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; Meredith, Tamika DeShea; 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

2017-11-01

Incretin and insulin responses to nutrient loads are suppressed in persons with diabetes, resulting in decreased glycemic control. Agents including sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP4i) partially reverse these effects and provide therapeutic benefit; however, their modes of action limit efficacy. Because somatostatin (SST) has been shown to suppress insulin and glucagonlike peptide-1 (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 potent and selective SSTR5 antagonist reverses the blunting effects of SST on insulin secretion from isolated human islets, and demonstrate 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 resulted in increases in systemic GLP-1 levels that were more than additive and resulted in greater glycemic control compared with 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.

Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

PubMed Central

Chen, Xiaochuan; Green, Alice S.; Macko, Antoni R.; Yates, Dustin T.; Kelly, Amy C.

2013-01-01

Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and β-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances β-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater (P < 0.05) plasma NE concentrations and exhibited hyperglycemia (P < 0.01) and hypoinsulinemia (P < 0.01) compared with controls. GSIS during the NE infusion was also reduced (P < 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater (P < 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (α1D, α2A, α2C, and β1), G protein subunit-αi-2, and uncoupling protein 2 were lower (P < 0.05) compared with controls, but β-cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets. PMID:24253046

Effect of Diacerein on Insulin Secretion and Metabolic Control in Drug-Naïve Patients With Type 2 Diabetes

PubMed Central

Ramos-Zavala, Maria G.; González-Ortiz, Manuel; Martínez-Abundis, Esperanza; Robles-Cervantes, José A.; González-López, Roberto; Santiago-Hernández, Nestor J.

2011-01-01

OBJECTIVE To assess the effect of diacerein on insulin secretion and metabolic control in drug-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A randomized, double-blind, placebo-controlled clinical trial was carried out in 40 drug-naïve adult patients with type 2 diabetes. A metabolic profile including interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and fasting insulin levels was carried out before the intervention and 2 months afterward. A hyperglycemic-hyperinsulinemic clamp technique was performed to assess the phases of insulin secretion and insulin sensitivity. After randomization, 20 patients received diacerein (50 mg once daily) for the first 15 days and twice daily for 45 additional days. The remaining patients received placebo. Intra- and intergroup differences were calculated by Wilcoxon signed rank and Mann-Whitney U tests. RESULTS There were significant increases in first (102 ± 63 vs. 130 ± 75 pmol/L; P < 0.01), late (219 ± 111 vs. 280 ± 135 pmol/L; P < 0.01), and total insulin (178 ± 91 vs. 216 ± 99 pmol/L; P < 0.01) secretions without changes in insulin sensitivity after diacerein administration. There were significant decreases in fasting glucose (7.9 ± 1.4 vs. 6.8 ± 1.0 mmol/L; P < 0.01) and in A1C levels (8.3 ± 1.0 vs. 7.0 ± 0.8%; P < 0.001) after diacerein administration. There were no significant changes after placebo administration in the above-mentioned evaluations. CONCLUSIONS Insulin secretion increased and metabolic control improved after diacerein administration in drug-naïve patients with type 2 diabetes. PMID:21610123

VAMP-2 and cellubrevin are expressed in pancreatic beta-cells and are essential for Ca(2+)-but not for GTP gamma S-induced insulin secretion.

PubMed Central

Regazzi, R; Wollheim, C B; Lang, J; Theler, J M; Rossetto, O; Montecucco, C; Sadoul, K; Weller, U; Palmer, M; Thorens, B

1995-01-01

VAMP proteins are important components of the machinery controlling docking and/or fusion of secretory vesicles with their target membrane. We investigated the expression of VAMP proteins in pancreatic beta-cells and their implication in the exocytosis of insulin. cDNA cloning revealed that VAMP-2 and cellubrevin, but not VAMP-1, are expressed in rat pancreatic islets and that their sequence is identical to that isolated from rat brain. Pancreatic beta-cells contain secretory granules that store and secrete insulin as well as synaptic-like microvesicles carrying gamma-aminobutyric acid. After subcellular fractionation on continuous sucrose gradients, VAMP-2 and cellubrevin were found to be associated with both types of secretory vesicle. The association of VAMP-2 with insulin-containing granules was confirmed by confocal microscopy of primary cultures of rat pancreatic beta-cells. Pretreatment of streptolysin-O permeabilized insulin-secreting cells with tetanus and botulinum B neurotoxins selectively cleaved VAMP-2 and cellubrevin and abolished Ca(2+)-induced insulin release (IC50 approximately 15 nM). By contrast, the pretreatment with tetanus and botulinum B neurotoxins did not prevent GTP gamma S-stimulated insulin secretion. Taken together, our results show that pancreatic beta-cells express VAMP-2 and cellubrevin and that one or both of these proteins selectively control Ca(2+)-mediated insulin secretion. Images PMID:7796801

Effect of Salsalate on Insulin Action, Secretion, and Clearance in Nondiabetic, Insulin-Resistant Individuals: A Randomized, Placebo-Controlled Study

PubMed Central

Liu, Alice; Ariel, Danit; Abbasi, Fahim; Lamendola, Cindy; Grove, Kaylene; Tomasso, Vanessa; Ochoa, Hector; Reaven, Gerald

2014-01-01

OBJECTIVE Salsalate treatment has been shown to improve glucose homeostasis, but the mechanism remains unclear. The aim of this study was to evaluate the effect of salsalate treatment on insulin action, secretion, and clearance rate in nondiabetic individuals with insulin resistance. RESEARCH DESIGN AND METHODS This was a randomized (2:1), single-blind, placebo-controlled study of salsalate (3.5 g daily for 4 weeks) in nondiabetic individuals with insulin resistance. All individuals had measurement of glucose tolerance (75-g oral glucose tolerance test), steady-state plasma glucose (SSPG; insulin suppression test), and insulin secretion and clearance rate (graded-glucose infusion test) before and after treatment. RESULTS Forty-one individuals were randomized to salsalate (n = 27) and placebo (n = 14). One individual from each group discontinued the study. Salsalate improved fasting (% mean change −7% [95% CI −10 to −14] vs. 1% [−3 to 5], P = 0.005) but not postprandial glucose concentration compared with placebo. Salsalate also lowered fasting triglyceride concentration (−25% [−34 to −15] vs. −6% [−26 to 14], P = 0.04). Salsalate had no effect on SSPG concentration or insulin secretion rate but significantly decreased insulin clearance rate compared with placebo (−23% [−30 to −16] vs. 3% [−10 to 15], P < 0.001). Salsalate was well tolerated, but four individuals needed a dose reduction due to symptoms. CONCLUSIONS Salsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentration. These improvements were associated with a decrease in insulin clearance rate without change in insulin action or insulin secretion. PMID:24963111

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

PubMed

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

2016-06-15

Secretagogin (SCGN), a Ca(2+)-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 Ca(2+)-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. © 2016 The Author(s).

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

Radiofrequency radiation emitted from Wi-Fi (2.4 GHz) causes impaired insulin secretion and increased oxidative stress in rat pancreatic islets.

PubMed

Masoumi, Ali; Karbalaei, Narges; Mortazavi, S M J; Shabani, Mohammad

2018-06-18

There is a great concern regarding the possible adverse effects of electromagnetic radiation (EMR). This study investigated the effects of EMR induced by Wi-Fi (2.45GHz) on insulin secretion and antioxidant redox systems in the rat pancreas. Adult male Sprague-Dawley rats in the weight range of 230 to 260 g were divided into control, sham, Wi-Fi exposed groups. After long term exposure (4 h/day for 45 days) to Wi-Fi electromagnetic radiation, plasma levels of glucose and insulin during intraperitoneal glucose tolerance test were measured. Islet insulin secretion and content, lipid peroxidation and antioxidant status in pancreas of rats were determined. Our data showed that the weight gain in the WI-FI exposed group was significantly lower than the control group (p<0.05). Wi-Fi (2.45 GHz) exposed group showed hyperglycemia. Plasma insulin level and glucose-stimulated insulin secretion from pancreatic islet were significantly reduced in the Wi-Fi exposed group. EMR emitted from Wi-Fi caused a significant increase in lipid peroxidation and a significant decrease in GSH level, SOD and GPx activities of the pancreas. these data showed that EMR of Wi-Fi leads to hyperglycemia, increased oxidative stress and impaired insulin secretion in the rat pancreatic islets.

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 that synergize with other signaling pathways for secretion. PMID:26909310

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.

Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

PubMed Central

Ingelsson, Erik; Langenberg, Claudia; Hivert, Marie-France; Prokopenko, Inga; Lyssenko, Valeriya; Dupuis, Josée; Mägi, Reedik; Sharp, Stephen; Jackson, Anne U.; Assimes, Themistocles L.; Shrader, Peter; Knowles, Joshua W.; Zethelius, Björn; Abbasi, Fahim A.; Bergman, Richard N.; Bergmann, Antje; Berne, Christian; Boehnke, Michael; Bonnycastle, Lori L.; Bornstein, Stefan R.; Buchanan, Thomas A.; Bumpstead, Suzannah J.; Böttcher, Yvonne; Chines, Peter; Collins, Francis S.; Cooper, Cyrus C.; Dennison, Elaine M.; Erdos, Michael R.; Ferrannini, Ele; Fox, Caroline S.; Graessler, Jürgen; Hao, Ke; Isomaa, Bo; Jameson, Karen A.; Kovacs, Peter; Kuusisto, Johanna; Laakso, Markku; Ladenvall, Claes; Mohlke, Karen L.; Morken, Mario A.; Narisu, Narisu; Nathan, David M.; Pascoe, Laura; Payne, Felicity; Petrie, John R.; Sayer, Avan A.; Schwarz, Peter E. H.; Scott, Laura J.; Stringham, Heather M.; Stumvoll, Michael; Swift, Amy J.; Syvänen, Ann-Christine; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Tönjes, Anke; Valle, Timo T.; Williams, Gordon H.; Lind, Lars; Barroso, Inês; Quertermous, Thomas; Walker, Mark; Wareham, Nicholas J.; Meigs, James B.; McCarthy, Mark I.; Groop, Leif; Watanabe, Richard M.; Florez, Jose C.

2010-01-01

OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. PMID:20185807

IL-6-Type Cytokine Signaling in Adipocytes Induces Intestinal GLP-1 Secretion.

PubMed

Wueest, Stephan; Laesser, Céline I; Böni-Schnetzler, Marianne; Item, Flurin; Lucchini, Fabrizio C; Borsigova, Marcela; Müller, Werner; Donath, Marc Y; Konrad, Daniel

2018-01-01

We recently showed that interleukin (IL)-6-type cytokine signaling in adipocytes induces free fatty acid release from visceral adipocytes, thereby promoting obesity-induced hepatic insulin resistance and steatosis. In addition, IL-6-type cytokines may increase the release of leptin from adipocytes and by those means induce glucagon-like peptide 1 (GLP-1) secretion. We thus hypothesized that IL-6-type cytokine signaling in adipocytes may regulate insulin secretion. To this end, mice with adipocyte-specific knockout of gp130, the signal transducer protein of IL-6, were fed a high-fat diet for 12 weeks. Compared with control littermates, knockout mice showed impaired glucose tolerance and circulating leptin, GLP-1, and insulin levels were reduced. In line, leptin release from isolated adipocytes was reduced, and intestinal proprotein convertase subtilisin/kexin type 1 ( Pcsk1 ) expression, the gene encoding PC1/3, which controls GLP-1 production, was decreased in knockout mice. Importantly, treatment with the GLP-1 receptor antagonist exendin 9-39 abolished the observed difference in glucose tolerance between control and knockout mice. Ex vivo, supernatant collected from isolated adipocytes of gp130 knockout mice blunted Pcsk1 expression and GLP-1 release from GLUTag cells. In contrast, glucose- and GLP-1-stimulated insulin secretion was not affected in islets of knockout mice. In conclusion, adipocyte-specific IL-6 signaling induces intestinal GLP-1 release to enhance insulin secretion, thereby counteracting insulin resistance in obesity. © 2017 by the American Diabetes Association.

Regulation of Protein Secretion Through Controlled Aggregation in the Endoplasmic Reticulum

NASA Astrophysics Data System (ADS)

Rivera, Victor M.; Wang, Xiurong; Wardwell, Scott; Courage, Nancy L.; Volchuk, Allen; Keenan, Terence; Holt, Dennis A.; Gilman, Michael; Orci, Lelio; Cerasoli, Frank; Rothman, James E.; Clackson, Tim

2000-02-01

A system for direct pharmacologic control of protein secretion was developed to allow rapid and pulsatile delivery of therapeutic proteins. A protein was engineered so that it accumulated as aggregates in the endoplasmic reticulum. Secretion was then stimulated by a synthetic small-molecule drug that induces protein disaggregation. Rapid and transient secretion of growth hormone and insulin was achieved in vitro and in vivo. A regulated pulse of insulin secretion resulted in a transient correction of serum glucose concentrations in a mouse model of hyperglycemia. This approach may make gene therapy a viable method for delivery of polypeptides that require rapid and regulated delivery.

THE EFFECT OF ADRENAL MEDULLECTOMY ON METABOLIC RESPONSES TO CHRONIC INTERMITTENT HYPOXIA

PubMed Central

Shin, Mi-Kyung; Han, Woobum; Bevans-Fonti, Shannon; Jun, Jonathan C.; Punjabi, Naresh M.; Polotsky, Vsevolod Y.

2014-01-01

Obstructive sleep apnea causes intermittent hypoxia (IH) and is associated with insulin resistance and type 2 diabetes. IH increases plasma catecholamine levels, which may increase insulin resistance and suppress insulin secretion. The objective of this study was to determine if adrenal medullectomy (MED) prevents metabolic dysfunction in IH. MED or sham surgery was performed in 60 male C57BL/6J mice, which were then exposed to IH or control conditions (intermittent air) for 6 weeks. IH increased plasma epinephrine and norepinephrine levels, increased fasting blood glucose and lowered basal and glucose-stimulated insulin secretion. MED decreased baseline epinephrine and prevented the IH induced increase in epinephrine, whereas the norepinephrine response remained intact. MED improved glucose tolerance in mice exposed to IH, attenuated the impairment in basal and glucose-stimulated insulin secretion, but did not prevent IH-induced fasting hyperglycemia or insulin resistance. We conclude that the epinephrine release from the adrenal medulla during IH suppresses insulin secretion causing hyperglycemia. PMID:25179887

Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet

PubMed Central

Molina, Judith; Rodriguez-Diaz, Rayner; Fachado, Alberto; Jacques-Silva, M. Caroline

2014-01-01

Acetylcholine regulates hormone secretion from the pancreatic islet and is thus crucial for glucose homeostasis. Little is known, however, about acetylcholine (cholinergic) signaling in the human islet. We recently reported that in the human islet, acetylcholine is primarily a paracrine signal released from α-cells rather than primarily a neural signal as in rodent islets. In this study, we demonstrate that the effects acetylcholine produces in the human islet are different and more complex than expected from studies conducted on cell lines and rodent islets. We found that endogenous acetylcholine not only stimulates the insulin-secreting β-cell via the muscarinic acetylcholine receptors M3 and M5, but also the somatostatin-secreting δ-cell via M1 receptors. Because somatostatin is a strong inhibitor of insulin secretion, we hypothesized that cholinergic input to the δ-cell indirectly regulates β-cell function. Indeed, when all muscarinic signaling was blocked, somatostatin secretion decreased and insulin secretion unexpectedly increased, suggesting a reduced inhibitory input to β-cells. Endogenous cholinergic signaling therefore provides direct stimulatory and indirect inhibitory input to β-cells to regulate insulin secretion from the human islet. PMID:24658304

A beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion in mice.

PubMed

Attané, Camille; Peyot, Marie-Line; Lussier, Roxane; Poursharifi, Pegah; Zhao, Shangang; Zhang, Dongwei; Morin, Johane; Pineda, Marco; Wang, Shupei; Dumortier, Olivier; Ruderman, Neil B; Mitchell, Grant A; Simons, Brigitte; Madiraju, S R Murthy; Joly, Erik; Prentki, Marc

2016-12-01

To directly assess the role of beta cell lipolysis in insulin secretion and whole-body energy homeostasis, inducible beta cell-specific adipose triglyceride lipase (ATGL)-deficient (B-Atgl-KO) mice were studied under normal diet (ND) and high-fat diet (HFD) conditions. Atgl flox/flox mice were cross-bred with Mip-Cre-ERT mice to generate Mip-Cre-ERT /+ ;Atgl flox/flox mice. At 8 weeks of age, these mice were injected with tamoxifen to induce deletion of beta cell-specific Atgl (also known as Pnpla2), and the mice were fed an ND or HFD. ND-fed male B-Atgl-KO mice showed decreased insulinaemia and glucose-induced insulin secretion (GSIS) in vivo. Changes in GSIS correlated with the islet content of long-chain saturated monoacylglycerol (MAG) species that have been proposed to be metabolic coupling factors for insulin secretion. Exogenous MAGs restored GSIS in B-Atgl-KO islets. B-Atgl-KO male mice fed an HFD showed reduced insulinaemia, glycaemia in the fasted and fed states and after glucose challenge, as well as enhanced insulin sensitivity. Moreover, decreased insulinaemia in B-Atgl-KO mice was associated with increased energy expenditure, and lipid metabolism in brown (BAT) and white (WAT) adipose tissues, leading to reduced fat mass and body weight. ATGL in beta cells regulates insulin secretion via the production of signalling MAGs. Decreased insulinaemia due to lowered GSIS protects B-Atgl-KO mice from diet-induced obesity, improves insulin sensitivity, increases lipid mobilisation from WAT and causes BAT activation. The results support the concept that fuel excess can drive obesity and diabetes via hyperinsulinaemia, and that an islet beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion.

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.

Ultra-structural study of insulin granules in pancreatic β-cells of db/db mouse by scanning transmission electron microscopy tomography.

PubMed

Xue, Yanhong; Zhao, Wei; Du, Wen; Zhang, Xiang; Ji, Gang; Ying, Wang; Xu, Tao

2012-07-01

Insulin granule trafficking is a key step in the secretion of glucose-stimulated insulin from pancreatic β-cells. The main feature of type 2 diabetes (T2D) is the failure of pancreatic β-cells to secrete sufficient amounts of insulin to maintain normal blood glucose levels. In this work, we developed and applied tomography based on scanning transmission electron microscopy (STEM) to image intact insulin granules in the β-cells of mouse pancreatic islets. Using three-dimensional (3D) reconstruction, we found decreases in both the number and the grey level of insulin granules in db/db mouse pancreatic β-cells. Moreover, insulin granules were closer to the plasma membrane in diabetic β-cells than in control cells. Thus, 3D ultra-structural tomography may provide new insights into the pathology of insulin secretion in T2D.

Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass

PubMed Central

Gelling, Richard W.; Vuguin, Patricia M.; Du, Xiu Quan; Cui, Lingguang; Rømer, John; Pederson, Raymond A.; Leiser, Margarita; Sørensen, Heidi; Holst, Jens J.; Fledelius, Christian; Johansen, Peter B.; Fleischer, Norman; McIntosh, Christopher H. S.; Nishimura, Erica; Charron, Maureen J.

2009-01-01

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic β-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. β-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic β-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, β-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT. PMID:19602585

Neuromedin U suppresses glucose-stimulated insulin secretion in pancreatic β cells.

PubMed

Zhang, Weidong; Sakoda, Hideyuki; Miura, Ayako; Shimizu, Koichiro; Mori, Kenji; Miyazato, Mikiya; Takayama, Kentaro; Hayashi, Yoshio; Nakazato, Masamitsu

2017-11-04

Neuromedin U (NMU), a highly conserved peptide in mammals, is implicated in energy homeostasis and glycemic control, and may also be involved in the regulation of adipoinsular axis function. However, the role of NMU in regulating insulin secretion has not been clearly established. In this study, we investigated the role of NMU in the regulation of insulin secretion both in vitro and in vivo. We found that NMU and NMU receptor (NMUR) 1 were expressed in mouse islets and β cell-derived MIN6-K8 cells. In mice, NMU suppressed glucose-stimulated insulin secretion (GSIS) both in vitro and in vivo. Additionally, an NMUR1 agonist inhibited GSIS in both MIN6-K8 cells and mice islets. Moreover, NMU attenuated intracellular Ca 2+ influx in MIN6-K8 cells, potentially causing a decrease in insulin secretion. siNmu-transfected MIN6-K8 cells showed elevated GSIS. Treatment with anti-NMU IgG increased GSIS in isolated mouse pancreatic islets. These results suggested that NMU can act directly on β cells through NMUR1 in an autocrine or paracrine fashion to suppress insulin secretion. Collectively, our results highlight the crucial role of NMU in suppressing pancreatic insulin secretion, and may improve our understanding of glucose homeostasis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Characterization of beta cell and incretin function in patients with MODY1 (HNF4A MODY) and MODY3 (HNF1A MODY) in a Swedish patient collection.

PubMed

Ekholm, E; Shaat, N; Holst, J J

2012-10-01

The aim of this study was to evaluate the beta cell and incretin function in patients with HNF4A and HNF1A MODY during a test meal. Clinical characteristics and biochemical data (glucose, proinsulin, insulin, C-peptide, GLP-1 and GIP) during a test meal were compared between MODY patients from eight different families. BMI-matched T2D and healthy subjects were used as two separate control groups. The early phase of insulin secretion was attenuated in HNF4A, HNF1A MODY and T2D (AUC0-30 controls: 558.2 ± 101.2, HNF4A MODY: 93.8 ± 57.0, HNF1A MODY: 170.2 ± 64.5, T2D: 211.2 ± 65.3, P < 0.01). Markedly reduced levels of proinsulin were found in HNF4A MODY compared to T2D and that tended to be so also in HNF1A MODY (HNF4A MODY: 3.7 ± 1.2, HNF1A MODY: 8.3 ± 3.8 vs. T2D: 26.6 ± 14.3). Patients with HNF4A MODY had similar total GLP-1 and GIP responses as controls (GLP-1 AUC: (control: 823.9 ± 703.8, T2D: 556.4 ± 698.2, HNF4A MODY: 1,257.0 ± 999.3, HNF1A MODY: 697.1 ± 818.4) but with a different secretion pattern. The AUC insulin during the test meal was strongly correlated with the GIP secretion (Correlation coefficient 1.0, P < 0.001). No such correlation was seen for insulin and GLP-1. Patients with HNF4A and HNF1A MODY showed an attenuated early phase of insulin secretion similar to T2Ds. AUC insulin during the test meal was strongly correlated with GIP secretion, whereas no such correlation was seen for insulin and GLP-1. Thus, GIP may be a more important factor for insulin secretion than GLP-1 in MODY patients.

Dual effect of cell-cell contact disruption on cytosolic calcium and insulin secretion.

PubMed

Jaques, Fabienne; Jousset, Hélène; Tomas, Alejandra; Prost, Anne-Lise; Wollheim, Claes B; Irminger, Jean-Claude; Demaurex, Nicolas; Halban, Philippe A

2008-05-01

Cell-to-cell interactions play an important role in insulin secretion. Compared with intact islets, dispersed pancreatic beta-cells show increased basal and decreased glucose-stimulated insulin secretion. In this study, we used mouse MIN6B1 cells to investigate the mechanisms that control insulin secretion when cells are in contact with each other or not. RNAi-mediated silencing of the adhesion molecule E-cadherin in confluent cells reduced glucose-stimulated secretion to the levels observed in isolated cells but had no impact on basal secretion. Dispersed cells presented high cytosolic Ca(2+) activity, depolymerized cytoskeleton and ERK1/2 activation in low glucose conditions. Both the increased basal secretion and the spontaneous Ca(2+) activity were corrected by transient removal of Ca(2+) or prolonged incubation of cells in low glucose, a procedure that restored the ability of dispersed cells to respond to glucose (11-fold stimulation). In conclusion, we show that dispersed pancreatic beta-cells can respond robustly to glucose once their elevated basal secretion has been corrected. The increased basal insulin secretion of dispersed cells is due to spontaneous Ca(2+) transients that activate downstream Ca(2+) effectors, whereas engagement of cell adhesion molecules including E-cadherin contributes to the greater secretory response to glucose seen in cells with normal intercellular contacts.

The Mitochondrial 2-Oxoglutarate Carrier Is Part of a Metabolic Pathway That Mediates Glucose- and Glutamine-stimulated Insulin Secretion*

PubMed Central

Odegaard, Matthew L.; Joseph, Jamie W.; Jensen, Mette V.; Lu, Danhong; Ilkayeva, Olga; Ronnebaum, Sarah M.; Becker, Thomas C.; Newgard, Christopher B.

2010-01-01

Glucose-stimulated insulin secretion from pancreatic islet β-cells is dependent in part on pyruvate cycling through the pyruvate/isocitrate pathway, which generates cytosolic α-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 β-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. PMID:20356834

Treatments for diabetes mellitus type II: New perspectives regarding the possible role of calcium and cAMP interaction.

PubMed

Carvalho, Diego Soares; de Almeida, Alexandre Aparecido; Borges, Aurélio Ferreira; Campos, Vannucci

2018-07-05

Diabetes mellitus (DM) is among the top ten causes of death worldwide. It is considered to be one of the major global epidemics of the 21st century, with a significant impact on public health budgets. DM is a metabolic disorder with multiple etiologies. Its pathophysiology is marked by dysfunction of pancreatic β-cells which compromises the synthesis and secretion of insulin along with resistance to insulin action in peripheral tissues (muscle and adipose). Subjects presenting insulin resistance in DM type 2 often also exhibit increased insulin secretion and hyperinsulinemia. Insulin secretion is controlled by several factors such as nutrients, hormones, and neural factors. Exocytosis of insulin granules has, as its main stimulus, increased intracellular calcium ([Ca +2 ]i) and it is further amplified by cyclic AMP (cAMP). In the event of this hyperfunction, it is very common for β-cells to go into exhaustion leading to failure or death. Several animal studies have demonstrated pleiotropic effects of L-type Ca 2+ channel blockers (CCBs). In animal models of obesity and diabetes, treatment with CCBs promoted restoration of insulin secretion, glycemic control, and reduction of pancreatic β-cell apoptosis. In addition, hypertensive individuals treated with CCBs presented a lower incidence of DM when compared with other antihypertensive agents. In this review, we propose that pharmacological manipulation of the Ca 2+ /cAMP interaction system could lead to important targets for pharmacological improvement of insulin secretion in DM type 2. Copyright © 2018 Elsevier B.V. All rights reserved.

Glycogen metabolism in the glucose-sensing and supply-driven β-cell.

PubMed

Andersson, Lotta E; Nicholas, Lisa M; Filipsson, Karin; Sun, Jiangming; Medina, Anya; Al-Majdoub, Mahmoud; Fex, Malin; Mulder, Hindrik; Spégel, Peter

2016-12-01

Glycogen metabolism in β-cells may affect downstream metabolic pathways controlling insulin release. We examined glycogen metabolism in human islets and in the rodent-derived INS-1 832/13 β-cells and found them to express the same isoforms of key enzymes required for glycogen metabolism. Our findings indicate that glycogenesis is insulin-independent but influenced by extracellular glucose concentrations. Levels of glycogen synthase decrease with increasing glucose concentrations, paralleling accumulation of glycogen. We did not find cAMP-elicited glycogenolysis and insulin secretion to be causally related. In conclusion, our results reveal regulated glycogen metabolism in human islets and insulin-secreting cells. Whether glycogen metabolism affects insulin secretion under physiological conditions remains to be determined. © 2016 Federation of European Biochemical Societies.

Aerobic Exercise Training Attenuates Tumor Growth and Reduces Insulin Secretion in Walker 256 Tumor-Bearing Rats

PubMed Central

Moreira, Veridiana Mota; da Silva Franco, Claudinéia Conationi; Prates, Kelly Valério; Gomes, Rodrigo Mello; de Moraes, Ana Maria Praxedes; Ribeiro, Tatiane Aparecida; Martins, Isabela Peixoto; Previate, Carina; Pavanello, Audrei; Matiusso, Camila Cristina Ianoni; Almeida, Douglas Lopes; Francisco, Flávio Andrade; Malta, Ananda; Tófolo, Laize Peron; da Silva Silveira, Sandra; Saavedra, Lucas Paulo Jacinto; Machado, Katia; da Silva, Paulo Henrique Olivieri; Fabrício, Gabriel S.; Palma-Rigo, Kesia; de Souza, Helenir Medri; de Fátima Silva, Flaviane; Biazi, Giuliana Regina; Pereira, Taís Susane; Vieira, Elaine; Miranda, Rosiane Aparecida; de Oliveira, Júlio Cezar; da Costa Lima, Luiz Delmar; Rinaldi, Wilson; Ravanelli, Maria Ida; de Freitas Mathias, Paulo Cezar

2018-01-01

Aerobic exercise training can improve insulin sensitivity in many tissues; however, the relationship among exercise, insulin, and cancer cell growth is unclear. We tested the hypothesis that aerobic exercise training begun during adolescence can attenuate Walker 256 tumor growth in adult rats and alter insulin secretion. Thirty-day-old male Wistar rats engaged in treadmill running for 8 weeks, 3 days/week, 44 min/day, at 55–65% VO2max until they were 90 days old (TC, Trained Control). An equivalently aged group was kept inactive during the same period (SC, Sedentary Control). Then, half the animals of the SC and TC groups were reserved as the control condition and the other half were inoculated with Walker 256 cancer cells, yielding two additional groups (Sedentary Walker and Trained Walker). Zero mortalities were observed in tumor-bearing rats. Body weight (BW), food intake, plasma glucose, insulin levels, and peripheral insulin sensitivity were analyzed before and after tumor cell inoculation. We also evaluated tumor growth, metastasis and cachexia. Isolated pancreatic islets secretory activity was analyzed. In addition, we evaluated mechanic sensibility. Our results showed improved physical performance according to the final workload and VO2max and reduced BW in trained rats at the end of the running protocol. Chronic adaptation to the aerobic exercise training decreased tumor weight, cachexia and metastasis and were associated with low glucose and insulin levels and high insulin sensitivity before and after tumor cell inoculation. Aerobic exercise started at young age also reduced pancreatic islet insulin content and insulin secretion in response to a glucose stimulus, without impairing islet morphology in trained rats. Walker 256 tumor-bearing sedentary rats also presented reduced pancreatic islet insulin content, without changing insulin secretion through isolated pancreatic islets. The mechanical sensitivity test indicated that aerobic exercise training did not cause injury or trigger inflammatory processes prior to tumor cell inoculation. Taken together, the current study suggests that aerobic exercise training applied during adolescence may mitigate tumor growth and related disorders in Walker 256 tumor-bearing adult rats. Improved insulin sensibility, lower glucose and insulin levels and/or reduced insulin secretion stimulated by glucose may be implicated in this tumor attenuation.

Aerobic Exercise Training Attenuates Tumor Growth and Reduces Insulin Secretion in Walker 256 Tumor-Bearing Rats.

PubMed

Moreira, Veridiana Mota; da Silva Franco, Claudinéia Conationi; Prates, Kelly Valério; Gomes, Rodrigo Mello; de Moraes, Ana Maria Praxedes; Ribeiro, Tatiane Aparecida; Martins, Isabela Peixoto; Previate, Carina; Pavanello, Audrei; Matiusso, Camila Cristina Ianoni; Almeida, Douglas Lopes; Francisco, Flávio Andrade; Malta, Ananda; Tófolo, Laize Peron; da Silva Silveira, Sandra; Saavedra, Lucas Paulo Jacinto; Machado, Katia; da Silva, Paulo Henrique Olivieri; Fabrício, Gabriel S; Palma-Rigo, Kesia; de Souza, Helenir Medri; de Fátima Silva, Flaviane; Biazi, Giuliana Regina; Pereira, Taís Susane; Vieira, Elaine; Miranda, Rosiane Aparecida; de Oliveira, Júlio Cezar; da Costa Lima, Luiz Delmar; Rinaldi, Wilson; Ravanelli, Maria Ida; de Freitas Mathias, Paulo Cezar

2018-01-01

Aerobic exercise training can improve insulin sensitivity in many tissues; however, the relationship among exercise, insulin, and cancer cell growth is unclear. We tested the hypothesis that aerobic exercise training begun during adolescence can attenuate Walker 256 tumor growth in adult rats and alter insulin secretion. Thirty-day-old male Wistar rats engaged in treadmill running for 8 weeks, 3 days/week, 44 min/day, at 55-65% VO 2max until they were 90 days old (TC, Trained Control). An equivalently aged group was kept inactive during the same period (SC, Sedentary Control). Then, half the animals of the SC and TC groups were reserved as the control condition and the other half were inoculated with Walker 256 cancer cells, yielding two additional groups (Sedentary Walker and Trained Walker). Zero mortalities were observed in tumor-bearing rats. Body weight (BW), food intake, plasma glucose, insulin levels, and peripheral insulin sensitivity were analyzed before and after tumor cell inoculation. We also evaluated tumor growth, metastasis and cachexia. Isolated pancreatic islets secretory activity was analyzed. In addition, we evaluated mechanic sensibility. Our results showed improved physical performance according to the final workload and VO 2max and reduced BW in trained rats at the end of the running protocol. Chronic adaptation to the aerobic exercise training decreased tumor weight, cachexia and metastasis and were associated with low glucose and insulin levels and high insulin sensitivity before and after tumor cell inoculation. Aerobic exercise started at young age also reduced pancreatic islet insulin content and insulin secretion in response to a glucose stimulus, without impairing islet morphology in trained rats. Walker 256 tumor-bearing sedentary rats also presented reduced pancreatic islet insulin content, without changing insulin secretion through isolated pancreatic islets. The mechanical sensitivity test indicated that aerobic exercise training did not cause injury or trigger inflammatory processes prior to tumor cell inoculation. Taken together, the current study suggests that aerobic exercise training applied during adolescence may mitigate tumor growth and related disorders in Walker 256 tumor-bearing adult rats. Improved insulin sensibility, lower glucose and insulin levels and/or reduced insulin secretion stimulated by glucose may be implicated in this tumor attenuation.

Insulin-like and IGF-like peptides in the silkmoth Bombyx mori: discovery, structure, secretion, and function

PubMed Central

Mizoguchi, Akira; Okamoto, Naoki

2013-01-01

A quarter of a century has passed since bombyxin, the first insulin-like peptide identified in insects, was discovered in the silkmoth Bombyx mori. During these years, bombyxin has been studied for its structure, genes, distribution, hemolymph titers, secretion control, as well as physiological functions, thereby stimulating a wide range of studies on insulin-like peptides in other insects. Moreover, recent studies have identified a new class of insulin family peptides, IGF-like peptides, in B. mori and Drosophila melanogaster, broadening the base of the research area of the insulin-related peptides in insects. In this review, we describe the achievements of the studies on insulin-like and IGF-like peptides mainly in B. mori with short histories of their discovery. Our emphasis is that bombyxins, secreted by the brain neurosecretory cells, regulate nutrient-dependent growth and metabolism, whereas the IGF-like peptides, secreted by the fat body and other peripheral tissues, regulate stage-dependent growth of tissues. PMID:23966952

A review of nateglinide in the management of patients with type 2 diabetes

PubMed Central

Tentolouris, Nicholas; Voulgari, Christina; Katsilambros, Nicholas

2007-01-01

Impaired insulin secretion occurs early in the pathogenesis of type 2 diabetes mellitus (T2DM) and is chronic and progressive, resulting initially in impaired glucose tolerance (IGT) and eventually in T2DM. As most patients with T2DM have both insulin resistance and insulin deficiency, therapy for T2DM should aim to control not only fasting, but also postprandial plasma glucose levels. While oral glucose-lowering treatment with metformin and thiazolidinediones corrects fasting plasma glucose, these agents do not address the problem of mealtime glucose spikes that have been shown to trigger atherogenic processes. Nateglinide is a derivative of the amino acid D-phenylalanine, which acts directly on the pancreatic β-cells to stimulate insulin secretion. Nateglinide monotherapy controls significantly mealtime hyperglycemia and results in improved overall glycemic control in patients with T2DM by reducing glycosylated hemoglobin (HbA1c) levels. The combination of nateglinide with insulin-sensitising agents, such as metformin and thiazolidinediones, targets both insulin deficiency and insulin resistance and results in reductions in HbA1c that could not be achieved by monotherapy with other antidiabetic agents. In prediabetic subjects with IGT, nateglinide restores early insulin secretion and reduces postprandial hyperglycemia. Nateglinide has an excellent safety and tolerability profile and provides a lifetime flexibility that other antidiabetic agents could not accomplish. The aim of this review is to identify nateglinide as an effective “gate-keeper” in T2DM, since it restores early-phase insulin secretion and prevents mealtime glucose spikes throughout the day and to evaluate the results of ongoing research into its potential role in delaying the progression to overt diabetes and reducing its complications and mortality. PMID:18200800

Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity

PubMed Central

Wu, Lindsay E.; Samocha-Bonet, Dorit; Whitworth, P. Tess; Fazakerley, Daniel J.; Turner, Nigel; Biden, Trevor J.; James, David E.; Cantley, James

2014-01-01

A critical feature of obesity is enhanced insulin secretion from pancreatic β-cells, enabling the majority of individuals to maintain glycaemic control despite adiposity and insulin resistance. Surprisingly, the factors coordinating this adaptive β-cell response with adiposity have not been delineated. Here we show that fatty acid binding protein 4 (FABP4/aP2) is an adipokine released from adipocytes under obesogenic conditions, such as hypoxia, to augment insulin secretion. The insulinotropic action of FABP4 was identified using an in vitro system that recapitulates adipocyte to β-cell endocrine signalling, with glucose-stimulated insulin secretion (GSIS) as a functional readout, coupled with quantitative proteomics. Exogenous FABP4 potentiated GSIS in vitro and in vivo, and circulating FABP4 levels correlated with GSIS in humans. Insulin inhibited FABP4 release from adipocytes in vitro, in mice and in humans, consistent with feedback regulation. These data suggest that FABP4 and insulin form an endocrine loop coordinating the β-cell response to obesity. PMID:24944906

Serum fatty acid-binding protein 4 (FABP4) concentration is associated with insulin resistance in peripheral tissues, A clinical study.

PubMed

Nakamura, Risa; Okura, Tsuyoshi; Fujioka, Yohei; Sumi, Keisuke; Matsuzawa, Kazuhiko; Izawa, Shoichiro; Ueta, Etsuko; Kato, Masahiko; Taniguchi, Shin-Ichi; Yamamoto, Kazuhiro

2017-01-01

Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and β cell dysfunction. In recent studies reported that several markers associated with insulin sensitivity in skeletal muscle, Adiponectin and other parameters, such as fatty acid-binding protein (FABP4), have been reported to regulate insulin resistance, but it remains unclear which factor mostly affects insulin resistance in T2DM. In this cross-sectional study, we evaluated the relationships between several kinds of biomarkers and insulin resistance, and insulin secretion in T2DM and healthy controls. We recruited 30 participants (12 T2DM and 18 non-diabetic healthy controls). Participants underwent a meal tolerance test during which plasma glucose, insulin and serum C-peptide immunoreactivity were measured. We performed a hyperinsulinemic-euglycemic clamp and measured the glucose-disposal rate (GDR). The fasting serum levels of adiponectin, insulin-like growth factor-1, irisin, autotaxin, FABP4 and interleukin-6 were measured by ELISA. We found a strong negative correlation between FABP4 concentration and GDR in T2DM (r = -0.657, p = 0.020). FABP4 also was positively correlated with insulin secretion during the meal tolerance test in T2DM (IRI (120): r = 0.604, p = 0.038) and was positively related to the insulinogenic index in non-DM subjects (r = 0.536, p = 0.022). Autotaxin was also related to GDR. However, there was no relationship with insulin secretion. We found that serum FABP4 concentration were associated with insulin resistance and secretion in T2DM. This suggests that FABP4 may play an important role in glucose homeostasis.

Serum fatty acid-binding protein 4 (FABP4) concentration is associated with insulin resistance in peripheral tissues, A clinical study

PubMed Central

Nakamura, Risa; Okura, Tsuyoshi; Fujioka, Yohei; Sumi, Keisuke; Matsuzawa, Kazuhiko; Izawa, Shoichiro; Ueta, Etsuko; Kato, Masahiko; Taniguchi, Shin-ichi; Yamamoto, Kazuhiro

2017-01-01

Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and β cell dysfunction. In recent studies reported that several markers associated with insulin sensitivity in skeletal muscle, Adiponectin and other parameters, such as fatty acid-binding protein (FABP4), have been reported to regulate insulin resistance, but it remains unclear which factor mostly affects insulin resistance in T2DM. In this cross-sectional study, we evaluated the relationships between several kinds of biomarkers and insulin resistance, and insulin secretion in T2DM and healthy controls. We recruited 30 participants (12 T2DM and 18 non-diabetic healthy controls). Participants underwent a meal tolerance test during which plasma glucose, insulin and serum C-peptide immunoreactivity were measured. We performed a hyperinsulinemic-euglycemic clamp and measured the glucose-disposal rate (GDR). The fasting serum levels of adiponectin, insulin-like growth factor-1, irisin, autotaxin, FABP4 and interleukin-6 were measured by ELISA. We found a strong negative correlation between FABP4 concentration and GDR in T2DM (r = -0.657, p = 0.020). FABP4 also was positively correlated with insulin secretion during the meal tolerance test in T2DM (IRI (120): r = 0.604, p = 0.038) and was positively related to the insulinogenic index in non-DM subjects (r = 0.536, p = 0.022). Autotaxin was also related to GDR. However, there was no relationship with insulin secretion. We found that serum FABP4 concentration were associated with insulin resistance and secretion in T2DM. This suggests that FABP4 may play an important role in glucose homeostasis. PMID:28654680

Effects of thyrotrophin-releasing hormone, and methionine-enkephalin on gastric acid and pepsin secretion in the cat.

PubMed

Gascoigne, A D; Hirst, B H; Reed, J D; Shaw, B

1980-07-01

1 The effect of intravenous administration of thyrotrophin-releasing hormone (TRH) and methionine-enkephalin on gastric acid and pepsin secretions was investigated in conscious cats prepared with chronic gastric fistulae.2 TRH, 20 mug kg(-1) h(-1), did not influence unstimulated gastric acid secretion, nor gastric acid secretion stimulated by submaximal doses of pentagastrin or histamine. Pepsin secretion stimulated by pentagastrin was not influenced by TRH.3 TRH, 20 mug kg(-1) h(-1), significantly reduced the gastric acid and pepsin responses to intravenous infusion of insulin. TRH also significantly reduced the degree of hypoglycaemia seen in response to insulin. TRH, 20 mug kg(-1) h(-1), but not 5 mug kg(-1) h(-1), infused alone resulted in a significant hyperglycaemia.4 It is concluded that the reduction of insulin-stimulated gastric secretion by TRH is not dependent on the hyperglycaemic action of the peptide. The mechanism of action of TRH on insulin-stimulated secretion is discussed with respect to its site of action.5 Methionine-enkephalin or the potent analogue, D-Ala(2), Met-enkephalinamide were without effect on unstimulated gastric secretion, or secretion stimulated by pentagastrin, histamine, and insulin. The opiate receptor antagonist, naloxone, did not significantly alter the gastric acid or pepsin response to insulin.6 It is concluded that there is no evidence that opiates stimulate oxyntic glands directly, nor that the oxyntic cells may possess high affinity binding sites for opiates, nor that endogenous opiates are involved in the control of gastric secretion.

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.

Family history of diabetes and its relationship with insulin secretion and insulin sensitivity in Iraqi immigrants and native Swedes: a population-based cohort study.

PubMed

Bennet, Louise; Franks, Paul W; Zöller, Bengt; Groop, Leif

2018-03-01

Middle Eastern immigrants to western countries are at high risk of developing type 2 diabetes. However, the heritability and impact of first-degree family history (FH) of type 2 diabetes on insulin secretion and action have not been adequately described. Citizens of Malmö, Sweden, aged 30-75 years born in Iraq or Sweden were invited to participate in this population-based study. Insulin secretion (corrected insulin response and oral disposition index) and action (insulin sensitivity index) were assessed by oral glucose tolerance tests. In total, 45.7% of Iraqis (616/1348) and 27.4% of native Swedes (201/733) had FH in parent(s), sibling(s) or single parent and sibling, i.e., FH+. Approximately 8% of Iraqis and 0.7% of Swedes had ≥ 3 sibling(s) and parent(s) with diabetes, i.e., FH++. Irrespective of family size, prediabetes and diabetes increased with family burden (FH- 29.4%; FH+ 38.8%; FH++ 61.7%) without significant differences across ethnicities. With increasing level of family burden, insulin secretion rather than insulin action decreased. Individuals with a combination of ≥ 3 siblings and parents with diabetes presented with the lowest levels of insulin secretion. The Iraqi immigrant population often present with a strong familial burden of type 2 diabetes with the worst glycemic control and highest diabetes risk in individuals with ≥ 3 siblings and parents with diabetes. Our data show that in a population still free from diabetes familial burden influences insulin secretion to a higher degree than insulin action and may be a logical target for intervention.

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.

Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes.

PubMed

Owens, D R; Luzio, S D; Ismail, I; Bayer, T

2000-04-01

To examine the dose-related pharmacodynamics and pharmacokinetics of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. A total of 16 Caucasian men with type 2 diabetes participated in two placebo-controlled double-blind randomized cross-over studies. Patients were randomized to receive a single oral dose of repaglinide (0.5, 1.0, and 2.0 mg in study 1 and 4.0 mg in study 2) or placebo (both studies) administered 15 min before the first of two sequential identical standard meals (breakfast and lunch) that were 4 h apart. During each of the study days, which were 1 week apart, blood samples were taken at frequent intervals over a period of approximately 8 h for measurement of plasma glucose, insulin, C-peptide, and repaglinide concentrations. During the first meal period (0-240 min), administration of repaglinide reduced significantly the area under the curve (AUC) for glucose concentration and significantly increased the AUC for insulin levels, C-peptide levels, and the insulin secretion rate. These results, compared with those of administering placebo, were dose dependent and log linear. The effect of repaglinide administration on insulin secretion was most pronounced in the early prandial period. Within 30 min, it caused a relative increase in insulin secretion of up to 150%. During the second meal period (240-480 min), there was no difference between repaglinide and placebo administration in the AUC for glucose concentration, C-peptide concentration, and the estimated insulin secretion rate. A single dose of repaglinide (0.5-4.0 mg) before breakfast improves insulin secretion and reduces prandial hyperglycemia dose-dependently Administration of repaglinide had no effect on insulin secretion with the second meal, which was consumed 4 h after breakfast.

Larval hemolymph of rhinoceros beetle, Allomyrina dichotoma, enhances insulin secretion through ATF3 gene expression in INS-1 pancreatic β-cells.

PubMed

Kim, Seung-Whan; Suh, Hyun-Woo; Yoo, Bo-Kyung; Kwon, Kisang; Yu, Kweon; Choi, Ji-Young; Kwon, O-Yu

2018-05-22

In this study, we show that INS-1 pancreatic β-cells treated for 2 h with hemolymph of larvae of rhinoceros beetle, Allomyrina dichotoma, secreted about twice as much insulin compared to control cells without such treatment. Activating transcription factor 3 (ATF3) was the highest upregulated gene in DNA chip analysis. The A. dichotoma hemolymph dose-dependently induced increased expression levels of genes encoding ATF3 and insulin. Conversely, treatment with ATF3 siRNA inhibited expression levels of both genes and curbed insulin secretion. These results suggest that the A. dichotoma hemolymph has potential for treating and preventing diabetes or diabetes-related complications.

Long-term effects of guar gum in subjects with non-insulin-dependent diabetes mellitus.

