % of healthcare budgets. Zn2+ ions are essential for a huge range of cellular functions and, in the specialised pancreatic β-cell, for the storage of insulin within the secretory granule. Correspondingly, genetic variants in the SLC30A8 gene, which encodes the diabetes-associated granule-resident Zn2+ transporter ZnT8, are associated with an altered risk of type 2 diabetes. Here, we focus on (i) recent advances in measuring free zinc concentrations dynamically in subcellular compartments, and (ii) studies dissecting the role of intracellular zinc in the control of glucose homeostasis in vitro and in vivo. We discuss the effects on insulin secretion and action of deleting or over-expressing Slc30a8 highly selectively in the pancreatic β-cell, and the role of zinc in insulin signalling. While modulated by genetic variability, healthy levels of dietary zinc, and hence normal cellular zinc homeostasis, are likely to play an important role in the proper release and action of insulin to maintain glucose homeostasis and lower diabetes risk.

  8. G6PC2: A Negative Regulator of Basal Glucose-Stimulated Insulin Secretion

    PubMed Central

    Pound, Lynley D.; Oeser, James K.; O’Brien, Tracy P.; Wang, Yingda; Faulman, Chandler J.; Dadi, Prasanna K.; Jacobson, David A.; Hutton, John C.; McGuinness, Owen P.; Shiota, Masakazu; O’Brien, Richard M.

    2013-01-01

    Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality. Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance. G6PC2 encodes an islet-specific, endoplasmic reticulum–resident glucose-6-phosphatase catalytic subunit. A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice. G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data. G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS). As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data. Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice. These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux. PMID:23274894

  9. G6PC2: a negative regulator of basal glucose-stimulated insulin secretion.

    PubMed

    Pound, Lynley D; Oeser, James K; O'Brien, Tracy P; Wang, Yingda; Faulman, Chandler J; Dadi, Prasanna K; Jacobson, David A; Hutton, John C; McGuinness, Owen P; Shiota, Masakazu; O'Brien, Richard M

    2013-05-01

    Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality. Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance. G6PC2 encodes an islet-specific, endoplasmic reticulum-resident glucose-6-phosphatase catalytic subunit. A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice. G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data. G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS). As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data. Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice. These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux.

  10. Effects of sodium tungstate on insulin and glucagon secretion in the perfused rat pancreas.

    PubMed

    Rodríguez-Gallardo, J; Silvestre, R A; Egido, E M; Marco, J

    2000-08-18

    Both the direct effect of sodium tungstate on insulin and glucagon secretion in the perfused rat pancreas, and the insulin response to glucose and arginine in pancreases isolated from tungstate-pretreated rats were studied. Infusion of tungstate stimulated insulin output in a dose-dependent manner. The insulinotropic effect of tungstate was observed at normal (5.5 mM), and moderately high (9 mM) glucose concentrations, but not at a low glucose concentration (3.2 mM). Tungstate-induced insulin output was blocked by diazoxide, somatostatin, and amylin, suggesting several targets for tungstate at the B-cell secretory machinery. Glucagon release was not modified by tungstate. Pancreases from chronically tungstate-treated rats showed an enhanced response to glucose but not to arginine. Our results indicate that the reported reduction of glycemia caused by tungstate administration is, at least in part, due to its direct insulinotropic activity. Furthermore, chronic tungstate treatment may prime the B-cell, leading to over-response to a glucose stimulus.

  11. PAX4 promotes PDX1-induced differentiation of mesenchymal stem cells into insulin-secreting cells

    PubMed Central

    Xu, Lifa; Xu, Congjing; Zhou, Shuping; Liu, Xueke; Wang, Jian; Liu, Xinkuang; Qian, Suping; Xin, Yingru; Gao, Yi; Zhu, Yongqiang; Tang, Xiaolong

    2017-01-01

    A shortage of postmortem pancreatic tissue for islet isolation impedes the application of cell replacement therapy in patients with diabetes. As an alternative for islet cell transplantation, transcription factors, including PDX1, PAX4, and neurogenin-3, that aid in the formation of insulin-producing β cells during development have been investigated. The present study evaluated the effects of PAX4 and PDX1 on the differentiation of mesenchymal stem cells (MSCs) into insulin-producing β-like cells in vitro using recombinant adenoviruses carrying PDX1 or PDX1 plus PAX4. RT-PCR, Western blot, and immunofluorescence assays were used to detect the expression levels of relevant genes and proteins, and enzyme-linked immunosorbent assays were used to determine the amount of insulin and C-peptide secreted by the virus-infected cells following stimulation with high glucose. The results showed that PAX4 markedly enhanced the propensity of PDX1-positive MSCs to form mature islet-like clusters and functional insulin-producing β-like cells. Our findings provide a novel foundation for generating β-like cells from MSCs with PAX4 and PDX1 for future clinical application. PMID:28386318

  12. 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

    PubMed Central

    Samad, Mehdi Bin; Kabir, Ashraf Ul; Ahmed, Arif; Jahan, Mohammad Rajib; Hannan, J. M. A.