PubMed

Groop, P H; Aro, A; Stenman, S; Groop, L

1993-10-01

The effects of 15 g guar gum/d on glycemic control, lipids, and insulin secretion were studied in 15 (8 male, 7 female) diet-treated subjects with non-insulin-dependent diabetes mellitus for 48 wk. Mean age (+/- SD) was 60 +/- 2 y (range 45-70 y), body mass index (in kg/m2) 28.6 +/- 0.9 (range 21.6 +/- 39.2), and duration of diabetes 6 +/- 1 y (range 2-14 y). Guar gum was preceded and followed by 8-wk placebo periods. Guar gum improved long-term glycemic control, postprandial glucose tolerance and lipid concentrations. The C-peptide response to a test meal increased by time during guar gum treatment, whereas the insulin response remained unchanged. This indicates that insulin secretion is enhanced by guar gum as reflected by increased C-peptide. A decreased molar ratio of insulin to C-peptide suggests that guar gum may increase hepatic insulin extraction. In conclusion, guar gum has favorable long-term effects on glycemic control and lipid concentrations.

FKBP12.6-knockout mice display hyperinsulinemia and resistance to high-fat diet-induced hyperglycemia.

PubMed

Chen, Zheng; Li, Zhengzheng; Wei, Bin; Yin, Wenxuan; Xu, Tao; Kotlikoff, Michael I; Ji, Guangju

2010-02-01

FK506 binding protein 12.6 kDa (FKBP12.6), a protein that regulates ryanodine Ca(2+) release channels, may act as an important regulator of insulin secretion. In this study, the role of FKBP12.6 in the control of insulin secretion and blood glucose is clarified using FKBP12.6(-/-) mice. FKBP12.6(-/-) mice showed significant fed hyperinsulinemia but exhibited normoglycemia, fasting normoinsulinemia, and normal body weight compared with wild-type (WT) littermate control mice. Deletion of FKBP12.6 resulted in enhanced glucose-stimulated insulin secretion (GSIS) both in vivo and in vitro, a result that is due to enhanced glucose-induced islet Ca(2+) elevation. After a high-fat dietary challenge (HF diet) for 3 mo, FKBP12.6(-/-) mice displayed higher body weight, hyperinsulinemia, and lower fed blood glucose concentrations compared with WT mice. FKBP12.6(-/-) mice displayed hyperinsulinemia, and resistance to HF diet-induced hyperglycemia, suggesting that FKBP12.6 plays an important role in insulin secretion and blood glucose control, and raising the possibility that it may be a potential therapeutic target for the treatment of type 2 diabetes.

Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans.

PubMed

Keaton, Jacob M; Gao, Chuan; Guan, Meijian; Hellwege, Jacklyn N; 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; Ng, Maggie C Y; Bowden, Donald W

2018-04-24

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10 -8 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (P interaction  = 1.43 × 10 -8 ; P joint  = 4.70 × 10 -8 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci. © 2018 WILEY PERIODICALS, INC.

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

PubMed

Anderson, Kristin A; Huynh, Frank K; Fisher-Wellman, Kelsey; Stuart, J Darren; Peterson, Brett S; Douros, Jonathan D; Wagner, Gregory R; Thompson, J Will; Madsen, Andreas S; Green, Michelle F; Sivley, R Michael; Ilkayeva, Olga R; Stevens, Robert D; Backos, Donald S; Capra, John A; Olsen, Christian A; Campbell, Jonathan E; Muoio, Deborah M; Grimsrud, Paul A; Hirschey, Matthew D

2017-04-04

Sirtuins are NAD + -dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging. Copyright © 2017 Elsevier Inc. All rights reserved.

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

PubMed

Pournourmohammadi, Shirin; Grimaldi, Mariagrazia; Stridh, Malin H; Lavallard, Vanessa; Waagepetersen, Helle S; Wollheim, Claes B; Maechler, Pierre

2017-07-01

Glucose homeostasis is determined by insulin secretion from the ß-cells in pancreatic islets and by glucose uptake in skeletal muscle and other insulin target tissues. While glutamate dehydrogenase (GDH) senses mitochondrial energy supply and regulates insulin secretion, its role in the muscle has not been elucidated. Here we investigated the possible interplay between GDH and the cytosolic energy sensing enzyme 5'-AMP kinase (AMPK), in both isolated islets and myotubes from mice and humans. The green tea polyphenol epigallocatechin-3-gallate (EGCG) was used to inhibit GDH. Insulin secretion was reduced by EGCG upon glucose stimulation and blocked in response to glutamine combined with the allosteric GDH activator BCH (2-aminobicyclo-[2,2,1] heptane-2-carboxylic acid). Insulin secretion was similarly decreased in islets of mice with ß-cell-targeted deletion of GDH (ßGlud1 -/- ). EGCG did not further reduce insulin secretion in the mutant islets, validating its specificity. In human islets, EGCG attenuated both basal and nutrient-stimulated insulin secretion. Glutamine/BCH-induced lowering of AMPK phosphorylation did not operate in ßGlud1 -/- islets and was similarly prevented by EGCG in control islets, while high glucose systematically inactivated AMPK. In mouse C2C12 myotubes, like in islets, the inhibition of AMPK following GDH activation with glutamine/BCH was reversed by EGCG. Stimulation of GDH in primary human myotubes caused lowering of insulin-induced 2-deoxy-glucose uptake, partially counteracted by EGCG. Thus, mitochondrial energy provision through anaplerotic input via GDH influences the activity of the cytosolic energy sensor AMPK. EGCG may be useful in obesity by resensitizing insulin-resistant muscle while blunting hypersecretion of insulin in hypermetabolic states. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Combined Calcium and Vitamin D Supplementation on Insulin Secretion, Insulin Sensitivity and β-Cell Function in Multi-Ethnic Vitamin D-Deficient Adults at Risk for Type 2 Diabetes: A Pilot Randomized, Placebo-Controlled Trial

PubMed Central

Gagnon, Claudia; Daly, Robin M.; Carpentier, André; Lu, Zhong X.; Shore-Lorenti, Catherine; Sikaris, Ken; Jean, Sonia; Ebeling, Peter R.

2014-01-01

Objectives To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity, insulin secretion, β-cell function, inflammation and metabolic markers. Design 6-month randomized, placebo-controlled trial. Participants Ninety-five adults with serum 25-hydroxyvitamin D [25(OH)D] ≤55 nmol/L at risk of type 2 diabetes (with prediabetes or an AUSDRISK score ≥15) were randomized. Analyses included participants who completed the baseline and final visits (treatment n = 35; placebo n = 45). Intervention Daily calcium carbonate (1,200 mg) and cholecalciferol [2,000–6,000 IU to target 25(OH)D >75 nmol/L] or matching placebos for 6 months. Measurements Insulin sensitivity (HOMA2%S, Matsuda index), insulin secretion (insulinogenic index, area under the curve (AUC) for C-peptide) and β-cell function (Matsuda index x AUC for C-peptide) derived from a 75 g 2-h OGTT; anthropometry; blood pressure; lipid profile; hs-CRP; TNF-α; IL-6; adiponectin; total and undercarboxylated osteocalcin. Results Participants were middle-aged adults (mean age 54 years; 69% Europid) at risk of type 2 diabetes (48% with prediabetes). Compliance was >80% for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group (91% achieved >75 nmol/L), but remained unchanged in controls. There were no significant changes in insulin sensitivity, insulin secretion and β-cell function, or in inflammatory and metabolic markers between or within the groups, before or after adjustment for potential confounders including waist circumference and season of recruitment. In a post hoc analysis restricted to participants with prediabetes, a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity (HOMA%S and Matsuda) was observed. Conclusions Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity, insulin secretion and β-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes. However, in participants with prediabetes, supplementation with vitamin D and calcium may improve insulin sensitivity. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000043235 PMID:25299668

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling.

PubMed

Nolan, C J; Leahy, J L; Delghingaro-Augusto, V; Moibi, J; Soni, K; Peyot, M-L; Fortier, M; Guay, C; Lamontagne, J; Barbeau, A; Przybytkowski, E; Joly, E; Masiello, P; Wang, S; Mitchell, G A; Prentki, M

2006-09-01

The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

Methscopolamine Inhibition of Sleep-Related Growth Hormone Secretion

PubMed Central

Mendelson, Wallace B.; Sitaram, Natarajan; Wyatt, Richard Jed; Gillin, J. Christian; Jacobs, Laurence S.

1978-01-01

We have examined the effects of cholinergic blockade with 0.5 mg methscopolamine bromide, intramuscularly, on sleep-related and insulin-induced growth hormone (GH) secretion. 17 normal young men were studied; 8 had sleep studies, and 12 (including 3 who also had sleep studies) had insulin tolerance tests (ITT) with 0.1 U/kg of regular insulin. After an adjustment night in the sleep laboratory, saline control night and methscopolamine night studies were done in random sequence; study procedures included electroencephalographic, electromyographic, and electrooculographic recordings, and blood sampling every 20 min for hormone radioimmunoassays. Prolactin levels were also measured during sleep. For methscopolamine night studies, the mean overall control GH level of 2.89±0.44 ng/ml and the mean peak control GH level of 11.09±3.11 ng/ml were dramatically reduced to 0.75±0.01 and 1.04±0.25 ng/ml, respectively (P<0.0001 and <0.001). Despite virtual absence of GH secretion during the night in every study subject, no measured sleep characteristic was affected by methscopolamine, including total slow-wave sleep (12.1±2.6% control vs. 10.3±2.5% drug, P>0.2). Sleep prolactin levels were not changed by methscopolamine. In contrast to the abolition of sleep-related GH secretion, administration of methscopolamine had only a marginal effect on the GH response to insulin hypoglycemia. None of nine time points differed significantly, as was also the case with peak levels, mean increments, and areas under the curves (P>0.2). Analysis of variance did, however, indicate that the lower GH concentrations achieved during ITT after methscopolamine (average 31.7% below control) were significantly different than control concentrations. We conclude that the burst of GH secretion which normally occurs after sleep onset is primed by a cholinergic mechanism which does not influence slow-wave sleep. Cholinergic mechanisms do not appear to play an important role in sleep-related prolactin secretion. The contrast between the complete suppression of sleep-related GH release and the relatively small inhibitory effect on ITT-induced GH secretion suggests that the neurotransmitter mechanisms, and presumably the pathways, which subserve sleep-related GH secretion in man may be different from those which mediate the GH response to pharmacologic stimuli such as insulin. PMID:659621

Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila

PubMed Central

Bai, Hua; Kang, Ping; Hernandez, Ana Maria; Tatar, Marc

2013-01-01

Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling. PMID:24244197

β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice.

PubMed

Ravier, Magalie A; Leduc, Michele; Richard, Joy; Linck, Nathalie; Varrault, Annie; Pirot, Nelly; Roussel, Morgane M; Bockaert, Joël; Dalle, Stéphane; Bertrand, Gyslaine

2014-03-01

Beta cell failure due to progressive secretory dysfunction and limited expansion of beta cell mass is a key feature of type 2 diabetes. Beta cell function and mass are controlled by glucose and hormones/neurotransmitters that activate G protein-coupled receptors or receptor tyrosine kinases. We have investigated the role of β-arrestin (ARRB)2, a scaffold protein known to modulate such receptor signalling, in the modulation of beta cell function and mass, with a specific interest in glucagon-like peptide-1 (GLP-1), muscarinic and insulin receptors. β-arrestin2-knockout mice and their wild-type littermates were fed a normal or a high-fat diet (HFD). Glucose tolerance, insulin sensitivity and insulin secretion were assessed in vivo. Beta cell mass was evaluated in pancreatic sections. Free cytosolic [Ca(2+)] and insulin secretion were determined using perifused islets. The insulin signalling pathway was evaluated by western blotting. Arrb2-knockout mice exhibited impaired glucose tolerance and insulin secretion in vivo, but normal insulin sensitivity compared with wild type. Surprisingly, the absence of ARRB2 did not affect glucose-stimulated insulin secretion or GLP-1- and acetylcholine-mediated amplifications from perifused islets, but it decreased the islet insulin content and beta cell mass. Additionally, there was no compensatory beta cell mass expansion through proliferation in response to the HFD. Furthermore, Arrb2 deletion altered the islet insulin signalling pathway. ARRB2 is unlikely to be involved in the regulation of insulin secretion, but it is required for beta cell mass plasticity. Additionally, we provide new insights into the mechanisms involved in insulin signalling in beta cells.

Mechanisms behind the superior effects of interval vs continuous training on glycaemic control in individuals with type 2 diabetes: a randomised controlled trial.

PubMed

Karstoft, Kristian; Winding, Kamilla; Knudsen, Sine H; James, Noemi G; Scheel, Maria M; Olesen, Jesper; Holst, Jens J; Pedersen, Bente K; Solomon, Thomas P J

2014-10-01

By use of a parallel and partly crossover randomised, controlled trial design we sought to elucidate the underlying mechanisms behind the advantageous effects of interval walking training (IWT) compared with continuous walking training (CWT) on glycaemic control in individuals with type 2 diabetes. We hypothesised that IWT, more than CWT, would improve insulin sensitivity including skeletal muscle insulin signalling, insulin secretion and disposition index (DI). By simple randomisation (sequentially numbered, opaque sealed envelopes), eligible individuals (diagnosed with type 2 diabetes, no exogenous insulin treatment) were allocated to three groups: a control group (CON, n = 8), an IWT group (n = 12) and an energy expenditure-matched CWT group (n = 12). Training groups were prescribed free-living training, five sessions per week (60 min/session). A three-stage hyperglycaemic clamp, including glucose isotope tracers and skeletal muscle biopsies, was performed before and after a 4 month intervention in a hospitalised setting. No blinding was performed. The improved glycaemic control, which was only seen in the IWT group, was consistent with IWT-induced increases in insulin sensitivity index (49.8 ± 14.6%; p < 0.001), peripheral glucose disposal (14.5 ± 4.9%; p < 0.05) and DI (66.2 ± 21.8%; p < 0.001), with no changes in the CWT or CON group. Moreover, only IWT improved insulin signalling in skeletal muscle via increased insulin-stimulated phosphorylation of AS160 (29.0 ± 10.8%; p < 0.05). No changes were seen in insulin secretion during hyperglycaemia alone, hyperglycaemia + glucagon-like peptide 1 infusion or arginine injection. IWT maintains insulin secretion and improves insulin sensitivity and DI, in contrast to energy expenditure-matched CWT. These results suggest that training with alternating intensity, and not just training volume and mean intensity, is a key determinant of changes in whole body glucose disposal in individuals with type 2 diabetes. ClinicalTrials (NCT01234155).

A coordinated control strategy for insulin and glucagon delivery in type 1 diabetes.

PubMed

Herrero, Pau; Bondia, Jorge; Oliver, Nick; Georgiou, Pantelis

2017-10-01

Type 1 diabetes is an autoimmune condition characterised by a pancreatic insulin secretion deficit, resulting in high blood glucose concentrations, which can lead to micro- and macrovascular complications. Type 1 diabetes also leads to impaired glucagon production by the pancreatic α-cells, which acts as a counter-regulatory hormone to insulin. A closed-loop system for automatic insulin and glucagon delivery, also referred to as an artificial pancreas, has the potential to reduce the self-management burden of type 1 diabetes and reduce the risk of hypo- and hyperglycemia. To date, bihormonal closed-loop systems for glucagon and insulin delivery have been based on two independent controllers. However, in physiology, the secretion of insulin and glucagon in the body is closely interconnected by paracrine and endocrine associations. In this work, we present a novel biologically-inspired glucose control strategy that accounts for such coordination. An in silico study using an FDA-accepted type 1 simulator was performed to evaluate the proposed coordinated control strategy compared to its non-coordinated counterpart, as well as an insulin-only version of the controller. The proposed coordinated strategy achieves a reduction of hyperglycemia without increasing hypoglycemia, when compared to its non-coordinated counterpart.

Ectonucleotidase NTPDase3 is abundant in pancreatic β-cells and regulates glucose-induced insulin secretion.

PubMed

Syed, Samreen K; Kauffman, Audra L; Beavers, Lisa S; Alston, James T; Farb, Thomas B; Ficorilli, James; Marcelo, Marialuisa C; Brenner, Martin B; Bokvist, Krister; Barrett, David G; Efanov, Alexander M

2013-11-15

Extracellular ATP released from pancreatic β-cells acts as a potent insulinotropic agent through activation of P2 purinergic receptors. Ectonucleotidases, a family of membrane-bound nucleotide-metabolizing enzymes, regulate extracellular ATP levels by degrading ATP and related nucleotides. Ectonucleotidase activity affects the relative proportion of ATP and its metabolites, which in turn will impact the level of purinergic receptor stimulation exerted by extracellular ATP. Therefore, we investigated the expression and role of ectonucleotidases in pancreatic β-cells. Of the ectonucleotidases studied, only ENTPD3 (gene encoding the NTPDase3 enzyme) mRNA was detected at fairly abundant levels in human and mouse pancreatic islets as well as in insulin-secreting MIN6 cells. ARL67156, a selective ectonucleotidase inhibitor, blocked degradation of extracellular ATP that was added to MIN6 cells. The compound also decreased degradation of endogenous ATP released from cells. Measurements of insulin secretion in MIN6 cells as well as in mouse and human pancreatic islets demonstrated that ARL67156 potentiated glucose-dependent insulin secretion. Downregulation of NTPDase3 expression in MIN6 cells with the specific siRNA replicated the effects of ARL67156 on extracellular ATP hydrolysis and insulin secretion. Our results demonstrate that NTPDase3 is the major ectonucleotidase in pancreatic β-cells in multiple species and that it modulates insulin secretion by controlling activation of purinergic receptors.

An In-situ glucose-stimulated insulin secretion assay under perfusion bioreactor conditions.

PubMed

Sharp, Jamie; Vermette, Patrick

2017-03-01

Perfusion bioreactors, unlike traditional in vitro cell culture systems, offer stringent control of physiological parameters such as pH, flow, temperature, and dissolved oxygen concentration which have been shown to have an impact on cellular behaviour and viability. Due to the relative infancy and the growing interest in these in vitro culture systems, detection methods to monitor cell function under dynamic perfusion bioreactor conditions remains one of the main challenges. In this study, INS-1 cells, a cell line which exhibit glucose-stimulated insulin secretion, were embedded in fibrin and cultured under perfusion bioreactor conditions for 48 h and then exposed to either a high-, or low-glucose concentration for 24 h. These cultures were compared to non-bioreacted controls. Bioreacted cultures exposed to a high-glucose concentration showed the highest glucose-stimulated insulin secretion when compared to those in a low-glucose environment. The stimulation index, a marker for insulin secretion functionality, increased over time. A lower incidence of apoptotic cells was observed in the bioreacted cultures when compared to non-bioreacted ones, as evaluated by a TUNEL assay. Immunofluorescence staining of Ki67 and insulin was performed and showed no differences in the incidence of proliferative cells between conditions (bioreacted and non-bioreacted), where all cells stained positive for insulin. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:454-462, 2017. © 2016 American Institute of Chemical Engineers.

Adrenaline: insights into its metabolic roles in hypoglycaemia and diabetes.

PubMed

Verberne, A J M; Korim, W S; Sabetghadam, A; Llewellyn-Smith, I J

2016-05-01

Adrenaline is a hormone that has profound actions on the cardiovascular system and is also a mediator of the fight-or-flight response. Adrenaline is now increasingly recognized as an important metabolic hormone that helps mobilize energy stores in the form of glucose and free fatty acids in preparation for physical activity or for recovery from hypoglycaemia. Recovery from hypoglycaemia is termed counter-regulation and involves the suppression of endogenous insulin secretion, activation of glucagon secretion from pancreatic α-cells and activation of adrenaline secretion. Secretion of adrenaline is controlled by presympathetic neurons in the rostroventrolateral medulla, which are, in turn, under the control of central and/or peripheral glucose-sensing neurons. Adrenaline is particularly important for counter-regulation in individuals with type 1 (insulin-dependent) diabetes because these patients do not produce endogenous insulin and also lose their ability to secrete glucagon soon after diagnosis. Type 1 diabetic patients are therefore critically dependent on adrenaline for restoration of normoglycaemia and attenuation or loss of this response in the hypoglycaemia unawareness condition can have serious, sometimes fatal, consequences. Understanding the neural control of hypoglycaemia-induced adrenaline secretion is likely to identify new therapeutic targets for treating this potentially life-threatening condition. © 2016 The British Pharmacological Society.

Central infusion of leptin improves insulin resistance and suppresses beta-cell function, but not beta-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model.

PubMed

Park, Sunmin; Ahn, Il Sung; Kim, Da Sol

2010-06-05

We investigated whether hypothalamic leptin alters beta-cell function and mass directly via the sympathetic nervous system (SNS) or indirectly as the result of altered insulin resistant states. The 90% pancreatectomized male Sprague Dawley rats had sympathectomy into the pancreas by applying phenol into the descending aorta (SNSX) or its sham operation (Sham). Each group was divided into two sections, receiving either leptin at 300ng/kgbw/h or artificial cerebrospinal fluid (aCSF) via intracerebroventricular (ICV) infusion for 3h as a short-term study. After finishing the infusion study, ICV leptin (3mug/kg bw/day) or ICV aCSF (control) was infused in rats fed 30 energy % fat diets by osmotic pump for 4weeks. At the end of the long-term study, glucose-stimulated insulin secretion and islet morphometry were analyzed. Acute ICV leptin administration in Sham rats, but not in SNSX rats, suppressed the first- and second-phase insulin secretion at hyperglycemic clamp by about 48% compared to the control. Regardless of SNSX, the 4-week administration of ICV leptin improved glucose tolerance during oral glucose tolerance tests and insulin sensitivity at hyperglycemic clamp, compared to the control, while it suppressed second-phase insulin secretion in Sham rats but not in SNSX rats. However, the pancreatic beta-cell area and mass were not affected by leptin and SNSX, though ICV leptin decreased individual beta-cell size and concomitantly increased beta-cell apoptosis in Sham rats. Leptin directly decreases insulin secretion capacity mainly through the activation of SNS without modulating pancreatic beta-cell mass.

The Brain–to–Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions

PubMed Central

Rosario, Wilfredo; Singh, Inderroop; Wautlet, Arnaud; Patterson, Christa; Flak, Jonathan; Becker, Thomas C.; Ali, Almas; Tamarina, Natalia; Philipson, Louis H.; Enquist, Lynn W.; Myers, Martin G.

2016-01-01

The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia. PMID:27207534

The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions.

PubMed

Rosario, Wilfredo; Singh, Inderroop; Wautlet, Arnaud; Patterson, Christa; Flak, Jonathan; Becker, Thomas C; Ali, Almas; Tamarina, Natalia; Philipson, Louis H; Enquist, Lynn W; Myers, Martin G; Rhodes, Christopher J

2016-09-01

The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia. © 2016 by the American Diabetes Association.

Effects of the herbal medicine Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) on insulin secretion and glucose tolerance in type 2 diabetic Goto-Kakizaki rats.

PubMed

Hirotani, Y; Ikeda, K; Myotoku, M

2010-04-01

Hachimi-jio-gan (HJ) is a Chinese medicine that has been widely used for the treatment of nephrotic syndromes, hypertension, and diabetes mellitus. We reported that HJ lowers plasma glucose in type 1 diabetic rats. We investigated the effects of HJ on diabetic hyperglycemia and insulin secretion in type 2 diabetic Goto-Kakizaki (GK) rats. Eight-week-old diabetic GK rats were given free access to pellets containing 1% HJ extract powder for 14 weeks. HJ consumption increased the food intake and body weight of these rats in comparison to control rats. HJ may control the body weight loss observed in GK rats. HJ also reduced hyperglycemia in diabetic GK rats, and it significantly increased insulin secretion in non-fasting GK rats over the experimental period. In oral glucose tolerance tests, HJ significantly improved the insulin response at 30 min and reduced the plasma glucose level at 60 min after glucose administration (p < 0.05). Ten weeks after administration, the plasma leptin levels significantly increased in the HJ group rats. These results demonstrate that in diabetic GK rats, HJ decreased the level of postprandial glucose via enhanced insulin secretion coupled with the regulation of food intake by leptin.

Ex vivo generation of glucose sensitive insulin secreting mesenchymal stem cells derived from human adipose tissue.

PubMed

Dave, Shruti D; Vanikar, Aruna V; Trivedi, Hargovind L

2012-03-01

Diabetics are incapable of producing insulin/have autoimmune mechanisms making it ineffective to control glucose secretion. We present a prospective study of glucose-sensitive insulin-secreting mesenchymal stem cells (IS-MSC) generated from human adipose tissue (h-AD) sans xenogenic material. Ten grams h-AD from donor anterior abdominal wall was collected in proliferation medium composed of α-Minimum Essential Media (α-MEM), albumin, fibroblast-growth factor and antibiotics, minced, incubated in collagenase-I at 37°C with shaker and centrifuged. Supernatant and pellets were separately cultured in proliferation medium on cell+ plates at 37°C with 5% CO(2) for 10 days. Cells were harvested by trypsinization, checked for viability, sterility, counts, flow-cytometry (CD45(-)/90(+)/73(+)), and differentiated into insulin-expressing cells using medium composed of DMEM, gene expressing up-regulators and antibiotics for 3 days. They were studied for transcriptional factors Pax-6, Isl-1, pdx-1 (immunofluorescence). C-peptide and insulin were measured by chemiluminescence. In vitro glucose sensitivity assay was carried out by measuring levels of insulin and C-peptide secretion in absence of glucose followed by 2 hours incubation after glucose addition. Mean IS-AD-MSC quantum was 3.21 ml, cell count, 1.5 ×10(3) cells/μl), CD45(-)/90(+)/73(+) cells were 44.37% /25.52%. All of them showed presence of pax-6, pdx-1, and Isl-1. Mean C-Peptide and insulin levels were 0.36 ng/ml and 234 μU/ml, respectively, pre-glucose and 0.87 ng/ml and 618.3 μU/ml post-glucose additions. The mean rise in secretion levels was 2.42 and 2.65 fold, respectively. Insulin-secreting h-AD-MSC can be generated safely and effectively showing in vitro glucose responsive alteration in insulin and C-peptide secretion levels.

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

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

Suzuki, Takahiro; Kanamori, Takao; Inouye, Satoshi

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- andmore » 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. - Highlights: • An imaging method for protein secretion from 3D-cultured cells was established. • The fused protein of insulin to GLase, Insulin-GLase, was used as a reporter. • Synchronous insulin secretion was visualized in rat islets and spheroidal beta cells. • A rat beta cell line stably expressing Insulin-GLase, named iGL, was established. • Effect of an antidiabetic drug on insulin secretion was visualized in iGL cells.« less

Mechanisms of β-cell functional adaptation to changes in workload

PubMed Central

Wortham, Matthew; Sander, Maike

2016-01-01

Insulin secretion must be tightly coupled to nutritional state to maintain blood glucose homeostasis. To this end, pancreatic β-cells sense and respond to changes in metabolic conditions, thereby anticipating insulin demands for a given physiological context. This is achieved in part through adjustments of nutrient metabolism, which is controlled at several levels including allosteric regulation, posttranslational modifications, and altered expression of metabolic enzymes. In this review, we discuss mechanisms of β-cell metabolic and functional adaptation in the context of two physiological states that alter glucose-stimulated insulin secretion: fasting and insulin resistance. We review current knowledge of metabolic changes that occur in the β-cell during adaptation and specifically discuss transcriptional mechanisms that underlie β-cell adaptation. A more comprehensive understanding of how β-cells adapt to changes in nutrient state could identify mechanisms to be co-opted for therapeutically modulating insulin secretion in metabolic disease. PMID:27615135

Use of First-phase Insulin Secretion in Early Diagnosis of Thyroid Diabetes and Type 2 Diabetes Mellitus

PubMed Central

Meng, Li-Heng; Huang, Yao; Zhou, Jia; Liang, Xing-Huan; Xian, Jing; Li, Li; Qin, Ying-Fen

2017-01-01

Background: A relationship between hyperthyroidism and insulin secretion in type 2 diabetes mellitus (T2DM) has been reported. Therefore, this study explored the use of first-phase insulin secretion in the differential diagnosis of thyroid diabetes (TDM) and T2DM. Methods: In total, 101 patients with hyperthyroidism were divided into hyperthyroidism with normal glucose tolerance (TNGT), hyperthyroidism with impaired glucose regulation (TIGR), and diabetes (TDM) groups. Furthermore, 96 patients without hyperthyroidism were recruited as control groups (normal glucose tolerance [NGT], impaired glucose regulation [IGR], and T2DM). The following parameters were evaluated: homeostasis model assessment (HOMA)-IR, HOMA-β, modified β-cell function index (MBCI), peak insulin/fasting insulin (IP/I0), AUCins-OGTT, and AUCins-OGTT/AUCglu-OGTT from the oral glucose tolerance test (OGTT) insulin release test were utilized to assess the second-phase insulin secretion, while the IP/I0, AIR0′~10′, and AUCins-IVGTT from the intravenous glucose tolerance test (IVGTT) insulin release test were used to assess the first-phase insulin secretion. Results: In the OGTT, the HOMA-β values of the TNGT and TDM groups were higher than those of the NGT and T2DM groups (all P < 0.05). In the hyperthyroidism groups, the MBCI of the TDM group was lower than that of the TNGT and TIGR groups (all P < 0.05). Among the control groups, the MBCI values of the IGR and T2DM groups were lower than that of the normal glucose tolerance (NGT) group (all P < 0.05). In the IVGTT, insulin secretion peaked for all groups at 2–4 min, except for the T2DM group, which showed a low plateau and no secretion peak. The IP values of the TNGT, TIGR, and TDM groups were higher than those of the NGT, IGR, and T2DM groups (all P < 0.05). The Ip/I0, AIR0′~10′, and AUCins-IVGTT values of the TDM group were higher than those of the T2DM group but were lower than those of the TNGT, TIGR, NGR, and IGR groups (all P < 0.05). Compared with the other five groups, the Ip/I0, AIR0′~10′, and AUCins-IVGTT values of the T2DM group were significantly decreased (all P < 0.05). The Ip/I0 and AUCins-IVGTT values of the TNGT group were higher than those of the NGT group (all P < 0.05). Conclusions: β-cell function in TDM patients is superior to that in T2DM patients. First-phase insulin secretion could be used as an early diagnostic marker to differentiate TDM and T2DM. PMID:28345543

Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men.

PubMed

Brøns, Charlotte; Jensen, Christine B; Storgaard, Heidi; Hiscock, Natalie J; White, Andrew; Appel, Julie S; Jacobsen, Stine; Nilsson, Emma; Larsen, Claus M; Astrup, Arne; Quistorff, Bjørn; Vaag, Allan

2009-05-15

A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by (31)P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.

[Rational therapy of Type II diabetes].

PubMed

Hanefeld, M; Fischer, S

1996-12-01

Noninsulin-dependent diabetes mellitus is a genetically determined form of diabetes, due to impaired insulin secretion by the B-cells as well as to insulin resistance of the peripheral tissues. According to the glucose toxicity theory hyperglycemia and hyperinsulinemia exist in a vicious circle. Therefore, it is a major therapeutical aim to put the B-cell to rest and improve insulin sensitivity by a strict control of fasting blood glucose and of postprandial hyperglycemia. Furthermore, associated abnormalities within the metabolic syndrome, such as hypertension, dyslipoproteinemia and hemostatic disorders should be corrected to avoid vessel complications. Therefore, it should be started with basic measures as body weight reduction, carbohydrate-rich and fat-poor diet and exercise. If these measures fail to achieve acceptable glycemic control, antihyperglycemic drugs (acarbose, metformin) are indicated, eventually in a combination with small doses of short-acting sulfonylureas. Further impairment of insulin secretion is the indication for sulfonylurea and/or insulin application. HbA1c of 7 to 7.5% should be the goal of antidiabetic therapy, also for patients in advanced age. The main criterion for the choice of antidiabetics is the present insulin secretion capacity. Simple indicators in this respect are changes of body weight, plasma triglycerides and C-Peptide after i.v. glucagon stimulation. Application of insulin in combination with other antidiabetics or in the form of intensified insulin therapy should not be too much postponed.

Emerging roles for β-arrestin-1 in the control of the pancreatic β-cell function and mass: new therapeutic strategies and consequences for drug screening.

PubMed

Dalle, Stéphane; Ravier, Magalie A; Bertrand, Gyslaine

2011-03-01

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in β-cell mass, decreased β-cell survival and impaired glucose-dependent insulin release. Pancreatic β-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. β-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that β-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for β-arrestin-1 in the regulation of insulin secretion and β-cell survival by GPCRs. Copyright © 2010 Elsevier Inc. All rights reserved.

Antidiabetic effect of Achillea millefollium through multitarget interactions: α-glucosidases inhibition, insulin sensitization and insulin secretagogue activities.

PubMed

Chávez-Silva, Fabiola; Cerón-Romero, Litzia; Arias-Durán, Luis; Navarrete-Vázquez, Gabriel; Almanza-Pérez, Julio; Román-Ramos, Rubén; Ramírez-Ávila, Guillermo; Perea-Arango, Irene; Villalobos-Molina, Rafael; Estrada-Soto, Samuel

2018-02-15

Achillea millefolium L. (Asteraceae) is a perennial herb used in Mexican folk medicine for treatment of several pathologies, including inflammatory and spasmodic gastrointestinal disorders, hepatobiliary complaints, overactive cardiovascular, respiratory ailments and diabetes. To evaluate the potential antidiabetic effect in vivo and to establish the potential mode of action through in vitro approaches of Achillea millefolium. The antidiabetic effect of hydroalcoholic extract of Achillea millefolium (HAEAm) was evaluated on the oral glucose tolerance tests, in normoglycemic and experimental Type 2 diabetic mice models. In addition, we evaluated the possible mode of action in in vitro assays to determine α-glucosidases inhibition, the insulin secretion and calcium mobilization in RINm5F cells and PPARγ and GLUT4 expression in 3T3-L1 cells. HAEAm showed significant glucose diminution on oral glucose tolerance test and in acute experimental Type 2 diabetic assay with respect to the control (p < 0.05). In addition, HAEAm promoted the α-glucosidases inhibition by 55% at 1mg/ml respect to control. On the other hand, HAEAm increased the PPARγ (five-times) and GLUT4 (two-fold) relative expression than control (p < 0.05). Finally, HAEAm significantly increased the insulin secretion and [Ca 2+ ] i compared with control. The HAEAm possesses in vivo antidiabetic effect, having such effect through multitarget modes of action that involve antihyperglycemic (α-glucosidases inhibition), hypoglycemic (insulin secretion) and potential insulin sensitizer (PPARγ/GLUT4 overexpression) actions. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Diabetes Mellitus and the Insulin Pump: What Teachers Need to Know

ERIC Educational Resources Information Center

Obringer, S. John; Coffey, Kenneth

2006-01-01

Diabetes is a condition where high amounts of glucose are found in the bloodstream due to impaired secretion of insulin. The hormone insulin was discovered by two physicians, Fredrick Banting and James Mcleod in 1921. Individuals with severe diabetes typically controlled their glucose level with multiple daily injections of insulin. Recently the…

Loss of circadian rhythm of circulating insulin concentration induced by high-fat diet intake is associated with disrupted rhythmic expression of circadian clock genes in the liver.

PubMed

Honma, Kazue; Hikosaka, Maki; Mochizuki, Kazuki; Goda, Toshinao

2016-04-01

Peripheral clock genes show a circadian rhythm is correlated with the timing of feeding in peripheral tissues. It was reported that these clock genes are strongly regulated by insulin action and that a high-fat diet (HFD) intake in C57BL/6J mice for 21days induced insulin secretion during the dark phase and reduced the circadian rhythm of clock genes. In this study, we examined the circadian expression patterns of these clock genes in insulin-resistant animal models with excess secretion of insulin during the day. We examined whether insulin resistance induced by a HFD intake for 80days altered blood parameters (glucose and insulin concentrations) and expression of mRNA and proteins encoded by clock and functional genes in the liver using male ICR mice. Serum insulin concentrations were continuously higher during the day in mice fed a HFD than control mice. Expression of lipogenesis-related genes (Fas and Accβ) and the transcription factor Chrebp peaked at zeitgeber time (ZT)24 in the liver of control mice. A HFD intake reduced the expression of these genes at ZT24 and disrupted the circadian rhythm. Expression of Bmal1 and Clock, transcription factors that compose the core feedback loop, showed circadian variation and were synchronously associated with Fas gene expression in control mice, but not in those fed a HFD. These results indicate that the disruption of the circadian rhythm of insulin secretion by HFD intake is closely associated with the disappearance of circadian expression of lipogenic and clock genes in the liver of mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Insulin secretion and insulin action in non-insulin-dependent diabetes mellitus: which defect is primary?

PubMed

Reaven, G M

1984-01-01

Defects in both insulin secretion and insulin action exist in patients with non-insulin-dependent diabetes mellitus (NIDDM). The loss of the acute plasma insulin response to intravenous glucose is seen in patients with relatively mild degrees of fasting hyperglycemia, but patients with severe fasting hyperglycemia also demonstrate absolute hypoinsulinemia in response to an oral glucose challenge. In contrast, day-long circulating insulin levels are within normal limits even in severely hyperglycemic patients with NIDDM. The relationship between NIDDM and insulin action in NIDDM is less complex, and is a characteristic feature of the syndrome. This metabolic defect is independent of obesity, and the severity of the resistance to insulin-stimulated glucose uptake increases with magnitude of hyperglycemia. Control of hyperglycemia with exogenous insulin ameliorates the degree of insulin resistance, and reduction of insulin resistance with weight loss in obese patients with NIDDM leads to an enhanced insulin response. Since neither therapeutic intervention is capable of restoring all metabolic abnormalities to normal, these observations do not tell us which of these two defects is primarily responsible for the development of NIDDM. Similarly, the observation that most patients with impaired glucose tolerance are hyperinsulinemic and insulin resistant does not prove that insulin resistance is the primary defect in NIDDM. In conclusion, reduction in both insulin secretion and action is seen in patients with NIDDM, and the relationship between these two metabolic abnormalities is very complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Hydrogel Microencapsulated Insulin-Secreting Cells Increase Keratinocyte Migration, Epidermal Thickness, Collagen Fiber Density, and Wound Closure in a Diabetic Mouse Model of Wound Healing.

PubMed

Aijaz, Ayesha; Faulknor, Renea; Berthiaume, François; Olabisi, Ronke M

2015-11-01

Wound healing is a hierarchical process of intracellular and intercellular signaling. Insulin is a potent chemoattractant and mitogen for cells involved in wound healing. Insulin's potential to promote keratinocyte growth and stimulate collagen synthesis in fibroblasts is well described. However, there currently lacks an appropriate delivery mechanism capable of consistently supplying a wound environment with insulin; current approaches require repeated applications of insulin, which increase the chances of infecting the wound. In this study, we present a novel cell-based therapy that delivers insulin to the wound area in a constant or glucose-dependent manner by encapsulating insulin-secreting cells in nonimmunogenic poly(ethylene glycol) diacrylate (PEGDA) hydrogel microspheres. We evaluated cell viability and insulin secretory characteristics of microencapsulated cells. Glucose stimulation studies verified free diffusion of glucose and insulin through the microspheres, while no statistical difference in insulin secretion was observed between cells in microspheres and cells in monolayers. Scratch assays demonstrated accelerated keratinocyte migration in vitro when treated with microencapsulated cells. In excisional wounds on the dorsa of diabetic mice, microencapsulated RIN-m cells accelerated wound closure by postoperative day 7; a statistically significant increase over AtT-20ins-treated and control groups. Histological results indicated significantly greater epidermal thickness in both microencapsulated RIN-m and AtT-20ins-treated wounds. The results suggest that microencapsulation enables insulin-secreting cells to persist long enough at the wound site for a therapeutic effect and thereby functions as an effective delivery vehicle to accelerate wound healing.

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.

A factorial design to identify process parameters affecting whole mechanically disrupted rat pancreata in a perfusion bioreactor.

PubMed

Sharp, Jamie; Spitters, Tim Wgm; Vermette, Patrick

2018-03-01

Few studies report whole pancreatic tissue culture, as it is a difficult task using traditional culture methods. Here, a factorial design was used to investigate the singular and combinational effects of flow, dissolved oxygen concentration (D.O.) and pulsation on whole mechanically disrupted rat pancreata in a perfusion bioreactor. Whole rat pancreata were cultured for 72 h under defined bioreactor process conditions. Secreted insulin was measured and histological (haematoxylin and eosin (H&E)) as well as immunofluorescent insulin staining were performed and quantified. The combination of flow and D.O. had the most significant effect on secreted insulin at 5 h and 24 h. The D.O. had the biggest effect on tissue histological quality, and pulsation had the biggest effect on the number of insulin-positive structures. Based on the factorial design analysis, bioreactor conditions using high flow, low D.O., and pulsation were selected to further study glucose-stimulated insulin secretion. Here, mechanically disrupted rat pancreata were cultured for 24 h under these bioreactor conditions and were then challenged with high glucose concentration for 6 h and high glucose + IBMX (an insulin secretagogue) for a further 6 h. These cultures secreted insulin in response to high glucose concentration in the first 6 h, however stimulated-insulin secretion was markedly weaker in response to high glucose concentration + IBMX thereafter. After this bioreactor culture period, higher tissue metabolic activity was found compared to that of non-bioreacted static controls. More insulin- and glucagon-positive structures, and extensive intact endothelial structures were observed compared to non-bioreacted static cultures. H&E staining revealed more intact tissue compared to static cultures. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:432-444, 2018. © 2017 American Institute of Chemical Engineers.

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)

The interplay between noncoding RNAs and insulin in diabetes.

PubMed

Tian, Yan; Xu, Jia; Du, Xiao; Fu, Xianghui

2018-04-10

Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs and circular RNAs, regulate various biological processes and are involved in the initiation and progression of human diseases. Insulin, a predominant hormone secreted from pancreatic β cells, is an essential factor in regulation of systemic metabolism through multifunctional insulin signaling. Insulin production and action are tightly controlled. Dysregulations of insulin production and action can impair metabolic homeostasis, and eventually lead to the development of multiple metabolic diseases, especially diabetes. Accumulating data indicates that ncRNAs modulate β cell mass, insulin synthesis, secretion and signaling, and their role in diabetes is dramatically emerging. This review summarizes our current knowledge of ncRNAs as regulators of insulin, with particular emphasis on the implications of this interplay in the development of diabetes. We outline the role of ncRNAs in pancreatic β cell mass and function, which is critical for insulin production and secretion. We also highlight the involvement of ncRNAs in insulin signaling in peripheral tissues including liver, muscle and adipose, and discuss ncRNA-mediated inter-organ crosstalk under diabetic conditions. A more in-depth understanding of the interplay between ncRNAs and insulin may afford valuable insights and novel therapeutic strategies for treatment of diabetes, as well as other human diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

High-fat diet-induced insulin resistance does not increase plasma anandamide levels or potentiate anandamide insulinotropic effect in isolated canine islets.

PubMed

Woolcott, Orison O; Richey, Joyce M; Kabir, Morvarid; Chow, Robert H; Iyer, Malini S; Kirkman, Erlinda L; Stefanovski, Darko; Lottati, Maya; Kim, Stella P; Harrison, L Nicole; Ionut, Viorica; Zheng, Dan; Hsu, Isabel R; Catalano, Karyn J; Chiu, Jenny D; Bradshaw, Heather; Wu, Qiang; Kolka, Cathryn M; Bergman, Richard N

2015-01-01

Obesity has been associated with elevated plasma anandamide levels. In addition, anandamide has been shown to stimulate insulin secretion in vitro, suggesting that anandamide might be linked to hyperinsulinemia. To determine whether high-fat diet-induced insulin resistance increases anandamide levels and potentiates the insulinotropic effect of anandamide in isolated pancreatic islets. Dogs were fed a high-fat diet (n = 9) for 22 weeks. Abdominal fat depot was quantified by MRI. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp. Fasting plasma endocannabinoid levels were analyzed by liquid chromatography-mass spectrometry. All metabolic assessments were performed before and after fat diet regimen. At the end of the study, pancreatic islets were isolated prior to euthanasia to test the in vitro effect of anandamide on islet hormones. mRNA expression of cannabinoid receptors was determined in intact islets. The findings in vitro were compared with those from animals fed a control diet (n = 7). Prolonged fat feeding increased abdominal fat content by 81.3±21.6% (mean±S.E.M, P<0.01). In vivo insulin sensitivity decreased by 31.3±12.1% (P<0.05), concomitant with a decrease in plasma 2-arachidonoyl glycerol (from 39.1±5.2 to 15.7±2.0 nmol/L) but not anandamide, oleoyl ethanolamide, linoleoyl ethanolamide, or palmitoyl ethanolamide. In control-diet animals (body weight: 28.8±1.0 kg), islets incubated with anandamide had a higher basal and glucose-stimulated insulin secretion as compared with no treatment. Islets from fat-fed animals (34.5±1.3 kg; P<0.05 versus control) did not exhibit further potentiation of anandamide-induced insulin secretion as compared with control-diet animals. Glucagon but not somatostatin secretion in vitro was also increased in response to anandamide, but there was no difference between groups (P = 0.705). No differences in gene expression of CB1R or CB2R between groups were found. In canines, high-fat diet-induced insulin resistance does not alter plasma anandamide levels or further potentiate the insulinotropic effect of anandamide in vitro.

Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion.

PubMed

Geffner, M E; Kaplan, S A; Bersch, N; Golde, D W; Landaw, E M; Chang, R J

1986-03-01

Six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, compared with controls after oral glucose (P less than 0.05). As an indicator of insulin sensitivity, in vitro proliferation of erythrocyte progenitor cells of PCOD subjects exposed to physiologic concentrations of insulin was significantly blunted (P less than 0.001). Monocyte insulin receptor binding was not impaired in the PCOD subjects. Three of the PCOD patients were treated with a long-acting gonadotropin-releasing hormone agonist for 6 months, which resulted in marked suppression of ovarian androgen secretion but no demonstrable changes in in vivo or in vitro indicators of insulin resistance. Thus insulin resistance in PCOD subjects appears to be unrelated to ovarian hyperandrogenism (or acanthosis or obesity). Although certain tissues are insulin-resistant in PCOD patients, the ovary may remain sensitive and overproduce androgens in response to high circulating insulin levels.

Pancreatic signals controlling food intake; insulin, glucagon and amylin

PubMed Central

Woods, Stephen C; Lutz, Thomas A; Geary, Nori; Langhans, Wolfgang

2006-01-01

The control of food intake and body weight by the brain relies upon the detection and integration of signals reflecting energy stores and fluxes, and their interaction with many different inputs related to food palatability and gastrointestinal handling as well as social, emotional, circadian, habitual and other situational factors. This review focuses upon the role of hormones secreted by the endocrine pancreas: hormones, which individually and collectively influence food intake, with an emphasis upon insulin, glucagon and amylin. Insulin and amylin are co-secreted by B-cells and provide a signal that reflects both circulating energy in the form of glucose and stored energy in the form of visceral adipose tissue. Insulin acts directly at the liver to suppress the synthesis and secretion of glucose, and some plasma insulin is transported into the brain and especially the mediobasal hypothalamus where it elicits a net catabolic response, particularly reduced food intake and loss of body weight. Amylin reduces meal size by stimulating neurons in the hindbrain, and there is evidence that amylin additionally functions as an adiposity signal controlling body weight as well as meal size. Glucagon is secreted from A-cells and increases glucose secretion from the liver. Glucagon acts in the liver to reduce meal size, the signal being relayed to the brain via the vagus nerves. To summarize, hormones of the endocrine pancreas are collectively at the crossroads of many aspects of energy homeostasis. Glucagon and amylin act in the short term to reduce meal size, and insulin sensitizes the brain to short-term meal-generated satiety signals; and insulin and perhaps amylin as well act over longer intervals to modulate the amount of fat maintained and defended by the brain. Hormones of the endocrine pancreas interact with receptors at many points along the gut–brain axis, from the liver to the sensory vagus nerve to the hindbrain to the hypothalamus; and their signals are conveyed both neurally and humorally. Finally, their actions include gastrointestinal and metabolic as well as behavioural effects. PMID:16815800

Islet-specific monoamine oxidase A and B expression depends on MafA transcriptional activity and is compromised in type 2 diabetes.

PubMed

Ganic, Elvira; Johansson, Jenny K; Bennet, Hedvig; Fex, Malin; Artner, Isabella

2015-12-25

Lack or dysfunction of insulin producing β cells results in the development of type 1 and type 2 diabetes mellitus, respectively. Insulin secretion is controlled by metabolic stimuli (glucose, fatty acids), but also by monoamine neurotransmitters, like dopamine, serotonin, and norepinephrine. Intracellular monoamine levels are controlled by monoamine oxidases (Mao) A and B. Here we show that MaoA and MaoB are expressed in mouse islet β cells and that inhibition of Mao activity reduces insulin secretion in response to metabolic stimuli. Moreover, analysis of MaoA and MaoB protein expression in mouse and human type 2 diabetic islets shows a significant reduction of MaoB in type 2 diabetic β cells suggesting that loss of Mao contributes to β cell dysfunction. MaoB expression was also reduced in β cells of MafA-deficient mice, a mouse model for β cell dysfunction, and biochemical studies showed that MafA directly binds to and activates MaoA and MaoB transcriptional control sequences. Taken together, our results show that MaoA and MaoB expression in pancreatic islets is required for physiological insulin secretion and lost in type 2 diabetic mouse and human β cells. These findings demonstrate that regulation of monoamine levels by Mao activity in β cells is pivotal for physiological insulin secretion and that loss of MaoB expression may contribute to the β cell dysfunction in type 2 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

Perilipin 5 Regulates Islet Lipid Metabolism and Insulin Secretion in a cAMP-Dependent Manner: Implication of Its Role in the Postprandial Insulin Secretion

PubMed Central

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

2015-01-01

Elevation of circulating fatty acids (FA) during fasting supports postprandial (PP) insulin secretion that is critical for glucose homeostasis and is impaired in diabetes. We tested our hypothesis that lipid droplet (LD) protein perilipin 5 (PLIN5) in β-cells aids PP insulin secretion by regulating intracellular lipid metabolism. We demonstrated that PLIN5 serves as an LD protein in human islets. In vivo, Plin5 and triglycerides were increased by fasting in mouse islets. MIN6 cells expressing PLIN5 (adenovirus [Ad]-PLIN5) and those expressing perilipin 2 (PLIN2) (Ad-PLIN2) had higher [3H]FA incorporation into triglycerides than Ad-GFP control, which support their roles as LD proteins. However, Ad-PLIN5 cells had higher lipolysis than Ad-PLIN2 cells, which increased further by 8-Br-cAMP, indicating that PLIN5 facilitates FA mobilization upon cAMP stimulation as seen postprandially. Ad-PLIN5 in islets enhanced the augmentation of glucose-stimulated insulin secretion by FA and 8-Br-cAMP in G-protein–coupled receptor 40 (GPR40)- and cAMP-activated protein kinase–dependent manners, respectively. When PLIN5 was increased in mouse β-cells in vivo, glucose tolerance after an acute exenatide challenge was improved. Therefore, the elevation of islet PLIN5 during fasting allows partitioning of FA into LD that is released upon refeeding to support PP insulin secretion in cAMP- and GPR40-dependent manners. PMID:25392244

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.

Hepatic Insulin Resistance is Sufficient to Produce Dyslipidemia and Susceptibility to Atherosclerosis

PubMed Central

Biddinger, Sudha B.; Hernandez-Ono, Antonio; Rask-Madsen, Christian; Haas, Joel T.; Alemán, José O.; Suzuki, Ryo; Scapa, Erez F.; Agarwal, Chhavi; Carey, Martin C.; Stephanopoulos, Gregory; Cohen, David E.; King, George L.; Ginsberg, Henry; Kahn, C. Ronald

2014-01-01

Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced HDL cholesterol and VLDL particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apoB-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of PGC-1β, which promotes VLDL secretion, but decreased expression of SREBP-1c, SREBP-2 and their targets, the lipogenic enzymes and the LDL receptor. Within twelve weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome. PMID:18249172

Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca2+ Sensitivity of Insulin Secretion Vesicles.

PubMed

Huang, Chen; Walker, Emily M; Dadi, Prasanna K; Hu, Ruiying; Xu, Yanwen; Zhang, Wenjian; Sanavia, Tiziana; Mun, Jisoo; Liu, Jennifer; Nair, Gopika G; Tan, Hwee Yim Angeline; Wang, Sui; Magnuson, Mark A; Stoeckert, Christian J; Hebrok, Matthias; Gannon, Maureen; Han, Weiping; Stein, Roland; Jacobson, David A; Gu, Guoqiang

2018-05-07

Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca 2+ concentrations, suggesting differences in the Ca 2+ sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca 2+ binding paralog of the β cell Ca 2+ sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca 2+ sensing plays in regulating β cell maturation. Copyright © 2018 Elsevier Inc. All rights reserved.

Improved human islet preparations using Glucocorticoid and Exendin-4

PubMed Central

Miki, Atsushi.; Ricordi, Camillo.; Yamamoto, Toshiyuki.; Sakuma, Yasunaru.; Misawa, Ryosuke.; Mita, Atsuyoshi.; Inverardi, Luca.; Alejandro, Rodolfo; Ichii, Hirohito.

2014-01-01

Objectives The effects of Glucocorticoid during culture on human islet cells have been controversial. Exendin-4 (EX) enhances the insulin secretion and significantly improves clinical outcomes in islet cell transplantation. In this study, we examined the effects of Glucocorticoids and exendin-4 on human islet cells during pre-transplant culture. Methods Methylprednisolone (MP) and/or EX were added to the standard culture medium for clinical islet cell transplantation. Islets were cultured for 24 hours with three different conditions (Control: no additives, MP alone, MP+EX). Beta cell fractional viability, cellular composition, multiple cytokine/chemokine production, multiple phosphorylation proteins and glucose induced insulin secretion were evaluated. Results Viable beta cell survival in MP and MP+EX group was significantly higher than in the control group. EX prevented MP induced reduction of insulin secretion. MP supplementation to the culture medium decreased cytokine and chemokine production. Moreover, Erk1/2 phosphorylation was significantly increased by MP and MP+EX. Conclusions Glucocorticoid supplementation into culture media significantly decreased the cytokine/chemokine production and increased the Erk1/2 phosphorylation, resulting in the improvement of human beta cell survival. In addition, EX maintained the insulin secretion suppressed by MP. The supplementation of MP and EX together could be a useful strategy to create suitable human islets for transplantation. PMID:25036907

Effect of the Glucagon-like Peptide-1 Analogue Exenatide Extended Release in Cats with Newly Diagnosed Diabetes Mellitus.

PubMed

Riederer, A; Zini, E; Salesov, E; Fracassi, F; Padrutt, I; Macha, K; Stöckle, T M; Lutz, T A; Reusch, C E

2016-01-01

Exenatide extended release (ER) is a glucagon-like peptide-1 analogue that increases insulin secretion, inhibits glucagon secretion and induces satiation in humans with type 2 diabetes mellitus. The use of exenatide ER is safe and stimulates insulin secretion in healthy cats. The objective of this study is to assess the safety of exenatide ER and its effect on body weight, remission and metabolic control in newly diagnosed diabetic cats receiving insulin and a low-carbohydrate diet. Thirty client-owned cats. Prospective placebo-controlled clinical trial. Cats were treated with exenatide ER or 0.9% saline, administered SC, once weekly. Both groups received insulin glargine and a low-carbohydrate diet. Exenatide ER was administered for 16 weeks, or in cats that achieved remission it was given for 4 weeks after discontinuing insulin treatment. Nonparametric tests were used for statistical analysis. Cats in the exenatide ER and placebo groups had transient adverse signs including decreased appetite (60% vs. 20%, respectively, P = .06) and vomiting (53% vs. 40%, respectively, P = .715). Body weight increased significantly in the placebo group (P = .002), but not in cats receiving exenatide ER. Cats on exenatide ER achieved remission or good metabolic control in 40% or 89%, respectively, whereas in control cats percentages were 20% or 58% (P = .427 and P = .178, respectively). Exenatide ER is safe in diabetic cats and does not result in weight gain. Our pilot study suggests that, should there be an additional clinically relevant beneficial effect of exenatide ER in insulin-treated cats on rate of remission and good metabolic control, it would likely approximate 20% and 30%, respectively. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control.

PubMed

Chisalita, Simona I; Lindström, Torbjörn; Eson Jennersjö, Pär; Paulsson, Johan F; Westermark, Gunilla T; Olsson, Anders G; Arnqvist, Hans J

2009-03-01

Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0+/-4.1 years (mean+/-SE), body weight 82.5+/-5.0 kg, BMI (body mass index) 27.7+/-1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.

Insulin oversecretion in MSG-obese rats is related to alterations in cholinergic muscarinic receptor subtypes in pancreatic islets.

PubMed

Miranda, Rosiane A; Agostinho, Aryane R; Trevenzoli, Isis H; Barella, Luiz F; Franco, Claudinéia C S; Trombini, Amanda B; Malta, Ananda; Gravena, Clarice; Torrezan, Rosana; Mathias, Paulo C F; de Oliveira, Júlio C

2014-01-01

Impaired pancreatic beta cell function and insulin secretion/action are a link between obesity and type 2 diabetes, which are worldwide public health burdens. We aimed to characterize the muscarinic acetylcholine receptor (mAChR) M1-M4 subtypes in isolated pancreatic islets from pre-diabetic obese rats that had been treated neonatally with monosodium L-glutamate (MSG). At 90 days of age, both the MSG and the control groups underwent biometric and biochemical evaluation. Anti-muscarinic drugs were used to study mAChR function either in vivo or in vitro. The results demonstrated that atropine treatment reduced insulin secretion in the MSG-treated and control groups, whereas treatment with an M2mAChR-selective antagonist increased secretion. Moreover, the insulinostatic effect of an M3mAChR-selective antagonist was significantly higher in the MSG-treated group. M1mAChR and M3mAChR expression was increased in the MSG-obese group by 55% and 73%, respectively. In contrast, M2mAChR expression decreased by 25% in the MSG group, whereas M4mAChR expression was unchanged. Functional changes in and altered content of the mAChR (M1-M4) subtypes are pivotal to the demand for high pancreatic beta cell insulin secretion in MSG-obese rats, which is directly associated with vagal hyperactivity and peripheral insulin resistance. © 2014 S. Karger AG, Basel.

Role of endogenously released cholecystokinin in determining postprandial insulin levels in man: effects of loxiglumide, a specific cholecystokinin receptor antagonist.

PubMed

Baum, F; Nauck, M A; Ebert, R; Cantor, P; Hoffmann, G; Choudhury, A R; Schmidt, W E; Creutzfeldt, W

1992-01-01

To estimate the contribution of postprandial cholecystokinin (CCK) responses to circulating insulin concentrations and insulin secretion, a specific CCK receptor antagonist (loxiglumide; 10 mg/kg body weight/h) or saline were infused intravenously in normal volunteers, beginning 90 min before insulin secretion was stimulated on separate occasions by the intraduodenal administrations of glucose, glucose and protein, and glucose plus protein with the admixture of pancreatin. The release of CCK (radioimmunoassay) was stimulated by the protein component of the nutrients from basal 2.4 +/- 0.4 to 8.0 +/- 1.2 pmol/l. CCK plasma levels were significantly higher with loxiglumide (p < 0.05). Glucose-dependent insulinotropic polypeptide (GIP) was also released by all nutrient mixtures. Loxiglumide significantly inhibited the amount of bilirubin and pancreatic enzymes recovered from duodenal aspirates. In contrast, in none of the experiments, C-peptide increments and hence insulin secretion rates were altered by loxiglumide. With glucose and protein as intraduodenal stimulus (no pancreatin added), the plasma amino acids rose significantly less (by approximately 50% of the control experiment) and the increment in insulin (but not C-peptide) concentrations was significantly reduced by loxiglumide. This is most likely explained by a change in insulin metabolic clearance. This effect cannot be a primary action of CCK because there was no similar effect of loxiglumide with the same intraduodenal stimulus plus added pancreatin. Pancreatic enzymes reduced maldigestion secondary to loxiglumide effects on pancreatic exocrine secretion: The increment in circulating amino acid concentrations was similar with and without loxiglumide. In conclusion, CCK does not alter insulin secretion and, therefore, is not an incretin hormone in man. Blocking CCK actions on the exocrine pancreas by loxiglumide, however, can secondarily cause reductions in postprandial insulin profiles by altering insulin clearance. These changes are possibly related to reductions in circulating amino acid concentrations.

Insulin secretion and insulin resistance in Korean women with gestational diabetes mellitus and impaired glucose tolerance.

PubMed

Yang, Sae Jeong; Kim, Tae Nyun; Baik, Sei Hyun; Kim, Tae Sun; Lee, Kwan Woo; Nam, Moonsuk; Park, Yong Soo; Woo, Jeong-Teak; Kim, Young Seol; Kim, Sung-Hoon

2013-05-01

The aim was to compare the insulin sensitivity and secretion index of pregnant Korean women with normal glucose tolerance (NGT), gestational impaired glucose tolerance (GIGT; only one abnormal value according to the Carpenter and Coustan criteria), and gestational diabetes mellitus (GDM). A cross-sectional study was performed with 1,163 pregnant women with positive (1-hour plasma glucose ≥ 7.2 mmol/L) in a 50-g oral glucose challenge test (OGCT). The 100-g oral glucose tolerance test (OGTT) was used to stratify the participants into three groups: NGT (n = 588), GIGT (n = 294), and GDM (n = 281). The GDM group had higher homeostasis model assessment of insulin resistance and lower insulin sensitivity index (ISOGTT), quantitative insulin sensitivity check index, homeostasis model assessment for estimation of index β-cell secretion (HOMA-B), first and second phase insulin secretion, and insulin secretion-sensitivity index (ISSI) than the NGT group (p ≤ 0.001 for all). Moreover, the GIGT group had lower ISOGTT, HOMA-B, first and second phase insulin secretion, and ISSI than the NGT group (p < 0.001 for all). Among the GIGT subjects, the 1-hour plasma glucose abnormal levels group showed significantly greater weight gain during pregnancy and higher values in the 50-g OGCT than the other two groups. Moreover, the 1-hour and 2-hour abnormal levels groups had poorer insulin secretion status than the 3-hour abnormal levels group. Korean women with GDM show impairments of both insulin secretion and insulin sensitivity. In addition, GIGT is associated with both β-cell dysfunction and insulin resistance.

Vitis vinifera L. grape skin extract activates the insulin-signalling cascade and reduces hyperglycaemia in alloxan-induced diabetic mice.

PubMed

Soares de Moura, Roberto; da Costa, Giselle França; Moreira, Annie Seixas Bello; Queiroz, Emerson Ferreira; Moreira, Daniele Dal Col; Garcia-Souza, Erica Patrícia; Resende, Angela Castro; Moura, Aníbal Sanchez; Teixeira, Michelle Teixeira

2012-02-01

This study examined the effect of Vitis vinifera grape skin extract (ACH09) on hyperglycaemia and the insulin-signalling cascade in alloxan-treated mice. Glycaemia, serum insulin and Western blot analysis of insulin cascade proteins were evaluated in the gastrocnemius muscles of four groups of adult mice: control, ACH09 (200 mg/kg per day, p.o.), alloxan (300 mg/kg, i.p.) and alloxan + ACH09. Insulin secretion in isolated pancreatic islets was also studied. Glycaemia values in the alloxan + ACH09 and ACH09 groups were significantly lower than in the alloxan-treated and control groups, respectively. Increased insulin resistance (HOMA index) was observed in the alloxan-treated group but not in the alloxan + ACH09 group. Insulin receptor content and Akt phosphorylation were significantly greater in the alloxan + ACH09 group compared with the alloxan-treated group. The glucose transporter (GLUT-4) content was reduced in alloxan-treated mice compared with the control group, while alloxan + ACH09 and ACH09-treated mice showed a significant increase in GLUT-4 content. ACH09 treatment did not change glucose-induced insulin secretion in isolated pancreatic islets. The results suggest that ACH09 has hypoglycaemic and antihyperglycaemic effects that are independent of an increase in insulin release but are probably dependent on an increase in insulin sensitivity resulting from an activation of the insulin-signalling cascade in skeletal muscle. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Polycystic ovary disease. A risk factor for gestational diabetes?

PubMed

Lanzone, A; Caruso, A; Di Simone, N; De Carolis, S; Fulghesu, A M; Mancuso, S

1995-04-01

We investigated the impact of pregestationally elevated insulin plasma levels on glycemic control in pregnant women with polycystic ovary disease (PCOD). Twelve patients with PCOD who became pregnant within six months following evaluation of their metabolic status were the study subjects. Four were obese and six (two obese) had a hyperinsulinemic response to the oral glucose tolerance test (OGTT). They were tested with the OGTT at 28-30 weeks of gestation. We also tested 12 normal patients and 10 consecutive patients with gestational diabetes; all were at the same gestational age. Plasma levels of insulin and glucose were determined in the samples collected for a period of four hours after glucose load (100 g). All PCOD patients significantly increased their insulin secretion in pregnancy. The hyperinsulinemic PCOD patients developed gestational diabetes (two patients) and impaired gestational glucose tolerance (three patients). The area under the insulin curve was greater in PCOD patients than in control and gestational diabetes patients (P < .01). In spite of their large increase in insulin secretion observed during pregnancy, patients with PCOD may develop a derangement of glycemic control, probably related to their pregestational insulinemic status.

Increased VLDL-triglyceride secretion precedes impaired control of endogenous glucose production in obese, normoglycemic men.

PubMed

Sørensen, Lars P; Søndergaard, Esben; Nellemann, Birgitte; Christiansen, Jens S; Gormsen, Lars C; Nielsen, Søren

2011-09-01

To assess basal and insulin-mediated VLDL-triglyceride (TG) kinetics and the relationship between VLDL-TG secretion and hepatic insulin resistance assessed by endogenous glucose production (EGP) in obese and lean men. A total of 12 normoglycemic, obese (waist-to-hip ratio >0.9, BMI >30 kg/m(2)) and 12 lean (BMI 20-25 kg/m(2)) age-matched men were included. Ex vivo-labeled [1-(14)C]VLDL-TGs and [3-(3)H]glucose were infused postabsorptively and during a hyperinsulinemic-euglycemic clamp to determine VLDL-TG kinetics and EGP. Body composition was determined by dual X-ray absorptiometry and computed tomography scanning. Energy expenditure and substrate oxidation rates were measured by indirect calorimetry. Basal VLDL-TG secretion rates were increased in obese compared with lean men (1.25 ± 0.34 vs. 0.86 ± 0.34 μmol/kg fat-free mass [FFM]/min; P = 0.011), whereas there was no difference in clearance rates (150 ± 56 vs. 162 ± 77 mL/min; P = NS), resulting in greater VLDL-TG concentrations (0.74 ± 0.40 vs. 0.38 ± 0.20 mmol/L; P = 0.011). The absolute insulin-mediated suppression of VLDL-TG secretion was similar in the groups. However, the percentage reduction (-36 ± 18 vs. -54 ± 10%; P = 0.008) and achieved VLDL-TG secretion rates (0.76 ± 0.20 vs. 0.41 ± 0.19 μmol/kg FFM/min; P < 0.001) were impaired in obese men. Furthermore, clearance rates decreased significantly in obese men, but there was no significant change in lean men (-17 ± 18 vs. 7 ± 20%; P = 0.007), resulting in less percentage reduction of VLDL-TG concentrations in obese men (-22 ± 20 vs. -56 ± 11%; P < 0.001). Insulin-suppressed EGP was similar (0.4 [0.0-0.8] vs. 0.1 [0.0-1.2] mg/kg FFM/min (median [range]); P = NS), and the percentage reduction was equivalent (-80% [57-98] vs. -98% [49-100], P = NS). Insulin-mediated glucose disposal was significantly reduced in obese men. Basal VLDL-TG secretion rates are increased in normoglycemic but insulin-resistant, obese men, resulting in hypertriglyceridemia. Insulin-mediated suppression of EGP is preserved in obese men, whereas suppression of VLDL-TG secretion is less pronounced in obese men. Compared with EGP, the inability to achieve suppression of VLDL-TG secretions to a level similar to control subjects during hyperinsulinemia seems to be an early manifestation in male obesity.

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

Iwasaki, Yuko; Iwasaki, Hitoshi; Yatoh, Shigeru

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, andmore » 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.« less

Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist Stimulates Insulin Secretion in Rodents and From Human Islets

PubMed Central

Sloop, Kyle W.; Willard, Francis S.; Brenner, Martin B.; Ficorilli, James; Valasek, Kathleen; Showalter, Aaron D.; Farb, Thomas B.; Cao, Julia X.C.; Cox, Amy L.; Michael, M. Dodson; Gutierrez Sanfeliciano, Sonia Maria; Tebbe, Mark J.; Coghlan, Michael J.

2010-01-01

OBJECTIVE The clinical effectiveness of parenterally-administered glucagon-like peptide-1 (GLP-1) mimetics to improve glucose control in patients suffering from type 2 diabetes strongly supports discovery pursuits aimed at identifying and developing orally active, small molecule GLP-1 receptor agonists. The purpose of these studies was to identify and characterize novel nonpeptide agonists of the GLP-1 receptor. RESEARCH DESIGN AND METHODS Screening using cells expressing the GLP-1 receptor and insulin secretion assays with rodent and human islets were used to identify novel molecules. The intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp characterized the insulinotropic effects of compounds in vivo. RESULTS Novel low molecular weight pyrimidine-based compounds that activate the GLP-1 receptor and stimulate glucose-dependent insulin secretion are described. These molecules induce GLP-1 receptor-mediated cAMP signaling in HEK293 cells expressing the GLP-1 receptor and increase insulin secretion from rodent islets in a dose-dependent manner. The compounds activate GLP-1 receptor signaling, both alone or in an additive fashion when combined with the endogenous GLP-1 peptide; however, these agonists do not compete with radiolabeled GLP-1 in receptor-binding assays. In vivo studies using the IVGTT and the hyperglycemic clamp in Sprague Dawley rats demonstrate increased insulin secretion in compound-treated animals. Further, perifusion assays with human islets isolated from a donor with type 2 diabetes show near-normalization of insulin secretion upon compound treatment. CONCLUSIONS These studies characterize the insulinotropic effects of an early-stage, small molecule GLP-1 receptor agonist and provide compelling evidence to support pharmaceutical optimization. PMID:20823098

Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome.

PubMed

Glintborg, Dorte; Mumm, Hanne; Holst, Jens Juul; Andersen, Marianne

2017-05-01

Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined. Outpatient clinic. Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol), metformin (2 g/day) or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT) measuring fasting and area under the curve (AUC) for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls. Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT. Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention ( P  < 0.01) and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P  = 0.01). Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI. AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion. © 2017 The authors.

A new scaffold containing small intestinal submucosa and mesenchymal stem cells improves pancreatic islet function and survival in vitro and in vivo

PubMed Central

Wang, Dan; Ding, Xiaoming; Xue, Wujun; Zheng, Jin; Tian, Xiaohui; Li, Yang; Wang, Xiaohong; Song, Huanjin; Liu, Hua; Luo, Xiaohui

2017-01-01

It is unknown whether a scaffold containing both small intestinal submucosa (SIS) and mesenchymal stem cells (MSCs) for transplantation may improve pancreatic islet function and survival. In this study, we examined the effects of a SIS-MSC scaffold on islet function and survival in vitro and in vivo. MSCs and pancreatic islets were isolated from Sprague-Dawley rats, and SIS was isolated from Bamei pigs. The islets were apportioned among 3 experimental groups as follows: SIS-islets, SIS-MSC-islets and control-islets. In vitro, islet function was measured by a glucose-stimulated insulin secretion test; cytokines in cultured supernatants were assessed by enzyme-linked immunosorbent assay; and gene expression was analyzed by reverse transcription-quantitative PCR. In vivo, islet transplantation was performed in rats, and graft function and survival were monitored by measuring the blood glucose levels. In vitro, the SIS-MSC scaffold was associated with improved islet viability and enhanced insulin secretion compared with the controls, as well as with the increased the expression of insulin 1 (Ins1), pancreatic and duodenal homeobox 1 (Pdx1), platelet endothelial cell adhesion molecule 1 [Pecam1; also known as cluster of differentiation 31 (CD31)] and vascular endothelial growth factor A (Vegfa) in the islets, increased growth factor secretion, and decreased tumor necrosis factor (TNF) secretion. In vivo, the SIS-MSC scaffold was associated with improved islet function and graft survival compared with the SIS and control groups. On the whole, our findings demonstrate that the SIS-MSC scaffold significantly improved pancreatic islet function and survival in vitro and in vivo. This improvement may be associated with the upregulation of insulin expression, the improvement of islet microcirculation and the secretion of cytokines. PMID:27909715

Repaglinide acutely amplifies pulsatile insulin secretion by augmentation of burst mass with no effect on burst frequency.

PubMed

Juhl, C B; Pørksen, N; Hollingdal, M; Sturis, J; Pincus, S; Veldhuis, J D; Dejgaard, A; Schmitz, O

2000-05-01

Repaglinide is a new oral hypoglycemic agent that acts as a prandial glucose regulator proposed for the treatment of type 2 diabetes by stimulating insulin secretion. The aim of this study was to explore actions of repaglinide on the rapid pulsatile insulin release by high-frequency insulin sampling and analysis of insulin-concentration time series. We examined 8 healthy lean male subjects in a single-dose double-blind placebo-controlled crossover design. After the subjects underwent an overnight fast, blood sampling was initiated and continued every minute for 120 min. After 40 min, a single dose (0.5 mg) of repaglinide or placebo was given. Serum insulin-concentration time series were assessed by deconvolution analyses and the regularity statistic by approximate entropy (ApEn). Average insulin concentration was increased after repaglinide administration (basal vs. stimulated period, P values are placebo vs. repaglinide) (25.1 +/- 3.6 vs. 33.5 +/- 4.1 pmol/l, P < 0.001). Insulin secretory burst mass (15.8 +/- 2.2 vs. 19.6 +/- 2.8 pmol x l(-1) x pulse(-1), P = 0.02) and amplitude (6.1 +/- 0.9 vs. 7.7 +/- 1.2 pmol x l(-1) x min(-1), P = 0.008) were augmented after repaglinide administration. A concomitant trend toward an increase in basal insulin secretion was observed (2.5 +/- 0.3 vs. 3.2 +/- 0.4 pmol x l(-1) x min(-1), p = 0.06), while the interpulse interval was unaltered (6.8 +/- 1.0 vs. 5.4 +/- 0.4 min/pulse, P = 0.38). ApEn increased significantly after repaglinide administration (0.623 +/- 0.045 vs. 0.670 +/- 0.034, P = 0.04), suggesting less orderly oscillatory patterns of insulin release. In conclusion, a single dose of repaglinide amplifies insulin secretory burst mass (and basal secretion) with no change in burst frequency. The possible importance of these mechanisms in the treatment of type 2 diabetes characterized by disrupted pulsatile insulin secretion remains to be clarified.

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

PubMed

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

2018-05-01

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

MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1.

PubMed

Wei, Jie; Ding, Dongxiao; Wang, Tao; Liu, Qiong; Lin, Yi

2017-12-01

Bisphenol A (BPA) can disrupt glucose homeostasis and impair pancreatic islet function; however, the mechanisms behind these effects are poorly understood. Male mice (4 wk old) were treated with BPA (50 or 500 μg/kg/d) for 8 wk. Whole-body glucose homeostasis, pancreatic islet morphology and function, and miR-338-mediated molecular signal transduction analyses were examined. We showed that BPA treatment led to a disruption of glucose tolerance and a compensatory increase of pancreatic islets insulin secretion and pancreatic and duodenal homeobox 1 ( Pdx1 ) expression in mice. Inhibition of Pdx1 reduced glucose-stimulated insulin secretion and ATP production in the islets of BPA-exposed mice. Based on primary pancreatic islets, we also confirmed that miR-338 regulated Pdx1 and thus contributed to BPA-induced insulin secretory dysfunction from compensation to decompensation. Short-term BPA exposure downregulated miR-338 through activation of G-protein-coupled estrogen receptor 1 (Gpr30), whereas long-term BPA exposure upregulated miR-338 through suppression of glucagon-like peptide 1 receptor (Glp1r). Taken together, our results reveal a molecular mechanism, whereby BPA regulates Gpr30/Glp1r to mediate the expression of miR-338, which acts to control Pdx1-dependent insulin secretion. The Gpr30/Glp1r-miR-338-Pdx1 axis should be represented as a novel mechanism by which BPA induces insulin secretory dysfunction in pancreatic islets.-Wei, J., Ding, D., Wang, T., Liu, Q., Lin, Y. MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1. © FASEB.

Role of insulin in the hyperandrogenemia of lean women with polycystic ovary syndrome and normal insulin sensitivity.

PubMed

Baillargeon, Jean-Patrice; Carpentier, André

2007-10-01

To determine the effect of reducing insulin secretion on hyperandrogenemia in lean normoinsulinemic women with polycystic ovary syndrome (PCOS) and normal metabolic insulin sensitivity. Transversal assessment at baseline and prospective follow-up of lean PCOS group after 8 days of diazoxide, which reduces insulin secretion, and 1 month of leuprolide, which suppresses LH. Clinical research center of an academic hospital. Nine lean women (body mass index

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 side effect of rosuvastatin treatment as it occurs through the same mechanisms as the lipid-lowering effects of the drug. PMID:26986474

Insulin secretion and insulin resistance in Korean women with gestational diabetes mellitus and impaired glucose tolerance

PubMed Central

Yang, Sae Jeong; Kim, Tae Nyun; Baik, Sei Hyun; Kim, Tae Sun; Lee, Kwan Woo; Nam, Moonsuk; Park, Yong Soo; Woo, Jeong-Teak; Kim, Young Seol

2013-01-01

Background/Aims The aim was to compare the insulin sensitivity and secretion index of pregnant Korean women with normal glucose tolerance (NGT), gestational impaired glucose tolerance (GIGT; only one abnormal value according to the Carpenter and Coustan criteria), and gestational diabetes mellitus (GDM). Methods A cross-sectional study was performed with 1,163 pregnant women with positive (1-hour plasma glucose ≥ 7.2 mmol/L) in a 50-g oral glucose challenge test (OGCT). The 100-g oral glucose tolerance test (OGTT) was used to stratify the participants into three groups: NGT (n = 588), GIGT (n = 294), and GDM (n = 281). Results The GDM group had higher homeostasis model assessment of insulin resistance and lower insulin sensitivity index (ISOGTT), quantitative insulin sensitivity check index, homeostasis model assessment for estimation of index β-cell secretion (HOMA-B), first and second phase insulin secretion, and insulin secretion-sensitivity index (ISSI) than the NGT group (p ≤ 0.001 for all). Moreover, the GIGT group had lower ISOGTT, HOMA-B, first and second phase insulin secretion, and ISSI than the NGT group (p < 0.001 for all). Among the GIGT subjects, the 1-hour plasma glucose abnormal levels group showed significantly greater weight gain during pregnancy and higher values in the 50-g OGCT than the other two groups. Moreover, the 1-hour and 2-hour abnormal levels groups had poorer insulin secretion status than the 3-hour abnormal levels group. Conclusions Korean women with GDM show impairments of both insulin secretion and insulin sensitivity. In addition, GIGT is associated with both β-cell dysfunction and insulin resistance. PMID:23682224

Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice.

PubMed

Shirakawa, Jun; Okuyama, Tomoko; Yoshida, Eiko; Shimizu, Mari; Horigome, Yuka; Tuno, Takayuki; Hayasaka, Moe; Abe, Shiori; Fuse, Masahiro; Togashi, Yu; Terauchi, Yasuo

2014-06-01

The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the β-cell mass may expand in response to chemotherapy with this drug.

The lack of effect of insulin on luteinizing hormone pulsatility in healthy male volunteers provides evidence of a sexual dimorphism in the metabolic regulation of reproductive hormones.

PubMed

Pesant, Marie-Hélène; Dwyer, Andrew; Marques Vidal, Pedro; Schneiter, Philippe; Giusti, Vittorio; Tappy, Luc; Pralong, François P

2012-08-01

The activity of the neuroendocrine reproductive axis is closely related to nutritional status. This link is particularly important in healthy women, in whom insulin is a positive signal for the reproductive system. In contrast, very little is known regarding this relation in men. This study was designed to evaluate the effect of insulin on the reproductive axis of young male volunteers and to study the effect of short-term hypercaloric feeding on this modulation. The activity of the neuroendocrine reproductive axis was characterized by the pattern of endogenous luteinizing hormone (LH) secretion on the basis of frequent blood sampling protocols. The effect of insulin was tested by comparing the LH secretion pattern between a baseline study and a hyperinsulinemic euglycemic clamp. These studies were performed first in subjects fed a controlled isocaloric diet for 6 d (calculated as 1.5 times their resting metabolic rate) then in the same subjects fed a controlled hypercaloric diet in which 30% extra calories were provided as fat and fructose (3 g · kg(-1) · d(-1)) before undergoing identical protocols. Serum gonadotropins, sex steroids, glucose, insulin, ghrelin, and leptin concentrations were assessed, and the HOMA-IR was calculated. The LH secretion pattern was not affected by insulin or by hypercaloric feeding. Insulin decreased ghrelin and increased leptin concentrations but had no additional effect of hypercaloric feeding despite significantly lower HOMA-IR indexes. Our data indicate that neither insulin nor short-term hypercaloric feeding has any effect on the activity of the male reproductive axis. They also further support the association between ghrelin and insulin and glucose metabolism. This trial was registered at clinicaltrials.gov as NCT01058681.

Adrenaline: insights into its metabolic roles in hypoglycaemia and diabetes

PubMed Central

Korim, W S; Sabetghadam, A; Llewellyn‐Smith, I J

2016-01-01

Adrenaline is a hormone that has profound actions on the cardiovascular system and is also a mediator of the fight‐or‐flight response. Adrenaline is now increasingly recognized as an important metabolic hormone that helps mobilize energy stores in the form of glucose and free fatty acids in preparation for physical activity or for recovery from hypoglycaemia. Recovery from hypoglycaemia is termed counter‐regulation and involves the suppression of endogenous insulin secretion, activation of glucagon secretion from pancreatic α‐cells and activation of adrenaline secretion. Secretion of adrenaline is controlled by presympathetic neurons in the rostroventrolateral medulla, which are, in turn, under the control of central and/or peripheral glucose‐sensing neurons. Adrenaline is particularly important for counter‐regulation in individuals with type 1 (insulin‐dependent) diabetes because these patients do not produce endogenous insulin and also lose their ability to secrete glucagon soon after diagnosis. Type 1 diabetic patients are therefore critically dependent on adrenaline for restoration of normoglycaemia and attenuation or loss of this response in the hypoglycaemia unawareness condition can have serious, sometimes fatal, consequences. Understanding the neural control of hypoglycaemia‐induced adrenaline secretion is likely to identify new therapeutic targets for treating this potentially life‐threatening condition. PMID:26896587

Gastric Inhibitory Peptide Controls Adipose Insulin Sensitivity via Activation of cAMP-response Element-binding Protein and p110β Isoform of Phosphatidylinositol 3-Kinase*

PubMed Central

Mohammad, Sameer; Ramos, Lavoisier S.; Buck, Jochen; Levin, Lonny R.; Rubino, Francesco; McGraw, Timothy E.

2011-01-01

Gastric inhibitory peptide (GIP) is an incretin hormone secreted in response to food intake. The best known function of GIP is to enhance glucose-dependent insulin secretion from pancreatic β-cells. Extra-pancreatic effects of GIP primarily occur in adipose tissues. Here, we demonstrate that GIP increases insulin-dependent translocation of the Glut4 glucose transporter to the plasma membrane and exclusion of FoxO1 transcription factor from the nucleus in adipocytes, establishing that GIP has a general effect on insulin action in adipocytes. Stimulation of adipocytes with GIP alone has no effect on these processes. Using pharmacologic and molecular genetic approaches, we show that the effect of GIP on adipocyte insulin sensitivity requires activation of both the cAMP/protein kinase A/CREB signaling module and p110β phosphoinositol-3′ kinase, establishing a novel signal transduction pathway modulating insulin action in adipocytes. This insulin-sensitizing effect is specific for GIP because isoproterenol, which elevates adipocyte cAMP and activates PKA/CREB signaling, does not affect adipocyte insulin sensitivity. The insulin-sensitizing activity points to a more central role for GIP in intestinal regulation of peripheral tissue metabolism, an emerging feature of inter-organ communication in the control of metabolism. PMID:22027830

The two pore channel TPC2 is dispensable in pancreatic β-cells for normal Ca2+ dynamics and insulin secretion

PubMed Central

Cane, Matthew C.; Parrington, John; Rorsman, Patrik; Galione, Antony; Rutter, Guy A.

2016-01-01

Ca2+ signals are central to the stimulation of insulin secretion from pancreatic β-cells by glucose and other agents, including glucagon-like peptide-1 (GLP-1). Whilst Ca2+ influx through voltage-gated Ca2+ channels on the plasma membrane is a key trigger for glucose-stimulated secretion, mobilisation of Ca2+ from acidic stores has been implicated in the control of more localised Ca2+ changes and membrane potential. Nicotinic acid adenine dinucleotide phosphate (NAADP), generated in β-cells in response to high glucose, is a potent mobiliser of these stores, and has been proposed to act through two pore channels (TPC1 and TPC2, murine gene names Tpcn1 and Tpcn2). Whilst the role of TPC1 in the control of Ca2+ mobilisation and insulin secretion was recently confirmed, conflicting data exist for TPC2. Here, we used the selective and efficient deleter strain, Ins1Cre to achieve β-cell selective deletion of the Tpcn2 gene in mice. βTpcn2 KO mice displayed normal intraperitoneal and oral glucose tolerance, and glucose-stimulated Ca2+ dynamics and insulin secretion from islets were similarly normal. GLP-1-induced Ca2+ increases involved an increase in oscillation frequency from 4.35 to 4.84 per minute (p = 0.04) at 8 mM glucose, and this increase was unaffected by the absence of Tpcn2. The current data thus indicate that TPC2 is not absolutely required for normal glucose- or incretin-stimulated insulin secretion from the β-cell. Our findings suggest that TPC1, whose expression tended to increase in Tpcn2 null islets, might be sufficient to support normal Ca2+ dynamics in response to stimulation by nutrients or incretins. PMID:26769314

Recent Advances in Obesity-Induced Inflammation and Insulin Resistance

PubMed Central

Tateya, Sanshiro; Kim, Francis; Tamori, Yoshikazu

2013-01-01

It has been demonstrated in rodents and humans that chronic inflammation characterized by macrophage infiltration occurs mainly in adipose tissue or liver during obesity, in which activation of immune cells is closely associated with insulin sensitivity. Macrophages can be classified as classically activated (M1) macrophages that support microbicidal activity or alternatively activated (M2) macrophages that support allergic and antiparasitic responses. In the context of insulin action, M2 macrophages sustain insulin sensitivity by secreting IL-4 and IL-10, while M1 macrophages induce insulin resistance through the secretion of proinflammatory cytokines, such as TNFα. Polarization of M1/M2 is controlled by various dynamic functions of other immune cells. It has been demonstrated that, in a lean state, TH2 cells, Treg cells, natural killer T cells, or eosinophils contribute to the M2 activation of macrophages by secreting IL-4 or IL-10. In contrast, obesity causes alteration of the constituent immune cells, in which TH1 cells, B cells, neutrophils, or mast cells induce M1 activation of macrophages by the elevated secretion of TNFα and IFNγ. Increased secretion of TNFα and free fatty acids from hypertrophied adipocytes also contributes to the M1 activation of macrophages. Since obesity-induced insulin resistance is established by macrophage infiltration and the activation of immune cells inside tissues, identification of the factors that regulate accumulation and the intracellular signaling cascades that define polarization of M1/M2 would be indispensable. Regulation of these factors would lead to the pharmacological inhibition of obesity-induced insulin resistance. In this review, we introduce molecular mechanisms relevant to the pathophysiology and review the most recent studies of clinical applications targeting chronic inflammation. PMID:23964268

Repaglinide is more efficient than glimepiride on insulin secretion and post-prandial glucose excursions in patients with type 2 diabetes. A short term study.

PubMed

Rizzo, M R; Barbieri, M; Grella, R; Passariello, N; Barone, M; Paolisso, G

2004-02-01

To compare the effect of Repaglinide vs Glimepiride on glucose- and meal-induced insulin secretion and on meal-test induced postprandial glucose excursions. After 2 weeks washout period, a 3-Month randomised, cross-over parallel group trial of R (1 mg x 2/die) vs G (2 mg/die) in 14 patients with type 2 diabetes "naive" in diet treatment was made. Both R and G significantly but similarly lowered fasting glucose levels and improved fasting plasma insulin levels vs baseline. Hyperglycemic clamp showed that both 1st (129.15 +/- 23.6 vs 106.90 +/- 18.6 pmol/L; p=0.01) and 2nd phase (189.42 +/- 34.4 vs 144.21 +/- 37.3 pmol/L; p=0.003) B-cell response to glucose as well as area under the curve (52.07 +/- 10.86 vs 39.54 +/- 10.27 micromol/L x 120'; p=0.005) were greater in R than G groups. Insulin action (4.0 +/- 1.1 vs 3.2 +/- 0.9 mg x Kg x 60'/microU/mL; p=0.046) was also improved by R than G administration. In the meal test, R therapy produced a more rapId induction of insulin secretion during the first part. In fact, the mean rise in insulin secretion peaked at 45 min in R (p=0.001 vs G) and at 60 min in G (p=0.001 vs R). Consequently, glucose spike at 60 min was higher in G group compared to glucose spike at 45 min in R group (p=0.002). Our study demonstrates that R is more efficient that G on improving glucose- and meal- induced insulin secretion as well as on controlling for postprandial glucose excursion.

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.

Patients With Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia

PubMed Central

Hyltén-Cavallius, Louise; Iepsen, Eva W.; Wewer Albrechtsen, Nicolai J.; Svendstrup, Mathilde; Lubberding, Anniek F.; Hartmann, Bolette; Jespersen, Thomas; Linneberg, Allan; Christiansen, Michael; Vestergaard, Henrik; Pedersen, Oluf; Holst, Jens J.; Kanters, Jørgen K.

2017-01-01

Background: Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long-QT syndrome type 2 (LQT2) because of prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), respectively. These hormones are crucial for glucose regulation, and long-QT syndrome may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β-cell function and decreased α-cell function, and thus lower glucose levels. Methods: Eleven patients with LQT2 and 22 sex-, age-, and body mass index–matched control participants underwent a 6-hour 75-g oral glucose tolerance test with ECG recording and blood sampling for measurements of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP. Results: In comparison with matched control participants, LQT2 patients had 56% to 78% increased serum insulin, serum C-peptide, plasma GLP-1, and plasma GIP responses (P=0.03–0.001) and decreased plasma glucose levels after glucose ingestion (P=0.02) with more symptoms of hypoglycemia (P=0.04). Sixty-three percent of LQT2 patients developed hypoglycemic plasma glucose levels (<70 mg/dL) versus 36% control participants (P=0.16), and 18% patients developed serious hypoglycemia (<50 mg/dL) versus none of the controls. LQT2 patients had defective glucagon responses to low glucose, P=0.008. β-Cell function (Insulin Secretion Sensitivity Index-2) was 2-fold higher in LQT2 patients than in controls (4398 [95% confidence interval, 2259–8562] versus 2156 [1961–3201], P=0.03). Pharmacological Kv11.1 blockade (dofetilide) in rats had similar effect, and small interfering RNA inhibition of hERG in β and L cells increased insulin and GLP-1 secretion up to 50%. Glucose ingestion caused cardiac repolarization disturbances with increased QTc intervals in both patients and controls, but with a 122% greater increase in QTcF interval in LQT2 patients (P=0.004). Conclusions: Besides a prolonged cardiac repolarization phase, LQT2 patients display increased GLP-1, GIP, and insulin secretion and defective glucagon secretion, causing decreased plasma glucose and thus increased risk of hypoglycemia. Furthermore, glucose ingestion increased QT interval and aggravated the cardiac repolarization disturbances in LQT2 patients. Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT02775513. PMID:28235848

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

PubMed

Teo, Adrian Kee Keong; Kulkarni, Rohit N

2012-10-17

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

Early alterations in glycemic control and pancreatic endocrine function in non-diabetic patients with chronic pancreatitis

PubMed Central

Lundberg, Rachel; Beilman, Gregory J.; Dunn, Ty B.; Pruett, Tim L.; Freeman, Martin L.; Ptacek, Peggy E.; Berry, K. Louise; Robertson, R. Paul; Moran, Antoinette; Bellin, Melena D.

2015-01-01

Objectives Diabetes mellitus (DM) is a frequent consequence of chronic pancreatitis (CP). Little is known about pancreatic endocrine function before the development of DM in CP, particularly in females, or those without calcific and/or alcoholic pancreatitis. Methods Twenty-five non-diabetic adult CP patients (19 female, age 34.2 ± 2.4 yrs) were compared to 25 healthy controls matched for age, gender, and BMI. Subjects underwent frequent sample intravenous glucose tolerance testing (FSIVGTT) and mixed meal tolerance testing (MMTT). Results Mean fasting glucose was higher in CP patients (89.5 ±2.3 mg/dL) than in controls (84.4 ±1.2 mg/dL, p=0.04). On MMTT, CP patients had a higher area under the curve (AUC) glucose and AUC glucagon compared to controls (p≤0.01). AUC C-peptide was equivalent (p=0.6) but stimulated C-peptide at 30 minutes was lower in CP patients (p=0.04). Mean insulin sensitivity index calculated from the FSIVGTT was lower in CP group, indicating reduced insulin sensitivity (p≤0.01). Disposition index (insulin secretion adjusted for insulin sensitivity on FSIVGTT) was lower in CP patients (p=0.01). Conclusions CP patients had higher fasting and MMTT glucose levels, without a compensatory increase in insulin secretion suggesting subtle early islet dysfunction. Our cohort had relative hyperglucagonemia and were less insulin sensitive than controls. PMID:26918872

Basal measures of insulin sensitivity and insulin secretion and simplified glucose tolerance tests in dogs.

PubMed

Verkest, K R; Fleeman, L M; Rand, J S; Morton, J M

2010-10-01

There is need for simple, inexpensive measures of glucose tolerance, insulin sensitivity, and insulin secretion in dogs. The aim of this study was to estimate the closeness of correlation between fasting and dynamic measures of insulin sensitivity and insulin secretion, the precision of fasting measures, and the agreement between results of standard and simplified glucose tolerance tests in dogs. A retrospective descriptive study using 6 naturally occurring obese and 6 lean dogs was conducted. Data from frequently sampled intravenous glucose tolerance tests (FSIGTTs) in 6 obese and 6 lean client-owned dogs were used to calculate HOMA, QUICKI, fasting glucose and insulin concentrations. Fasting measures of insulin sensitivity and secretion were compared with MINMOD analysis of FSIGTTs using Pearson correlation coefficients, and they were evaluated for precision by the discriminant ratio. Simplified sampling protocols were compared with standard FSIGTTs using Lin's concordance correlation coefficients, limits of agreement, and Pearson correlation coefficients. All fasting measures except fasting plasma glucose concentration were moderately correlated with MINMOD-estimated insulin sensitivity (|r| = 0.62-0.80; P < 0.03), and those that combined fasting insulin and glucose were moderately closely correlated with MINMOD-estimated insulin secretion (r = 0.60-0.79; P < 0.04). HOMA calculated using the nonlinear formulae had the closest estimated correlation (r = 0.77 and 0.74) and the best discrimination for insulin sensitivity and insulin secretion (discriminant ratio 4.4 and 3.4, respectively). Simplified sampling protocols with half as many samples collected over 3 h had close agreement with the full sampling protocol. Fasting measures and simplified intravenous glucose tolerance tests reflect insulin sensitivity and insulin secretion derived from frequently sampled glucose tolerance tests with MINMOD analysis in dogs. Copyright 2010 Elsevier Inc. All rights reserved.