    2014-01-01

    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. PMID:24860609

  13. Novel GPR40 agonist AS2575959 exhibits glucose metabolism improvement and synergistic effect with sitagliptin on insulin and incretin secretion.

    PubMed

    Tanaka, Hirotsugu; Yoshida, Shigeru; Minoura, Hideaki; Negoro, Kenji; Shimaya, Akiyoshi; Shimokawa, Teruhiko; Shibasaki, Masayuki

    2014-01-17

    GPR40 is a free fatty acid receptor that regulates glucose-dependent insulin secretion at pancreatic β-cells and glucagon-like peptide-1 (GLP-1), one of the major incretins, secretion at the endocrine cells of the gastrointestinal tract. We investigated the synergistic effect of AS2575959, a novel GPR40 agonist, in combination with sitagliptin, a major dipeptidyl peptidase-IV (DPP-IV) inhibitor, on glucose-dependent insulin secretion and GLP-1 secretion. In addition, we investigated the chronic effects of AS2575959 on whole-body glucose metabolism. We evaluated acute glucose metabolism on insulin and GLP-1 secretion using an oral glucose tolerance test (OGTT) as well as assessed the chronic glucose metabolism in diabetic ob/ob mice following the repeated administration of AS2575959. We discovered the novel GPR40 agonist sodium [(3S)-6-({4'-[(3S)-3,4-dihydroxybutoxy]-2,2',6'-trimethyl[1,1'-biphenyl]-3-yl}methoxy)-3H-spiro[1-benzofuran-2,1'-cyclopropan]-3-yl]acetate (AS2575959) and found that the compound influenced glucose-dependent insulin secretion both in vitro pancreas β-cell-derived cells and in vivo mice OGTT. Further, we observed a synergistic effect of AS2575959 and DPP-IV inhibitor on insulin secretion and plasma GLP-1 level. In addition, we discovered the improvement in glucose metabolism on repeated administration of AS2575959. To our knowledge, this study is the first to demonstrate the synergistic effect of a GPR40 agonist and DPP-IV inhibitor on the glucose-dependent insulin secretion and GLP-1 concentration increase. These findings suggest that GPR40 agonists may represent a promising therapeutic strategy for the treatment of type 2 diabetes mellitus, particularly when used in combination with DPP-IV inhibitors. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Leucine metabolism in regulation of insulin secretion from pancreatic beta cells

    PubMed Central

    Yang, Jichun; Chi, Yujing; Burkhardt, Brant R.; Guan, Youfei; Wolf, Bryan A

    2010-01-01

    Leucine, a the branched-chain amino acids that must be supplied in daily diet, plays an important role in controlling protein synthesis and regulating cell metabolism in various cell types. In pancreatic β cells, leucine acutely stimulates insulin secretion by serving as both metabolic fuel and allosteric activator of glutamate dehydrogenase to enhance glutaminolysis. Leucine has also been shown to regulate gene transcription and protein synthesis in pancreatic islet β cells via both mTOR-dependent and -independent pathways at physiological concentrations. Long-term treatment of leucine has been shown to improve insulin secretory dysfunction of human diabetic islets via upregulation of certain key metabolic genes. In vivo, leucine administration improves glycemic control in humans and rodents with type 2 diabetes. This review aims to summarize and discuss the recent findings regarding the effects of leucine metabolism on pancreatic β cell function. PMID:20500788

  15. Serotonin regulates glucose-stimulated insulin secretion from pancreatic β cells during pregnancy.

    PubMed

    Ohara-Imaizumi, Mica; Kim, Hail; Yoshida, Masashi; Fujiwara, Tomonori; Aoyagi, Kyota; Toyofuku, Yukiko; Nakamichi, Yoko; Nishiwaki, Chiyono; Okamura, Tadashi; Uchida, Toyoyoshi; Fujitani, Yoshio; Akagawa, Kimio; Kakei, Masafumi; Watada, Hirotaka; German, Michael S; Nagamatsu, Shinya

    2013-11-26

    In preparation for the metabolic demands of pregnancy, β cells in the maternal pancreatic islets increase both in number and in glucose-stimulated insulin secretion (GSIS) per cell. Mechanisms have been proposed for the increased β cell mass, but not for the increased GSIS. Because serotonin production increases dramatically during pregnancy, we tested whether flux through the ionotropic 5-HT3 receptor (Htr3) affects GSIS during pregnancy. Pregnant Htr3a(-/-) mice exhibited impaired glucose tolerance despite normally increased β cell mass, and their islets lacked the increase in GSIS seen in islets from pregnant wild-type mice. Electrophysiological studies showed that activation of Htr3 decreased the resting membrane potential in β cells, which increased Ca(2+) uptake and insulin exocytosis in response to glucose. Thus, our data indicate that serotonin, acting in a paracrine/autocrine manner through Htr3, lowers the β cell threshold for glucose and plays an essential role in the increased GSIS of pregnancy.

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

    PubMed

    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-transpla