Angelica dahurica Extracts Improve Glucose Tolerance through the Activation of GPR119

PubMed Central

Kim, Mi-Hwi; Choung, Jin-Seung; Oh, Yoon-Sin; Moon, Hong-Sub; Jun, Hee-Sook

2016-01-01

G protein-coupled receptor (GPR) 119 is expressed in pancreatic β-cells and intestinal L cells, and is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, respectively. Therefore, the development of GPR119 agonists is a potential treatment for type 2 diabetes. We screened 1500 natural plant extracts for GPR119 agonistic actions and investigated the most promising extract, that from Angelica dahurica (AD), for hypoglycemic actions in vitro and in vivo. Human GPR119 activation was measured in GeneBLAzer T-Rex GPR119-CRE-bla CHO-K1 cells; intracellular cAMP levels and insulin secretion were measured in INS-1 cells; and GLP-1 release was measured in GLUTag cells. Glucose tolerance tests and serum plasma insulin levels were measured in normal C57BL6 mice and diabetic db/db mice. AD extract-treated cells showed significant increases in GPR119 activation, intracellular cAMP levels, GLP-1 levels and glucose-stimulated insulin secretion as compared with controls. In normal mice, a single treatment with AD extract improved glucose tolerance and increased insulin secretion. Treatment with multiple doses of AD extract or n-hexane fraction improved glucose tolerance in diabetic db/db mice. Imperatorin, phellopterin and isoimperatorin were identified in the active fraction of AD extract. Among these, phellopterin activated GPR119 and increased active GLP-1 and insulin secretion in vitro and enhanced glucose tolerance in normal and db/db mice. We suggest that phellopterin might have a therapeutic potential for the treatment of type 2 diabetes. PMID:27391814

Combining insulins for optimal blood glucose control in type 1 and 2 diabetes: Focus on insulin glulisine

PubMed Central

Ulrich, Heather; Snyder, Benjamin; K Garg, Satish

2007-01-01

Normalization of blood glucose is essential for the prevention of diabetes mellitus (DM)-related microvascular and macrovascular complications. Despite substantial literature to support the benefits of glucose lowering and clear treatment targets, glycemic control remains suboptimal for most people with DM in the United States. Pharmacokinetic limitations of conventional insulins have been a barrier to achieving treatment targets secondary to adverse effects such as hypoglycemia and weight gain. Recombinant DNA technology has allowed modification of the insulin molecule to produce insulin analogues that overcome these pharmacokinetic limitations. With time action profiles that more closely mimic physiologic insulin secretion, rapid acting insulin analogues (RAAs) reduce post-prandial glucose excursions and hypoglycemia when compared to regular human insulin (RHI). Insulin glulisine (Apidra®) is a rapid-acting insulin analogue created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin. The quick absorption of insulin glulisine more closely reproduces physiologic first-phase insulin secretion and its rapid acting profile is maintained across patient subtypes. Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or RHI, respectively. Efficacy is maintained even when insulin glulisine is administered post-meal. In addition, glulisine appears to have a more rapid time action profile compared with insulin lispro across various body mass indexes (BMIs). The safety and tolerability profile of insulin glulisine is also comparable to that of insulin lispro or RHI in type 1 or 2 DM and it has been shown to be as safe and effective when used in a continuous subcutaneous insulin infusion (CSII). In summary, insulin glulisine is a safe, effective, and well tolerated rapid-acting insulin analogue across all BMIs and a worthy option for prandial glucose control in type 1 or 2 DM. PMID:17703632

E-cadherin and cell adhesion: a role in architecture and function in the pancreatic islet.

PubMed

Rogers, Gareth J; Hodgkin, Matthew N; Squires, Paul E

2007-01-01

The efficient secretion of insulin from beta-cells requires extensive intra-islet communication. The cell surface adhesion protein epithelial (E)-cadherin (ECAD) establishes and maintains epithelial tissues such as the islets of Langerhans. In this study, the role of ECAD in regulating insulin secretion from pseudoislets was investigated. The effect of an immuno-neutralising ECAD on gross morphology, cytosolic calcium signalling, direct cell-to-cell communication and insulin secretion was assessed by fura-2 microfluorimetry, Lucifer Yellow dye injection and insulin ELISA in an insulin-secreting model system. Antibody blockade of ECAD reduces glucose-evoked changes in [Ca(2+)](i) and insulin secretion. Neutralisation of ECAD causes a breakdown in the glucose-stimulated synchronicity of calcium oscillations between discrete regions within the pseudoislet, and the transfer of dye from an individual cell within a cell cluster is attenuated in the absence of ECAD ligation, demonstrating that gap junction communication is disrupted. The functional consequence of neutralising ECAD is a significant reduction in insulin secretion. Cell adhesion via ECAD has distinct roles in the regulation of intercellular communication between beta-cells within islets, with potential repercussions for insulin secretion.

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

Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial.

PubMed

Sawada, Takahiro; Tsubata, Hideo; Hashimoto, Naoko; Takabe, Michinori; Miyata, Taishi; Aoki, Kosuke; Yamashita, Soichiro; Oishi, Shogo; Osue, Tsuyoshi; Yokoi, Kiminobu; Tsukishiro, Yasue; Onishi, Tetsuari; Shimane, Akira; Taniguchi, Yasuyo; Yasaka, Yoshinori; Ohara, Takeshi; Kawai, Hiroya; Yokoyama, Mitsuhiro

2016-08-26

Recent experimental studies have revealed that n-3 fatty acids, such as eicosapentaenoic acid (EPA) regulate postprandial insulin secretion, and correct postprandial glucose and lipid abnormalities. However, the effects of 6-month EPA treatment on postprandial hyperglycemia and hyperlipidemia, insulin secretion, and concomitant endothelial dysfunction remain unknown in patients with impaired glucose metabolism (IGM) and coronary artery disease (CAD). We randomized 107 newly diagnosed IGM patients with CAD to receive either 1800 mg/day of EPA (EPA group, n = 53) or no EPA (n = 54). Cookie meal testing (carbohydrates: 75 g, fat: 28.5 g) and endothelial function testing using fasting-state flow-mediated dilatation (FMD) were performed before and after 6 months of treatment. The primary outcome of this study was changes in postprandial glycemic and triglyceridemic control and secondary outcomes were improvement of insulin secretion and endothelial dysfunction. After 6 months, the EPA group exhibited significant improvements in EPA/arachidonic acid, fasting triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). The EPA group also exhibited significant decreases in the incremental TG peak, area under the curve (AUC) for postprandial TG, incremental glucose peak, AUC for postprandial glucose, and improvements in glycometabolism categorization. No significant changes were observed for hemoglobin A1c and fasting plasma glucose levels. The EPA group exhibited a significant increase in AUC-immune reactive insulin/AUC-plasma glucose ratio (which indicates postprandial insulin secretory ability) and significant improvements in FMD. Multiple regression analysis revealed that decreases in the TG/HDL-C ratio and incremental TG peak were independent predictors of FMD improvement in the EPA group. EPA corrected postprandial hypertriglyceridemia, hyperglycemia and insulin secretion ability. This amelioration of several metabolic abnormalities was accompanied by recovery of concomitant endothelial dysfunction in newly diagnosed IGM patients with CAD. Clinical Trial Registration UMIN Registry number: UMIN000011265 ( https://www.upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000013200&language=E ).

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

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

Yu, Yunli, E-mail: chrisyu1255@yahoo.com.cn; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009; Wang, Xinting, E-mail: wxinting1986@yahoo.com.cn

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-daymore » 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 involved in gatifloxacin-induced hyperglycemia.« less

Metabolic and steroidogenic alterations related to increased frequency of polycystic ovaries in women with a history of gestational diabetes.

PubMed

Koivunen, R M; Juutinen, J; Vauhkonen, I; Morin-Papunen, L C; Ruokonen, A; Tapanainen, J S

2001-06-01

The prevalence of polycystic ovaries (PCO) and clinical, endocrine, and metabolic features were investigated in women with previous gestational diabetes (GDM). Thirty-three women with a history of GDM and 48 controls were studied. Glucose and insulin secretion capacity was evaluated by means of the oral glucose tolerance test (OGTT), and insulin action was determined by means of a euglycemic insulin clamp. Compared with control women, women with previous GDM more often had significantly abnormal OGTT, a higher prevalence of PCO (39.4% vs. 16.7%; P = 0.03), higher serum concentrations of cortisol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate and a greater area under the glucose curve. Women with previous GDM showed a lowered early phase insulin response to glucose and impaired insulin sensitivity, which was accounted for mainly by decreased glucose nonoxidation. They also demonstrated a significantly lower fasting serum C peptide/insulin ratio than the controls, indicating that women with previous GDM have impaired hepatic insulin extraction, which tended to be more marked among women with PCO. This may explain why women with PCO and previous GDM were significantly more hyperinsulinemic than women with normal ovaries. In conclusion, our data demonstrate that women with previous GDM often have PCO and abnormal OGTT. They are insulin resistant as a result of lowered glucose nonoxidation and show inappropriately low insulin responses to glucose, reflecting impaired beta-cell function. They also have higher adrenal androgen secretion, which may be associated with abdominal obesity.

Effectiveness of basal-supported oral therapy (BOT) using insulin glargine in patients with poorly controlled type 2 diabetes.

PubMed

Suzuki, Daisuke; Umezono, Tomoya; Miyauchi, Masaaki; Kimura, Moritsugu; Yamamoto, Naoyuki; Tanaka, Eitaro; Kuriyama, Yusuke; Sato, Hiroki; Miyatake, Han; Kondo, Masumi; Toyoda, Masao; Fukagawa, Masafumi

2012-07-20

To determine the clinical usefulness of basal-supported oral therapy (BOT) using insulin glargine in Japanese patients with type 2 diabetes. We compared HbA1c levels, body weight, and insulin doses before the introduction of BOT and in the final month of the observation period in 122 patients with type 2 diabetes who received BOT with insulin glargine between October 2007 and July 2009. To exclude the possible effects of seasonal changes in glycemic control, 57 of the 122 patients were followed-up for one year and examined for changes in HbA1c levels, body weight, and insulin dose. Examination of all cases (n=122) showed a significant decrease in HbA1c (before BOT: 8.7±1.8, after: 7.1±1.1%), but no significant change in body weight (before: 63.1±16.1, after: 63.8±17.0 kg). The mean observation period was 10.5±6.4 months. Insulin doses were significantly increased during the study. HbA1c levels improved significantly in patients on non-insulin-secreting drugs (biguanide, α-glucosidase inhibitor and thiazolidine derivatives) than those on insulin-secreting drugs (SU agents and glinides). BOT with insulin glargine is a useful strategy that can achieve good glycemic control in clinical practice without causing serious hypoglycemia. The introduction of BOT before exhaustion of pancreatic β cells may increase its effectiveness.

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

Branched-chain amino acids supplementation protects streptozotocin-induced insulin secretion and the correlated mechanism.

PubMed

Lu, Ming; Zhang, Xiujuan; Zheng, Dongmei; Jiang, Xiuyun; Chen, Qing

2015-01-01

Significant evidence demonstrates that oxidative stress can impair insulin secretion and contribute to the development of type 2 diabetes. Branched-chain amino acids (BCAAs) are reported to be positively related to insulin secretion. This study aimed to determine how oxidative stress affects the function of islets and whether BCAAs can ameliorate the oxidative stress, and accompanying c-jun N-terminal kinase (JNK), protein kinase D1 (PKD1), and pancreatic/duodenal homeobox-1 (PDX-1) changes induced by streptozotocin (STZ). Plasma glucose, plasma insulin, and JNK, PKD1 and PDX-1 mRNA and protein expression were measured in rats treated with STZ and BCAAs. The glucose level in STZ-induced diabetic rats was much higher than that in control animals, and the elevated plasma glucose level in diabetic rats could be significantly inhibited by BCAAs treatment. Consistent with the change in glucose levels, the levels of insulin were also affected by BCAAs treatment. The mRNA and protein expression of JNK, PDX-1, and PKD1 were significantly altered in diabetic rats compared with the control group (P<0.01) and treatment with a low dose of BCAA reversed these changes in those above markers significantly (P<0.01). The present study demonstrated that STZ-induced oxidative stress could reduce serum insulin levels and alter the JNK, PDX-1, and PKD1 expression. BCAAs restored the levels of serum insulin reversed changes in JNK, PDX-1, and PKD1 expression. © 2014 International Union of Biochemistry and Molecular Biology.

Characteristics of repaglinide effects on insulin secretion.

PubMed

Takahashi, Harumi; Hidaka, Shihomi; Seki, Chihiro; Yokoi, Norihide; Seino, Susumu

2018-06-05

The dynamics of insulin secretion stimulated by repaglinide, a glinide, and the combinatorial effects of repaglinide and incretin were investigated. At 4.4 mM glucose, repaglinide induced insulin secretion with a gradually increasing first phase, showing different dynamics from that induced by glimepiride, a sulfonylurea. In the presence of glucagon-like peptide-1 (GLP-1), insulin secretion by repaglinide was augmented significantly but to lesser extent and showed different dynamics from that by glimepiride. At 4.4 mM glucose, the intracellular Ca 2+ level was gradually increased by repaglinide alone or repaglinide plus GLP-1, which differs from the Ca 2+ dynamics by glimepiride alone or glimepiride plus GLP-1, suggesting that the difference in Ca 2+ dynamics contributes to the difference in the dynamics of insulin secretion. At a higher concentration (8.8 mM) of glucose, the dynamics of insulin secretion stimulated by repaglinide was similar to that by glimepiride. Combination of repaglinide and GLP-1 significantly augmented insulin secretion, the amount of which was comparable to that by the combination of glimepiride and GLP-1. The Ca 2+ dynamics was similar for repaglinide and glimepiride at 8.8 mM glucose. Our data indicate that repaglinide has characteristic properties in its effects on the dynamics of insulin secretion and intracellular Ca 2+ and that the combination of repaglinide and GLP-1 stimulates insulin secretion more effectively than the combination of glimepiride and GLP-1 at a high concentration of glucose, providing a basis for its use in clinical settings. Copyright © 2018 Elsevier B.V. All rights reserved.

Quantitative measurement of zinc secretion from pancreatic islets with high temporal resolution using droplet-based microfluidics

PubMed Central

Easley, Christopher J.; Rocheleau, Jonathan V.; Head, W. Steven; Piston, David W.

2009-01-01

We assayed glucose-stimulated insulin secretion (GSIS) from live, murine islets of Langerhans in microfluidic devices by the downstream formation of aqueous droplets. Zinc ions, which are co-secreted with insulin from β-cells, were quantitatively measured from single islets with high temporal resolution using a fluorescent indicator, FluoZin-3. Real-time storage of secretions into droplets (volume of 0.470 ± 0.009 nL) effectively preserves the temporal chemical information, allowing reconstruction of the secretory time record. The use of passive flow control within the device removes the need for syringe pumps, requiring only a single handheld syringe. Under stimulatory glucose levels (11 mM), bursts of zinc as high as ~800 fg islet−1 min−1 were measured. Treatment with diazoxide effectively blocked zinc secretion, as expected. High temporal resolution reveals two major classes of oscillations in secreted zinc, with predominate periods at ~20-40 s and ~ 5-10 min. The more rapid oscillation periods match closely with those of intraislet calcium oscillations, while the slower oscillations are consistent with insulin pulses typically measured in bulk islet experiments or in the bloodstream. This droplet sampling technique should be widely applicable to time-resolved cellular secretion measurements, either in real-time or for post-processing. PMID:19874061

Plasma HDL-cholesterol and triglycerides, but not LDL-cholesterol, are associated with insulin secretion in non-diabetic subjects.

PubMed

Natali, Andrea; Baldi, Simona; Bonnet, Fabrice; Petrie, John; Trifirò, Silvia; Tricò, Domenico; Mari, Andrea

2017-04-01

Experimental data support the notion that lipoproteins might directly affect beta cell function, however clinical data are sparse and inconsistent. We aimed at verifying whether, independently of major confounders, serum lipids are associated with alterations in insulin secretion or clearance non-diabetic subjects. Cross sectional and observational prospective (3.5yrs), multicentre study in which 1016 non-diabetic volunteers aged 30-60yrs. and with a wide range of BMI (20.0-39.9kg/m 2 ) were recruited in a setting of University hospital ambulatory care (RISC study). baseline fasting lipids, fasting and OGTT-induced insulin secretion and clearance (measured by glucose and C-peptide modeling), peripheral insulin sensitivity (by the euglycemic clamp). Lipids and OGTT were repeated in 980 subjects after 3.5years. LDL-cholesterol did not show independent associations with fasting or stimulated insulin secretion or clearance. After accounting for potential confounders, HDL-cholesterol displayed negative and triglycerides positive independent associations with fasting and OGTT insulin secretion; neither with insulin clearance. Low HDL-cholesterol and high triglycerides were associated with an increase in glucose-dependent and a decrease in non-glucose-dependent insulin secretion. Over 3.5years both an HDL-cholesterol decline and a triglycerides rise were associated with an increase in fasting insulin secretion independent of changes in body weight or plasma glucose. LDL-cholesterol does not seem to influence any major determinant of insulin bioavailability while low HDL-cholesterol and high triglycerides might contribute to sustain the abnormalities in insulin secretion that characterize the pre-diabetic state. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) on insulin and glucagon secretion in isolated perfused rat pancreas.

PubMed

Hirose, H; Maruyama, H; Ito, K; Seto, Y; Kido, K; Koyama, K; Dan, K; Saruta, T; Kato, R

1994-04-01

N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) has a structure which differs from those of other known blood glucose-lowering agents including sulfonylureas. It has been shown that oral administration of A-4166 exerts blood glucose-lowering effects in animal in vivo studies. In the present study, we investigated the effects of A-4166 on insulin and glucagon secretion at several glucose concentrations using isolated perfused rat pancreas preparations. Both 3.0 and 30 mumol/l A-4166 significantly stimulated insulin secretion as compared with basal levels at glucose concentrations of 8.0 and 11.0 mmol (p < 0.01 and p < 0.05, respectively). In contrast, glucagon secretion was not affected by administration of A-4166 up to 30 mumol/l at these glucose concentrations. At a glucose concentration of 5.6 mmol/l, neither 0.3 nor 3.0 mumol/l A-4166 produced significant changes in insulin and glucagon secretion. However, A-4166 at 30 mumol/l significantly stimulated insulin secretion and inhibited glucagon secretion as compared with basal levels (p < 0.01 and p < 0.01, respectively). We conclude that A-4166 at 3.0 and 30 mumol/l directly stimulates insulin secretion but has little effect on glucagon secretion in isolated perfused rat pancreas at glucose concentrations of 8.0 and 11.0 mmol/l. these results, taken together with previously published data, suggest that oral administration of A-4166 could be a useful strategy for stimulating endogenous insulin secretion in non-insulin-dependent diabetic patients.

Antiaging Gene Klotho Enhances Glucose-Induced Insulin Secretion by Up-Regulating Plasma Membrane Levels of TRPV2 in MIN6 β-Cells

PubMed Central

Lin, Yi

2012-01-01

Klotho is a recently discovered antiaging gene. Klotho is expressed in mouse pancreatic islets and in insulinoma β-cells (MIN6 β-cells). The purpose of this study was to investigate whether Klotho plays a role in the regulation of insulin secretion in MIN6 β-cells by overexpression and silencing of Klotho. It is interesting that overexpression of Klotho increased glucose-induced insulin secretion in MIN6 β-cells. Overexpression of mouse Klotho protein also significantly increased plasma membrane levels of transient receptor potential V2 (TRPV2), calcium entry, and the glucose-induced increase in intracellular calcium. On the other hand, knockdown of Klotho by siRNA significantly decreased plasma membrane levels of TRPV2 and attenuated glucose-induced calcium entry and insulin secretion. Tranilast, a selective inhibitor of TRPV2, abolished the promoting effects of overexpression of Klotho on glucose-induced calcium entry and insulin secretion in MIN6 cells. Thus, TRPV2 lies in the downstream of Klotho in the regulation of glucose-induced insulin secretion. This study demonstrated, for the first time, that Klotho may enhance glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 and thus glucose-induced calcium responses. These findings reveal a previously unidentified role of Klotho in the regulation of glucose-induced insulin secretion in MIN6 β-cells. PMID:22597535

Antiaging gene Klotho enhances glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 in MIN6 β-cells.

PubMed

Lin, Yi; Sun, Zhongjie

2012-07-01

Klotho is a recently discovered antiaging gene. Klotho is expressed in mouse pancreatic islets and in insulinoma β-cells (MIN6 β-cells). The purpose of this study was to investigate whether Klotho plays a role in the regulation of insulin secretion in MIN6 β-cells by overexpression and silencing of Klotho. It is interesting that overexpression of Klotho increased glucose-induced insulin secretion in MIN6 β-cells. Overexpression of mouse Klotho protein also significantly increased plasma membrane levels of transient receptor potential V2 (TRPV2), calcium entry, and the glucose-induced increase in intracellular calcium. On the other hand, knockdown of Klotho by siRNA significantly decreased plasma membrane levels of TRPV2 and attenuated glucose-induced calcium entry and insulin secretion. Tranilast, a selective inhibitor of TRPV2, abolished the promoting effects of overexpression of Klotho on glucose-induced calcium entry and insulin secretion in MIN6 cells. Thus, TRPV2 lies in the downstream of Klotho in the regulation of glucose-induced insulin secretion. This study demonstrated, for the first time, that Klotho may enhance glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 and thus glucose-induced calcium responses. These findings reveal a previously unidentified role of Klotho in the regulation of glucose-induced insulin secretion in MIN6 β-cells.

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

miR-124a expression contributes to the monophasic pattern of insulin secretion in islets from pregnant rats submitted to a low-protein diet.

PubMed

de Siqueira, Kariny Cassia; de Lima, Faena Moura; Lima, Fernanda Souza; Taki, Marina Satie; da Cunha, Clarissa Felfili; de Lima Reis, Sílvia Regina; Camargo, Rafael Ludemann; Batista, Thiago Martins; Vanzela, Emerielle Cristine; Nardelli, Tarlliza Romanna; Carneiro, Everardo Magalhães; Bordin, Silvana; Ignácio-Souza, Letícia Martins; Latorraca, Márcia Queiroz

2018-06-01

To evaluate the role of miR-124a in the regulation of genes involved in insulin exocytosis and its effects on the kinetics of insulin secretion in pancreatic islets from pregnant rats submitted to a low-protein diet. Adult control non-pregnant (CNP) and control pregnant (CP) rats were fed a normal protein diet (17%), whereas low-protein non-pregnant (LPNP) and low-protein pregnant (LPP) rats were fed a low-protein diet (6%) from days 1 to 15 of pregnancy. Kinetics of the glucose-induced insulin release and measurement of [Ca 2+ ] i in pancreatic islets were assessed by standard protocols. The miR-124a expression and gene transcriptions from pancreatic islets were determined by real-time polymerase chain reaction. In islets from LPP rats, the first phase of insulin release was abrogated. The AUC [Ca 2+ ] i from the LPP group was lower compared with the other groups. miR-124a expression was reduced by a low-protein diet. SNAP-25 mRNA, protein expression, and Rab3A protein content were lower in the LPP rats than in CP rats. Syntaxin 1A and Kir6.2 mRNA levels were decreased in islets from low-protein rats compared with control rats, whereas their protein content was reduced in islets from pregnant rats. Loss of biphasic insulin secretion in islets from LPP rats appears to have resulted from reduced [Ca 2+ ] i due, at least in part, to Kir6.2 underexpression and from the changes in exocytotic elements that are influenced either directly or indirectly by miR-124a.

[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.

Resveratrol Influences Pancreatic Islets by Opposing Effects on Electrical Activity and Insulin Release.

PubMed

Brouwer, Simone; Hoffmeister, Theresa; Gresch, Anne; Schönhoff, Lisa; Düfer, Martina

2018-03-01

Resveratrol is suggested to improve glycemic control by activation of sirtuin 1 (SIRT1) and has already been tested clinically. Our investigation characterizes the targets of resveratrol in pancreatic beta cells and their contribution to short- and long-term effects on insulin secretion. Islets or beta cells are isolated from C57BL/6N mice. Electrophysiology is performed with microelectrode arrays and patch-clamp technique, insulin secretion and content are determined by radioimmunoassay, cAMP is measured by enzyme-linked immunosorbent assay, and cytosolic Ca 2+ concentration by fluorescence methods. Resveratrol (25 μmol L -1 ) elevates [Ca 2+ ] c and potentiates glucose-stimulated insulin secretion. These effects are associated with increased intracellular cAMP and are sensitive to the SIRT1 blocker Ex-527. Inhibition of EPAC1 by CE3F4 also abolishes the stimulatory effect of resveratrol. The underlying mechanism does not involve membrane depolarization as resveratrol even reduces electrical activity despite blocking K ATP channels. Importantly, after prolonged exposure to resveratrol (14 days), the beneficial influence of the polyphenol on insulin release is lost. Resveratrol addresses multiple targets in pancreatic islets. Potentiation of insulin secretion is mediated by SIRT1-dependent activation of cAMP/EPAC1. Considering resveratrol as therapeutic supplement for patients with type 2 diabetes mellitus, the inhibitory influence on electrical excitability attenuates positive effects. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Sensitivity*

PubMed Central

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

2016-01-01

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. PMID:27662905

Impact of 9 Days of Bed Rest on Hepatic and Peripheral Insulin Action, Insulin Secretion, and Whole-Body Lipolysis in Healthy Young Male Offspring of Patients With Type 2 Diabetes

PubMed Central

Alibegovic, Amra C.; Højbjerre, Lise; Sonne, Mette P.; van Hall, Gerrit; Stallknecht, Bente; Dela, Flemming; Vaag, Allan

2009-01-01

OBJECTIVE The aim of this study was to investigate the impact of 9 days of bed rest on insulin secretion, insulin action, and whole-body glucose and fat metabolism in first-degree relative (FDR) and matched control (CON) subjects. RESEARCH DESIGN AND METHODS A total of 13 FDR and 20 CON subjects participated in the study. All were studied before and after 9 days of bed rest using the clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. Glucose and glycerol turnover rates were studied using stable isotope kinetics. RESULTS Bed rest caused a significant decrease in whole-body insulin sensitivity in both groups. Hepatic insulin resistance was elevated in FDR subjects prior to bed rest and was significantly augmented by bed rest in FDR (P < 0.01) but not in CON (P = NS) subjects. The rate of whole-body lipolysis decreased during bed rest in both FDR and CON subjects, with no significant differences between the groups. Insulin resistance induced by bed rest was fully accounted for by the impairment of nonoxidative glucose metabolism in both groups (overall P < 0.001). CONCLUSIONS Whole-body insulin action in both insulin-resistant FDR and healthy CON subjects deteriorates with 9 days of bed rest, converging toward similar degrees of whole-body insulin resistance. FDR subjects exhibit hepatic insulin resistance (HIR), which, in contrast to CON subjects, deteriorates in response to physical inactivity. FDR subjects exhibit reduced insulin secretion when seen in relation to their degree of HIR but not peripheral insulin resistance. PMID:19720789

Effects of dexamethasone and insulin on the synthesis of triacylglycerols and phosphatidylcholine and the secretion of very-low-density lipoproteins and lysophosphatidylcholine by monolayer cultures of rat hepatocytes.

PubMed Central

Mangiapane, E H; Brindley, D N

1986-01-01

Rat hepatocytes in monolayer culture were preincubated for 19 h with 1 microM-dexamethasone, and the incubation was continued for a further 23 h with [14C]oleate, [3H]glycerol and 1 microM-dexamethasone. Dexamethasone increased the secretion of triacylglycerol into the medium in particles that had the properties of very-low-density lipoproteins. The increased secretion was matched by a decrease in the triacylglycerol and phosphatidylcholine that remained in the hepatocytes. Preincubating the hepatocytes for the total 42 h period with 36 nM-insulin decreased the amount of triacylglycerol in the medium and in the cells after the final incubation for 23 h with radioactive substrates. However, insulin had no significant effect on the triacylglycerol content of the cell and medium when it was present only in the final 23 h incubation. Insulin antagonized the effects of dexamethasone in stimulating the secretion of triacylglycerol from the hepatocytes, especially when it was present throughout the total 42 h period. The labelling of lysophosphatidylcholine in the medium when hepatocytes were incubated with [14C]oleate and [3H]glycerol was greater than that of phosphatidylcholine. The appearance of this lipid in the medium, unlike that of triacylglycerol and phosphatidylcholine, was not stimulated by dexamethasone, or inhibited by colchicine. However, the presence of lysophosphatidylcholine in the medium was decreased when the hepatocytes were incubated with both dexamethasone and insulin. These findings are discussed in relation to the control of the synthesis of glycerolipids and the secretion of very-low-density lipoproteins and lysophosphatidylcholine by the liver, particularly in relation to the interactions of glucocorticoids and insulin. PMID:3513755

Generation of glucose-sensitive insulin-secreting beta-like cells from human embryonic stem cells by incorporating a synthetic lineage-control network.

PubMed

Saxena, Pratik; Bojar, Daniel; Zulewski, Henryk; Fussenegger, Martin

2017-10-10

We previously reported novel technology to differentiate induced pluripotent stem cells (IPSCs) into glucose-sensitive insulin-secreting beta-like cells by engineering a synthetic lineage-control network regulated by the licensed food additive vanillic acid. This genetic network was able to program intricate expression dynamics of the key transcription factors Ngn3 (neurogenin 3, OFF-ON-OFF), Pdx1 (pancreatic and duodenal homeobox 1, ON-OFF-ON) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A, OFF-ON) to guide the differentiation of IPSC-derived pancreatic progenitor cells to beta-like cells. In the present study, we show for the first time that this network can also program the expression dynamics of Ngn3, Pdx1 and MafA in human embryonic stem cell (hESC)-derived pancreatic progenitor cells and drive differentiation of these cells into glucose-sensitive insulin-secreting beta-like cells. Therefore, synthetic lineage-control networks appear to be a robust methodology for differentiating pluripotent stem cells into somatic cell types for basic research and regenerative medicine. Copyright © 2017 Elsevier B.V. All rights reserved.

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. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

C-Peptide, Baseline and Postprandial Insulin Resistance after a Carbohydrate-Rich Test Meal - Evidence for an Increased Insulin Clearance in PCOS Patients?

PubMed

Stassek, J; Erdmann, J; Ohnolz, F; Berg, F D; Kiechle, M; Seifert-Klauss, V

2017-01-01

Introduction Known characteristics of patients with PCOS include infertility, menstrual disorders, hirsutism and also often insulin resistance. These symptoms increase with increasing body weight. In the LIPCOS study ( L ifestyle I ntervention for Patients with Polycystic Ovary Syndrome [ PCOS ]) long-term changes of the PCOS in dependence on pregnancy and parenthood were systematically assessed. In the framework of the LIPCOS study, PCOS patients were given a standardised carbohydrate-rich test meal in order to examine glucose homeostasis and insulin secretion. The results were compared with those of a eumenorrhoeic control group who all had corresponding BMI values and corresponding ages. Methods and Patients 41 PCOS patients (without diabetes) and 68 controls received a standardised carbohydrate-rich test meal (260 kcal, 62 % carbohydrates, 32 % fat, 6 % proteins) in order to generate a submaximal insulin and glucose stimulation. The values were determined at baseline and postprandial after 60, 120 and 180 minutes. In addition, the corresponding C-peptide levels were recorded. Results In the PCOS patients (n = 41), the insulin secretion test after a standardised test meal showed almost identical baseline and postprandial insulin levels when compared with those of the age- and BMI-matched eumenorrhoeic controls (n = 68). In the PCOS patients, the baseline and postprandial glucose levels were significantly elevated (92.88 ± 10.28 [PCOS] vs. 85.07 ± 9.42 mg/dL [controls]; p < 0.001) so was C-peptide (p < 0.025). Conclusions In the present study we have shown for the first time that, after consumption of a standardised test meal, PCOS patients formally exhibit a higher fasting insulin resistance than controls. In spite of the higher stimulated C-peptide levels, the insulin levels did not increase more strongly with increasing glucose levels than in controls which may be indicative of a higher insulin clearance in PCOS patients.

CRYOPRESERVATION EFFECTS ON RECOMBINANT MYOBLASTS ENCAPSULATED IN ADHESIVE ALGINATE HYDROGELS

PubMed Central

Ahmad, Hajira F.; Sambanis, Athanassios

2013-01-01

Cell encapsulation in hydrogels is widely used in tissue engineering applications, including encapsulation of islets or other insulin-secreting cells in pancreatic substitutes. Use of adhesive, bio-functionalized hydrogels is receiving increasing attention, as cell-matrix interactions in 3-D can be important for various cell processes. With pancreatic substitutes, studies have indicated benefits of 3-D adhesion on the viability and/or function of insulin-secreting cells. As long-term storage of microencapsulated cells is critical for their clinical translation, cryopreservation of cells in hydrogels is actively being investigated. Previous studies have examined the cryopreservation response of cells encapsulated in non-adhesive hydrogels using conventional freezing and/or vitrification (ice-free cryopreservation), however, none have systematically compared the two cryopreservation methods with cells encapsulated within an adhesive 3-D environment. The latter would be significant, as evidence suggests adhesion influences cellular response to cryopreservation. Thus, the objective of this study was to determine the response to conventional freezing and vitrification of insulin-secreting cells encapsulated in an adhesive biomimetic hydrogel. Recombinant insulin-secreting C2C12 myoblasts were encapsulated in oxidized RGD-alginate and cultured 1 or 4 days post-encapsulation, cryopreserved, and assessed up to 3 days post-warming for metabolic activity and insulin secretion, and one day post-warming for cell morphology. Besides certain transient differences of the vitrified group relative to the Fresh control, both conventional freezing and vitrification maintained metabolism, secretion and morphology of the recombinant C2C12 cells. Thus, due to a simpler procedure and slightly superior results, conventional freezing is recommended over vitrification for the cryopreservation of C2C12 cells in oxidized RGD-modified alginate. PMID:23499987

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. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Changes of insulin resistance and β-cell function in women with gestational diabetes mellitus and normal pregnant women during mid- and late pregnant period: a case-control study.

PubMed

Wang, Yun-Hui; Wu, Hui-Hua; Ding, Hong; Li, Yan; Wang, Zhen-Hua; Li, Feng; Zhang, Jian-Ping

2013-03-01

The aim of this study was to observe insulin resistance and β-cell function changes among women diagnosed with gestational impaired glucose tolerance or gestational diabetes mellitus (GDM) in mid-pregnancy. Sixty-four pregnant women receiving prenatal care underwent an oral glucose tolerance test at 20-24 weeks of gestation and an insulin release test. The GDM group included 34 pregnant women diagnosed with gestational impaired glucose tolerance or GDM, and the subjects with normal blood glucose were the control group. Insulin resistance and islet β-cell function changes were observed with the oral glucose tolerance test and insulin release test. The homeostatic model assessment-β levels in late pregnancy were higher than those in mid-pregnancy for both groups, and the primary time effect was statistically significant. The early insulin secretion index (ΔI(30)/ΔG(30)) values in mid- and late pregnancy were lower in the GDM group. The values of the area under the curve of blood glucose in mid- and late pregnancy were higher in the GDM group than those in the control group. Insulin resistance was higher in GDM patients than in normal pregnant women. Insulin resistance was aggravated, and β-cell's ability to compensate for the increased insulin resistance by modulating insulin secretion was aggravated, as gestational week increased in women with gestational diabetes and normal pregnant women. Insulin resistance in women with GDM is higher than in pregnant women with normal metabolism of glucose. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

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.

The disposition index does not reflect β-cell function in IGT subjects treated with pioglitazone.

PubMed

DeFronzo, Ralph A; Tripathy, Devjit; Abdul-Ghani, Muhammad; Musi, Nicolas; Gastaldelli, Amalia

2014-10-01

The insulin secretion/insulin resistance (IR) (disposition) index (ΔI/ΔG ÷ IR, where Δ is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of β-cell function. This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide (ΔCP) (instead of Δ plasma insulin) was plotted against insulin sensitivity. A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years. Pioglitazone reduced IGT conversion to diabetes by 72% (P < .0001). ΔI/ΔG vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism wherein the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia. These results demonstrate the validity of the disposition index when relating the plasma insulin response to insulin sensitivity but underscore the pitfall of this index when drawing conclusions about β-cell function, because insulin secretion declined despite an increase in the plasma insulin response.

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

PubMed Central

Hani, E H; Suaud, L; Boutin, P; Chèvre, J C; Durand, E; Philippi, A; Demenais, F; Vionnet, N; Furuta, H; Velho, G; Bell, G I; Laine, B; Froguel, P

1998-01-01

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family. PMID:9449683

Stimulatory effect of exogenous diadenosine tetraphosphate on insulin and glucagon secretion in the perfused rat pancreas

PubMed Central

Silvestre, Ramona A; Rodríguez-Gallardo, Jovita; Egido, Eva M; Marco, José

1999-01-01

Diadenosine triphosphate (AP3A) and diadenosine tetraphosphate (AP4A) are released by various cells (e.g. platelets and chromaffin cells), and may act as extracellular messengers. In pancreatic B-cells, AP3A and AP4A are inhibitors of the ATP-regulated K+ channels, and glucose increases intracellular levels of both substances.We have studied the effect of exogenous AP3A and AP4A on insulin and glucagon secretion by the perfused rat pancreas.AP3A did not significantly modify insulin or glucagon release, whereas AP4A induced a prompt, short-lived insulin response (≈4 fold higher than basal value; P<0.05) in pancreases perfused at different glucose concentrations (3.2, 5.5 or 9 mM). AP4A-induced insulin release was abolished by somatostatin and by diazoxide. These two substances share the capacity to activate ATP-dependent K+ channels, suggesting that these channels are a potential target for AP4A in the B-cell.AP4A stimulated glucagon release at both 3.2 and 5.5 mM glucose. This effect was abolished by somatostatin.The results suggest that extracellular AP4A may play a physiological role in the control of insulin and glucagon secretion. PMID:10516664

Stimulatory effect of exogenous diadenosine tetraphosphate on insulin and glucagon secretion in the perfused rat pancreas.

PubMed

Silvestre, R A; Rodríguez-Gallardo, J; Egido, E M; Marco, J

1999-10-01

1. Diadenosine triphosphate (AP3A) and diadenosine tetraphosphate (AP4A) are released by various cells (e.g. platelets and chromaffin cells), and may act as extracellular messengers. In pancreatic B-cells, AP3A and AP4A are inhibitors of the ATP-regulated K+ channels, and glucose increases intracellular levels of both substances. 2. We have studied the effect of exogenous AP3A and AP4A on insulin and glucagon secretion by the perfused rat pancreas. 3. AP3A did not significantly modify insulin or glucagon release, whereas AP4A induced a prompt, short-lived insulin response ( approximately 4 fold higher than basal value; P<0.05) in pancreases perfused at different glucose concentrations (3.2, 5.5 or 9 mM). AP4A-induced insulin release was abolished by somatostatin and by diazoxide. These two substances share the capacity to activate ATP-dependent K+ channels, suggesting that these channels are a potential target for AP4A in the B-cell. 4. AP4A stimulated glucagon release at both 3.2 and 5.5 mM glucose. This effect was abolished by somatostatin. 5. The results suggest that extracellular AP4A may play a physiological role in the control of insulin and glucagon secretion.

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.

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

PubMed Central

Olivier, Alicia K.; Yi, Yaling; Sun, Xingshen; Sui, Hongshu; Liang, Bo; Hu, Shanming; Xie, Weiliang; Fisher, John T.; Keiser, Nicholas W.; Lei, Diana; Zhou, Weihong; Yan, Ziying; Li, Guiying; Evans, Turan I.A.; Meyerholz, David K.; Wang, Kai; Stewart, Zoe A.; Norris, Andrew W.; Engelhardt, John F.

2012-01-01

Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas. PMID:22996690

Decreased insulin secretion in pregnant rats fed a low protein diet.

PubMed

Gao, Haijun; Ho, Eric; Balakrishnan, Meena; Yechoor, Vijay; Yallampalli, Chandra

2017-10-01

Low protein (LP) diet during pregnancy leads to reduced plasma insulin levels in rodents, but the underlying mechanisms remain unclear. Glucose is the primary insulin secretagogue, and enhanced glucose-stimulated insulin secretion (GSIS) in beta cells contributes to compensation for insulin resistance and maintenance of glucose homeostasis during pregnancy. In this study, we hypothesized that plasma insulin levels in pregnant rats fed LP diet are reduced due to disrupted GSIS of pancreatic islets. We first confirmed reduced plasma insulin levels, then investigated in vivo insulin secretion by glucose tolerance test and ex vivo GSIS of pancreatic islets in the presence of glucose at different doses, and KCl, glibenclamide, and L-arginine. Main findings include (1) plasma insulin levels were unaltered on day 10, but significantly reduced on days 14-22 of pregnancy in rats fed LP diet compared to those of control (CT) rats; (2) insulin sensitivity was unchanged, but glucose intolerance was more severe in pregnant rats fed LP diet; (3) GSIS in pancreatic islets was lower in LP rats compared to CT rats in the presence of glucose, KCl, and glibenclamide, and the response to L-arginine was abolished in LP rats; and (4) the total insulin content in pancreatic islets and expression of Ins2 were reduced in LP rats, but expression of Gcg was unaltered. These studies demonstrate that decreased GSIS in beta cells of LP rats contributes to reduced plasma insulin levels, which may lead to placental and fetal growth restriction and programs hypertension and other metabolic diseases in offspring. © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

β-Cell Replacement Strategies: The Increasing Need for a "β-Cell Dogma".

PubMed

Vieira, Andhira; Druelle, Noémie; Avolio, Fabio; Napolitano, Tiziana; Navarro-Sanz, Sergi; Silvano, Serena; Collombat, Patrick

2017-01-01

Type 1 diabetes is an auto-immune disease resulting in the loss of pancreatic β-cells and, consequently, in chronic hyperglycemia. Insulin supplementation allows diabetic patients to control their glycaemia quite efficiently, but treated patients still display an overall shortened life expectancy and an altered quality of life as compared to their healthy counterparts. In this context and due to the ever increasing number of diabetics, establishing alternative therapies has become a crucial research goal. Most current efforts therefore aim at generating fully functional insulin-secreting β-like cells using multiple approaches. In this review, we screened the literature published since 2011 and inventoried the selected markers used to characterize insulin-secreting cells generated by in vitro differentiation of stem/precursor cells or by means of in vivo transdifferentiation. By listing these features, we noted important discrepancies when comparing the different approaches for the initial characterization of insulin-producing cells as true β-cells. Considering the recent advances achieved in this field of research, the necessity to establish strict guidelines has become a subject of crucial importance, especially should one contemplate the next step, which is the transplantation of in vitro or ex vivo generated insulin-secreting cells in type 1 diabetic patients.

Allyl isothiocyanate increases carbohydrate oxidation through enhancing insulin secretion by TRPV1.

PubMed

Mori, Noriyuki; Kurata, Manami; Yamazaki, Hanae; Matsumura, Shigenobu; Hashimoto, Takashi; Kanazawa, Kazuki; Nadamoto, Tomonori; Inoue, Kazuo; Fushiki, Tohru

2018-04-01

The transient receptor potential (TRP) V1 is a cation channel belonging to the TRP channel family and it has been reported to be involved in energy metabolism, especially glucose metabolism. While, we have previously shown that intragastric administration of allyl isothiocyanate (AITC) enhanced glucose metabolism via TRPV1, the underlying mechanism has not been elucidated. In this study, we examined the relationship between insulin secretion and the increase in carbohydrate oxidation due to AITC. Intragastric administration of AITC elevated blood insulin levels in mice and AITC directly enhanced insulin secretion from isolated islets. These observations were not reproduced in TRPV1 knockout mice. Furthermore, AITC did not increase carbohydrate oxidation in streptozotocin-treated mice. These results suggest that intragastric administration of AITC could induce insulin secretion from islets via TRPV1 and that enhancement of insulin secretion was related to the increased carbohydrate oxidation due to AITC.

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.

Development of a Rapid Insulin Assay by Homogenous Time-Resolved Fluorescence

PubMed Central

Vallaghe, Julie; Gregor, Nathalie; Donthamsetti, Prashant; Harris, Paul E.; Pierre, Nicolas; Freyberg, Robin; Charrier-Savournin, Fabienne; Javitch, Jonathan A.; Freyberg, Zachary

2016-01-01

Direct measurement of insulin is critical for basic and clinical studies of insulin secretion. However, current methods are expensive and time-consuming. We developed an insulin assay based on homogenous time-resolved fluorescence that is significantly more rapid and cost-effective than current commonly used approaches. This assay was applied effectively to an insulin secreting cell line, INS-1E cells, as well as pancreatic islets, allowing us to validate the assay by elucidating mechanisms by which dopamine regulates insulin release. We found that dopamine functioned as a significant negative modulator of glucose-stimulated insulin secretion. Further, we showed that bromocriptine, a known dopamine D2/D3 receptor agonist and newly approved drug used for treatment of type II diabetes mellitus, also decreased glucose-stimulated insulin secretion in islets to levels comparable to those caused by dopamine treatment. PMID:26849707

Effects of the beta-carbolines, harmane and pinoline, on insulin secretion from isolated human islets of Langerhans.

PubMed

Cooper, E Jane; Hudson, Alan L; Parker, Christine A; Morgan, Noel G

2003-12-15

It is well known that certain imidazoline compounds can stimulate insulin secretion and this has been attributed to the activation of imidazoline I(3) binding sites in the pancreatic beta-cell. Recently, it has been proposed that beta-carbolines may be endogenous ligands having activity at imidazoline sites and we have, therefore, studied the effects of beta-carbolines on insulin secretion. The beta-carbolines harmane, norharmane and pinoline increased insulin secretion two- to threefold from isolated human islets of Langerhans. The effects of harmane and pinoline were dose-dependent (EC(50): 5 and 25 microM, respectively) and these agents also blocked the inhibitory effects of the potassium channel agonist, diazoxide, on glucose-induced insulin release. Stimulation of insulin secretion by harmane was glucose-dependent but, unlike the imidazoline I(3) receptor agonist efaroxan, it increased the rate of insulin release beyond that elicited by 20 mM glucose (20 mM glucose alone: 253+/-34% vs. basal; 20 mM glucose plus 100 microM harmane: 327+/-15%; P<0.01). Stimulation of insulin secretion by harmane was attenuated by the imidazoline I(3) receptor antagonist KU14R (2 (2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole) and was reduced when islets were treated with efaroxan for 18 h, prior to the addition of harmane. The results reveal that beta-carbolines can potentiate the rate of insulin secretion from human islets and suggest that these agents may be useful prototypes for the development of novel insulin secretagogues.

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

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

PubMed

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

2015-09-01

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

Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats.

PubMed

Adeghate, Ernest; Ponery, Abdul Samad

2004-12-01

To examine the effect of ipamorelin (IPA), a novel pentapeptide with a strong growth hormone releasing potency, on insulin secretion from pancreatic tissue fragments of normal and diabetic rats. Diabetes mellitus was induced by streptozotocin (60 mg kg(-1)). Four weeks after the induction of diabetes, pancreatic tissue fragments of normal and diabetic rats were removed and incubated with different concentrations (10(-12) - 10(-6) M) of IPA. Insulin release from the pancreas was measured by radioimmunoassay. Ipamorelin evoked significant (p<0.04) increases in insulin secretion from the pancreas of normal and diabetic rats. Either diltiazem or yohimbine or propranolol or a combination of atropine, propranolol and yohimbine inhibited IPA-evoked insulin secretion significantly (p<0.03) from the pancreas of normal and diabetic rats. Atropine caused a significant (p<0.007) reduction in the IPA-induced insulin secretion in diabetic but not in normal rats. IPA stimulates insulin release through the calcium channel and the adrenergic receptor pathways. This is the first study to examine the effect of ipamorelin on insulin secretion in the pancreas.

Management of the hormonal syndrome of neuroendocrine tumors

PubMed Central

Waligórska-Stachura, Joanna; Czarnywojtek, Agata; Sawicka-Gutaj, Nadia; Bączyk, Maciej; Ziemnicka, Katarzyna; Fischbach, Jakub; Woliński, Kosma; Kaznowski, Jarosław; Wrotkowska, Elżbieta; Ruchała, Marek

2016-01-01

Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and rare neoplasms that present many clinical challenges. They characteristically synthesize store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndrome, however many are clinically silent until late presentation with mass effects. Management strategies include surgery cure and cytoreduction with the use of somatostatin analogues. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Somatostatin analogues include octreotide and lanreotide are effective medical tools in the treatment and present selectivity for SSTR2 and SSTR5. During treatment is seen disapperance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and as such, is a promising potential new treatment for patients with carcinoid syndrome. To pancreatic functionig neuroendocrine tumors belongs insulinoma, gastrinoma, glucagonoma and VIP-oma. Medical management in patients with insulinoma include diazoxide which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma include both proton pump inhibitors (PPIs) and histamine H2 – receptor antagonists. In patients with glucagonomas hyperglycaemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas smatostatin analogues are effective in controlling necrolytic migratory erythemia. Severe cases of the VIP-oma syndrome require supplementation of fluid losses. Octreotide reduce tumoral VIP secretion and control secretory diarrhoea. PMID:28507564

Polymorphism at the 5' end flanking region of the insulin gene is associated with reduced insulin secretion in healthy individuals.

PubMed

Cocozza, S; Riccardi, G; Monticelli, A; Capaldo, B; Genovese, S; Krogh, V; Celentano, E; Farinaro, E; Varrone, S; Avvedimento, V E

1988-12-01

Sixty-four unrelated healthy subjects were studied for the detection of a DNA polymorphism at the 5' end of the insulin gene. No significant difference between the groups was found in blood glucose values at fasting and after an oral glucose load. A significant association was found between fasting (P less than 0.05) and after load plasma C-peptide levels (P less than 0.01) and the presence of a 1.6 Kb insertion at the 5' end of the insulin gene. A gene dose-dependent effect was noted, class 3/3 individuals having the lowest after-load C-peptide concentration and class 1/3 an intermediate level (F for the linear trend: P = 0.007). This might suggest that insulin gene polymorphism affects insulin secretion in healthy individuals. In order to confirm this, a subgroup of six class 3/3 and eight class 1/1 individuals subsequently underwent a hyperglycaemic clamp. The tissue sensitivity to insulin was similar in the two groups but glucose-stimulated insulin secretion was markedly impaired in homozygotes for the class 3 allele. In this group, insulin secretion was, on average, only one-third of that in class 1/1 individuals (P less than 0.02). Similarly impaired in class 3/3 persons was the glucose + arginine-stimulated insulin secretion (P less than 0.05). We conclude that the polymorphism at the 5' end of the insulin gene is associated with variations in insulin secretion in healthy humans.

Quantitative measurement of zinc secretion from pancreatic islets with high temporal resolution using droplet-based microfluidics.

PubMed

Easley, Christopher J; Rocheleau, Jonathan V; Head, W Steven; Piston, David W

2009-11-01

We assayed glucose-stimulated insulin secretion (GSIS) from live, murine islets of Langerhans in microfluidic devices by the downstream formation of aqueous droplets. Zinc ions, which are cosecreted with insulin from beta-cells, were quantitatively measured from single islets with high temporal resolution using a fluorescent indicator, FluoZin-3. Real-time storage of secretions into droplets (volume of 0.470 +/- 0.009 nL) effectively preserves the temporal chemical information, allowing reconstruction of the secretory time record. The use of passive flow control within the device removes the need for syringe pumps, requiring only a single hand-held syringe. Under stimulatory glucose levels (11 mM), bursts of zinc as high as approximately 800 fg islet(-1) min(-1) were measured. Treatment with diazoxide effectively blocked zinc secretion, as expected. High temporal resolution reveals two major classes of oscillations in secreted zinc, with predominate periods at approximately 20-40 s and approximately 5-10 min. The more rapid oscillation periods match closely with those of intraislet calcium oscillations, while the slower oscillations are consistent with insulin pulses typically measured in bulk islet experiments or in the bloodstream. This droplet sampling technique should be widely applicable to time-resolved cellular secretion measurements, either in real-time or for postprocessing.

β cell membrane remodelling and procoagulant events occur in inflammation-driven insulin impairment: a GLP-1 receptor dependent and independent control.

PubMed

Gleizes, Céline; Kreutter, Guillaume; Abbas, Malak; Kassem, Mohamad; Constantinescu, Andrei Alexandru; Boisramé-Helms, Julie; Yver, Blandine; Toti, Florence; Kessler, Laurence

2016-02-01

Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell-derived microparticles (MPs) are the conveyors of active procoagulant tissue factor (TF) and circulate at high concentration in diabetic patients. Liraglutide, a glucagon-like peptide (GLP)-1 analogue, is known to promote insulin secretion and β-cell preservation. In this in vitro study, we examined the link between insulin impairment, procoagulant activity and plasma membrane remodelling, under inflammatory conditions. Rin-m5f β-cell function, TF activity mediated by MPs and their modulation by 1 μM liraglutide were examined in a cell cross-talk model. Methyl-β-cyclodextrine (MCD), a cholesterol depletor, was used to evaluate the involvement of raft on TF activity, MP shedding and insulin secretion as well as Soluble N-éthylmaleimide-sensitive-factor Attachment protein Receptor (SNARE)-dependent exocytosis. Cytokines induced a two-fold increase in TF activity at MP surface that was counteracted by liraglutide. Microparticles prompted TF activity on the target cells and a two-fold decrease in insulin secretion via protein kinase A (PKA) and p38 signalling, that was also abolished by liraglutide. Large lipid raft clusters were formed in response to cytokines and liraglutide or MCD-treated cells showed similar patterns. Cells pre-treated by saturating concentration of the GLP-1r antagonist exendin (9-39), showed a partial abolishment of the liraglutide-driven insulin secretion and liraglutide-decreased TF activity. Measurement of caspase 3 cleavage and MP shedding confirmed the contribution of GLP-1r-dependent and -independent pathways. Our results confirm an integrative β-cell response to GLP-1 that targets receptor-mediated signalling and membrane remodelling pointing at the coupling of insulin secretion and inflammation-driven procoagulant events. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion.

PubMed

Aslanoglou, Despoina; George, Emily W; Freyberg, Zachary

2018-05-10

The detection of insulin secretion is critical for elucidating mechanisms of regulated secretion as well as in studies of metabolism. Though numerous insulin assays have existed for decades, the recent advent of homogeneous time-resolved Förster Resonance Energy Transfer (HTRF) technology has significantly simplified these measurements. This is a rapid, cost-effective, reproducible, and robust optical assay reliant upon antibodies conjugated to bright fluorophores with long lasting emission which facilitates time-resolved Förster Resonance Energy Transfer. Moreover, HTRF insulin detection is amenable for the development of high-throughput screening assays. Here we use HTRF to detect insulin secretion in INS-1E cells, a rat insulinoma-derived cell line. This allows us to estimate basal levels of insulin and their changes in response to glucose stimulation. In addition, we use this insulin detection system to confirm the role of dopamine as a negative regulator of glucose-stimulated insulin secretion (GSIS). In a similar manner, other dopamine D2-like receptor agonists, quinpirole, and bromocriptine, reduce GSIS in a concentration-dependent manner. Our results highlight the utility of the HTRF insulin assay format in determining the role of numerous drugs in GSIS and their pharmacological profiles.

HNF1α defect influences post-prandial lipid regulation

PubMed Central

St-Jean, Matthieu; Boudreau, François; Carpentier, André C.

2017-01-01

Purpose Hepatocyte nuclear factor 1 alpha (HNF1α) defects cause Mature Onset Diabetes of the Young type 3 (MODY3), characterized by defects in beta-cell insulin secretion. However, HNF1α is involved in many other metabolic pathways with relevance for monogenic or polygenic type 2 diabetes. We aimed to investigate gut hormones, lipids, and insulin regulation in response to a meal test in HNF1α defect carriers (MODY3) compared to non-diabetic subjects (controls) and type 2 diabetes (T2D). Methods We administered a standardized liquid meal to each participant. Over 6 hours, we measured post-meal responses of insulin regulation (blood glucose, c-peptide, insulin), gut hormones (ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) and lipids (non-esterified fatty acids [NEFA] and triglycerides). Results We found that MODY3 participants had lower insulin secretion indices than controls and T2D participants, showing the expected β-cell defect. MODY3 had similar glycated hemoglobin levels (HbA1c median [IQR]: 6.5 [5.6–7.6]%) compared to T2D (median: 6.6 [6.2–6.9]%; P<0.05). MODY3 had greater insulin sensitivity (Matsuda index: 71.9 [29.6; 125.5]) than T2D (3.2 [4.0; 6.0]; P<0.05). MODY3 experienced a larger decrease in the ratio of NEFA to insulin (NEFA 30–0 / insulin 30–0: -39 [-78; -30] x104) in the early post-prandial period (0–30 minutes) compared to controls and to T2D (-2.0 [-0.6; -6.4] x104; P<0.05). MODY3 had lower fasting (0.66 [0.46; 1.2] mM) and post-meal triglycerides levels compared to T2D (fasting: 2.3 [1.7; 2.7] mM; P<0.05). We did not detect significant post-meal differences in ghrelin and incretins between MODY3 and other groups. Conclusion In response to a standard meal test, MODY3 showed greater early post-prandial NEFA diminution in response to relatively low early insulin secretion, and they maintained very low post-prandial triglycerides levels. PMID:28493909

A 70% Ethanol Extract of Mistletoe Rich in Betulin, Betulinic Acid, and Oleanolic Acid Potentiated β-Cell Function and Mass and Enhanced Hepatic Insulin Sensitivity

PubMed Central

Ko, Byoung-Seob; Kang, Suna; Moon, Bo Reum; Ryuk, Jin Ah; Park, Sunmin

2016-01-01

We investigated that the long-term consumption of the water (KME-W) and 70% ethanol (KME-E) mistletoe extracts had antidiabetic activities in partial pancreatectomized (Px) rats. Px rats were provided with a high-fat diet containing 0.6% KME-E, 0.6% KME-W, and 0.6% dextrin (control) for 8 weeks. As normal-control, Sham-operated rats were provided with 0.6% dextrin. In cell-based studies, the effects of its main terpenoids (betulin, betulinic acid, and oleanolic acid) on glucose metabolism were measured. Both KME-W and KME-E decreased epididymal fat mass by increasing fat oxidation in diabetic rats. KME-E but not KME-W exhibited greater potentiation of first-phase insulin secretion than the Px-control in a hyperglycemic clamp. KME-E also made β-cell mass greater than the control by increasing β-cell proliferation and decreasing its apoptosis. In a euglycemic-hyperinsulinemic clamp, whole-body glucose infusion rate and hepatic glucose output increased with potentiating hepatic insulin signaling in the following order: Px-control, KME-W, KME-E, and normal-control. Betulin potentiated insulin-stimulated glucose uptake via increased PPAR-γ activity and insulin signaling in 3T3-L1 adipocytes, whereas oleanolic acid enhanced glucose-stimulated insulin secretion and cell proliferation in insulinoma cells. In conclusion, KME-E prevented the deterioration of glucose metabolism in diabetic rats more effectively than KME-W and KME-E can be a better therapeutic agent for type 2 diabetes than KME-W. PMID:26884795

Increased CD19+CD24+CD27+ B regulatory cells are associated with insulin resistance in patients with type I Hashimoto's thyroiditis.

PubMed

Yang, Min; Du, Changji; Wang, Yinping; Liu, Jun

2017-06-01

Hashimoto's thyroiditis (HT) is characterized by dysregulated immune responses and is commonly associated with insulin resistance. However, the mechanism of insulin resistance in HT remains to be fully elucidated. The aim of the present study was to investigate the correlation between the percentage of B regulatory lymphocytes (Bregs) and insulin resistance in patients with HT but with normal thyroid function (type I). A total of 59 patients with type I HT and 38 healthy volunteers were enrolled in the study. An oral glucose tolerance test was performed to measure insulin secretion and assess β‑cell functions. Flow cytometry was performed to examine the percentages of lymphocyte populations. The patients with HT exhibited normal fasting and postprandial glucose and fasting insulin secretion, but increased secretion of early‑phase and total insulin. The patients with HT also had insufficient β‑cell compensation for insulin resistance, indicated by a reduced disposition index, in the fasting state. An elevation in the percentage of CD19+CD24+CD27+ Bregs was also observed, which correlated positively with insulin secretion and insulin resistance in the fasting state. The patients with type I HT had postprandial insulin resistance and insufficient β‑cell compensation for fasting insulin resistance. Therefore, the increase in CD19+CD24+CD27+ Bregs was closely associated with fasting insulin secretion. These results provide novel insight into the mechanism of insulin resistance in HT.

Mechanism of hyperinsulinemia after reticuloendothelial system phagocytosis.

PubMed

Filkins, J P; Yelich, M R

1982-02-01

Endocytic loading of the reticuloendothelial system (RES) results in acute hyperinsulinemia and functional hyperinsulinism. Colloidal carbon blockade of the RES in rats resulted in elevations of both portal vein and systemic serum immunoreactive insulin and increases in the hepatic portal vein insulin glucose ratios. Two mechanisms for the hyperinsulinemia were evaluated: 1) decreased removal of insulin by the postendocytic liver and 2) increased secretion of insulin by the isolated perfused pancreas. Colloidal carbon blockade did not alter removal of 125I-insulin as evaluated in the isolated perfused rat liver. Pancreases from postendocytic donor rats when perfused according to the technique of Grodsky manifested enhanced insulin secretion. Macrophage culture-conditioned media enhanced glucose-mediated insulin secretion both as assayed in vivo and in the isolated perfused rat pancreas. The data suggest that postendocytic activated macrophages secrete a monokine that alters insulin release and thus produces the hyperinsulinemia of RES blockade. The acronym MIRA for macrophage insulin-releasing activity is proposed for the monokine.

Importance of NADPH oxidase-mediated redox signaling in the detrimental effect of CRP on pancreatic insulin secretion.

PubMed

Chan, Pei-Chi; Wang, Ya-Chin; Chen, Yi-Ling; Hsu, Wan-Ning; Tian, Yu-Feng; Hsieh, Po-Shiuan

2017-11-01

Elevations in C-reactive protein (CRP) levels are positively correlated with the progress of type 2 diabetes mellitus. However, the effect of CRP on pancreatic insulin secretion is unknown. Here, we showed that purified human CRP impaired insulin secretion in isolated mouse islets and NIT-1 insulin-secreting cells in dose- and time-dependent manners. CRP increased NADPH oxidase-mediated ROS (reactive oxygen species) production, which simultaneously promoted the production of nitrotyrosine (an indicator of RNS, reactive nitrogen species) and TNFα, to diminish cell viability, insulin secretion in islets and insulin-secreting cells. These CRP-mediated detrimental effects on cell viability and insulin secretion were significantly reversed by adding NAC (a potent antioxidant), apocynin (a selective NADPH oxidase inhibitor), L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor), aminoguanidine (a selective iNOS inhibitor), PDTC (a selective NFκB inhibitor) or Enbrel (an anti-TNFα fusion protein). However, CRP-induced ROS production failed to change after adding L-NAME, aminoguanidine or PDTC. In isolated islets and NIT-1 cells, the elevated nitrotyrosine contents by CRP pretreatment were significantly suppressed by adding L-NAME but not PDTC. Conversely, CRP-induced increases in TNF-α production were significantly reversed by administration of PDTC but not L-NAME. In addition, wild-type mice treated with purified human CRP showed significant decreases in the insulin secretion index (HOMA-β cells) and the insulin stimulation index in isolated islets that were reversed by the addition of L-NAME, aminoguanidine or NAC. It is suggested that CRP-activated NADPH-oxidase redox signaling triggers iNOS-mediated RNS and NFκB-mediated proinflammatory cytokine production to cause β cell damage in state of inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Insulin hypersecretion together with high luteinizing hormone concentration augments androgen secretion in oral glucose tolerance test in women with polycystic ovarian disease.

PubMed

Anttila, L; Koskinen, P; Jaatinen, T A; Erkkola, R; Irjala, K; Ruutiainen, K

1993-08-01

Female hyperandrogenism is often associated with hyperinsulinaemia and insulin resistance. We evaluated the hormone responses in an oral glucose tolerance test to investigate the interactions of gonadotrophins, insulin, C-peptide and androgens in women with polycystic ovarian disease (PCOD). In 28 patients with ultrasonographically diagnosed PCOD, hyperinsulinaemia and insulin resistance were mainly associated with obesity. Both basal and cumulative sum of insulin to C-peptide ratios were high in obese subjects, suggesting decreasing hepatic removal of insulin caused by obesity. Nevertheless, in some lean PCOD women, despite normal fasting insulin concentrations, insulin hypersecretion existed. The mean concentration of testosterone decreased significantly during the oral glucose tolerance test both in PCOD and control women, and of androstenedione in the PCOD patients only. However, an increase in androgen responses was found in a subgroup of PCOD patients, who had both elevated luteinizing hormone (LH) concentrations and hyperinsulinaemic response to oral glucose. In the remaining PCOD patients an inverse correlation between LH and insulin was found. The patients with hyperinsulinaemia together with LH hypersecretion may represent a subgroup of PCOD with deranged regulation of androgen secretion.

[Secretion of growth hormone in hyperthyroidism].

PubMed

Hervás, F; Morreale de Escobar, G; Escobar Del Rey, F; Pozuelo, V

1976-01-01

The authors studied growth hormone (GH) secretion in a group of adult controls and another group of hyperthyroid patients after stimulation with intravenous insulin-induced (0,1 IU/kg) hypoglycemia, aiming to clear out the problem of discrepancies in literature concerning GH secretion in hyperthyroidism. They concluded that in this syndrome, GH levels are significantly higher than those of controls. The GH releasing response is normal, though it could be expected to be decreased due to decreased pituitary GH contents as a result of permanent somatotrophic cell stimulation.

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. Copyright © 2012 Elsevier Inc. All rights reserved.

Mechanism of action of hypoglycemic effects of an intestine-specific inhibitor of microsomal triglyceride transfer protein (MTP) in obese rats.

PubMed

Sakata, Shohei; Katsumi, Sohei; Mera, Yasuko; Kuroki, Yukiharu; Nashida, Reiko; Kakutani, Makoto; Ohta, Takeshi

2015-01-01

Diminished insulin sensitivity in the peripheral tissues and failure of pancreatic beta cells to secrete insulin are known major determinants of type 2 diabetes mellitus. JTT-130, an intestine-specific microsomal transfer protein inhibitor, has been shown to suppress high fat-induced obesity and ameliorate impaired glucose tolerance while enhancing glucagon-like peptide-1 (GLP-1) secretion. We investigated the effects of JTT-130 on glucose metabolism and elucidated the mechanism of action, direct effects on insulin sensitivity and glucose-stimulated insulin secretion in a high fat diet-induced obesity rat model. Male Sprague Dawley rats fed a high-fat diet were treated with a single administration of JTT-130. Glucose tolerance, hyperglycemic clamp and hyperinsulinemic-euglycemic testing were performed to assess effects on insulin sensitivity and glucose-stimulated insulin secretion, respectively. Plasma GLP-1 and tissue triglyceride content were also determined under the same conditions. A single administration of JTT-130 suppressed plasma glucose elevations after oral glucose loading and increased the disposition index while elevating GLP-1. JTT-130 also enhanced glucose-stimulated insulin secretion in hyperglycemic clamp tests, whereas increased insulin sensitivity was observed in hyperinsulinemic-euglycemic clamp tests. Single-dose administration of JTT-130 decreased lipid content in the liver and skeletal muscle. JTT-130 demonstrated acute and direct hypoglycemic effects by enhancing insulin secretion and/or insulin sensitivity. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function.

PubMed

Lortz, S; Lenzen, S; Mehmeti, I

2015-08-01

Oxidative folding of nascent proteins in the endoplasmic reticulum (ER), catalysed by one or more members of the protein disulfide isomerase family and the sulfhydryl oxidase ER oxidoreductin 1 (ERO1), is accompanied by generation of hydrogen peroxide (H2O2). Because of the high rate of insulin biosynthesis and the low expression of H2O2-inactivating enzymes in pancreatic β cells, it has been proposed that the luminal H2O2 concentration might be very high. As the role of this H2O2 in ER stress and proinsulin processing is still unsolved, an ER-targeted and luminal-active catalase variant, ER-Catalase N244, was expressed in insulin-secreting INS-1E cells. In these cells, the influence of ER-specific H2O2 removal on cytokine-mediated cytotoxicity and ER stress, insulin gene expression, insulin content and secretion was analysed. The expression of ER-Catalase N244 reduced the toxicity of exogenously added H2O2 significantly with a threefold increase of the EC50 value for H2O2. However, the expression of cytokine-induced ER stress genes and viability after incubation with β cell toxic cytokines (IL1β alone or together with TNFα+IFNγ) was not affected by ER-Catalase N244. In control and ER-Catalase N244 expressing cells, insulin secretion and proinsulin content was identical, while removal of luminal H2O2 reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H2O2 toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H2O2 in the ER in spite of a reduced insulin transcription and processing. © 2015 Society for Endocrinology.

A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells

PubMed Central

Saxena, Pratik; Heng, Boon Chin; Bai, Peng; Folcher, Marc; Zulewski, Henryk; Fussenegger, Martin

2016-01-01

Synthetic biology has advanced the design of standardized transcription control devices that programme cellular behaviour. By coupling synthetic signalling cascade- and transcription factor-based gene switches with reverse and differential sensitivity to the licensed food additive vanillic acid, we designed a synthetic lineage-control network combining vanillic acid-triggered mutually exclusive expression switches for the transcription factors Ngn3 (neurogenin 3; OFF-ON-OFF) and Pdx1 (pancreatic and duodenal homeobox 1; ON-OFF-ON) with the concomitant induction of MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A; OFF-ON). This designer network consisting of different network topologies orchestrating the timely control of transgenic and genomic Ngn3, Pdx1 and MafA variants is able to programme human induced pluripotent stem cells (hIPSCs)-derived pancreatic progenitor cells into glucose-sensitive insulin-secreting beta-like cells, whose glucose-stimulated insulin-release dynamics are comparable to human pancreatic islets. Synthetic lineage-control networks may provide the missing link to genetically programme somatic cells into autologous cell phenotypes for regenerative medicine. PMID:27063289

Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

PubMed

Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

2015-11-01

Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Elevated Glucose Oxidation, Reduced Insulin Secretion, and a Fatty Heart May Be Protective Adaptions in Ischemic CAD.

PubMed

Hannukainen, J C; Lautamäki, R; Mari, A; Pärkkä, J P; Bucci, M; Guzzardi, M A; Kajander, S; Tuokkola, T; Knuuti, J; Iozzo, P

2016-07-01

Insulin resistance, β-cell dysfunction, and ectopic fat deposition have been implicated in the pathogenesis of coronary artery disease (CAD) and type 2 diabetes, which is common in CAD patients. We investigated whether CAD is an independent predictor of these metabolic abnormalities and whether this interaction is influenced by superimposed myocardial ischemia. We studied CAD patients with (n = 8) and without (n = 14) myocardial ischemia and eight non-CAD controls. Insulin sensitivity and secretion and substrate oxidation were measured during fasting and oral glucose tolerance testing. We used magnetic resonance imaging/spectroscopy, positron emission and computerized tomography to characterize CAD, cardiac function, pericardial and abdominal adipose tissue, and myocardial, liver, and pancreatic triglyceride contents. Ischemic CAD was characterized by elevated oxidative glucose metabolism and a proportional decline in β-cell insulin secretion and reduction in lipid oxidation. Cardiac function was preserved in CAD groups, whereas cardiac fat depots were elevated in ischemic CAD compared to non-CAD subjects. Liver and pancreatic fat contents were similar in all groups and related with surrounding adipose masses or systemic insulin sensitivity. In ischemic CAD patients, glucose oxidation is enhanced and correlates inversely with insulin secretion. This can be seen as a mechanism to prevent glucose lowering because glucose is required in oxygen-deprived tissues. On the other hand, the accumulation of cardiac triglycerides may be a physiological adaptation to the limited fatty acid oxidative capacity. Our results underscore the urgent need of clinical trials that define the optimal/safest glycemic range in situations of myocardial ischemia.

Elevated Glucose Oxidation, Reduced Insulin Secretion, and a Fatty Heart May Be Protective Adaptions in Ischemic CAD

PubMed Central

Hannukainen, J. C.; Lautamäki, R.; Mari, A.; Pärkkä, J. P.; Bucci, M.; Guzzardi, M. A.; Kajander, S.; Tuokkola, T.; Knuuti, J.

2016-01-01

Background: Insulin resistance, β-cell dysfunction, and ectopic fat deposition have been implicated in the pathogenesis of coronary artery disease (CAD) and type 2 diabetes, which is common in CAD patients. We investigated whether CAD is an independent predictor of these metabolic abnormalities and whether this interaction is influenced by superimposed myocardial ischemia. Methods and Results: We studied CAD patients with (n = 8) and without (n = 14) myocardial ischemia and eight non-CAD controls. Insulin sensitivity and secretion and substrate oxidation were measured during fasting and oral glucose tolerance testing. We used magnetic resonance imaging/spectroscopy, positron emission and computerized tomography to characterize CAD, cardiac function, pericardial and abdominal adipose tissue, and myocardial, liver, and pancreatic triglyceride contents. Ischemic CAD was characterized by elevated oxidative glucose metabolism and a proportional decline in β-cell insulin secretion and reduction in lipid oxidation. Cardiac function was preserved in CAD groups, whereas cardiac fat depots were elevated in ischemic CAD compared to non-CAD subjects. Liver and pancreatic fat contents were similar in all groups and related with surrounding adipose masses or systemic insulin sensitivity. Conclusions: In ischemic CAD patients, glucose oxidation is enhanced and correlates inversely with insulin secretion. This can be seen as a mechanism to prevent glucose lowering because glucose is required in oxygen-deprived tissues. On the other hand, the accumulation of cardiac triglycerides may be a physiological adaptation to the limited fatty acid oxidative capacity. Our results underscore the urgent need of clinical trials that define the optimal/safest glycemic range in situations of myocardial ischemia. PMID:27045985

Insulin: its Role in the Central Control of Reproduction

PubMed Central

Sliwowska, Joanna H.; Fergani, Chrysanthi; Gawałek, Monika; Skowronska, Bogda; Fichna, Piotr; Lehman, Michael N.

2014-01-01

Insulin has long been recognized as a key regulator of energy homeostasis via its actions at the level of the brain, but in addition, plays a role in regulating neural control of reproduction. In this review, we consider and compare evidence from animal models demonstrating a role for insulin for physiological control of reproduction by effects on GnRH/LH secretion. We also review the role that insulin plays in prenatal programming of adult reproduction, and consider specific candidate neurons in the adult hypothalamus by which insulin may act to regulate reproductive function. Finally, we review clinical evidence of the role that insulin may play in adult human fertility and reproductive disorders. Overall, while insulin appears to have a significant impact on reproductive neuroendocrine function, there are many unanswered questions regarding its precise sites and mechanisms of action, and their impact on developing and adult reproductive neuroendocrine function. PMID:24874777

Insulin: its role in the central control of reproduction.

PubMed

Sliwowska, Joanna H; Fergani, Chrysanthi; Gawałek, Monika; Skowronska, Bogda; Fichna, Piotr; Lehman, Michael N

2014-06-22

Insulin has long been recognized as a key regulator of energy homeostasis via its actions at the level of the brain, but in addition, plays a role in regulating neural control of reproduction. In this review, we consider and compare evidence from animal models demonstrating a role for insulin for physiological control of reproduction by effects on GnRH/LH secretion. We also review the role that insulin plays in prenatal programming of adult reproduction, and consider specific candidate neurons in the adult hypothalamus by which insulin may act to regulate reproductive function. Finally, we review clinical evidence of the role that insulin may play in adult human fertility and reproductive disorders. Overall, while insulin appears to have a significant impact on reproductive neuroendocrine function, there are many unanswered questions regarding its precise sites and mechanisms of action, and their impact on developing and adult reproductive neuroendocrine function. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison of Regulation Mechanisms of Five Mulberry Ingredients on Insulin Secretion under Oxidative Stress.

PubMed

Zheng, Yun-Chong; He, Hao; Wei, Xing; Ge, Sheng; Lu, Yan-Hua

2016-11-23

The effects of mulberry ingredients including 1-deoxynojrimycin (DNJ), resveratrol (RES), oxyresveratrol (OXY), cyanidin-3-glucoside (C3G), and cyanidin-3-rutinoside (C3R) on insulin secretion under oxidative stress were investigated. The results revealed that they had distinct effects on insulin secretion in H 2 O 2 -induced MIN 6 cells, especially DNJ, C3G, and C3R, while RES and OXY showed modest effects in low dose (12.5 μM). The mechanisms were demonstrated in signal pathway that after treatment with DNJ, C3G, and C3R, the expressions of glucokinase (GK) were up-regulated, leading to intracellular ATP accumulation and insulin secretion. They also bound to glucagon-like peptide-1 receptor (GLP-1R), improved GLP-1R, duodenal homeobox factor-1 (PDX-1) expression, and stimulated insulin secretion. Moreover, ROS production was inhibited, followed by a decreasing apoptosis rate, while RES and OXY accelerated the apoptosis at high dose (50 μM). This work expounded the potential mechanisms of mulberry ingredients on insulin secretion, indicating the potential application in the intervention against hyperglycemia.

Effect of oral glucose administration on rebound growth hormone release in normal and obese women: the role of adiposity, insulin sensitivity and ghrelin.

PubMed

Pena-Bello, Lara; Pertega-Diaz, Sonia; Outeiriño-Blanco, Elena; Garcia-Buela, Jesus; Tovar, Sulay; Sangiao-Alvarellos, Susana; Dieguez, Carlos; Cordido, Fernando

2015-01-01

Metabolic substrates and nutritional status play a major role in growth hormone (GH) secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG) administration in normal and obese patients is a pending issue. The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity. We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC) were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed. The AUC of GH (μg/L•min) was lower in obese (249.8±41.8) than in healthy women (490.4±74.6), P=0.001. The AUC of total ghrelin (pg/mL•min) was lower in obese (240995.5±11094.2) than in healthy women (340797.5±37757.5), P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH.

Effect of Oral Glucose Administration on Rebound Growth Hormone Release in Normal and Obese Women: The Role of Adiposity, Insulin Sensitivity and Ghrelin

PubMed Central

Pena-Bello, Lara; Pertega-Diaz, Sonia; Outeiriño-Blanco, Elena; Garcia-Buela, Jesus; Tovar, Sulay; Sangiao-Alvarellos, Susana; Dieguez, Carlos; Cordido, Fernando

2015-01-01

Context Metabolic substrates and nutritional status play a major role in growth hormone (GH) secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG) administration in normal and obese patients is a pending issue. Objective The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity. Participants and Methods We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC) were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed. Results The AUC of GH (μg/L•min) was lower in obese (249.8±41.8) than in healthy women (490.4±74.6), P=0.001. The AUC of total ghrelin (pg/mL•min) was lower in obese (240995.5±11094.2) than in healthy women (340797.5±37757.5), P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH. PMID:25782001

Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications.

PubMed

Charmandari, Evangelia; Weise, Martina; Bornstein, Stefan R; Eisenhofer, Graeme; Keil, Margaret F; Chrousos, George P; Merke, Deborah P

2002-05-01

Leptin is secreted by the white adipose tissue and modulates energy homeostasis. Nutritional, neural, neuroendocrine, paracrine, and autocrine factors, including the sympathetic nervous system and the adrenal medulla, have been implicated in the regulation of leptin secretion. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in cortisol and aldosterone secretion, impaired development and function of the adrenal medulla, and adrenal hyperandrogenism. To examine leptin secretion in patients with classic CAH in relation to their adrenomedullary function and insulin and androgen secretion, we studied 18 children with classic CAH (12 boys and 6 girls; age range 2-12 yr) and 28 normal children (16 boys and 12 girls; age range 5-12 yr) matched for body mass index (BMI). Serum leptin concentrations were significantly higher in patients with CAH than in control subjects (8.1 +/- 2.0 vs. 2.5 +/- 0.6 ng/ml, P = 0.01), and this difference persisted when leptin values were corrected for BMI. When compared with their normal counterparts, children with CAH had significantly lower plasma epinephrine (7.1 +/- 1.3 vs. 50.0 +/- 4.2, P < 0.001) and free metanephrine concentrations (18.4 +/- 2.4 vs. 46.5 +/- 4.0, P < 0.001) and higher fasting serum insulin (10.6 +/- 1.4 vs. 3.2 +/- 0.2 microU/ml, P < 0.001) and testosterone (23.7 +/- 5.3 vs. 4.6 +/- 0.5 ng/dl, P = 0.003) concentrations. Insulin resistance determined by the homeostasis model assessment method was significantly greater in children with classic CAH than in normal children (2.2 +/- 0.3 vs. 0.7 +/- 0.04, P < 0.001). Leptin concentrations were significantly and negatively correlated with epinephrine (r = -0.50, P = 0.001) and free metanephrine (r = -0.48, P = 0.002) concentrations. Stepwise multiple linear regression analysis indicated that serum leptin concentrations were best predicted by BMI in both patients and controls. Gender predicted serum leptin concentrations in controls but not in patients with classic CAH. No association was found between the dose of hydrocortisone and serum leptin (r = -0.17, P = 0.5) or insulin (r = 0.24, P = 0.3) concentrations in children with CAH. Our findings indicate that children with classic CAH have elevated fasting serum leptin and insulin concentrations, and insulin resistance. These most likely reflect differences in long-term adrenomedullary hypofunction and glucocorticoid therapy. Elevated leptin and insulin concentrations in patients with CAH may further enhance adrenal and ovarian androgen production, decrease the therapeutic efficacy of glucocorticoids, and contribute to later development of polycystic ovary syndrome and/or the metabolic syndrome and their complications.

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

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

Takahashi, Iwao; Noguchi, Naoya; Nata, Koji

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 glucosemore » 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.« less

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

PubMed

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

2012-04-01

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

Effects of D-phenylalanine-derivative hypoglycemic agent A-4166 on pancreatic alpha- and beta-cells: comparative study with glibenclamide.

PubMed

Hirose, H; Maruyama, H; Seto, Y; Ito, K; Fujita, T; Dan, K; Kanda, N; Saruta, T; Kato, R

1995-03-01

We have reported that N-[(trans-4-isopropyl-cyclohexyl)-carbonyl]-D-phenylalanine (A-4166) stimulates insulin secretion in animal studies. To further elucidate the mechanisms underlying the actions of this agent, we investigated the effects of A-4166 on insulin and glucagon secretion with or without diazoxide, an ATP-sensitive potassium channel opener, using isolated perfused rat pancreas preparations, and compared the results with those of glibenclamide. Both 30 mumol/l A-4166 and 3 mumol/l glibenclamide significantly stimulated insulin secretion and reduced glucagon secretion to similar levels at a glucose concentration of 5.6 mmol/l (p < 0.01 for both vs. basal levels). After infusion of A-4166 was stopped, insulin levels promptly returned to the basal values, while insulin levels increased further even after discontinuation of glibenclamide. Furthermore, 100 mumol/l diazoxide significantly inhibited the insulin-stimulatory effects of both 30 mumol/l A-4166 and 3 mumol/l glibenclamide (p < 0.05 and p < 0.01, respectively). However, the effects of diazoxide on glucagon secretion differed between the two groups; 30 mumol/l A-4166 produced a transient increase in glucagon secretion (p < 0.05 vs. basal levels) but 3 mumol/l glibenclamide suppressed glucagon secretion further (p < 0.01 vs. without diazoxide) with concomitant administration of 100 mumol/l diazoxide. These findings suggest that A-4166 directly stimulates insulin secretion, at least in part, through mechanisms resembling those of sulfonylurea, but exerts different effect on glucagon secretion in isolated perfused rat pancreas.

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

Adipose differentiation-related protein regulates lipids and insulin in pancreatic islets

PubMed Central

Faleck, D. M.; Ali, K.; Roat, R.; Graham, M. J.; Crooke, R. M.; Battisti, R.; Garcia, E.; Ahima, R. S.

2010-01-01

The excess accumulation of lipids in islets is thought to contribute to the development of diabetes in obesity by impairing β-cell function. However, lipids also serve a nutrient function in islets, and fatty acids acutely increase insulin secretion. A better understanding of lipid metabolism in islets will shed light on complex effects of lipids on β-cells. Adipose differentiation-related protein (ADFP) is localized on the surface of lipid droplets in a wide range of cells and plays an important role in intracellular lipid metabolism. We found that ADFP was highly expressed in murine β-cells. Moreover, islet ADFP was increased in mice on a high-fat diet (3.5-fold of control) and after fasting (2.5-fold of control), revealing dynamic changes in ADFP in response to metabolic cues. ADFP expression was also increased by addition of fatty acids in human islets. The downregulation of ADFP in MIN6 cells by antisense oligonucleotide (ASO) suppressed the accumulation of triglycerides upon fatty acid loading (56% of control) along with a reduction in the mRNA levels of lipogenic genes such as diacylglycerol O-acyltransferase-2 and fatty acid synthase. Fatty acid uptake, oxidation, and lipolysis were also reduced by downregulation of ADFP. Moreover, the reduction of ADFP impaired the ability of palmitate to increase insulin secretion. These findings demonstrate that ADFP is important in regulation of lipid metabolism and insulin secretion in β-cells. PMID:20484013

Effects of phenylbutazone on glucose tolerance and on secretion of insulin in healthy geldings.

PubMed

Zicker, S C; Brumbaugh, G W

1989-05-01

The effect of phenylbutazone (4.4 mg/kg of body weight, IV, q 24 h, for 5 days) on glucose tolerance and on secretion of insulin in 6 healthy geldings was determined. Phenylbutazone significantly lowered fasting concentrations of glucose in plasma but did not significantly change the concentration of insulin in serum. There was no significant effect of phenylbutazone on glucose tolerance, on secretion of insulin, or on the area under the insulin/glucose ratio vs time curve in healthy geldings, as determined by paired t test analysis.

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

Cline, Gary W., E-mail: gary.cline@yale.edu; Department of Surgery, University of Minnesota-Twin Cities, Minneapolis, MN 55455; Pongratz, Rebecca L.

Highlights: Black-Right-Pointing-Pointer We studied media effects on mechanisms of insulin secretion of INS-1 cells. Black-Right-Pointing-Pointer Insulin secretion was higher in DMEM than KRB despite identical ATP synthesis rates. Black-Right-Pointing-Pointer Insulin secretion rates correlated with rates of anaplerosis and TCA cycle. Black-Right-Pointing-Pointer Mitochondria metabolism and substrate cycles augment secretion signal of ATP. -- Abstract: Mechanistic models of glucose stimulated insulin secretion (GSIS) established in minimal media in vitro, may not accurately describe the complexity of coupling metabolism with insulin secretion that occurs in vivo. As a first approximation, we have evaluated metabolic pathways in a typical growth media, DMEM as amore » surrogate in vivo medium, for comparison to metabolic fluxes observed under the typical experimental conditions using the simple salt-buffer of KRB. Changes in metabolism in response to glucose and amino acids and coupling to insulin secretion were measured in INS-1 832/13 cells. Media effects on mitochondrial function and the coupling efficiency of oxidative phosphorylation were determined by fluorometrically measured oxygen consumption rates (OCRs) combined with {sup 31}P NMR measured rates of ATP synthesis. Substrate preferences and pathways into the TCA cycle, and the synthesis of mitochondrial 2nd messengers by anaplerosis were determined by {sup 13}C NMR isotopomer analysis of the fate of [U-{sup 13}C] glucose metabolism. Despite similar incremental increases in insulin secretion, the changes of OCR in response to increasing glucose from 2.5 to 15 mM were blunted in DMEM relative to KRB. Basal and stimulated rates of insulin secretion rates were consistently higher in DMEM, while ATP synthesis rates were identical in both DMEM and KRB, suggesting greater mitochondrial uncoupling in DMEM. The relative rates of anaplerosis, and hence synthesis and export of 2nd messengers from the mitochondria were found to be similar in DMEM to those in KRB. And, the correlation of total PC flux with insulin secretion rates in DMEM was found to be congruous with the correlation in KRB. Together, these results suggest that signaling mechanisms associated with both TCA cycle flux and with anaplerotic flux, but not ATP production, may be responsible for the enhanced rates of insulin secretion in more complex, and physiologically-relevant media.« less

Pharmacokinetic and Pharmacodynamic Properties of a Novel Inhaled Insulin

PubMed Central

Heinemann, Lutz; Baughman, Robert; Boss, Anders; Hompesch, Marcus

2016-01-01

Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not able to fully mimic the physiological time–action profile of endogenously secreted insulin after a meal. The delayed onset of metabolic action and prolonged period of effect induce the risk of postprandial hyperglycemia and late postprandial hypoglycemia. A number of alternative routes of insulin administration have been investigated over time in an attempt to overcome the limitations associated with subcutaneous administration and to provide an improved time–action insulin profile more closely simulating physiological prandial insulin release. Among these, pulmonary insulin delivery has shown the most promise. Technosphere® Inhaled Insulin (TI) is a rapid-acting inhaled human insulin recently approved by the FDA for prandial insulin therapy. In this article we discuss the pharmacokinetic and pharmacodynamic properties of TI, and, based on key studies performed during its clinical development, the implications for improved postprandial glucose control. PMID:27378794

Stress-induced dissociations between intracellular calcium signaling and insulin secretion in pancreatic islets.

PubMed

Qureshi, Farhan M; Dejene, Eden A; Corbin, Kathryn L; Nunemaker, Craig S

2015-05-01

In healthy pancreatic islets, glucose-stimulated changes in intracellular calcium ([Ca(2+)]i) provide a reasonable reflection of the patterns and relative amounts of insulin secretion. We report that [Ca(2+)]i in islets under stress, however, dissociates with insulin release in different ways for different stressors. Islets were exposed for 48h to a variety of stressors: cytokines (low-grade inflammation), 28mM glucose (28G, glucotoxicity), free fatty acids (FFAs, lipotoxicity), thapsigargin (ER stress), or rotenone (mitochondrial stress). We then measured [Ca(2+)]i and insulin release in parallel studies. Islets exposed to all stressors except rotenone displayed significantly elevated [Ca(2+)]i in low glucose, however, increased insulin secretion was only observed for 28G due to increased nifedipine-sensitive calcium-channel flux. Following 3-11mM glucose stimulation, all stressors substantially reduced the peak glucose-stimulated [Ca(2+)]i response (first phase). Thapsigargin and cytokines also substantially impacted aspects of calcium influx and ER calcium handling. Stressors did not significantly impact insulin secretion in 11mM glucose for any stressor, although FFAs showed a borderline reduction, which contributed to a significant decrease in the stimulation index (11:3mM glucose) observed for FFAs and also for 28G. We also clamped [Ca(2+)]i using 30mM KCl+250μM diazoxide to test the amplifying pathway. Only rotenone-treated islets showed a robust increase in 3-11mM glucose-stimulated insulin secretion under clamped conditions, suggesting that low-level mitochondrial stress might activate the metabolic amplifying pathway. We conclude that different stressors dissociate [Ca(2+)]i from insulin secretion differently: ER stressors (thapsigargin, cytokines) primarily affect [Ca(2+)]i but not conventional insulin secretion and 'metabolic' stressors (FFAs, 28G, rotenone) impacted insulin secretion. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells*

PubMed Central

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.

2015-01-01

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 Ca2+ 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. PMID:26272612

Modulation of insulin secretion by fatty acyl analogs.

PubMed

Las, Guy; Mayorek, Nina; Dickstein, Kobie; Bar-Tana, Jacob

2006-12-01

The secretagogue, the incretin-like, and the suppressive activities of long-chain fatty acids (LCFAs) in modulating insulin secretion in vivo and in cultured islets were simulated here by beta,beta'-tetramethyl-hexadecanedioic acid (M16) and alpha,alpha'-tetrachloro-tetradecanedioic acid (Cl-DICA). M16, but not Cl-DICA, serves as a substrate for ATP-dependent CoA thioesterification but is not further metabolized. M16, but not Cl-DICA, acted as a potent insulin secretagogue in islets cultured in basal but not high glucose. Short-term exposure to M16 or Cl-DICA resulted in activation of glucose- but not arginine-stimulated insulin secretion. Long-term exposure to M16, but not to Cl-DICA, resulted in suppression of glucose-, arginine-, and K(+)-stimulated insulin secretion; inhibition of glucose-induced proinsulin biosynthesis; and depletion of islets insulin. beta-Cell mass and islet ATP content remained unaffected. Hence, nonmetabolizable LCFA analogs may highlight discrete LCFA metabolites and pathways involved in modulating insulin secretion, which could be overlooked due to the rapid turnover of natural LCFA.

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

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

PubMed

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

2017-11-01

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

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

Novel actions of IGFBP-3 on intracellular signaling pathways of insulin-secreting cells

PubMed Central

Chen, Xiaoyan; Ferry, Robert J.

2011-01-01

Understanding mechanisms underlying apoptotic destruction of insulin-secreting cells is critical to validate therapeutic targets for type 1 diabetes mellitus. We recently reported insulin-like growth factor binding protein-3 (IGFBP-3) as a novel mediator of apoptosis in insulin-secreting cells. In light of emerging IGF-independent roles for IGFBP-3, we investigated the mechanisms underlying actions of the novel, recombinant human mutant G56G80G81-IGFBP-3, which lacks intrinsic IGF binding affinity. Using the rat insulinoma RINm5F cell line, we report the first studies in insulin-secreting cells that IGFBP-3 selectively suppresses multiple, key intracellular phosphorelays. By immunoblot, we demonstrate that G56G80G81-IGFBP-3 suppresses phosphorylation of c-raf-MEK-ERK pathway and p38 kinase in time-dependent and dose-dependent manners. SAPK/JNK signaling was unaffected. These data delineate several novel intracellular sites of action for IGFBP-3 in insulin-secreting cells. PMID:16275148

Cinnamon water extracts increase glucose uptake but inhibit adiponectin secretion in 3T3-L1 adipose cells.

PubMed

Roffey, Benjamin; Atwal, Avtar; Kubow, Stan

2006-08-01

The effects of three concentrations (0.2, 0.3, and 0.4 mg/mL) of a cinnamon extract (CE) (Cinnamomum zeylanicum) on glucose uptake and adiponectin secretion in 3T3-L1 adipocytes were examined in the presence and absence of 0.5 nM and 50 nM insulin. In the absence of insulin, adipocytes exposed to 0.2 mg/mL CE showed an approximate two-fold increase in glucose uptake relative to controls although glucose uptake was unaffected by the two higher concentrations of CE. No effect of CE on glucose uptake was noted in the presence of 0.5 nM insulin whereas the two highest concentrations (0.3 and 0.4 mg/mL) of CE showed a significant dose-dependent decrease in glucose uptake in the presence of 50 nM insulin. Treatment of the adipocytes with 50 nM wortmannin, an irreversible inhibitor of the p110 isoform of phosphoinositide 3'-kinase, was associated with complete inhibition of the stimulated glucose uptake induced by 0.2 mg/mL CE. Treatment of the adipocytes with 0.2 mg/mL CE was associated with an inhibition of adiponectin secretion to levels that were nondetectable. The present study indicates that although 0.2 mg/mL CE has insulin-mimetic action in 3T3-adipocytes in terms of glucose uptake, secretion of the antidiabetic hormone adiponectin is adversely affected.

Reproducible insulin secretion from isolated rat pancreas preparations using an organ bath.

PubMed

Morita, Asuka; Ouchi, Motoshi; Terada, Misao; Kon, Hiroe; Kishimoto, Satoko; Satoh, Keitaro; Otani, Naoyuki; Hayashi, Keitaro; Fujita, Tomoe; Inoue, Ken-Ichi; Anzai, Naohiko

2018-02-09

Diabetes mellitus is a lifestyle-related disease that is characterized by inappropriate or diminished insulin secretion. Ex vivo pharmacological studies of hypoglycemic agents are often conducted using perfused pancreatic preparations. Pancreas preparations for organ bath experiments do not require cannulation and are therefore less complex than isolated perfused pancreas preparations. However, previous research has generated almost no data on insulin secretion from pancreas preparations using organ bath preparations. The purpose of this study was to investigate the applicability of isolated rat pancreas preparations using the organ bath technique in the quantitative analysis of insulin secretion from β-cells. We found that insulin secretion significantly declined during incubation in the organ bath, whereas it was maintained in the presence of 1 µM GLP-1. Conversely, amylase secretion exhibited a modest increase during incubation and was not altered in the presence of GLP-1. These results demonstrate that the pancreatic organ bath preparation is a sensitive and reproducible method for the ex vivo assessment of the pharmacological properties of hypoglycemic agents.

Mitochondrial matrix pH controls oxidative phosphorylation and metabolism-secretion coupling in INS-1E clonal beta cells.

PubMed

Akhmedov, Dmitry; Braun, Matthias; Mataki, Chikage; Park, Kyu-Sang; Pozzan, Tullio; Schoonjans, Kristina; Rorsman, Patrik; Wollheim, Claes B; Wiederkehr, Andreas

2010-11-01

Glucose-evoked mitochondrial signals augment ATP synthesis in the pancreatic β cell. This activation of energy metabolism increases the cytosolic ATP/ADP ratio, which stimulates plasma membrane electrical activity and insulin granule exocytosis. We have recently demonstrated that matrix pH increases during nutrient stimulation of the pancreatic β cell. Here, we have tested whether mitochondrial matrix pH controls oxidative phosphorylation and metabolism-secretion coupling in the rat β-cell line INS-1E. Acidification of the mitochondrial matrix pH by nigericin blunted nutrient-dependent respiratory and ATP responses (continuously monitored in intact cells). Using electrophysiology and single cell imaging, we find that the associated defects in energy metabolism suppress glucose-stimulated plasma membrane electrical activity and cytosolic calcium transients. The same parameters were unaffected after direct stimulation of electrical activity with tolbutamide, which bypasses mitochondrial function. Furthermore, lowered matrix pH strongly inhibited sustained, but not first-phase, insulin secretion. Our results demonstrate that the matrix pH exerts a control function on oxidative phosphorylation in intact cells and that this mode of regulation is of physiological relevance for the generation of downstream signals leading to insulin granule exocytosis. We propose that matrix pH serves a novel signaling role in sustained cell activation.

Current trend in drug delivery considerations for subcutaneous insulin depots to treat diabetes.

PubMed

P V, Jayakrishnapillai; Nair, Shantikumar V; Kamalasanan, Kaladhar

2017-05-01

Diabetes mellitus (DM) is a metabolic disorder due to irregularities in glucose metabolism, as a result of insulin disregulation. Chronic DM (Type 1) is treated by daily insulin injections by subcutaneous route. Daily injections cause serious patient non-compliance and medication non-adherence. Insulin Depots (ID) are parenteral formulations designed to release the insulin over a specified period of time, to control the plasma blood glucose level for intended duration. Physiologically, pancreas produces and secretes insulin in basal and pulsatile mode into the blood. Delivery systems mimicking basal release profiles are known as open-loop systems and current marketed products are open-loop systems. Future trend in open-loop systems is to reduce the number of injections per week by enhancing duration of action, by modifying the depot properties. The next generation technologies are closed-loop systems that mimic the pulsatile mode of delivery by pancreas. In closed-loop systems insulin will be released in response to plasma glucose. This review focuses on future trend in open-loop systems; by understanding (a) the secretion of insulin from pancreas, (b) the insulin regulation normal and in DM, (c) insulin depots and (d) the recent progress in open-loop depot technology particularly with respect to nanosystems. Copyright © 2017 Elsevier B.V. All rights reserved.

Shared Genetic Control of Brain Activity During Sleep and Insulin Secretion: A Laboratory-Based Family Study.

PubMed

Morselli, Lisa L; Gamazon, Eric R; Tasali, Esra; Cox, Nancy J; Van Cauter, Eve; Davis, Lea K

2018-01-01

Over the past 20 years, a large body of experimental and epidemiologic evidence has linked sleep duration and quality to glucose homeostasis, although the mechanistic pathways remain unclear. The aim of the current study was to determine whether genetic variation influencing both sleep and glucose regulation could underlie their functional relationship. We hypothesized that the genetic regulation of electroencephalographic (EEG) activity during non-rapid eye movement sleep, a highly heritable trait with fingerprint reproducibility, is correlated with the genetic control of metabolic traits including insulin sensitivity and β-cell function. We tested our hypotheses through univariate and bivariate heritability analyses in a three-generation pedigree with in-depth phenotyping of both sleep EEG and metabolic traits in 48 family members. Our analyses accounted for age, sex, adiposity, and the use of psychoactive medications. In univariate analyses, we found significant heritability for measures of fasting insulin sensitivity and β-cell function, for time spent in slow-wave sleep, and for EEG spectral power in the delta, theta, and sigma ranges. Bivariate heritability analyses provided the first evidence for a shared genetic control of brain activity during deep sleep and fasting insulin secretion rate. © 2017 by the American Diabetes Association.

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

PubMed

Sharma, Geetanjali; Prossnitz, Eric R

2011-08-01

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

PubMed Central

Stassek, J.; Erdmann, J.; Ohnolz, F.; Berg, F. D.; Kiechle, M.; Seifert-Klauss, V.

2017-01-01

Introduction Known characteristics of patients with PCOS include infertility, menstrual disorders, hirsutism and also often insulin resistance. These symptoms increase with increasing body weight. In the LIPCOS study (Lifestyle Intervention for Patients with Polycystic Ovary Syndrome [PCOS]) long-term changes of the PCOS in dependence on pregnancy and parenthood were systematically assessed. In the framework of the LIPCOS study, PCOS patients were given a standardised carbohydrate-rich test meal in order to examine glucose homeostasis and insulin secretion. The results were compared with those of a eumenorrhoeic control group who all had corresponding BMI values and corresponding ages. Methods and Patients 41 PCOS patients (without diabetes) and 68 controls received a standardised carbohydrate-rich test meal (260 kcal, 62 % carbohydrates, 32 % fat, 6 % proteins) in order to generate a submaximal insulin and glucose stimulation. The values were determined at baseline and postprandial after 60, 120 and 180 minutes. In addition, the corresponding C-peptide levels were recorded. Results In the PCOS patients (n = 41), the insulin secretion test after a standardised test meal showed almost identical baseline and postprandial insulin levels when compared with those of the age- and BMI-matched eumenorrhoeic controls (n = 68). In the PCOS patients, the baseline and postprandial glucose levels were significantly elevated (92.88 ± 10.28 [PCOS] vs. 85.07 ± 9.42 mg/dL [controls]; p < 0.001) so was C-peptide (p < 0.025). Conclusions In the present study we have shown for the first time that, after consumption of a standardised test meal, PCOS patients formally exhibit a higher fasting insulin resistance than controls. In spite of the higher stimulated C-peptide levels, the insulin levels did not increase more strongly with increasing glucose levels than in controls which may be indicative of a higher insulin clearance in PCOS patients. PMID:28190890

Kir6.2 Variant E23K Increases ATP-Sensitive K+ Channel Activity and Is Associated With Impaired Insulin Release and Enhanced Insulin Sensitivity in Adults With Normal Glucose Tolerance

PubMed Central

Villareal, Dennis T.; Koster, Joseph C.; Robertson, Heather; Akrouh, Alejandro; Miyake, Kazuaki; Bell, Graeme I.; Patterson, Bruce W.; Nichols, Colin G.; Polonsky, Kenneth S.

2009-01-01

OBJECTIVE The E23K variant in the Kir6.2 subunit of the ATP-sensitive K+ channel (KATP channel) is associated with increased risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance. RESEARCH DESIGN AND METHODS Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance tests (OGTTs), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope–labeled tracer infusions to assess insulin secretion, action, and clearance. A total of 461 volunteers consecutively genotyped for the E23K variant also underwent OGTTs. Functional studies of the wild-type and E23K variant potassium channels were conducted. RESULTS Insulin secretory responses to oral and intravenous glucose were reduced by ∼40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The hyperinsulinemic-euglycemic clamp revealed that hepatic insulin sensitivity is ∼40% greater in subjects with the E23K variant, and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion. CONCLUSIONS The E23K variant leads to overactivity of the KATP channel, resulting in reduced insulin secretion. Initially, insulin sensitivity is enhanced, thereby maintaining normal glucose tolerance. Presumably, over time, as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in type 2 diabetes. PMID:19491206

Three-component homeostasis control

NASA Astrophysics Data System (ADS)

Xu, Jin; Hong, Hyunsuk; Jo, Junghyo

2014-03-01

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

Anchored phosphatases modulate glucose homeostasis

PubMed Central

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

2012-01-01

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

Glucose acutely decreases pH of secretory granules in mouse pancreatic islets. Mechanisms and influence on insulin secretion.

PubMed

Stiernet, Patrick; Guiot, Yves; Gilon, Patrick; Henquin, Jean-Claude

2006-08-04

Glucose-induced insulin secretion requires a rise in beta-cell cytosolic Ca2+ ([Ca2+]c) that triggers exocytosis and a mechanistically unexplained amplification of the action of [Ca2+]c. Insulin granules are kept acidic by luminal pumping of protons with simultaneous Cl- uptake to maintain electroneutrality. Experiments using patched, dialyzed beta-cells prompted the suggestion that acute granule acidification by glucose underlies amplification of insulin secretion. However, others found glucose to increase granular pH in intact islets. In this study, we measured islet granular pH with Lysosensor DND-160, a fluorescent dye that permits ratiometric determination of pH < 6 in acidic compartments. Stimulation of mouse islets with glucose reversibly decreased granular pH by mechanisms that are dependent on metabolism and Cl- ions but independent of changes in [Ca2+]c and protein kinase A or C activity. Granular pH was increased by concanamycin (blocker of the vesicular type H+-ATPase) > methylamine (weak base) > Cl- omission. Concanamycin and methylamine did not alter glucose-induced [Ca2+]c increase in islets but strongly inhibited the two phases of insulin secretion. Omission of Cl- did not affect the first phase but decreased the second phase of both [Ca2+]c and insulin responses. Neither experimental condition affected the [Ca2+]c rise induced by 30 mM KCl, but the insulin responses were inhibited by concanamycin > methylamine and not affected by Cl- omission. The amplification of insulin secretion by glucose was not suppressed. We conclude that an acidic granular pH is important for insulin secretion but that the acute further acidification produced by glucose is not essential for the augmentation of secretion via the amplifying pathway.

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.

Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity.

PubMed

Yamamoto, Soh; Kuramoto, Kenta; Wang, Nan; Situ, Xiaolei; Priyadarshini, Medha; Zhang, Weiran; Cordoba-Chacon, Jose; Layden, Brian T; He, Congcong

2018-06-12

Autophagy, a stress-induced lysosomal degradative pathway, has been assumed to exert similar metabolic effects in different organs. Here, we establish a model where autophagy plays different roles in insulin-producing β cells versus insulin-responsive cells, utilizing knockin (Becn1 F121A ) mice manifesting constitutively active autophagy. With a high-fat-diet challenge, the autophagy-hyperactive mice unexpectedly show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal autophagy. Autophagy hyperactivation enhances insulin signaling, via suppressing ER stress in insulin-responsive cells, but decreases insulin secretion by selectively sequestrating and degrading insulin granule vesicles in β cells, a process we term "vesicophagy." The reduction in insulin storage, insulin secretion, and glucose tolerance is reversed by transient treatment of autophagy inhibitors. Thus, β cells and insulin-responsive tissues require different autophagy levels for optimal function. To improve insulin sensitivity without hampering secretion, acute or intermittent, rather than chronic, activation of autophagy should be considered in diabetic therapy development. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Insulin stimulates synthesis and release of human chorionic gonadotropin by choriocarcinoma cell lines

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

Ren, S.G.; Braunstein, G.D.

1991-03-01

Recent studies have shown that insulin regulates placental lactogen, progesterone, and estrogen production from human trophoblast cells. This study was performed to examine whether insulin also regulates the production of hCG by this type of cell. After 24-36 h of preincubation, JEG-3 and JAR cells (2-3 x 10(5) cells/ml.well) or human term trophoblast cells (1 x 10(6) cells/ml.well) were exposed to the test hormone in serum-free Dulbecco's Modified Eagle's Medium for 24-96 h. Secretion of hCG from JEG-3 cells was stimulated by human insulin, human proinsulin, or porcine insulin in a dose-dependent manner, with lowest effective doses of 6.7, 96,more » and 53 mg/L, respectively. Time-course studies showed that hCG secretion peaked at 72-96 h with insulin exposure; in contrast, no decernable peak was seen without insulin in serum-free media. Exposure of JEG-3 cells for 24 h to 209 mg/liter insulin stimulated hCG synthesis, with 40 +/- 3% more immunoreactive intracellular hCG (P less than 0.05). Cells grown in the presence of insulin and (35S)methionine had 47 +/- 21% more labeled intracellular hCG and 56 +/- 13% more immunoprecipitable (35S)methionine-hCG secreted into the medium than the control cultures (P less than 0.05). During this time period, human placental lactogen release and total trichloroacetice acid-precipitable (35S)methionine protein were not increased. The insulin-induced stimulation of hCG synthesis was inhibited by cycloheximide. Additionally, insulin did not significantly affect total intracellular protein during 24-96 h of incubation. Insulin also increased hCG release from JAR cells, but not from human term trophoblast cells. A mouse monoclonal antibody to the IGF-I receptor inhibited the stimulation of insulin in JEG-3 cells.« less

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

PubMed Central

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

2016-01-01

Background Effects of major dietary macronutrients on glucose-insulin homeostasis remain controversial and may vary by the clinical measures examined. We aimed to assess how saturated fat (SFA), monounsaturated fat (MUFA), polyunsaturated fat (PUFA), and carbohydrate affect key metrics of glucose-insulin homeostasis. Methods and Findings We systematically searched multiple databases (PubMed, EMBASE, OVID, BIOSIS, Web-of-Knowledge, CAB, CINAHL, Cochrane Library, SIGLE, Faculty1000) for randomised controlled feeding trials published by 26 Nov 2015 that tested effects of macronutrient intake on blood glucose, insulin, HbA1c, insulin sensitivity, and insulin secretion in adults aged ≥18 years. We excluded trials with non-isocaloric comparisons and trials providing dietary advice or supplements rather than meals. Studies were reviewed and data extracted independently in duplicate. Among 6,124 abstracts, 102 trials, including 239 diet arms and 4,220 adults, met eligibility requirements. Using multiple-treatment meta-regression, we estimated dose-response effects of isocaloric replacements between SFA, MUFA, PUFA, and carbohydrate, adjusted for protein, trans fat, and dietary fibre. Replacing 5% energy from carbohydrate with SFA had no significant effect on fasting glucose (+0.02 mmol/L, 95% CI = -0.01, +0.04; n trials = 99), but lowered fasting insulin (-1.1 pmol/L; -1.7, -0.5; n = 90). Replacing carbohydrate with MUFA lowered HbA1c (-0.09%; -0.12, -0.05; n = 23), 2 h post-challenge insulin (-20.3 pmol/L; -32.2, -8.4; n = 11), and homeostasis model assessment for insulin resistance (HOMA-IR) (-2.4%; -4.6, -0.3; n = 30). Replacing carbohydrate with PUFA significantly lowered HbA1c (-0.11%; -0.17, -0.05) and fasting insulin (-1.6 pmol/L; -2.8, -0.4). Replacing SFA with PUFA significantly lowered glucose, HbA1c, C-peptide, and HOMA. Based on gold-standard acute insulin response in ten trials, PUFA significantly improved insulin secretion capacity (+0.5 pmol/L/min; 0.2, 0.8) whether replacing carbohydrate, SFA, or even MUFA. No significant effects of any macronutrient replacements were observed for 2 h post-challenge glucose or insulin sensitivity (minimal-model index). Limitations included a small number of trials for some outcomes and potential issues of blinding, compliance, generalisability, heterogeneity due to unmeasured factors, and publication bias. Conclusions This meta-analysis of randomised controlled feeding trials provides evidence that dietary macronutrients have diverse effects on glucose-insulin homeostasis. In comparison to carbohydrate, SFA, or MUFA, most consistent favourable effects were seen with PUFA, which was linked to improved glycaemia, insulin resistance, and insulin secretion capacity. PMID:27434027

The TRPA1 channel and oral hypoglycemic agents: is there complicity in β-cell exhaustion?

PubMed

Diaz-Garcia, Carlos Manlio

2013-01-01

Diabetes mellitus type 2 (DM2) results from the combination of insulin unresponsiveness in target tissues and the failure of pancreatic β cells to secrete enough insulin. (1) It is a highly prevalent chronic disease that is aggravated with time, leading to major complications, such as cardiovascular disease and peripheral and ocular neuropathies. (2) Interestingly, therapies to improve glucose homeostasis in diabetic patients usually involve the use of glibenclamide, an oral hypoglycemic drug that blocks ATP-sensitive K(+) channels (KATP), (3)(,) (4) forcing β cells to release more insulin to overcome peripheral insulin resistance. However, sulfonylureas are ineffective for long-term treatments and ultimately result in the administration of insulin to control glucose levels. (5) The mechanisms underlying β-cell failure to respond effectively with glibenclamide after long-term treatments still needs clarification. A recent study demonstrating that this drug activates TRPA1, (6) a member of the Transient Receptor Potential (TRP) family of ion channels and a functional protein in insulin secreting cells, (7)(,) (8) has highlighted a possible role for TRPA1 as a potential mediator of sulfonylurea-induced toxicity.

Hyperinsulinemia in the physiologic range is not superior to short-term fasting in suppressing insulin secretion in obese men.

PubMed

Pincelli, A I; Brunani, A; Caumo, A; Scacchi, M; Pasqualinotto, L; Tibaldi, A; Dubini, A; Bonadonna, S; Cavagnini, F

2001-01-01

The negative-feedback control exerted by plasma insulin on beta-cell insulin release in normal-weight and obese subjects is still a matter of debate. Subjects submitted to a euglycemic insulin clamp undergo a suppression of insulin secretion that is due to both the infused insulin and the 2- to 3-hour fast during the procedure. We elected to elucidate the role of physiologic hyperinsulinemia per se in the insulin negative autofeedback in obese men. Ten men with massive uncomplicated obesity (age, 18 to 37 years; body mass index [BMI], 41 +/- 1.15 kg/m2) and 6 normal-weight healthy men (age, 22 to 30 years; BMI, 22 +/- 0.28 kg/m2) underwent 2 studies in random order: (1) a euglycemic-hyperinsulinemic glucose clamp with an insulin infusion rate of 1 mU/kg/min and (2) a control study with saline infusion. Serum C-peptide concentrations were significantly higher in obese versus control subjects at baseline (2.54 +/- 0.178 v 1.63 +/- 0.256 ng/mL, P < .05). Exogenous insulin infusion significantly suppressed serum C-peptide at steady state ([SS] last 30 minutes of insulin or saline infusion) in controls (mean of the last 4 measurements from 120 minutes to 150 minutes, 0.86 +/- 0.306 ng/mL, P < .05 vbaseline) but not in obese patients (2.03 +/- 0.26 ng/mL, nonsignificant [NS] v baseline). During the saline infusion studies, C-peptide levels slightly and similarly declined over time in both groups (2.71 +/- 0.350 at baseline v 2.31 +/- 0.300 ng/mL at SS in obese patients, NS, and 1.96 +/- 0.189 v 1.62 +/- 0.150 ng/mL in controls, NS). This study shows that in obese men hyperinsulinemia within the postprandial range is not superior to a 2.5-hour fast for the suppression of beta-cell activity, suggesting an impairment of the insulin negative autofeedback in this clinical condition.

l-Cysteine supplementation increases insulin sensitivity mediated by upregulation of GSH and adiponectin in high glucose treated 3T3-L1 adipocytes.

PubMed

Achari, Arunkumar E; Jain, Sushil K

2017-09-15

Diabetic patients have lower blood levels of l-cysteine (LC) and glutathione (GSH). This study examined the hypothesis that LC supplementation positively up regulates the effects of insulin on GSH and glucose metabolism in 3T3-L1 adipocyte model. 3T3L1 adipocytes were treated with LC (250 μM, 2 h) and/or insulin (15 or 30 nM, 2 h), and high glucose (HG, 25 mM, 20 h). Results showed that HG caused significant increase (95%) in ROS and reduction in the protein levels of DsbA-L (43%), adiponectin (64%), GCLC (20%), GCLM (21%), GSH (50%), and GLUT-4 (23%) in adipocytes. Furthermore, HG caused a reduction in total (35%) and HMW adiponectin (30%) secretion. Treatment with insulin alone significantly (p < 0.05) reduced ROS levels as well as increased DsbA-L, adiponectin, GCLC, GCLM, GSH, and GLUT-4 protein levels, glucose utilization, and improved total and HMW adiponectin secretion in HG treated adipocytes compared to HG alone. Interestingly, LC supplementation along with insulin caused greater reduction in ROS levels and significantly (p < 0.05) boosted the DsbA-L (41% vs LC, 29% vs Insulin), adiponectin (92% Vs LC, 84% Vs insulin) protein levels and total (32% Vs LC, 22% Vs insulin) and HMW adiponectin (75% Vs LC, 39% Vs insulin) secretion compared with the either insulin or LC alone in HG-treated cells. In addition, LC supplementation along with insulin increased GCLC (21% Vs LC, 14% insulin), GCLM (28% Vs LC, 16% insulin) and GSH (25% Vs LC and insulin) levels compared with the either insulin or LC alone in HG-treated cells. Furthermore, LC and insulin increases GLUT-4 protein expression (65% Vs LC, 18% Vs Insulin), glucose utilization (57% Vs LC, 27% Vs insulin) compared with the either insulin or LC alone in HG-treated cells. Similarly, LC supplementation increased insulin action significantly in cells maintained in medium contained control glucose. To explore the beneficial effect of LC is mediated by the upregulation of GCLC, we knocked down GCLC using siRNA in adipoctyes. There was a significant decrease in DsbA-L and GLUT-4 mRNA levels and GSH levels in GCLC knockdown adipocytes and LC supplementation up regulates GCLC, DsbA-L and GLUT-4 mRNA expression and GSH levels in GCLC knockdown cells. These results demonstrated that LC along with insulin increases GSH levels thereby improving adiponectin secretion and glucose utilization in adipocytes. This suggests that LC supplementation can increase insulin sensitivity and can be used as an adjuvant therapy for diabetes. Copyright © 2017. Published by Elsevier Inc.

Valsartan Improves β-Cell Function and Insulin Sensitivity in Subjects With Impaired Glucose Metabolism

PubMed Central

van der Zijl, Nynke J.; Moors, Chantalle C.M.; Goossens, Gijs H.; Hermans, Marc M.H.; Blaak, Ellen E.; Diamant, Michaela

2011-01-01

OBJECTIVE Recently, the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research Trial demonstrated that treatment with the angiotensin receptor blocker (ARB) valsartan for 5 years resulted in a relative reduction of 14% in the incidence of type 2 diabetes in subjects with impaired glucose metabolism (IGM). We investigated whether improvements in β-cell function and/or insulin sensitivity underlie these preventive effects of the ARB valsartan in the onset of type 2 diabetes. RESEARCH DESIGN AND METHODS In this randomized controlled, double-blind, two-center study, the effects of 26 weeks of valsartan (320 mg daily; n = 40) or placebo (n = 39) on β-cell function and insulin sensitivity were assessed in subjects with impaired fasting glucose and/or impaired glucose tolerance, using a combined hyperinsulinemic-euglycemic and hyperglycemic clamp with subsequent arginine stimulation and a 2-h 75-g oral glucose tolerance test (OGTT). Treatment effects were analyzed using ANCOVA, adjusting for center, glucometabolic status, and sex. RESULTS Valsartan increased first-phase (P = 0.028) and second-phase (P = 0.002) glucose-stimulated insulin secretion compared with placebo, whereas the enhanced arginine-stimulated insulin secretion was comparable between groups (P = 0.25). In addition, valsartan increased the OGTT-derived insulinogenic index (representing first-phase insulin secretion after an oral glucose load; P = 0.027). Clamp-derived insulin sensitivity was significantly increased with valsartan compared with placebo (P = 0.049). Valsartan treatment significantly decreased systolic and diastolic blood pressure compared with placebo (P < 0.001). BMI remained unchanged in both treatment groups (P = 0.89). CONCLUSIONS Twenty-six weeks of valsartan treatment increased glucose-stimulated insulin release and insulin sensitivity in normotensive subjects with IGM. These findings may partly explain the beneficial effects of valsartan in the reduced incidence of type 2 diabetes. PMID:21330640

An adenovirus-derived protein: A novel candidate for anti-diabetic drug development

PubMed Central

Hegde, Vijay; Na, Ha-Na; Dubuisson, Olga; Burke, Susan J.; Collier, J. Jason; Burk, David; Mendoza, Tamra; Dhurandhar, Nikhil V.

2016-01-01

Aims Exposure to human adenovirus Ad36 is causatively and correlatively linked with better glycemic control in animals and humans, respectively. Although the anti-hyperglycemic property of Ad36 may offer some therapeutic potential, it is impractical to use an infectious agent for therapeutic benefit. Cell- based studies identified that Ad36 enhances cellular glucose disposal via its E4orf1 protein. Ability to improve glycemic control in vivo is a critical prerequisite for further investigating the therapeutic potential of E4orf1. Therefore, the aim of this study was to determine the ability of E4orf1 to improve glycemic control independent of insulin despite high fat diet. Materials & Methods 8–9wk old male C57BL/6J mice fed a high-fat diet (60% kcal) were injected with a retrovirus plasmid expressing E4orf1, or a null vector (Control). Glycemic control was determined by glucose and insulin tolerance test. Islet cell size, amount of insulin and glucagon were determined in formalin-fixed pancreas. Rat insulinoma cell line (832/13) was infected with E4orf1 or control to determine changes in glucose stimulated insulin secretion. Protein from flash frozen adipose tissue depots, liver and muscle was used to determine molecular signaling by western blotting. Results In multiple experiments, retrovirus-mediated E4orf1 expression in C57BL/6J mice significantly and reproducibly improved glucose excursion following a glucose load despite a high fat diet (60% energy). Importantly, E4orf1 improved glucose clearance without increasing insulin sensitivity, production or secretion, underscoring its insulin-independent effect. E4orf1 modulated molecular signaling in mice tissue, which included greater protein abundance of adiponectin, p-AKT and Glucose transporter Glu4. Conclusions This study provides the proof of concept for translational development of E4orf1 as a potential anti-diabetic agent. High fat intake and impaired insulin signaling are often associated with obesity, diabetes and insulin resistance. Hence, the ability of E4orf1 to improve glycemic control despite high fat diet and independent of insulin, is particularly attractive. PMID:26700141

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

Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion.

PubMed

Patterson, Jessica N; Cousteils, Katelyn; Lou, Jennifer W; Manning Fox, Jocelyn E; MacDonald, Patrick E; Joseph, Jamie W

2014-05-09

It is well known that mitochondrial metabolism of pyruvate is critical for insulin secretion; however, we know little about how pyruvate is transported into mitochondria in β-cells. Part of the reason for this lack of knowledge is that the carrier gene was only discovered in 2012. In the current study, we assess the role of the recently identified carrier in the regulation of insulin secretion. Our studies show that β-cells express both mitochondrial pyruvate carriers (Mpc1 and Mpc2). Using both pharmacological inhibitors and siRNA-mediated knockdown of the MPCs we show that this carrier plays a key role in regulating insulin secretion in clonal 832/13 β-cells as well as rat and human islets. We also show that the MPC is an essential regulator of both the ATP-regulated potassium (KATP) channel-dependent and -independent pathways of insulin secretion. Inhibition of the MPC blocks the glucose-stimulated increase in two key signaling molecules involved in regulating insulin secretion, the ATP/ADP ratio and NADPH/NADP(+) ratio. The MPC also plays a role in in vivo glucose homeostasis as inhibition of MPC by the pharmacological inhibitor α-cyano-β-(1-phenylindol-3-yl)-acrylate (UK5099) resulted in impaired glucose tolerance. These studies clearly show that the newly identified mitochondrial pyruvate carrier sits at an important branching point in nutrient metabolism and that it is an essential regulator of insulin secretion.

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.

Indian culinary plants enhance glucose-induced insulin secretion and glucose consumption in INS-1 β-cells and 3T3-L1 adipocytes.

PubMed

Kaur, Lovedeep; Han, Kyoung-Sik; Bains, Kiran; Singh, Harjinder

2011-12-01

Six Indian plants, commonly used as culinary plants, herbs or spices (kikar; jamun; neem; harad; fenugreek; bitter gourd), were screened and compared for their antidiabetic potential in vitro. Aqueous plant extracts were prepared and assessed for their effect on the insulin secretion activity of rat pancreatic INS-1 β-cells and glucose consumption in mouse 3T3-L1 adipocytes in order to study their specific mechanisms of action. The effect of the plant extract concentration (25-1000μg/ml) on insulin release and glucose consumption was also studied. All the extracts had a significant stimulatory effect on the insulin secretion of INS-1 cells. In the presence of kikar extract (100μg/ml), an increase of 228% in insulin release was recorded compared to the control (5.6mM glucose) whereas that was 270% and 367% in the presence of kikar and jamun extracts (500μg/ml), respectively. 3T3-L1 cells treated with jamun extract (100μg/ml) exhibited the highest increase in glucose consumption by the cells (94%, compared with the control) followed by harad (53%) and fenugreek (50%) extracts. A significant inhibitory effect of the fenugreek, kikar and jamun extracts on glucose diffusion across a dialysis membrane suggested that these extracts could partly act by decreasing glucose absorption in the small intestine. The results showed that a combination of these plants in diet could help in the management of both type 1 and type 2 diabetes. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

Insulin secretion and its association with physical activity, fitness and screen time in children.

PubMed

Henderson, M; Gray-Donald, K; Rabasa-Lhoret, R; Bastard, J-P; Barnett, T A; Benedetti, A; Chaput, J-P; Tremblay, A; Lambert, M

2014-02-01

To determine the independent associations of moderate to vigorous physical activity (MVPA), fitness, screen time, and adiposity with insulin secretion in children. Caucasian youth (n = 423/630), 8-10 years old, with at least one obese biological parent, were studied (QUALITY cohort). Insulin secretion was measured using HOMA2-%B, area under the curve (AUC) of insulin to glucose over the first 30 minutes (AUC I/G(t30min)) of the OGTT and AUC I/G(t120min) over 2 hours. Fitness was measured by VO₂peak ; percent fat mass (PFM) by DXA; 7-day MVPA by accelerometry; self-reported screen time included television, video game, or computer use. Models were adjusted for age, sex, season, puberty, PFM, and insulin sensitivity [IS] (HOMA2-IS, Matsuda-ISI). PFM was strongly associated with insulin secretion, even after adjustment for IS: for every 1% increase in PFM, insulin secretion increased from 0.3% to 0.8% across indices. MVPA was negatively associated with HOMA2-%B (P < 0.05), but not with OGTT-derived measures. Fitness was negatively associated with AUC I/G(t120min) (P < 0.05). Screen time showed a trend toward higher HOMA2-%B in girls (P = 0.060). In children with an obese parent, lower insulin secretion is associated with lower adiposity, higher MVPA, better fitness, and possibly reduced screen time. Copyright © 2013 The Obesity Society.

Adjunct therapy for type 1 diabetes mellitus.

PubMed

Lebovitz, Harold E

2010-06-01

Insulin replacement therapy in type 1 diabetes mellitus (T1DM) is nonphysiologic. Hyperinsulinemia is generated in the periphery to achieve normal insulin concentrations in the liver. This mismatch results in increased hypoglycemia, increased food intake with weight gain, and insufficient regulation of postprandial glucose excursions. Islet amyloid polypeptide is a hormone synthesized in pancreatic beta cells and cosecreted with insulin. Circulating islet amyloid polypeptide binds to receptors located in the hindbrain and increases satiety, delays gastric emptying and suppresses glucagon secretion. Thus, islet amyloid polypeptide complements the effects of insulin. T1DM is a state of both islet amyloid polypeptide and insulin deficiency. Pramlintide, a synthetic analog of islet amyloid polypeptide, can replace this hormone in patients with T1DM. When administered as adjunctive therapy to such patients treated with insulin, pramlintide decreases food intake and causes weight loss. Pramlintide therapy is also associated with suppression of glucagon secretion and delayed gastric emptying, both of which decrease postprandial plasma glucose excursions. Pramlintide therapy improves glycemic control and lessens weight gain. Agents that decrease intestinal carbohydrate digestion (alpha-glucosidase inhibitors) or decrease insulin resistance (metformin) might be alternative adjunctive therapies in T1DM, though its benefits are marginally supported by clinical data.

Exocyst sec5 regulates exocytosis of newcomer insulin granules underlying biphasic insulin secretion.

PubMed

Xie, Li; Zhu, Dan; Kang, Youhou; Liang, Tao; He, Yu; Gaisano, Herbert Y

2013-01-01

The exocyst complex subunit Sec5 is a downstream effector of RalA-GTPase which promotes RalA-exocyst interactions and exocyst assembly, serving to tether secretory granules to docking sites on the plasma membrane. We recently reported that RalA regulates biphasic insulin secretion in pancreatic islet β cells in part by tethering insulin secretory granules to Ca(2+) channels to assist excitosome assembly. Here, we assessed β cell exocytosis by patch clamp membrane capacitance measurement and total internal reflection fluorescence microscopy to investigate the role of Sec5 in regulating insulin secretion. Sec5 is present in human and rodent islet β cells, localized to insulin granules. Sec5 protein depletion in rat INS-1 cells inhibited depolarization-induced release of primed insulin granules from both readily-releasable pool and mobilization from the reserve pool. This reduction in insulin exocytosis was attributed mainly to reduction in recruitment and exocytosis of newcomer insulin granules that undergo minimal docking time at the plasma membrane, but which encompassed a larger portion of biphasic glucose stimulated insulin secretion. Sec5 protein knockdown had little effect on predocked granules, unless vigorously stimulated by KCl depolarization. Taken together, newcomer insulin granules in β cells are more sensitive than predocked granules to Sec5 regulation.

Bone: from a reservoir of minerals to a regulator of energy metabolism

PubMed Central

Confavreux, Cyrille B

2011-01-01

Besides locomotion, organ protection, and calcium–phosphorus homeostasis, the three classical functions of the skeleton, bone remodeling affects energy metabolism through uncarboxylated osteocalcin, a recently discovered hormone secreted by osteoblasts. This review traces how energy metabolism affects osteoblasts through the central control of bone mass involving leptin, serotoninergic neurons, the hypothalamus, and the sympathetic nervous system. Next, the role of osteocalcin (insulin secretion, insulin sensitivity, and pancreas β-cell proliferation) in the regulation of energy metabolism is described. Then, the connections between insulin signaling on osteoblasts and the release of uncarboxylated osteocalcin during osteoclast bone resorption through osteoprotegerin are reported. Finally, the understanding of this new bone endocrinology will provide some insights into bone, kidney, and energy metabolism in patients with chronic kidney disease. PMID:21346725

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

Partial deficiency of CTRP12 alters hepatic lipid metabolism

PubMed Central

Tan, Stefanie Y.; Little, Hannah C.; Lei, Xia; Li, Shuoyang; Rodriguez, Susana

2016-01-01

Secreted hormones play pivotal roles in tissue cross talk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted protein involved in regulating glucose metabolism whose circulating levels are reduced in obese and insulin-resistant mouse models. Its role in lipid metabolism, however, is unknown. Using a novel heterozygous mouse model, we show that the loss of a single copy of the Ctrp12 gene (also known as Fam132a and adipolin) affects whole body lipid metabolism. In Ctrp12 (+/−) male mice fed a control low-fat diet, hepatic fat oxidation was upregulated while hepatic VLDL-triglyceride secretion was reduced relative to wild-type (WT) littermates. When challenged with a high-fat diet, Ctrp12 (+/−) male mice had impaired lipid clearance in response to acute lipid gavage, reduced hepatic triglyceride secretion, and greater steatosis with higher liver triglyceride and cholesterol levels. Unlike male mice, Ctrp12 (+/−) female mice fed a control low-fat diet were indistinguishable from WT littermates. When obesity was induced by high-fat feeding, Ctrp12 (+/−) female mice developed mild insulin resistance with impaired insulin tolerance. In contrast to male mice, hepatic triglyceride secretion was increased in Ctrp12 (+/−) female mice fed a high-fat diet. Thus, in different dietary and metabolic contexts, loss of a single Ctrp12 allele affects glucose and lipid metabolism in a sex-dependent manner, highlighting the importance of genetic and environmental determinants of metabolic phenotypes. PMID:27815536

Partial deficiency of CTRP12 alters hepatic lipid metabolism.

PubMed

Tan, Stefanie Y; Little, Hannah C; Lei, Xia; Li, Shuoyang; Rodriguez, Susana; Wong, G William

2016-12-01

Secreted hormones play pivotal roles in tissue cross talk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted protein involved in regulating glucose metabolism whose circulating levels are reduced in obese and insulin-resistant mouse models. Its role in lipid metabolism, however, is unknown. Using a novel heterozygous mouse model, we show that the loss of a single copy of the Ctrp12 gene (also known as Fam132a and adipolin) affects whole body lipid metabolism. In Ctrp12 (+/-) male mice fed a control low-fat diet, hepatic fat oxidation was upregulated while hepatic VLDL-triglyceride secretion was reduced relative to wild-type (WT) littermates. When challenged with a high-fat diet, Ctrp12 (+/-) male mice had impaired lipid clearance in response to acute lipid gavage, reduced hepatic triglyceride secretion, and greater steatosis with higher liver triglyceride and cholesterol levels. Unlike male mice, Ctrp12 (+/-) female mice fed a control low-fat diet were indistinguishable from WT littermates. When obesity was induced by high-fat feeding, Ctrp12 (+/-) female mice developed mild insulin resistance with impaired insulin tolerance. In contrast to male mice, hepatic triglyceride secretion was increased in Ctrp12 (+/-) female mice fed a high-fat diet. Thus, in different dietary and metabolic contexts, loss of a single Ctrp12 allele affects glucose and lipid metabolism in a sex-dependent manner, highlighting the importance of genetic and environmental determinants of metabolic phenotypes. Copyright © 2016 the American Physiological Society.

Insulin secretion enhancing activity of roselle calyx extract in normal and streptozotocin-induced diabetic rats

PubMed Central

Wisetmuen, Eamruthai; Pannangpetch, Patchareewan; Kongyingyoes, Bunkerd; Kukongviriyapan, Upa; Yutanawiboonchai, Wiboonchai; Itharat, Arunporn

2013-01-01

Background and Objective: Our recent study revealed the antihyperglycemic activity of an ethanolic extract of roselle calyxes (Hibiscus sabdariffa) in diabetic rats. The present study had, therefore, an objective to investigate the mechanism underlying this activity. Materials and Methods: Male Sprague Dawley rats were induced to be diabetes by intraperitoneal injection of 45 mg/kg streptozotocin (STZ). Normal rats as well as diabetic rats were administered with the ethanolic extract of H. sabdariffa calyxes (HS-EE) at 0.1 and 1.0 g/kg/day, respectively, for 6 weeks. Then, blood glucose and insulin levels, at basal and glucose-stimulated secretions, were measured. The pancreas was dissected to examine histologically. Results: HS-EE 1.0 g/kg/day significantly decreased the blood glucose level by 38 ± 12% in diabetic rats but not in normal rats. In normal rats, treatment with 1.0 g/kg HS-EE increased the basal insulin level significantly as compared with control normal rats (1.28 ± 0.25 and 0.55 ± 0.05 ng/ml, respectively). Interestingly, diabetic rats treated with 1.0 g/kg HS-EE also showed a significant increase in basal insulin level as compared with the control diabetic rats (0.30 ± 0.05 and 0.15 ± 0.01 ng/ml, respectively). Concerning microscopic histological examination, HS-EE 1.0 g/kg significantly increased the number of islets of Langerhans in both normal rats (1.2 ± 0.1 and 2.0 ± 0.1 islet number/10 low-power fields (LPF) for control and HS-EE treated group, respectively) and diabetic rats (1.0 ± 0.3 and 3.9 ± 0.6 islet number/10 LPF for control and HS-EE treated group, respectively). Conclusion: The antidiabetic activity of HS-EE may be partially mediated via the stimulating effect on insulin secretion. PMID:23798879

One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes.

PubMed

Vatier, C; Fetita, S; Boudou, P; Tchankou, C; Deville, L; Riveline, Jp; Young, J; Mathivon, L; Travert, F; Morin, D; Cahen, J; Lascols, O; Andreelli, F; Reznik, Y; Mongeois, E; Madelaine, I; Vantyghem, Mc; Gautier, Jf; Vigouroux, C

2016-07-01

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies. © 2015 John Wiley & Sons Ltd.

Effect of Weight Loss, Exercise, or Both on Undercarboxylated Osteocalcin and Insulin Secretion in Frail, Obese Older Adults

PubMed Central

Napoli, Nicola; Phadnis, Uma; Armamento-Villareal, Reina

2017-01-01

Background Obesity exacerbates age-related decline in glucometabolic control. Undercarboxylated osteocalcin (UcOC) regulates pancreatic insulin secretion. The long-term effect of lifestyle interventions on UcOC and insulin secretion has not been investigated. Methods One hundred seven frail, obese older adults were randomized into the control (N = 27), diet (N = 26), exercise (N = 26), and diet-exercise (N = 28) groups for 1 year. Main outcomes included changes in UcOC and disposition index (DI). Results UcOC increased in the diet group (36 ± 11.6%) but not in the other groups (P < 0.05 between groups). Although similar increases in DI occurred in the diet-exercise and diet groups at 6 months, DI increased more in the diet-exercise group (92.4 ± 11.4%) than in the diet group (61.9 ± 15.3%) at 12 months (P < 0.05). UcOC and body composition changes predicted DI variation in the diet group only (R2 = 0.712), while adipocytokines and physical function changes contributed to DI variation in both the diet (∆R2 = 0.140 and 0.107) and diet-exercise (∆R2 = 0.427 and 0.243) groups (P < 0.05 for all). Conclusions Diet, but not exercise or both, increases UcOC, whereas both diet and diet-exercise increase DI. UcOC accounts for DI variation only during active weight loss, while adipocytokines and physical function contribute to diet-exercise-induced DI variation, highlighting different mechanisms for lifestyle-induced improvements in insulin secretion. This trial was registered with ClinicalTrials.gov number NCT00146107. PMID:28951766

Effect of Weight Loss, Exercise, or Both on Undercarboxylated Osteocalcin and Insulin Secretion in Frail, Obese Older Adults.

PubMed

Colleluori, Georgia; Napoli, Nicola; Phadnis, Uma; Armamento-Villareal, Reina; Villareal, Dennis T

2017-01-01

Obesity exacerbates age-related decline in glucometabolic control. Undercarboxylated osteocalcin (UcOC) regulates pancreatic insulin secretion. The long-term effect of lifestyle interventions on UcOC and insulin secretion has not been investigated. One hundred seven frail, obese older adults were randomized into the control ( N = 27), diet ( N = 26), exercise ( N = 26), and diet-exercise ( N = 28) groups for 1 year. Main outcomes included changes in UcOC and disposition index (DI). UcOC increased in the diet group (36 ± 11.6%) but not in the other groups ( P < 0.05 between groups). Although similar increases in DI occurred in the diet-exercise and diet groups at 6 months, DI increased more in the diet-exercise group (92.4 ± 11.4%) than in the diet group (61.9 ± 15.3%) at 12 months ( P < 0.05). UcOC and body composition changes predicted DI variation in the diet group only ( R 2 = 0.712), while adipocytokines and physical function changes contributed to DI variation in both the diet (∆ R 2 = 0.140 and 0.107) and diet-exercise (∆ R 2 = 0.427 and 0.243) groups ( P < 0.05 for all). Diet, but not exercise or both, increases UcOC, whereas both diet and diet-exercise increase DI. UcOC accounts for DI variation only during active weight loss, while adipocytokines and physical function contribute to diet-exercise-induced DI variation, highlighting different mechanisms for lifestyle-induced improvements in insulin secretion. This trial was registered with ClinicalTrials.gov number NCT00146107.

Polyphenol-rich diets improve glucose metabolism in people at high cardiometabolic risk: a controlled randomised intervention trial.

PubMed

Bozzetto, Lutgarda; Annuzzi, Giovanni; Pacini, Giovanni; Costabile, Giuseppina; Vetrani, Claudia; Vitale, Marilena; Griffo, Ettore; Giacco, Angela; De Natale, Claudia; Cocozza, Sara; Della Pepa, Giuseppe; Tura, Andrea; Riccardi, Gabriele; Rivellese, Angela A

2015-07-01

Dietary polyphenols and long chain n-3 polyunsaturated fatty acids (LCn3) are associated with lower cardiovascular risk. This may relate to their influence on glucose metabolism and diabetes risk. We evaluated the effects of diets naturally rich in polyphenols and/or LCn3 of marine origin on glucose metabolism in people at high cardiometabolic risk. According to a 2 × 2 factorial design, individuals with high waist circumference and at least one more component of the metabolic syndrome were recruited at the obesity outpatient clinic. Eighty-six participants were randomly assigned by MINIM software to an isoenergetic diet: (1) control, low in LCn3 and polyphenol (analysed n = 20); (2) rich in LCn3 (n = 19); (3) rich in polyphenols (n = 19); or (4) rich in LCn3 and polyphenols (n = 19). The assigned diets were known for the participants and blinded for people doing measurements. Before and after the 8 week intervention, participants underwent a 3 h OGTT and a test meal with a similar composition as the assigned diet for the evaluation of plasma glucose, insulin and glucagon-like peptide 1 (GLP-1) concentrations, and indices of insulin sensitivity and beta cell function. During OGTT, polyphenols significantly reduced plasma glucose total AUC (p = 0.038) and increased early insulin secretion (p = 0.048), while LCn3 significantly reduced beta cell function (p = 0.031) (two-factor ANOVA). Moreover, polyphenols improved post-challenge oral glucose insulin sensitivity (OGIS; p = 0.05 vs control diet by post hoc ANOVA). At test meal, LCn3 significantly reduced GLP-1 total postprandial AUC (p < 0.001; two-factor ANOVA). Diets naturally rich in polyphenols reduce blood glucose response, likely by increasing early insulin secretion and insulin sensitivity. These effects may favourably influence diabetes and cardiovascular risk. The implications of the decrease in insulin secretion and postprandial GLP-1 observed with diets rich in marine LCn3 need further clarification. ClinicalTrials.gov NCT01154478. The trial was funded by European Community's Seventh Framework Programme FP7/2009-2012 under grant agreement FP7-KBBE-222639, Etherpaths Project and 'Ministero Istruzione Università e Ricerca' PRIN 2010-2011 - 2010JCWWKM.

Insulin and glucose sensitivity, insulin secretion and beta-cell distribution in endocrine pancreas of the fruit bat Artibeus lituratus.

PubMed

Protzek, A O P; Rafacho, A; Viscelli, B A; Bosqueiro, J R; Cappelli, A P; Paula, F M M; Boschero, A C; Pinheiro, E C

2010-10-01

The fruit bat Artibeus lituratus absorbs large amounts of glucose in short periods of time and maintains normoglycemia even after a prolonged starvation period. Based on these data, we aimed to investigate various aspects related with glucose homeostasis analyzing: blood glucose and insulin levels, intraperitoneal glucose and insulin tolerance tests (ipGTT and ipITT), glucose-stimulated insulin secretion (2.8, 5.6 or 8.3 mmol/L glucose) in pancreas fragments, cellular distribution of beta cells, and the amount of pAkt/Akt in the pectoral muscle and liver. Blood glucose levels were higher in fed bats (6.88+/-0.5 mmol/L) than fasted bats (4.0+/-0.8 mmol/L), whereas insulin levels were similar in both conditions. The values of the area-under-the curve obtained from ipGTT were significantly higher when bats received 2 (5.5-fold) or 3g/kg glucose (7.5-fold) b.w compared to control (saline). These bats also exhibited a significant decrease of blood glucose values after insulin administration during the ipITT. Insulin secretion from fragments of pancreas under physiological concentrations of glucose (5.6 or 8.3 mmol/L) was similar but higher than in 2.8 mmol/L glucose 1.8- and 2.0-fold, respectively. These bats showed a marked beta-cell distribution along the pancreas, and the pancreatic beta cells are not exclusively located at the central part of the islet. The insulin-induced Akt phosphorylation was more pronounced in the pectoral muscle, compared to liver. The high sensitivity to glucose and insulin, the proper insulin response to glucose, and the presence of an apparent large beta-cell population could represent benefits for the management of high influx of glucose from a carbohydrate-rich meal, which permits appropriate glucose utilization. 2010 Elsevier Inc. All rights reserved.

Advanced glycation end products impair glucose-induced insulin secretion from rat pancreatic β-cells.

PubMed

Hachiya, Hiroyuki; Miura, Yoshikazu; Inoue, Ken-Ichi; Park, Kyung Hwa; Takeuchi, Masayoshi; Kubota, Keiichi

2014-02-01

Advanced glycation end products (AGEs) are derivative compounds generated from non-enzymatic glycosylation and oxidation. In comparison with glucose-derived AGEs (Glu-AGEs), glyceraldehyde-derived AGEs (Glycer-AGEs) have stronger toxicity to living systems. In this study, we compared the effects of Glu-AGE and Glycer-AGE on insulin secretion. Rat pancreatic islets were isolated by collagenase digestion and primary-cultured in the presence of 0.1 mg/ml bovine serum albumin (BSA) or 0.1 mg/ml Glu-AGE or Glycer-AGE-albumin. After 48 h of culture, we performed an insulin secretion test and identified the defects by a battery of rescue experiments [corrected]. Also, mRNA expression of genes associated with insulin secretion was measured. Insulin secretion induced by a high glucose concentration was 164.1 ± 6.0, 124.4 ± 4.4 (P < 0.05) and 119.8 ± 7.1 (P < 0.05) μU/3 islets/h in the presence of BSA, Glu-AGE, and Glycer-AGE, respectively. Inhibition of insulin secretion by Glu-AGE or Glycer-AGE was rescued by a high extracellular potassium concentration, tolbutamide and α-ketoisocaproic acid, but not by glyceraldehyde, dihydroxacetone, methylpyruvate, glucagon-like peptide-1 and acetylcholine. Glu-AGE or Glycer-AGE reduced the expression of the malate dehydrogenase (Mdh1/2) gene, which plays a critical role in the nicotinamide adenine dinucleotide (NADH) shuttle. Despite its reported cytotoxicity, the effects of Glycer-AGE on insulin secretion are similar to those of Glu-AGE. © 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Leucine Stimulates Insulin Secretion via Down-regulation of Surface Expression of Adrenergic α2A Receptor through the mTOR (Mammalian Target of Rapamycin) Pathway

PubMed Central

Yang, Jun; Dolinger, Michael; Ritaccio, Gabrielle; Mazurkiewicz, Joseph; Conti, David; Zhu, Xinjun; Huang, Yunfei

2012-01-01

The amino acid leucine is a potent secretagogue, capable of inducing insulin secretion. It also plays an important role in the regulation of mTOR activity, therefore, providing impetus to investigate if a leucine-sensing mechanism in the mTOR pathway is involved in insulin secretion. We found that leucine-induced insulin secretion was inhibited by both the mTOR inhibitor rapamycin as well as the adrenergic α2 receptor agonist clonidine. We also demonstrated that leucine down-regulated the surface expression of adrenergic α2A receptor via activation of the mTOR pathway. The leucine stimulatory effect on insulin secretion was attenuated in diabetic Goto-Kakizaki rats that overexpress adrenergic α2A receptors, confirming the role of leucine in insulin secretion. Thus, our data demonstrate that leucine regulates insulin secretion by modulating adrenergic α2 receptors through the mTOR pathway. The role of the mTOR pathway in metabolic homeostasis led us to a second important finding in this study; retrospective analysis of clinical data showed that co-administration of rapamycin and clonidine was associated with an increased incidence of new-onset diabetes in renal transplantation patients over those receiving rapamycin alone. We believe that inhibition of mTOR by rapamycin along with activation of adrenergic α2 receptors by clonidine represents a double-hit to pancreatic islets that synergistically disturbs glucose homeostasis. This new insight may have important implications for the clinical management of renal transplant patients. PMID:22645144

Nuclear hormone retinoid X receptor (RXR) negatively regulates the glucose-stimulated insulin secretion of pancreatic ß-cells.

PubMed

Miyazaki, Satsuki; Taniguchi, Hidenori; Moritoh, Yusuke; Tashiro, Fumi; Yamamoto, Tsunehiko; Yamato, Eiji; Ikegami, Hiroshi; Ozato, Keiko; Miyazaki, Jun-ichi

2010-11-01

Retinoid X receptors (RXRs) are members of the nuclear hormone receptor superfamily and are thought to be key regulators in differentiation, cellular growth, and gene expression. Although several experiments using pancreatic β-cell lines have shown that the ligands of nuclear hormone receptors modulate insulin secretion, it is not clear whether RXRs have any role in insulin secretion. To elucidate the function of RXRs in pancreatic β-cells, we generated a double-transgenic mouse in which a dominant-negative form of RXRβ was inducibly expressed in pancreatic β-cells using the Tet-On system. We also established a pancreatic β-cell line from an insulinoma caused by the β-cell-specific expression of simian virus 40 T antigen in the above transgenic mouse. In the transgenic mouse, expression of the dominant-negative RXR enhanced the insulin secretion with high glucose stimulation. In the pancreatic β-cell line, the suppression of RXRs also enhanced glucose-stimulated insulin secretion at a high glucose concentration, while 9-cis-retinoic acid, an RXR agonist, repressed it. High-density oligonucleotide microarray analysis showed that expression of the dominant-negative RXR affected the expression levels of a number of genes, some of which have been implicated in the function and/or differentiation of β-cells. These results suggest that endogenous RXR negatively regulates the glucose-stimulated insulin secretion. Given these findings, we propose that the modulation of endogenous RXR in β-cells may be a new therapeutic approach for improving impaired insulin secretion in type 2 diabetes.

Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients.

PubMed

Konturek, S J; Swierczek, J; Kwiecień, N; Mikoś, E; Oleksy, J; Wierzbicki, Z

1977-11-01

The effect of somatostatin, a growth hormone releasing-inhibiting hormone (GH-RIH) on basal and meal-, pentagastrin-, or histamine-stimulated gastric acid and pepsin secretion was studied in six duodenal ulcer patients. Intravenous GH-RIH infused in graded doses ranging from 0.62 to 5.0 microgram/kg/hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 15% of control level at the dose of 5.0 microgram/kg/hr. Acid inhibition was paralleled by a decrease in the pepsin output and accompanied by a dose-dependent reduction in serum growth hormone and insulin levels measured by radioimmunoassay. GH-RIH used in a single dose of 2.5 microgram/kg/hr produced about 85% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in serum gastrin and insulin levels. The effect of GH-RIH on histamine-stimulated secretion was very modest and observed only after stopping the GH-RIH infusion. Thus GH-RIH suppressed acid and pepsin secretion induced by pentagastrin and a meal, and this effect was accompanied by a suppression of serum growth hormone and gastrin levels which may contribute to the inhibition of gastric secretion observed.

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

PubMed Central

Sharma, Geetanjali

2011-01-01

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

Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb's cycle flux independent of ATP synthesis.

PubMed

Cline, Gary W; Pongratz, Rebecca L; Zhao, Xiaojian; Papas, Klearchos K

2011-11-11

Mechanistic models of glucose stimulated insulin secretion (GSIS) established in minimal media in vitro, may not accurately describe the complexity of coupling metabolism with insulin secretion that occurs in vivo. As a first approximation, we have evaluated metabolic pathways in a typical growth media, DMEM as a surrogate in vivo medium, for comparison to metabolic fluxes observed under the typical experimental conditions using the simple salt-buffer of KRB. Changes in metabolism in response to glucose and amino acids and coupling to insulin secretion were measured in INS-1 832/13 cells. Media effects on mitochondrial function and the coupling efficiency of oxidative phosphorylation were determined by fluorometrically measured oxygen consumption rates (OCRs) combined with (31)P NMR measured rates of ATP synthesis. Substrate preferences and pathways into the TCA cycle, and the synthesis of mitochondrial 2nd messengers by anaplerosis were determined by (13)C NMR isotopomer analysis of the fate of [U-(13)C] glucose metabolism. Despite similar incremental increases in insulin secretion, the changes of OCR in response to increasing glucose from 2.5 to 15mM were blunted in DMEM relative to KRB. Basal and stimulated rates of insulin secretion rates were consistently higher in DMEM, while ATP synthesis rates were identical in both DMEM and KRB, suggesting greater mitochondrial uncoupling in DMEM. The relative rates of anaplerosis, and hence synthesis and export of 2nd messengers from the mitochondria were found to be similar in DMEM to those in KRB. And, the correlation of total PC flux with insulin secretion rates in DMEM was found to be congruous with the correlation in KRB. Together, these results suggest that signaling mechanisms associated with both TCA cycle flux and with anaplerotic flux, but not ATP production, may be responsible for the enhanced rates of insulin secretion in more complex, and physiologically-relevant media. Copyright © 2011 Elsevier Inc. All rights reserved.

Physiological concentrations of interleukin-6 directly promote insulin secretion, signal transduction, nitric oxide release, and redox status in a clonal pancreatic β-cell line and mouse islets.

PubMed

da Silva Krause, Mauricio; Bittencourt, Aline; Homem de Bittencourt, Paulo Ivo; McClenaghan, Neville H; Flatt, Peter R; Murphy, Colin; Newsholme, Philip

2012-09-01

Interleukin-6 (IL6) has recently been reported to promote insulin secretion in a glucagon-like peptide-1-dependent manner. Herein, the direct effects of IL6 (at various concentrations from 0 to 1000 pg/ml) on pancreatic β-cell metabolism, AMP-activated protein kinase (AMPK) signaling, insulin secretion, nitrite release, and redox status in a rat clonal β-cell line and mouse islets are reported. Chronic insulin secretion (in μg/mg protein per 24  h) was increased from 128·7±7·3 (no IL6) to 178·4±7·7 (at 100  pg/ml IL6) in clonal β-cells and increased significantly in islets incubated in the presence of 5·5  mM glucose for 2  h, from 0·148 to 0·167±0·003  ng/islet. Pretreatment with IL6 also induced a twofold increase in basal and nutrient-stimulated insulin secretion in subsequent 20 min static incubations. IL6 enhanced both glutathione (GSH) and glutathione disulphide (GSSG) by nearly 20% without changing intracellular redox status (GSSG/GSH). IL6 dramatically increased iNOS expression (by ca. 100-fold) with an accompanying tenfold rise in nitrite release in clonal β-cells. Phosphorylated AMPK levels were elevated approximately twofold in clonal β-cells and mouse islet cells. Calmodulin-dependent protein kinase kinase levels (CaMKK), an upstream kinase activator of AMPK, were also increased by 50% after IL6 exposure (in β-cells and islets). Our data have demonstrated that IL6 can stimulate β-cell-dependent insulin secretion via direct cell-based mechanisms. AMPK, CaMKK (an upstream kinase activator of AMPK), and the synthesis of nitric oxide appear to alter cell metabolism to benefit insulin secretion. In summary, IL6 exerts positive effects on β-cell signaling, metabolism, antioxidant status, and insulin secretion.

Utility of C-peptide for a reliable estimate of insulin secretion in children with growth hormone deficiency.

PubMed

Ciresi, Alessandro; Cicciò, Floriana; Radellini, Stefano; Giordano, Carla

2016-08-01

GH treatment (GHT) can lead to glucose metabolism impairment through decreased insulin sensitivity and impaired pancreatic β-cell function, which are the two key components of the pathogenesis of diabetes. Therefore, in addition to insulin sensitivity, during GHT it is very important to perform a reliable evaluation of insulin secretion. However, conflicting data exist regarding the insulin secretion in children during GHT. C-peptide provides a more reliable estimate of β-cell function than insulin, but few studies evaluated it during GHT. Our aim was to assess the usefulness of C-peptide in the evaluation of insulin secretion in GH deficiency (GHD) children. In 48 GHD children, at baseline and after 12 and 24months of GHT, and in 56 healthy subjects we evaluated fasting and glucagon-stimulated (AUCCpep) C-peptide levels in addition to other commonly used secretion indexes, such as fasting and oral glucose tolerance test-stimulated insulin levels (AUCINS), Homa-β, and insulinogenic index. The main outcomes were the change in C-peptide during GHT and its correlation with the auxological and hormonal parameters. At baseline GHD children showed a significant lower AUCCpep (p=0.006), while no difference was found for the other indexes. Both fasting C-peptide (beta 0.307, p=0.016) and AUCCpep (beta 0.379, p=0.002) were independently correlated with IGF-I SDS, while no correlation was found for all other indexes. After 12months an increase in Homa-β (p<0.001), fasting C-peptide (p=0.002) and AUCCpep (p<0.001) was found. At multivariate analysis, only fasting C-peptide (beta 0.783, p=0.001) and AUCCpep (beta 0.880, p<0.001) were independently correlated with IGF-I SDS. C-peptide, rather than the insulin-derived indexes, has proved to be the most useful marker of insulin secretion correlated to IGF-I levels in GHD children. Therefore, we suggest the use of glucagon test both as diagnostic test for the GH assessment and as a useful tool for the evaluation of insulin secretion during GHT in children. Copyright © 2016 Elsevier Ltd. All rights reserved.

Betacellulin overexpression in mesenchymal stem cells induces insulin secretion in vitro and ameliorates streptozotocin-induced hyperglycemia in rats.

PubMed

Paz, Ana H; Salton, Gabrielle Dias; Ayala-Lugo, Ana; Gomes, Cristiano; Terraciano, Paula; Scalco, Rosana; Laurino, Claudia Cilene Fernandes Correia; Passos, Eduardo Pandolfi; Schneider, Marlon R; Meurer, Luise; Cirne-Lima, Elizabeth

2011-02-01

Betacellulin (BTC), a ligand of the epidermal growth factor receptor, has been shown to promote growth and differentiation of pancreatic β-cells and to improve glucose metabolism in experimental diabetic rodent models. Mesenchymal stem cells (MSCs) have been already proved to be multipotent. Recent work has attributed to rat and human MSCs the potential to differentiate into insulin-secreting cells. Our goal was to transfect rat MSCs with a plasmid containing BTC cDNA to guide MSC differentiation into insulin-producing cells. Prior to induction of cell MSC transfection, MSCs were characterized by flow cytometry and the ability to in vitro differentiate into mesoderm cell types was evaluated. After rat MSC characterization, these cells were electroporated with a plasmid containing BTC cDNA. Transfected cells were cultivated in Dulbecco's modified Eagle medium high glucose (H-DMEM) with 10 mM nicotinamide. Then, the capability of MSC-BTC to produce insulin in vitro and in vivo was evaluated. It was possible to demonstrate by radioimmunoassay analysis that 10(4) MSC-BTC cells produced up to 0.4 ng/mL of insulin, whereas MSCs transfected with the empty vector (negative control) produced no detectable insulin levels. Moreover, MSC-BTC were positive for insulin in immunohistochemistry assay. In parallel, the expression of pancreatic marker genes was demonstrated by molecular analysis of MSC-BTC. Further, when MSC-BTC were transplanted to streptozotocin diabetic rats, BTC-transfected cells ameliorated hyperglycemia from over 500 to about 200 mg/dL at 35 days post-cell transplantation. In this way, our results clearly demonstrate that BTC overabundance enhances glucose-induced insulin secretion in MSCs in vitro as well as in vivo.

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

PubMed

Limesand, Sean W; Rozance, Paul J

2017-08-01

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

Dose- and Glucose-Dependent Effects of Amino Acids on Insulin Secretion from Isolated Mouse Islets and Clonal INS-1E Beta-Cells

PubMed Central

Liu, Zhenping; Jeppesen, Per B.; Gregersen, Søren; Chen, Xiaoping; Hermansen, Kjeld

2008-01-01

BACKGROUND: The influence of glucose and fatty acids on beta-cell function is well established whereas little is known about the role of amino acids (AAs). METHODS: Islets isolated from NMRI mice were incubated overnight. After preincubation, isolated islets as well as clonal INS-1E beta-cells were incubated for 60 min in a modified Krebs Ringer buffer containing glucose and AAs. RESULTS: At 16.7 mmol/l (mM) glucose, L-arginine, L-lysine, L-alanine, L-proline, L-leucine, and L-glutamine potentiated glucose-stimulated insulin secretion dose-dependently, while DL-homocysteine inhibited insulin secretion. Maximal insulin stimulation was obtained at 20 mM L-proline, L-lysine, L-alanine, L-arginine (islets: 2.5 to 6.7 fold increase; INS-1E cells: 1.6 to 2.2 fold increase). L-glutamine and L-leucine only increased glucose-stimulated (16.7 mM) insulin secretion (INS-1E cells: 1.5 and 1.3 fold, respectively) at an AA concentration of 20 mM. Homocysteine inhibited insulin secretion both at 5.6 mM and 16.7 mM glucose. At glucose levels ranging from 1.1 to 25 mM, the equimolar concentration of 10 mM, L-proline, L-lysine, L-arginine increased insulin secretion from mouse islets and INS-1E cells at all glucose levels applied, with a maximal effect obtained at 25 mM glucose. At a concentration of 10 mM, L-arginine and L-lysine had the highest insulinotropic potency among the AAs investigated. CONCLUSION: L-arginine, L-lysine, L-alanine, L-proline, L-leucine and L-glutamine acutely stimulate insulin secretion from mouse islets and INS-1E cells in a dose- and glucose-dependent manner, whereas DL-homocysteine inhibits insulin release. PMID:19290384

Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort.

PubMed

Cederberg, Henna; Stančáková, Alena; Yaluri, Nagendra; Modi, Shalem; Kuusisto, Johanna; Laakso, Markku

2015-05-01

The aim of this work was to investigate the mechanisms underlying the risk of type 2 diabetes associated with statin treatment in the population-based Metabolic Syndrome in Men (METSIM) cohort. A total of 8,749 non-diabetic participants, aged 45-73 years, were followed up for 5.9 years. New diabetes was diagnosed in 625 men by means of an OGTT, HbA1c ≥6.5% (48 mmol/mol) or glucose-lowering medication started during the follow-up. Insulin sensitivity and secretion were evaluated with OGTT-derived indices. Participants on statin treatment (N = 2,142) had a 46% increased risk of type 2 diabetes (adjusted HR 1.46 [95% CI 1.22, 1.74]). The risk was dose dependent for simvastatin and atorvastatin. Statin treatment significantly increased 2 h glucose (2hPG) and glucose AUC of an OGTT at follow-up, with a nominally significant increase in fasting plasma glucose (FPG). Insulin sensitivity was decreased by 24% and insulin secretion by 12% in individuals on statin treatment (at FPG and 2hPG <5.0 mmol/l) compared with individuals without statin treatment (p < 0.01). Decreases in insulin sensitivity and insulin secretion were dose dependent for simvastatin and atorvastatin. Statin treatment increased the risk of type 2 diabetes by 46%, attributable to decreases in insulin sensitivity and insulin secretion.

Insulin-secreting non-islet cells are resistant to autoimmune destruction.

PubMed Central

Lipes, M A; Cooper, E M; Skelly, R; Rhodes, C J; Boschetti, E; Weir, G C; Davalli, A M

1996-01-01

Transgenic nonobese diabetic mice were created in which insulin expression was targeted to proopiomelanocortin-expressing pituitary cells. Proopiomelanocortin-expressing intermediate lobe pituitary cells efficiently secrete fully processed, mature insulin via a regulated secretory pathway, similar to islet beta cells. However, in contrast to the insulin-producing islet beta cells, the insulin-producing intermediate lobe pituitaries are not targeted or destroyed by cells of the immune system. Transplantation of the transgenic intermediate lobe tissues into diabetic nonobese diabetic mice resulted in the restoration of near-normoglycemia and the reversal of diabetic symptoms. The absence of autoimmunity in intermediate lobe pituitary cells engineered to secrete bona fide insulin raises the potential of these cell types for beta-cell replacement therapy for the treatment of insulin-dependent diabetes mellitus. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8710916

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

PubMed Central

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

2017-01-01

Objective To compare the effects of biliopancreatic diversion (BPD) and laparoscopic gastric banding (LAGB) on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P). Methods A total of 52 obese women (age 30-66 years) suffering from type 2 diabetes mellitus (T2DM) were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. Results Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity) increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. Conclusion We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion), but without increasing the beta cell glucose sensitivity. PMID:27951535

The growth hormone-insulin-like growth factor axis in glycogen storage disease type 1: evidence of different growth patterns and insulin-like growth factor levels in patients with glycogen storage disease type 1a and 1b.

PubMed

Melis, Daniela; Pivonello, Rosario; Parenti, Giancarlo; Della Casa, Roberto; Salerno, Mariacarolina; Balivo, Francesca; Piccolo, Pasquale; Di Somma, Carolina; Colao, Annamaria; Andria, Generoso

2010-04-01

To investigate the growth hormone (GH)-insulin-like growth factor (IGF) system in patients with glycogen storage disease type 1 (GSD1). This was a prospective, case-control study. Ten patients with GSD1a and 7 patients with GSD1b who were given dietary treatment and 34 sex-, age-, body mass index-, and pubertal stage-matched control subjects entered the study. Auxological parameters were correlated with circulating GH, either at basal or after growth hormone releasing hormone plus arginine test, insulin-like growth factors (IGF-I and IGF-II), and anti-pituitary antibodies (APA). Short stature was detected in 10.0% of patients with GSD1a, 42.9% of patients with GSD1b (P = .02), and none of the control subjects. Serum IGF-I levels were lower in patients with GSD1b (P = .0001). An impaired GH secretion was found in 40% of patients with GSD1a (P = .008), 57.1% of patients with GSD1b (P = .006), and none of the control subjects. Short stature was demonstrated in 3 of 4 patients with GSD1b and GH deficiency. The prevalence of APA was significantly higher in patients with GSD1b than in patients with GSD1a (P = .02) and control subjects (P = .03). The GH response to the provocative test inversely correlated with the presence of APA (P = .003). Compared with levels in control subjects, serum IGF-II and insulin levels were higher in both groups of patients, in whom IGF-II levels directly correlated with height SD scores (P = .003). Patients with GSD1a have an impaired GH secretion associated with reference range serum IGF-I levels and normal stature, whereas in patients with GSD1b, the impaired GH secretion, probably because of the presence of APA, was associated with reduced IGF-I levels and increased prevalence of short stature. The increased IGF-II levels, probably caused by increased insulin levels, in patients with GSD1 are presumably responsible for the improved growth pattern observed in patients receiving strict dietary treatment. Copyright 2010 Mosby, Inc. All rights reserved.

Effects of experimentally induced mild hyperthyroidism on growth hormone and insulin secretion and sex steroid levels in healthy young men.

PubMed

Lovejoy, J C; Smith, S R; Bray, G A; Veldhuis, J D; Rood, J C; Tulley, R

1997-12-01

Although triiodothyronine (T3) exerts major regulatory actions in both animals and humans, most clinical studies of T3 administration have been relatively short-term. The present study examined the effects of more than 2 months (63 days) of low-dose T3 treatment on overnight pulsatile growth hormone (GH) secretion, short-term insulin secretion, and of sex steroid levels in seven healthy, lean men studied at an inpatient metabolic unit. At baseline, there were strong correlations between sex hormone-binding globulin (SHBG) and several measures of GH production, including total GH production (r = .99), GH interburst interval (r = -.75), and GH mass (r = .82). SHBG was also inversely correlated with basal insulin secretion (r = -.74). There was a 42% increase in serum levels of total testosterone (18.5 +/- 1.3 to 26.3 +/- 1.8 nmol/L, P = .005) and a 150% increase in SHBG (18.0 +/- 2.2 to 44.9 +/- 7.0 nmol/L, P = .008) following T3 treatment. Estradiol and free testosterone levels were unchanged by treatment, although free testosterone decreased from 142.8 +/- 18.4 to 137.3 +/- 19.5 pmol/L. T3 treatment significantly reduced the GH interburst interval (P < .05) and produced slight increases in the measures of GH secretion. There were no statistically significant effects of T3 treatment on insulin secretion, although insulin peak amplitude, mass secreted per burst, and total production all decreased. We conclude that experimentally induced T3 excess in healthy men produces significant and sustained changes in sex hormone levels and GH secretion. Furthermore, there are strong associations between SHBG and both GH and insulin secretion independent of thyroid hormone excess that require additional study.

Zinc Up-Regulates Insulin Secretion from β Cell-Like Cells Derived from Stem Cells from Human Exfoliated Deciduous Tooth (SHED).

PubMed

Kim, Gyuyoup; Shin, Ki-Hyuk; Pae, Eung-Kwon

2016-12-13

Stem cells from human exfoliated deciduous tooth (SHED) offer several advantages over other stem cell sources. Using SHED, we examined the roles of zinc and the zinc uptake transporter ZIP8 (Zrt- and irt-like protein 8) while inducing SHED into insulin secreting β cell-like stem cells (i.e., SHED-β cells). We observed that ZIP8 expression increased as SHED differentiated into SHED-β cells, and that zinc supplementation at day 10 increased the levels of most pancreatic β cell markers-particularly Insulin and glucose transporter 2 (GLUT2). We confirmed that SHED-β cells produce insulin successfully. In addition, we note that zinc supplementation significantly increases insulin secretion with a significant elevation of ZIP8 transporters in SHED-β cells. We conclude that SHED can be converted into insulin-secreting β cell-like cells as zinc concentration in the cytosol is elevated. Insulin production by SHED-β cells can be regulated via modulation of zinc concentration in the media as ZIP8 expression in the SHED-β cells increases.

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.

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

PubMed Central

Rorsman, Patrik; Ashcroft, Frances M

2018-01-01

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

Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat.

PubMed

Holness, M J; Greenwood, G K; Smith, N D; Sugden, M C

2005-11-01

Hyperthyroidism modifies lipid dynamics (increased oxidation), impairs insulin action and can suppress insulin secretion. We therefore examined the impact of hyperthyroidism on the relationship between glucose-stimulated insulin secretion (GSIS) and insulin action, using late pregnancy as a model of physiological insulin resistance that is associated with compensatory insulin hypersecretion to maintain glucose tolerance. Our aim was to examine whether hyperthyroidism compromises the regulation of insulin secretion and the ability of insulin to modulate circulating lipid concentrations in late pregnancy. Hyperthyroidism was induced by tri-iodothyronine (T(3)) administration from day 17 to 19 of pregnancy. GSIS was assessed during an IVGTT and during hyperglycaemic clamps in vivo and in vitro, using step-up and -down islet perifusions. Hyperthyroidism in pregnancy elevated the glucose threshold for GSIS and impaired GSIS at low and high glucose concentrations in islet perifusions. In the intact animal, insulin secretion (after bolus glucose) was more rapidly curtailed following removal of the glucose stimulus to secretion. In contrast, GSIS was maintained during protracted hyperglycaemia (hyperglycaemic clamps) in the hyperthyroid pregnant state in vivo. Hyperthyroidism in vivo during late pregnancy blunts GSIS in subsequently isolated and perifused islets at low and high glucose concentrations. It also adversely affects GSIS under conditions of an acute glucose challenge in vivo. In contrast, GSIS is maintained during sustained hyperglycaemia in vivo, suggesting that in vivo factors can rescue GSIS. The ability of insulin to suppress systemic lipid levels during hyperglycaemic clamps was impaired. We therefore suggest that higher circulating lipids may preserve GSIS under conditions of sustained hyperglycaemia in the hyperthyroid pregnancy.

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.

β-Cell lipotoxicity in response to free fatty acid elevation in prepubertal youth: African American versus Caucasian contrast.

PubMed

Michaliszyn, Sara F; Bonadonna, Riccardo C; Sjaarda, Lindsey A; Lee, Sojung; Farchoukh, Lama; Arslanian, Silva A

2013-08-01

Prepubertal African American (AA) youth compared with their Caucasian (C) peers have higher insulin secretion, which correlates positively with free fatty acid (FFA) concentration. In our continued efforts to explain the racial disparity in insulinemia, and because FFAs modulate insulin secretion, we hypothesized that AA youth would have a greater response to FFA-induced β-cell insulin secretion than C youth. We compared the short-term effects of FFA elevation on fasting and glucose-stimulated C-peptide-modeled insulin secretion in prepubertal normal-weight AA versus C peers during a 2-h hyperglycemic clamp (12.5 mmol/L) on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid (IL). During IL infusion, insulin sensitivity (IS) declined comparably in AA and C youth. Glucose sensitivity of first- and second-phase insulin secretion showed a significant condition × race interaction being higher in AA youth. Disposition index, β-cell function relative to IS, declined with IL infusion in AA and C youth, with a significantly greater decrease in Cs compared with AAs. In conclusion, AA and C prepubertal youth both demonstrated a decline in β-cell function relative to IS during IL infusion, indicative of acute lipotoxicity. The greater decline in C youth compared with AAs may suggest that C youth are more susceptible to β-cell lipotoxicity than AA youth, or alternatively, that AA youth are hypersensitive to FFA stimulation of β-cell insulin secretion, consistent with our theory.

Novel Insights into the Relationship between Diabetes and Osteoporosis

PubMed Central

de Paula, Francisco J. A.; Horowitz, Mark C.; Rosen, Clifford J.

2012-01-01

Only three decades ago adipose tissue was considered inert with little relationship to insulin resistance. Similarly bone has long been thought purely in its structural context. In the last decade, emerging evidence has revealed important endocrine roles for both bone and adipose tissue. The interaction between these two tissues is remarkable. Bone marrow mesenchymal stem cells give rise to both osteoblasts and adipocytes. Leptin and adiponectin, two adipokines secreted by fat tissue, control energy homeostasis, but also have complex actions on the skeleton. In turn, the activities of bone cells are not limited to their bone remodeling activities, but also to modulation of adipose sensitivity and insulin secretion. This review will discuss these new insights linking bone remodeling to the control of fat metabolism and the association between diabetes mellitus and osteoporosis. PMID:20938995

D-Xylose as a sugar complement regulates blood glucose levels by suppressing phosphoenolpyruvate carboxylase (PEPCK) in streptozotocin-nicotinamide-induced diabetic rats and by enhancing glucose uptake in vitro

PubMed Central

Kim, Eunju; Kim, Yoo-Sun; Kim, Kyung-Mi; Jung, Sangwon; Yoo, Sang-Ho

2016-01-01

BACKGROUND/OBJECTIVES Type 2 diabetes (T2D) is more frequently diagnosed and is characterized by hyperglycemia and insulin resistance. D-Xylose, a sucrase inhibitor, may be useful as a functional sugar complement to inhibit increases in blood glucose levels. The objective of this study was to investigate the anti-diabetic effects of D-xylose both in vitro and stretpozotocin (STZ)-nicotinamide (NA)-induced models in vivo. MATERIALS/METHODS Wistar rats were divided into the following groups: (i) normal control; (ii) diabetic control; (iii) diabetic rats supplemented with a diet where 5% of the total sucrose content in the diet was replaced with D-xylose; and (iv) diabetic rats supplemented with a diet where 10% of the total sucrose content in the diet was replaced with D-xylose. These groups were maintained for two weeks. The effects of D-xylose on blood glucose levels were examined using oral glucose tolerance test, insulin secretion assays, histology of liver and pancreas tissues, and analysis of phosphoenolpyruvate carboxylase (PEPCK) expression in liver tissues of a STZ-NA-induced experimental rat model. Levels of glucose uptake and insulin secretion by differentiated C2C12 muscle cells and INS-1 pancreatic β-cells were analyzed. RESULTS In vivo, D-xylose supplementation significantly reduced fasting serum glucose levels (P < 0.05), it slightly reduced the area under the glucose curve, and increased insulin levels compared to the diabetic controls. D-Xylose supplementation enhanced the regeneration of pancreas tissue and improved the arrangement of hepatocytes compared to the diabetic controls. Lower levels of PEPCK were detected in the liver tissues of D-xylose-supplemented rats (P < 0.05). In vitro, both 2-NBDG uptake by C2C12 cells and insulin secretion by INS-1 cells were increased with D-xylose supplementation in a dose-dependent manner compared to treatment with glucose alone. CONCLUSIONS In this study, D-xylose exerted anti-diabetic effects in vivo by regulating blood glucose levels via regeneration of damaged pancreas and liver tissues and regulation of PEPCK, a key rate-limiting enzyme in the process of gluconeogenesis. In vitro, D-xylose induced the uptake of glucose by muscle cells and the secretion of insulin cells by β-cells. These mechanistic insights will facilitate the development of highly effective strategy for T2D. PMID:26865911

An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice.

PubMed

Holland, William L; Adams, Andrew C; Brozinick, Joseph T; Bui, Hai H; Miyauchi, Yukiko; Kusminski, Christine M; Bauer, Steven M; Wade, Mark; Singhal, Esha; Cheng, Christine C; Volk, Katherine; Kuo, Ming-Shang; Gordillo, Ruth; Kharitonenkov, Alexei; Scherer, Philipp E

2013-05-07

FGF21, a member of the fibroblast growth factor (FGF) superfamily, has recently emerged as a regulator of metabolism and energy utilization. However, the exact mechanism(s) whereby FGF21 mediates its actions have not been elucidated. There is considerable evidence that insulin resistance may arise from aberrant accumulation of intracellular lipids in insulin-responsive tissues due to lipotoxicity. In particular, the sphingolipid ceramide has been implicated in this process. Here, we show that FGF21 rapidly and robustly stimulates adiponectin secretion in rodents while diminishing accumulation of ceramides in obese animals. Importantly, adiponectin-knockout mice are refractory to changes in energy expenditure and ceramide-lowering effects evoked by FGF21 administration. Moreover, FGF21 lowers blood glucose levels and enhances insulin sensitivity in diabetic Lep(ob/ob) mice and diet-induced obese (DIO) mice only when adiponectin is functionally present. Collectively, these data suggest that FGF21 is a potent regulator of adiponectin secretion and that FGF21 critically depends on adiponectin to exert its glycemic and insulin sensitizing effects. Copyright © 2013 Elsevier Inc. All rights reserved.

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

PubMed

Johnson, Michelle H; de Mejia, Elvira Gonzalez

2016-03-30

Berries are a rich source of bioactive phenolic compounds that are able to bind and inhibit the enzyme dipeptidyl peptidase-IV (DPP-IV), a current target for type-2 diabetes therapy. The objectives were to determine the role of berry phenolic compounds to modulate incretin-cleaving DPP-IV and its substrate glucagon-like peptide-1 (GLP-1), insulin secretion from pancreatic β-cells, and genes and proteins involved in the insulin secretion pathway using cell culture. Anthocyanins (ANC) from 50% blueberry-50% blackberry (Blu-Bla) and 100% blackberry (Bla) fermented beverages at 50 μM cyanidin-3-glucoside equivalents increased (p < 0.05) glucose-stimulated insulin secretion from pancreatic β-cells (iNS-1E) both when applied directly and following simulated absorption through Caco-2 cells (by 233 and 100 μIU insulin/mL, respectively). ANC 50%Blu-Bla and ANC 100%Bla upregulated the gene for incretin hormone GLP-1 (fold-change 3.0 ± 1.4 and 2.0 ± 0.3, respectively) and genes in the insulin secretory pathway including insulin-like growth factor 1 receptor (iGF1R, 2.3 ± 0.6 and 1.6 ± 0.3, respectively), and increased (p < 0.05) the protein expression of insulin-like growth factor 2 (IGF-II), insulin-like growth factor binding proteins (IGFBP-2 and 3), and vascular endothelial growth factor (VEGF) in iNS-1E cells. Taken together, anthocyanins, predominantly delphinidin-3-arabinoside, from fermented berry beverages have the potential to modulate DPP-IV and its substrate GLP-1, to increase insulin secretion, and to upregulate expression of mRNA of insulin-receptor associated genes and proteins in pancreatic β-cells.

[Role of growth hormone in the pathogenesis of dawn phenomenon in IDDM].

PubMed

Mimura, A; Kageyama, S; Itoh, K; Miura, J; Kurata, H; Yokoyama, J; Ikeda, Y

1992-06-20

The early morning hyperglycemia of diabetic patients has been commonly referred to as the "dawn phenomenon". Recently the nocturnal surges of growth hormone (GH) have been suggested as an important factor in the pathogenesis of the dawn phenomenon. In order to reassess the role of the nocturnal GH secretion in the dawn phenomenon, seven C-peptide negative diabetic patients were studied during 48hr-feedback control using a closed-loop insulin infusion device (Biostator). They received oral sleeping medication only on the first night (control) and sleeping medication with anticholinergic agent (pirenzepine 75mg) on the second night, and blood glucose, insulin requirements, GH and cortisol concentrations during 0000hr and 0700hr were measured. The peak of sleep-induced GH secretions was markedly suppressed by pirenzepine in comparison with the control night (19.8 +/- 3.7 vs. 3.0 +/- 1.2ng/ml; p less than 0.05). Insulin requirements during 0500hr and 0700hr were suppressed significantly by pirenzepine (3.0 +/- 0.2 vs. 2.0 +/- 0.2U/2hr; p less than 0.05). Insulin infusion ratio, i.e. insulin requirements during 0500hr and 0700hr divided by those during 0000hr and 0200hr, was decreased by pirenzepine (2.2 +/- 0.3 vs. 1.5 +/- 0.2; p less than 0.05). There were no significant differences in blood glucose and cortisol concentrations whether or not the anticholinergic agent was given. In conclusion, these results have shown that an anticholinergic agent may be useful in the management of insulin-treated patients with marked dawn phenomenon.

Sleep duration and insulin resistance in individuals without type 2 diabetes: the PPP-Botnia study.

PubMed

Pyykkönen, Antti-Jussi; Isomaa, Bo; Pesonen, Anu-Katriina; Eriksson, Johan G; Groop, Leif; Tuomi, Tiinamaija; Räikkönen, Katri

2014-08-01

Both short and long sleep duration may increase risk of type 2 diabetes (diabetes). We studied if short and long sleep durations were associated with insulin resistance (IR) and insulin secretion in individuals without diabetes, and if the associations remained after we excluded individuals who reported more frequent and severe complaints of sleep apnea and insomnia. An oral glucose tolerance test (OGTT) was performed for 722 adults without diabetes. Indices of IR and insulin secretion were calculated. Sleep duration and complaints of sleep apnea and insomnia were self-reported. In comparison to average sleepers (6-9 h/night), short sleepers (< 6 h/night) had higher 120-min insulin and AUC glucose, and long sleepers (≥ 9 h/night) had higher fasting and 120-min insulin, 120-min glucose, and HOMAIR and lower Insulin Sensitivity Index. After adjusting for confounders and after excluding individuals who reported more frequent and severe complaints of sleep apnea and insomnia, long sleep duration remained significantly associated with IR and insulin secretion. Long but not short sleep duration is associated with IR and insulin secretion in individuals without diabetes whether or not accompanied by sleep complaints. Long sleepers may benefit from targeted preventions and interventions that aim at reducing risk of future diabetes.

Effects of 12 weeks' treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study.

PubMed

Hove, K D; Brøns, C; Færch, K; Lund, S S; Petersen, J S; Karlsen, A E; Rossing, P; Rehfeld, J F; Vaag, A

2013-01-01

Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA(1c) and cardiovascular risk factors in type 2 diabetes. Forty-one patients with type 2 diabetes using dietary control or oral glucose-lowering treatment were randomised to receive add-on esomeprazole 40 mg (n = 20) or placebo (n = 21) for 12 weeks. Randomisation was carried out prior to inclusion on the basis of a computer-generated random-number list. The allocation sequence was concealed in sealed envelopes from the researcher enrolling and assessing participants. The study was undertaken at Steno Diabetes Center, Gentofte, Denmark. The primary outcome was change in AUC for insulin levels during a meal test. Secondary outcomes were the levels of HbA(1c) and biochemical markers of cardiovascular risk, including lipids, coagulation factors, inflammation markers, markers of endothelial function and 24 h ambulatory BP measurements. Forty-one participants were analysed. In the esomeprazole-treated group the AUC for insulin did not change (before vs after treatment: 28,049 ± 17,659 vs 27,270 ± 32,004 pmol/l × min (p = 0.838). In the placebo group AUC for insulin decreased from 27,392 ± 14,348 pmol/l × min to 22,938 ± 11,936 pmol/l × min (p = 0.002). Esomeprazole treatment (n = 20) caused a ninefold increase in the AUC for gastrin. HbA(1c) increased from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.3 ± 0.8% (56 ± 6 mmol/mol) in the esomeprazole-treated group and from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.4 ± 0.8% (57 ± 6 mmol/mol) in the placebo group (n = 21) (p for difference in change >0.05). Except for BP, there were no differences between the groups in the markers of cardiovascular risk (p > 0.05). Monitoring of 24 h ambulatory BP showed a significant decrease in daytime systolic BP, daytime diastolic BP and 24 h diastolic BP in the placebo group (p < 0.05). No change in BP was seen in the patients treated with esomeprazole. Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.

Genetically Engineered Islets and Alternative Sources of Insulin-Producing Cells for Treating Autoimmune Diabetes: Quo Vadis?

PubMed Central

Chou, Feng-Cheng; Huang, Shing-Hwa; Sytwu, Huey-Kang

2012-01-01

Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1) detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2) inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells. PMID:22690214

Randomized Controlled Trial of a MUFA or Fiber-Rich Diet on Hepatic Fat in Prediabetes

PubMed Central

Errazuriz, Isabel; Dube, Simmi; Slama, Michael; Visentin, Roberto; Nayar, Sunita; O’Connor, Helen; Cobelli, Claudio; Das, Swapan Kumar; Basu, Ananda; Kremers, Walter Karl; Port, John

2017-01-01

Context: Increased prevalence of type 2 diabetes mellitus and prediabetes worldwide is attributed in part to an unhealthy diet. Objective: To evaluate whether 12 weeks of high monounsaturated fatty acid (MUFA) or fiber-rich weight-maintenance diet lowers hepatic fat and improves glucose tolerance in people with prediabetes. Design: Subjects underwent a [6, 6-2H2]–labeled 75-g oral glucose tolerance test to estimate hepatic insulin sensitivity and liver fat fraction (LFF) using magnetic resonance spectroscopy before and after intervention. Setting: Mayo Clinic Clinical Research Trials Unit. Participants: 43 subjects with prediabetes. Intervention: Subjects were randomized into three isocaloric weight-maintaining diets containing MUFA (olive oil), extra fiber, and standard US food (control-habitual diet). Outcome Measures: LFF, glucose tolerance, and indices of insulin action and secretion. Results: Body weight was maintained constant in all groups during the intervention. Glucose and hormonal concentrations were similar in all groups before, and unchanged after, 12 weeks of intervention. LFF was significantly lower after intervention in the MUFA group (P < 0.0003) but remained unchanged in the fiber (P = 0.25) and control groups (P = 0.45). After 12 weeks, LFF was significantly lower in the MUFA than in the control group (P = 0.01), but fiber and control groups did not differ (P = 0.41). Indices of insulin action and secretion were not significantly different between the MUFA and control groups after intervention (P ≥ 0.11), but within-group comparison showed higher hepatic (P = 0.01) and total insulin sensitivity (P < 0.04) with MUFA. Conclusions: Twelve weeks of a MUFA diet decreases hepatic fat and improves both hepatic and total insulin sensitivity. PMID:28323952

mRNA destabilization improves glycemic responsiveness of transcriptionally regulated hepatic insulin gene therapy in vitro and in vivo.

PubMed

Thulé, Peter M; Lin, Yulin; Jia, Dingwu; Olson, Darin E; Tang, Shiue-Cheng; Sambanis, Athanassios

2017-03-01

Hepatic insulin gene therapy (HIGT) employing a glucose and insulin sensitive promoter to direct insulin transcription can lower blood sugars within 2 h of an intraperitoneal glucose challenge. However, post-challenge blood sugars frequently decline to below baseline. We hypothesize that this 'over-shoot' hypoglycemia results from sustained translation of long-lived transgene message, and that reducing pro-insulin message half-life will ameliorate post-challenge hypoglycemia. We compared pro-insulin message content and insulin secretion from primary rat hepatocytes expressing insulin from either a standard construct (2xfur), or a construct producing a destabilized pro-insulin message (InsTail), following exposure to stimulating or inhibitory conditions. Hepatocytes transduced with a 2xfur construct accumulated pro-insulin message, and exhibited increased insulin secretion, under conditions that both inhibit or stimulate transcription. By contrast, pro-insulin message content remained stable in InsTail expressing cells, and insulin secretion increased less than 2xfur during prolonged stimulation. During transitions from stimulatory to inhibitory conditions, or vice versa, amounts of pro-insulin message changed more rapidly in InsTail expressing cells than 2xfur expressing cells. Importantly, insulin secretion increased during the transition from stimulation to inhibition in 2xfur expressing cells, although it remained unchanged in InsTail expressing cells. Use of the InsTail destabilized insulin message tended to more rapidly reduce glucose induced glycemic excursions, and limit post-load hypoglycemia in STZ-diabetic mice in vivo. The data obtained in the present study suggest that combining transcriptional and post-transcriptional regulatory strategies may reduce undesirable glycemic excursion in models of HIGT. Copyright © 2017 John Wiley & Sons, Ltd.

Oxytocin increases extrapancreatic glucagon secretion and glucose production in pancreatectomized dogs

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

Altszuler, N.; Puma, F.; Winkler, B.

1986-05-01

Infusion of oxytocin into normal dogs increases plasma levels of insulin and glucagon and glucose production and uptake. To determine whether infused oxytocin also increases glucagon secretion from extrapancreatic sites, pancreatectomized dogs, off insulin of 18 hr, were infused with oxytocin and plasma glucagon, and glucose production and uptake were measured using the (6-/sup 3/H)glucose primer-infusion technique. The diabetic dogs, in the control period, had elevated plasma glucose and glucagon levels, an increased rate of glucose production, and a relative decrease in glucose uptake (decreased clearance). Infusion of oxytocin (500 ..mu..U/kg/min) caused a rise in plasma glucagon and glucose levels,more » increased glucose production, and further decreased glucose clearance. it is concluded that oxytocin can stimulate secretion of extrapancreatic glucagon, which contributes to the increased glucose production.« less

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

PubMed

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

2016-11-01

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

Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation.

PubMed

Frank, N; Hermida, P; Sanchez-Londoño, A; Singh, R; Gradil, C M; Uricchio, C K

2017-07-01

Octreotide is a somatostatin analog that suppresses insulin secretion. We hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide. Twelve horses, N = 5, ID = 7. Prospective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1.0 μg/kg IV) was then administered, and blood was collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 minute, and 2, 3, 4, 6, 8, 12, and 24 hour for measurement of glucose and insulin concentrations. Area under the curve (AUC) values were calculated. Mean AUC values for glucose and insulin did not differ between normal (n = 5) and ID (n = 7) groups after octreotide injection. Significant time (P < .001) effects were detected for glucose and insulin concentrations. A group × time interaction (P = .091) was detected for insulin concentrations after administration of octreotide, but the group (P = .33) effect was not significant. Octreotide suppresses insulin secretion, resulting in hyperglycemia, and then concentrations increase above baseline as glycemic control is restored. Our hypothesis that octreotide causes insulin concentrations to decrease in horses was supported, but differences between N and ID groups did not reach statistical significance when blood glucose and insulin responses were compared. The utility of an octreotide response test remains to be determined. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Insulin response to a spontaneously ingested standard meal during the development of obesity in GTG-injected mice.

PubMed

Blair, S C; Caterson, I D; Cooney, G J

1996-04-01

(1) To determine glucose and insulin levels in response to ingestion of a standard meal during the development of gold-thioglucose (GTG)-induced obesity. (2) To examine whether the pancreatic beta-cells of GTG-injected mice possess sufficient insulin secretory capacity to compensate for the increasing tissue insulin resistance that occurs with the development of this obesity. The insulin secretory response to a standard meal of chow was examined in chronically catheterised conscious mice 2, 5 and 10 weeks after induction of obesity by a single injection of GTG. At 2 weeks after administration of GTG both the basal insulinaemia and the incremental area under the curve (iAUC) of insulin release after a chow meal were increased compared with age-matched lean control mice (2 week control: 1004 +/- 316 min/microU/ml; 2 week GTG: 1968 +/- 300 min/microU/ml; P < 0.05). By 5 weeks, the GTG-injected mice were approximately 42% heavier than their lean controls and showed a marked glucose intolerance. This was accompanied by hyperinsulinaemia in both the basal state and also in response to ingestion of the chow meal as indicated by the increase in the iAUC of insulin (5 week control: 1113 +/- 331 min/microU/ml; 5 week GTG: 2682 +/- 295 min/microU/ml; P < 0.05). At 10 weeks after GTG administration body weight was further increased, as was the degree of glucose intolerance. Plasma insulin levels, in both the basal state and in response to the ingestion of chow, were also further elevated by 10 weeks following GTG injection (10 week control: 1234 +/- 311 min/microU/ml; 10 week GTG: 6640 +/- 1198 min/microU/ml; P < 0.05). It is apparent that the secretion of insulin in response to a standard chow meal increases progressively with the development of obesity. This finding, in conjunction with an earlier study showing that the insulin secretory response to intravenously administered glucose becomes impaired in the latter stages of the development of obesity in GTG-injected mice [Blair SC, Caterson ID, Cooney GJ. Diabetes 1993; 42: 1153-1158], suggests that the ability of beta-cells of GTG-obese animals to produce and secrete insulin is not impaired but that the beta-cells may become insensitive to glucose within the circulation.

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

PubMed Central

Pachanski, Michele J.; Kirkland, Melissa E.; Kosinski, Daniel T.; Mane, Joel; Cheewatrakoolpong, Boonlert; Xue, Jiyan; Szeto, Daphne; Forrest, Gail; Miller, Corin; Bunzel, Michelle; Plummer, Christopher W.; Chobanian, Harry R.; Miller, Michael W.; Souza, Sarah; Thomas-Fowlkes, Brande S.; Ogawa, Aimie M.; Weinglass, Adam B.; Di Salvo, Jerry; Li, Xiaoyan; Feng, Yue; Tatosian, Daniel A.; Howard, Andrew D.; Colletti, Steven L.

2017-01-01

GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient. PMID:29053717

The Generation of Insulin Producing Cells from Human Mesenchymal Stem Cells by MiR-375 and Anti-MiR-9.

PubMed

Jafarian, Arefeh; Taghikani, Mohammad; Abroun, Saeid; Allahverdi, Amir; Lamei, Maryam; Lakpour, Niknam; Soleimani, Masoud

2015-01-01

MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs that regulate gene expression at the post-transcriptional level. A number of studies have led to the notion that some miRNAs have key roles in control of pancreatic islet development and insulin secretion. Based on some studies on miRNAs pattern, the researchers in this paper investigated the pancreatic differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) by up-regulation of miR-375 and down-regulation of miR-9 by lentiviruses containing miR-375 and anti-miR-9. After 21 days of induction, islet-like clusters containing insulin producing cells (IPCs) were confirmed by dithizone (DTZ) staining. The IPCs and β cell specific related genes and proteins were detected using qRT-PCR and immunofluorescence on days 7, 14 and 21 of differentiation. Glucose challenge test was performed at different concentrations of glucose so extracellular and intracellular insulin and C-peptide were assayed using ELISA kit. Although derived IPCs by miR-375 alone were capable to express insulin and other endocrine specific transcription factors, the cells lacked the machinery to respond to glucose. It was found that over-expression of miR-375 led to a reduction in levels of Mtpn protein in derived IPCs, while treatment with anti-miR-9 following miR-375 over-expression had synergistic effects on MSCs differentiation and insulin secretion in a glucose-regulated manner. The researchers reported that silencing of miR-9 increased OC-2 protein in IPCs that may contribute to the observed glucose-regulated insulin secretion. Although the roles of miR-375 and miR-9 are well known in pancreatic development and insulin secretion, the use of these miRNAs in transdifferentiation was never demonstrated. These findings highlight miRNAs functions in stem cells differentiation and suggest that they could be used as therapeutic tools for gene-based therapy in diabetes mellitus.

Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep.

PubMed

Rozance, Paul J; Anderson, Miranda; Martinez, Marina; Fahy, Anna; Macko, Antoni R; Kailey, Jenai; Seedorf, Gregory J; Abman, Steven H; Hay, William W; Limesand, Sean W

2015-02-01

Hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGFA) are paracrine hormones that mediate communication between pancreatic islet endothelial cells (ECs) and β-cells. Our objective was to determine the impact of intrauterine growth restriction (IUGR) on pancreatic vascularity and paracrine signaling between the EC and β-cell. Vessel density was less in IUGR pancreata than in controls. HGF concentrations were also lower in islet EC-conditioned media (ECCM) from IUGR, and islets incubated with control islet ECCM responded by increasing insulin content, which was absent with IUGR ECCM. The effect of ECCM on islet insulin content was blocked with an inhibitory anti-HGF antibody. The HGF receptor was not different between control and IUGR islets, but VEGFA was lower and the high-affinity VEGF receptor was higher in IUGR islets and ECs, respectively. These findings show that paracrine actions from ECs increase islet insulin content, and in IUGR ECs, secretion of HGF was diminished. Given the potential feed-forward regulation of β-cell VEGFA and islet EC HGF, these two growth factors are highly integrated in normal pancreatic islet development, and this regulation is decreased in IUGR fetuses, resulting in lower pancreatic islet insulin concentrations and insulin secretion. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel.

PubMed

Remedi, Maria S; Friedman, Jonathan B; Nichols, Colin G

2017-01-01

Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of K ATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second K ATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K + depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic K ATP channels and a contributory role for these subunits in the control of insulin secretion. © 2017 Remedi et al.

Suppression in growth hormone during overeating ameliorates the increase in insulin resistance and cardiovascular disease risk

PubMed Central

Cornford, Andrea S.; Barkan, Ariel L.; Hinko, Alexander

2012-01-01

Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate ∼4,000 kcal/day (70 kcal·kg fat-free mass−1·day−1; 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P < 0.05) and increased fasting lipidemia (all P < 0.05 vs. control). In addition, preventing the suppression in GH with overeating also blunted the increase in systemic proteolysis (P < 0.05 GHT vs. control). However, GHT did not alter lipolysis or FSR in response to overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating. PMID:23011065

Suppression in growth hormone during overeating ameliorates the increase in insulin resistance and cardiovascular disease risk.

PubMed

Cornford, Andrea S; Barkan, Ariel L; Hinko, Alexander; Horowitz, Jeffrey F

2012-11-15

Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate ∼4,000 kcal/day (70 kcal·kg fat-free mass(-1)·day(-1); 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P < 0.05) and increased fasting lipidemia (all P < 0.05 vs. control). In addition, preventing the suppression in GH with overeating also blunted the increase in systemic proteolysis (P < 0.05 GHT vs. control). However, GHT did not alter lipolysis or FSR in response to overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating.

Fuel-induced amplification of insulin secretion in mouse pancreatic islets exposed to a high sulfonylurea concentration: role of the NADPH/NADP+ ratio.

PubMed

Panten, U; Rustenbeck, I

2008-01-01

The aim of this study was to examine whether the cytosolic NADPH/NADP+ ratio of beta cells serves as an amplifying signal in fuel-induced insulin secretion and whether such a function is mediated by cytosolic alpha-ketoglutarate. Pancreatic islets and islet cells were isolated from albino mice by collagenase digestion. Insulin secretion of incubated or perifused islets was measured by ELISA. The NADPH and NADP+ content of incubated islets was determined by enzymatic cycling. The cytosolic Ca2+ concentration ([Ca2+]c) in islets was measured by microfluorimetry and the activity of ATP-sensitive K+ channels in islet cells by patch-clamping. Both 30 mmol/l glucose and 10 mmol/l alpha-ketoisocaproate stimulated insulin secretion and elevated the NADPH/NADP+ ratio of islets preincubated in the absence of fuel. The increase in the NADPH/NADP+ ratio was abolished in the presence of 2.7 micromol/l glipizide (closing all ATP-sensitive K+ channels). However, alpha-ketoisocaproate, but not glucose, still stimulated insulin secretion. That glipizide did not inhibit alpha-ketoisocaproate-induced insulin secretion was not the result of elevated [Ca2+]c, as glucose caused a more marked [Ca2+]c increase. Insulin release triggered by glipizide alone was moderately amplified by dimethyl alpha-ketoglutarate (which is cleaved to produce cytosolic alpha-ketoglutarate), but there was no indication of a signal function of cytosolic alpha-ketoglutarate. The results strongly suggest that the NADPH/NADP+ ratio in the beta cell cytosol does not serve as an amplifying signal in fuel-induced insulin release. The study supports the view that amplification results from the intramitochondrial production of citrate by citrate synthase and from the associated export of citrate into the cytosol.

The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion

PubMed Central

Heart, Emma; Palo, Meridith; Womack, Trayce; Smith, Peter J. S.; Gray, Joshua P.

2011-01-01

Pancreatic β-cells release insulin in response to elevation of glucose from basal (4-7 mM) to stimulatory (8-16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H2O2), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H2O2 inhibit insulin secretion. Menadione, which produces H2O2 via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H2O2 production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H2O2 formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H2O2 and menadione on insulin secretion. PMID:22115979

The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion.

PubMed

Heart, Emma; Palo, Meridith; Womack, Trayce; Smith, Peter J S; Gray, Joshua P

2012-01-15

Pancreatic β-cells release insulin in response to elevation of glucose from basal (4-7mM) to stimulatory (8-16mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H(2)O(2)), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H(2)O(2) inhibit insulin secretion. Menadione, which produces H(2)O(2) via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H(2)O(2) production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H(2)O(2) formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H(2)O(2) and menadione on insulin secretion. Published by Elsevier Inc.

Effects of Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) on hyperglycemia in streptozotocin-induced diabetic rats.

PubMed

Hirotani, Yoshihiko; Ikeda, Takuya; Yamamoto, Kaoru; Kurokawa, Nobuo

2007-05-01

The present study investigated the effects of Hachimi-jio-gan (HJ) on diabetic hyperglycemia in streptozotocin (STZ)-induced diabetic rats. After STZ administration, rats had free access to pellets containing 1% HJ extract powder for four weeks. HJ markedly suppressed hyperglycemia in STZ-induced diabetic rats at three and four weeks after the start of administration. There were also significant increases in serum and pancreatic immunoreactive insulin levels in STZ and HJ co-administering rats. However, in the present study, the number of beta cells in the pancreatic Langerhans' islets did not increase. Next, in order to investigate the action mechanism besides the glycemic control action of insulin, the expression of glucose transporter 2 (GLUT2) protein, which is involved in glucose uptake and release in the liver, was investigated. GLUT2 protein expression was increased by STZ administration but was normalized after four weeks of HJ administration. Therefore, irrespective of the structural changes in pancreatic beta-cells due to STZ, HJ increased insulin production and secretion by the pancreas and significantly suppressed GLUT2 synthesis in the liver. Amylase secretion from the pancreas was measured to assess pancreatic secretion. Amylase activity was decreased by STZ but was increased by HJ. Therefore, the effects of HJ on STZ-induced hyperglycemia in rats could be summarized as follows: besides increasing insulin synthesis and release, HJ normalizes GLUT2 protein expression in the liver to suppress hyperglycemia. Hence, the results of the present study suggest for the first time that HJ affects not only the production and secretion of insulin, but also the release of glucose from the liver.

The antidiabetic action of camel milk in experimental type 2 diabetes mellitus: an overview on the changes in incretin hormones, insulin resistance, and inflammatory cytokines.

PubMed

Korish, A A

2014-06-01

Folk medicine stories accredited the aptitude of camel milk (CMK) as a hypoglycemic agent and recent studies have confirmed this in the diabetic patients and experimental animals. However, the mechanism(s) by which CMK influences glucose homeostasis is yet unclear. The current study investigated the changes in the glucose homeostatic parameters, the incretin hormones, and the inflammatory cytokines in the CMK-treated diabetic animals. A model of type 2 diabetes mellitus was induced in rats by intraperitoneal injection of streptozotocin 40 mg/kg/day for 4 repeated doses. Camel milk treatment was administered for 8 weeks. The changes in glucagon like peptide-1 (GLP-1), glucose dependent insulinotropic peptide (GIP), glucose tolerance, fasting and glucose-stimulated insulin secretion, insulin resistance (IR), TNF-α, TGF-β1, lipid profile, atherogenic index (AI), and body weight were investigated. The untreated diabetic animals showed hyperglycemia, increased HOMA-IR, hyperlipidemia, elevated AI, high serum incretins [GLP-1 and GIP], TNF-α, and TGF-β1 levels and weight loss as compared with the control group. Camel milk treatment to the diabetic animals resulted in significant lowered fasting glucose level, hypolipidemia, decreased HOMA-IR, recovery of insulin secretion, weight gain, and no mortality during the study. Additionally, CMK inhibits the diabetes-induced elevation in incretin hormones, TNF-α and TGF-β1 levels. The increase in glucose-stimulated insulin secretion, decreased HOMA-IR, modulation of the secretion and/or the action of incretins, and the anti-inflammatory effect are anticipated mechanisms to the antidiabetic effect of CMK and suggest it as a valuable adjuvant antidiabetic therapy. © Georg Thieme Verlag KG Stuttgart · New York.

The origins of western obesity: a role for animal protein?

PubMed

McCarty, M F

2000-03-01

A reduced propensity to oxidize fat, as indicated by a relatively high fasting respiratory quotient, is a major risk factor for weight gain. Increased insulin secretion works in various ways to impede fat oxidation and promote fat storage. The substantial 'spontaneous' weight loss often seen with very-low-fat dietary regimens may reflect not only a reduced rate of fat ingestion, but also an improved insulin sensitivity of skeletal muscle that down-regulates insulin secretion. Reduction of diurnal insulin secretion may also play a role in the fat loss often achieved with exercise training, low-glycemic-index diets, supplementation with soluble fiber or chromium, low-carbohydrate regimens, and biguanide therapy. The exceptional leanness of vegan cultures may reflect an additional factor - the absence of animal protein. Although dietary protein by itself provokes relatively little insulin release, it can markedly potentiate the insulin response to co-ingested carbohydrate; Western meals typically unite starchy foods with an animal protein-based main course. Thus, postprandial insulin secretion may be reduced by either avoiding animal protein, or segregating it in low-carbohydrate meals; the latter practice is a feature of fad diets stressing 'food combining'. Vegan diets tend to be relatively low in protein, legume protein may be slowly absorbed, and, as compared to animal protein, isolated soy protein provokes a greater release of glucagon, an enhancer of fat oxidation. The low insulin response to rice may mirror its low protein content. Minimizing diurnal insulin secretion in the context of a low fat intake may represent an effective strategy for achieving and maintaining leanness. Copyright 2000 Harcourt Publishers Ltd.

Characterisation of insulin-producing cells differentiated from tonsil derived mesenchymal stem cells.

PubMed

Kim, So-Yeon; Kim, Ye-Ryung; Park, Woo-Jae; Kim, Han Su; Jung, Sung-Chul; Woo, So-Youn; Jo, Inho; Ryu, Kyung-Ha; Park, Joo-Won

2015-01-01

Tonsil-derived (T-) mesenchymal stem cells (MSCs) display mutilineage differentiation potential and self-renewal capacity and have potential as a banking source. Diabetes mellitus is a prevalent disease in modern society, and the transplantation of pancreatic progenitor cells or various stem cell-derived insulin-secreting cells has been suggested as a novel therapy for diabetes. The potential of T-MSCs to trans-differentiate into pancreatic progenitor cells or insulin-secreting cells has not yet been investigated. We examined the potential of human T-MSCs to trans-differentiate into pancreatic islet cells using two different methods based on β-mercaptoethanol and insulin-transferin-selenium, respectively. First, we compared the efficacy of the two methods for inducing differentiation into insulin-producing cells. We demonstrated that the insulin-transferin-selenium method is more efficient for inducing differentiation into insulin-secreting cells regardless of the source of the MSCs. Second, we compared the differentiation potential of two different MSC types: T-MSCs and adipose-derived MSCs (A-MSCs). T-MSCs had a differentiation capacity similar to that of A-MSCs and were capable of secreting insulin in response to glucose concentration. Islet-like clusters differentiated from T-MSCs had lower synaptotagmin-3, -5, -7, and -8 levels, and consequently lower secreted insulin levels than cells differentiated from A-MSCs. These results imply that T-MSCs can differentiate into functional pancreatic islet-like cells and could provide a novel, alternative cell therapy for diabetes mellitus. Copyright © 2015 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Subjective sleep complaints are associated with insulin resistance in individuals without diabetes: the PPP-Botnia Study.

PubMed

Pyykkönen, Antti-Jussi; Isomaa, Bo; Pesonen, Anu-Katriina; Eriksson, Johan G; Groop, Leif; Tuomi, Tiinamaija; Räikkönen, Katri

2012-11-01

Sleep disorders and subjective sleep complaints have been associated with increased risk of type 2 diabetes. The evidence with respect to insulin resistance (IR) and insulin secretion in individuals without type 2 diabetes has been scarce and elusive. We examined if subjective sleep complaints and their co-occurrence were associated with IR and insulin secretion in adult women and men without diabetes. Women (n = 442) and men (n = 354) 18-75 years of age without type 2 diabetes underwent an oral glucose tolerance test (OGTT), with insulin and glucose measured at fasting and at 30 and 120 min. Complaints related to sleep apnea, insomnia, and daytime sleepiness were self-rated with the Basic Nordic Sleep Questionnaire. In comparison with individuals with no or minor sleep complaints, those with more frequent complaints of sleep apnea, insomnia, and daytime sleepiness were more insulin resistant, as evidenced by higher fasting insulin concentrations and insulin and glucose responses to OGTT, and more frequently had high homeostasis model assessment of IR and low insulin sensitivity index values. The likelihood of being insulin resistant increased significantly and linearly according to the accumulation of co-occurring sleep complaints. These associations changed only a little when adjusted for mediating and confounding factors and for depressive symptoms. Sleep complaints were not associated with indices of deficiency in insulin secretion. Subjective sleep complaints were associated with IR. The likelihood of being insulin resistant increased according to accumulation of co-occurring sleep complaints. Sleep complaints were not associated with deficiency in insulin secretion.

Insulin/phosphoinositide 3-kinase pathway accelerates the glucose-induced first-phase insulin secretion through TrpV2 recruitment in pancreatic β-cells.

PubMed

Aoyagi, Kyota; Ohara-Imaizumi, Mica; Nishiwaki, Chiyono; Nakamichi, Yoko; Nagamatsu, Shinya

2010-12-01

Functional insulin receptor and its downstream effector PI3K (phosphoinositide 3-kinase) have been identified in pancreatic β-cells, but their involvement in the regulation of insulin secretion from β-cells remains unclear. In the present study, we investigated the physiological role of insulin and PI3K in glucose-induced biphasic insulin exocytosis in primary cultured β-cells and insulinoma Min6 cells using total internal reflection fluorescent microscopy. The pretreatment of β-cells with insulin induced the rapid increase in intracellular Ca2+ levels and accelerated the exocytotic response without affecting the second-phase insulin secretion. The inhibition of PI3K not only abolished the insulin-induced rapid development of the exocytotic response, but also potentiated the second-phase insulin secretion. The rapid development of Ca2+ and accelerated exocytotic response induced by insulin were accompanied by the translocation of the Ca2+-permeable channel TrpV2 (transient receptor potential V2) in a PI3K-dependent manner. Inhibition of TrpV2 by the selective blocker tranilast, or the expression of shRNA (short-hairpin RNA) against TrpV2 suppressed the effect of insulin in the first phase, but the second phase was not affected. Thus our results demonstrate that insulin treatment induced the acceleration of the exocytotic response during the glucose-induced first-phase response by the insertion of TrpV2 into the plasma membrane in a PI3K-dependent manner.

Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp

PubMed Central

Farmer, Tiffany D.; Jenkins, Erin C.; O'Brien, Tracy P.; McCoy, Gregory A.; Havlik, Allison E.; Nass, Erik R.; Nicholson, Wendell E.; Printz, Richard L.

2014-01-01

To understand the underlying pathology of metabolic diseases, such as diabetes, an accurate determination of whole body glucose flux needs to be made by a method that maintains key physiological features. One such feature is a positive differential in insulin concentration between the portal venous and systemic arterial circulation (P/S-IG). P/S-IG during the determination of the relative contribution of liver and extra-liver tissues/organs to whole body glucose flux during an insulin clamp with either systemic (SID) or portal (PID) insulin delivery was examined with insulin infusion rates of 1, 2, and 5 mU·kg−1·min−1 under either euglycemic or hyperglycemic conditions in 6-h-fasted conscious normal rats. A P/S-IG was initially determined with endogenous insulin secretion to exist with a value of 2.07. During an insulin clamp, while inhibiting endogenous insulin secretion by somatostatin, P/S-IG remained at 2.2 with PID, whereas, P/S-IG disappeared completely with SID, which exhibited higher arterial and lower portal insulin levels compared with PID. Consequently, glucose disappearance rates and muscle glycogen synthetic rates were higher, but suppression of endogenous glucose production and liver glycogen synthetic rates were lower with SID compared with PID. When the insulin clamp was performed with SID at 2 and 5 mU·kg−1·min−1 without managing endogenous insulin secretion under euglycemic but not hyperglycemic conditions, endogenous insulin secretion was completely suppressed with SID, and the P/S-IG disappeared. Thus, compared with PID, an insulin clamp with SID underestimates the contribution of liver in response to insulin to whole body glucose flux. PMID:25516552

An adenovirus-derived protein: A novel candidate for anti-diabetic drug development.

PubMed

Hegde, Vijay; Na, Ha-Na; Dubuisson, Olga; Burke, Susan J; Collier, J Jason; Burk, David; Mendoza, Tamra; Dhurandhar, Nikhil V

2016-02-01

Exposure to human adenovirus Ad36 is causatively and correlatively linked with better glycemic control in animals and humans, respectively. Although the anti-hyperglycemic property of Ad36 may offer some therapeutic potential, it is impractical to use an infectious agent for therapeutic benefit. Cell-based studies identified that Ad36 enhances cellular glucose disposal via its E4orf1 protein. Ability to improve glycemic control in vivo is a critical prerequisite for further investigating the therapeutic potential of E4orf1. Therefore, the aim of this study was to determine the ability of E4orf1 to improve glycemic control independent of insulin despite high fat diet. 8-9wk old male C57BL/6J mice fed a high-fat diet (60% kcal) were injected with a retrovirus plasmid expressing E4orf1, or a null vector (Control). Glycemic control was determined by glucose and insulin tolerance test. Islet cell size, amount of insulin and glucagon were determined in formalin-fixed pancreas. Rat insulinoma cell line (832/13) was infected with E4orf1 or control to determine changes in glucose stimulated insulin secretion. Protein from flash frozen adipose tissue depots, liver and muscle was used to determine molecular signaling by western blotting. In multiple experiments, retrovirus-mediated E4orf1 expression in C57BL/6J mice significantly and reproducibly improved glucose excursion following a glucose load despite a high fat diet (60% energy). Importantly, E4orf1 improved glucose clearance without increasing insulin sensitivity, production or secretion, underscoring its insulin-independent effect. E4orf1 modulated molecular signaling in mice tissue, which included greater protein abundance of adiponectin, p-AKT and Glucose transporter Glu4. This study provides the proof of concept for translational development of E4orf1 as a potential anti-diabetic agent. High fat intake and impaired insulin signaling are often associated with obesity, diabetes and insulin resistance. Hence, the ability of E4orf1 to improve glycemic control despite high fat diet and independent of insulin, is particularly attractive. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Glucose and Insulin Secretory Response Patterns Following Diet and Tolazamide Therapy in Diabetes

PubMed Central

Turtle, J. R.

1970-01-01

Glucose and insulin secretory response patterns during glucose tolerance tests were determined in 28 maturity-onset diabetics, and the sequential effects of diet and a sulphonylurea, tolazamide, were assessed. Untreated diabetics showed hyperglycaemia, increased serum immunoreactive insulin response patterns, delayed insulin release, and relative insulin deficiency. Diet alone partially corrected the hyperglycaemia and serum immunoreactive insulin response but had no effect on the delayed insulin release or relative insulin deficiency. Tolazamide plus diet restored all values towards normal. The net effect of maintenance tolazamide therapy was to (1) restore the insulin secretory response pattern to normal, (2) reduce total pancreatic insulin output, and (3) improve the efficiency of insulin secretion. The results suggest that there is a rational basis for the use of sulphonylurea in all maturity-onset diabetics, including patients with mild carbohydrate intolerance and those who are apparently controlled by diet alone. PMID:5470087

Increased plasma ghrelin suppresses insulin release in wethers fed with a high-protein diet.

PubMed

Takahashi, T; Sato, K; Kato, S; Yonezawa, T; Kobayashi, Y; Ohtani, Y; Ohwada, S; Aso, H; Yamaguchi, T; Roh, S G; Katoh, K

2014-06-01

Ghrelin is a multifunctional peptide that promotes an increase of food intake and stimulates GH secretion. Ghrelin secretion is regulated by nutritional status and nutrients. Although a high-protein (HP) diet increases plasma ghrelin secretion in mammals, the mechanisms and the roles of the elevated ghrelin concentrations due to a HP diet have not been fully established. To clarify the roles of elevated acylated ghrelin upon intake of a HP diet, we investigated the regulation of ghrelin concentrations in plasma and tissues in wethers fed with either the HP diet or the control (CNT) diet for 14 days, and examined the action of the elevated plasma ghrelin by using a ghrelin-receptor antagonist. The HP diet gradually increased the plasma acylated-ghrelin concentrations, but the CNT diet did not. Although the GH concentrations did not vary significantly across the groups, an injection of ghrelin-receptor antagonist enhanced insulin levels in circulation in the HP diet group. In the fundus region of the stomach, the ghrelin levels did not differ between the HP and CNT diet groups, whereas ghrelin O-acyltransferase mRNA levels were higher in the group fed with HP diet than those of the CNT diet group were. These results indicate that the HP diet elevated the plasma ghrelin levels by increasing its synthesis; this elevation strongly suppresses the appearance of insulin in the circulation of wethers, but it is not involved in GH secretion. Overall, our findings indicate a role of endogenous ghrelin action in secretion of insulin, which acts as a regulator after the consumption of a HP diet. © 2014 Society for Endocrinology.

Quercetin induces insulin secretion by direct activation of L-type calcium channels in pancreatic beta cells

PubMed Central

Bardy, G; Virsolvy, A; Quignard, J F; Ravier, M A; Bertrand, G; Dalle, S; Cros, G; Magous, R; Richard, S; Oiry, C

2013-01-01

Background and Purpose Quercetin is a natural polyphenolic flavonoid that displays anti-diabetic properties in vivo. Its mechanism of action on insulin-secreting beta cells is poorly documented. In this work, we have analysed the effects of quercetin both on insulin secretion and on the intracellular calcium concentration ([Ca2+]i) in beta cells, in the absence of any co-stimulating factor. Experimental Approach Experiments were performed on both INS-1 cell line and rat isolated pancreatic islets. Insulin release was quantified by the homogeneous time-resolved fluorescence method. Variations in [Ca2+]i were measured using the ratiometric fluorescent Ca2+ indicator Fura-2. Ca2+ channel currents were recorded with the whole-cell patch-clamp technique. Key Results Quercetin concentration-dependently increased insulin secretion and elevated [Ca2+]i. These effects were not modified by the SERCA inhibitor thapsigargin (1 μmol·L−1), but were nearly abolished by the L-type Ca2+ channel antagonist nifedipine (1 μmol·L−1). Similar to the L-type Ca2+ channel agonist Bay K 8644, quercetin enhanced the L-type Ca2+ current by shifting its voltage-dependent activation towards negative potentials, leading to the increase in [Ca2+]i and insulin secretion. The effects of quercetin were not inhibited in the presence of a maximally active concentration of Bay K 8644 (1 μmol·L−1), with the two drugs having cumulative effects on [Ca2+]i. Conclusions and Implications Taken together, our results show that quercetin stimulates insulin secretion by increasing Ca2+ influx through an interaction with L-type Ca2+ channels at a site different from that of Bay K 8644. These data contribute to a better understanding of quercetin's mechanism of action on insulin secretion. PMID:23530660

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

NASA Astrophysics Data System (ADS)

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

2013-11-01

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

Review of methods for measuring β-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium.

PubMed

Hannon, Tamara S; Kahn, Steven E; Utzschneider, Kristina M; Buchanan, Thomas A; Nadeau, Kristen J; Zeitler, Philip S; Ehrmann, David A; Arslanian, Silva A; Caprio, Sonia; Edelstein, Sharon L; Savage, Peter J; Mather, Kieren J

2018-01-01

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of β-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of β-cell function and changes in β-cell function in response to interventions. In the present paper, we review approaches for measurement of β-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of β-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure β-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in β-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine. © 2017 John Wiley & Sons Ltd.

Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo.

PubMed

Kalbag, J B; Walter, Y H; Nedelman, J R; McLeod, J F

2001-01-01

This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects. Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose. Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 microU x ml(-1) x min(-1), respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose. In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia.

Effects of nutritional status on plasma leptin levels and in vitro regulation of adipocyte leptin expression and secretion in rainbow trout.

PubMed

Salmerón, Cristina; Johansson, Marcus; Angotzi, Anna R; Rønnestad, Ivar; Jönsson, Elisabeth; Björnsson, Björn Thrandur; Gutiérrez, Joaquim; Navarro, Isabel; Capilla, Encarnación

2015-01-01

As leptin has a key role on appetite, knowledge about leptin regulation is important in order to understand the control of energy balance. We aimed to explore the modulatory effects of adiposity on plasma leptin levels in vivo and the role of potential regulators on leptin expression and secretion in rainbow trout adipocytes in vitro. Fish were fed a regular diet twice daily ad libitum or a high-energy diet once daily at two ration levels; satiation (SA group) or restricted (RE group) to 25% of satiation, for 8weeks. RE fish had significantly reduced growth (p<0.001) and adipose tissue weight (p<0.001), and higher plasma leptin levels (p=0.022) compared with SA fish. Moreover, plasma leptin levels negatively correlated with mesenteric fat index (p=0.009). Adipocytes isolated from the different fish were treated with insulin, ghrelin, leucine, eicosapentaenoic acid or left untreated (control). In adipocytes from fish fed regular diet, insulin and ghrelin increased leptin secretion dose-dependently (p=0.002; p=0.033, respectively). Leptin secretion in control adipocytes was significantly higher in RE than in SA fish (p=0.022) in agreement with the in vivo findings, indicating that adipose tissue may contribute to the circulating leptin levels. No treatment effects were observed in adipocytes from the high-energy diet groups, neither in leptin expression nor secretion, except that leptin secretion was significantly reduced by leucine in RE fish adipocytes (p=0.025). Overall, these data show that the regulation of leptin in rainbow trout adipocytes by hormones and nutrients seems to be on secretion, rather than at the transcriptional level. Copyright © 2014 Elsevier Inc. All rights reserved.

Therapeutics of diabetes mellitus: focus on insulin analogues and insulin pumps.

PubMed

Valla, Vasiliki

2010-01-01

Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insulin delivery systems and the artificial pancreas. Intensive insulin therapy with multiple daily injections (MDI) allows better imitation of the physiological rhythm of insulin secretion. Longer-acting, basal insulin analogues provide concomitant improvements in safety, efficacy and variability of glycaemic control, followed by low risks of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII) provides long-term glycaemic control especially in type 1 diabetic patients, while reducing hypoglycaemic episodes and glycaemic variability. Continuous subcutaneous glucose monitoring (CGM) systems provide information on postprandial glucose excursions and nocturnal hypo- and/or hyperglycemias. This information enhances treatment options, provides a useful tool for self-monitoring and allows safer achievement of treatment targets. In the absence of a cure-like pancreas or islets transplants, artificial "closed-loop" systems mimicking the pancreatic activity have been also developed. Individualized treatment plans for insulin initiation and administration mode are critical in achieving target glycaemic levels. Progress in these fields is expected to facilitate and improve the quality of life of diabetic patients.

Is exenatide improving the treatment of type 2 diabetes? Analysis of the individual clinical trials with exenatide.

PubMed

Doggrell, Sheila A

2007-01-01

The obesity epidemic in the developed and developing world is being followed by an epidemic of type 2 diabetes. In type 2 diabetes, subjects cannot manage glucose properly because they do not produce enough insulin, and the peripheral tissues have become resistant to insulin. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. One of the actions of GLP-1 is to stimulate insulin secretion. In subjects with type 2 diabetes, intravenous or subcutaneous GLP-1 stimulated insulin production and decreased blood glucose levels. However, as GLP-1 is rapidly metabolised, it is not suitable for use in most subjects with type 2 diabetes. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the GLP-1 receptor. After subcutaneous administration, synthetic exendin-4 (exenatide) decreased postprandial concentrations of glucose and insulin, and fasting glucose levels in subjects with type 2 diabetes, and the effects lasted several hours. Subsequently, exenatide was been trialled in subjects taking metformin only, a sulfonylurea only, or metformin and a sulfonylurea, and shown to improve glycemic control with few adverse events, initially over 30 weeks, and then extended to 82 weeks. Exenatide may also be as effective as insulin glargine in subjects with type 2 diabetes not adequately controlled with the oral agents. In conclusion, exenatide represents a new and beneficial addition to the medicines used to treat type 2 diabetes.

β-Cell Hyperplasia Induced by Hepatic Insulin Resistance

PubMed Central

Escribano, Oscar; Guillén, Carlos; Nevado, Carmen; Gómez-Hernández, Almudena; Kahn, C. Ronald; Benito, Manuel

2009-01-01

OBJECTIVE Type 2 diabetes results from a combination of insulin resistance and impaired insulin secretion. To directly address the effects of hepatic insulin resistance in adult animals, we developed an inducible liver-specific insulin receptor knockout mouse (iLIRKO). RESEARCH DESIGN AND METHODS Using this approach, we were able to induce variable insulin receptor (IR) deficiency in a tissue-specific manner (liver mosaicism). RESULTS iLIRKO mice presented progressive hepatic and extrahepatic insulin resistance without liver dysfunction. Initially, iLIRKO mice displayed hyperinsulinemia and increased β-cell mass, the extent of which was proportional to the deletion of hepatic IR. Our studies of iLIRKO suggest a cause-and-effect relationship between progressive insulin resistance and the fold increase of plasma insulin levels and β-cell mass. Ultimately, the β-cells failed to secrete sufficient insulin, leading to uncontrolled diabetes. We observed that hepatic IGF-1 expression was enhanced in iLIRKO mice, resulting in an increase of circulating IGF-1. Concurrently, the IR-A isoform was upregulated in hyperplastic β-cells of iLIRKO mice and IGF-1–induced proliferation was higher than in the controls. In mouse β-cell lines, IR-A, but not IR-B, conferred a proliferative capacity in response to insulin or IGF-1, providing a potential explanation for the β-cell hyperplasia induced by liver insulin resistance in iLIRKO mice. CONCLUSIONS Our studies of iLIRKO mice suggest a liver-pancreas endocrine axis in which IGF-1 functions as a liver-derived growth factor to promote compensatory pancreatic islet hyperplasia through IR-A. PMID:19136656

Voluntary running exercise prevents β-cell failure in susceptible islets of the Zucker diabetic fatty rat.

PubMed

Delghingaro-Augusto, Viviane; Décary, Simon; Peyot, Marie-Line; Latour, Martin G; Lamontagne, Julien; Paradis-Isler, Nicolas; Lacharité-Lemieux, Marianne; Akakpo, Huguette; Birot, Olivier; Nolan, Christopher J; Prentki, Marc; Bergeron, Raynald

2012-01-15

Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.

Beyond the morphology of the glucose curve following an oral glucose tolerance test in obese youth.

PubMed

Nolfe, Giuseppe; Spreghini, Maria Rita; Sforza, Rita Wietrzycowska; Morino, Giuseppe; Manco, Melania

2012-01-01

To describe the morphology of glucose curve during the oral glucose tolerance test (OGTT) and any association with glucose tolerance, insulin action and secretion in obese youth. Cross-sectional. OGTT data of 553 patients were analysed. Subjects were divided in groups based on the morphology (i.e. monophasic, biphasic, triphasic and upward monotonous) of glucose curve. Insulin action was estimated by the homeostasis model assessment of insulin resistance, the insulin sensitivity, the muscle insulin sensitivity and the hepatic insulin resistance indexes (HIRI), and the oral glucose insulin sensitivity (OGIS). Insulin secretion was estimated by the insulinogenic index (IGI). Disposition index, including the insulin secretion-sensitivity index-2, and areas under glucose (AUC(G)) and insulin (AUC(I)) curves were computed. In patients with normal glucose tolerance (n=522), prevalent morphology of the glucose curve was monophasic (n=285, 54%). Monophasic morphology was associated with the highest concentration of 1 h plasma glucose (P<0.0001) and AUC(G) (P<0.0001); biphasic morphology with better insulin sensitivity as estimated by OGIS (P<0.03) and lower AUC(I) (P<0.0001); triphasic morphology with the highest values of HIRI (P<0.02) and IGI (P<0.007). By combining morphologies of glucose and insulin curves or time of the glucose peak, a deeper characterisation of different phenotypes of glucose metabolism emerged. Morphologies of the glucose curve seem reflecting different metabolic phenotypes of insulin action and secretion, particularly when combined with morphologies of insulin curve or time of glucose peak. Such findings may deserve validation in cohort study, in which glucose metabolism would be estimated by using gold standard techniques.

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

Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis.

PubMed

Gautam, D; Han, S-J; Duttaroy, A; Mears, D; Hamdan, F F; Li, J H; Cui, Y; Jeon, J; Wess, J

2007-11-01

The release of insufficient amounts of insulin in the presence of elevated blood glucose levels is one of the key features of type 2 diabetes. Various lines of evidence indicate that acetylcholine (ACh), the major neurotransmitter of the parasympathetic nervous system, can enhance glucose-stimulated insulin secretion from pancreatic beta-cells. Studies with isolated islets prepared from whole body M(3) muscarinic ACh receptor knockout mice showed that cholinergic amplification of glucose-dependent insulin secretion is exclusively mediated by the M(3) muscarinic receptor subtype. To investigate the physiological relevance of this muscarinic pathway, we used Cre/loxP technology to generate mutant mice that lack M(3) receptors only in pancreatic beta-cells. These mutant mice displayed impaired glucose tolerance and significantly reduced insulin secretion. In contrast, transgenic mice overexpressing M(3) receptors in pancreatic beta-cells showed a pronounced increase in glucose tolerance and insulin secretion and were resistant to diet-induced glucose intolerance and hyperglycaemia. These findings indicate that beta-cell M(3) muscarinic receptors are essential for maintaining proper insulin secretion and glucose homeostasis. Moreover, our data suggest that enhancing signalling through beta-cell M(3) muscarinic receptors may represent a new avenue in the treatment of glucose intolerance and type 2 diabetes.

Kinesin-dependent mechanism for controlling triglyceride secretion from the liver.

PubMed

Rai, Priyanka; Kumar, Mukesh; Sharma, Geetika; Barak, Pradeep; Das, Saumitra; Kamat, Siddhesh S; Mallik, Roop

2017-12-05

Despite massive fluctuations in its internal triglyceride content, the liver secretes triglyceride under tight homeostatic control. This buffering function is most visible after fasting, when liver triglyceride increases manyfold but circulating serum triglyceride barely fluctuates. How the liver controls triglyceride secretion is unknown, but is fundamentally important for lipid and energy homeostasis in animals. Here we find an unexpected cellular and molecular mechanism behind such control. We show that kinesin motors are recruited to triglyceride-rich lipid droplets (LDs) in the liver by the GTPase ARF1, which is a key activator of lipolysis. This recruitment is activated by an insulin-dependent pathway and therefore responds to fed/fasted states of the animal. In fed state, ARF1 and kinesin appear on LDs, consequently transporting LDs to the periphery of hepatocytes where the smooth endoplasmic reticulum (sER) is present. Because the lipases that catabolize LDs in hepatocytes reside on the sER, LDs can now be catabolized efficiently to provide triglyceride for lipoprotein assembly and secretion from the sER. Upon fasting, insulin is lowered to remove ARF1 and kinesin from LDs, thus down-regulating LD transport and sER-LD contacts. This tempers triglyceride availabiity for very low density lipoprotein assembly and allows homeostatic control of serum triglyceride in a fasted state. We further show that kinesin knockdown inhibits hepatitis-C virus replication in hepatocytes, likely because translated viral proteins are unable to transfer from the ER to LDs. Copyright © 2017 the Author(s). Published by PNAS.

Switching from high-fat to low-fat diet normalizes glucose metabolism and improves glucose-stimulated insulin secretion and insulin sensitivity but not body weight in C57BL/6J mice.

PubMed

Agardh, Carl-David; Ahrén, Bo

2012-03-01

Environmental factors such as a high-fat diet contribute to type 2 diabetes and obesity. This study examined glycemia, insulin sensitivity, and β-cell function after switching from a high-fat diet to a low-fat diet in mice. C57BL/6J mice were fed a high-fat diet or low-fat diet for 18 months, after which mice on the high-fat diet either maintained this diet or switched to a low-fat diet for 4 weeks. Body weight and glucose and insulin responses to intraperitoneal glucose were determined. Insulin secretion (insulinogenic index: the 10-minute insulin response divided by the 10-minute glucose level) and insulin sensitivity (1 divided by basal insulin) were determined. After 18 months on a high-fat diet, mice had glucose intolerance, marked hyperinsulinemia, and increased body weight compared to mice on a low-fat diet (P < 0.001). Switching from a high-fat diet to low-fat diet normalized glucose tolerance, reduced but not normalized body weight (P < 0.001), increased insulin secretion (248 ± 39 vs 141 ± 46 pmol/mmol; P = 0.028) and improved but not normalized insulin sensitivity (3.2 ± 0.1 vs 1.0 ± 0.1 [pmol/L]; P = 0.012). Switching from a high-fat diet to low-fat diet normalizes glucose tolerance and improves but not normalizes insulin secretion and insulin sensitivity. These effects are more pronounced than the reduced body weight.

Abnormal Glucose Metabolism and High-Energy Expenditure in Idiopathic Pulmonary Arterial Hypertension

PubMed Central

Malin, Steven K.; Barnes, Jarrod W.; Tian, Liping; Kirwan, John P.; Dweik, Raed A.

2017-01-01

Rationale: Insulin resistance has emerged as a potential mechanism related to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). However, direct measurements of insulin and glucose metabolism have not been performed in patients with IPAH to date. Objectives: To perform comprehensive metabolic phenotyping of humans with IPAH. Methods: We assessed plasma insulin and glucose, using an oral glucose tolerance test and estimated insulin resistance, and β-cell function in 14 patients with IPAH and 14 control subjects matched for age, sex, blood pressure, and body mass index. Body composition (dual-energy X-ray absorptiometry), inflammation (CXC chemokine ligand 10, endothelin-1), physical fitness (6-min walk test), and energy expenditure (indirect calorimetry) were also assessed. Measurements and Main Results: Patients with IPAH had a higher rate of impaired glucose tolerance (57 vs. 14%; P < 0.05) and reduced glucose-stimulated insulin secretion compared with matched control subjects (IPAH: 1.31 ± 0.76 μU/ml⋅mg/dl vs. control subjects: 2.21 ± 1.27 μU/ml⋅mg/dl; P < 0.05). Pancreatic β-cell function was associated with circulating endothelin-1 (r = –0.71, P < 0.01) and CXC chemokine ligand 10 (r = –0.56, P < 0.05). Resting energy expenditure was elevated in IPAH (IPAH: 32 ± 3.4 vs. control subjects: 28.8 ± 2.9 kcal/d/kg fat-free mass; P < 0.05) and correlated with the plasma glucose response (r = 0.51, P < 0.01). Greater insulin resistance was associated with reduced 6-minute walk distance (r = 0.55, P < 0.05). Conclusions: Independent of age, sex, blood pressure, and body mass index, patients with IPAH have glucose intolerance, decreased insulin secretion in response to glucose, and elevated resting energy expenditure. These abnormalities are associated with circulating markers of inflammation and vascular dysfunction. PMID:27922752

Glucose Acutely Reduces Cytosolic and Mitochondrial H2O2 in Rat Pancreatic Beta Cells.

PubMed

Deglasse, Jean-Philippe; Roma, Leticia Prates; Pastor-Flores, Daniel; Gilon, Patrick; Dick, Tobias P; Jonas, Jean-Christophe

2018-06-14

Whether H 2 O 2 contributes to the glucose-dependent stimulation of insulin secretion (GSIS) by pancreatic β cells is highly controversial. We used two H 2 O 2 -sensitive probes, roGFP2-Orp1 (reduction/oxidation-sensitive enhanced green fluorescent protein fused to oxidant receptor peroxidase 1) and HyPer (hydrogen peroxide sensor) with its pH-control SypHer, to test the acute effects of glucose, monomethyl succinate, leucine with glutamine, and α-ketoisocaproate on β cell cytosolic and mitochondrial H 2 O 2 concentrations. We then tested the effects of low H 2 O 2 and menadione concentrations on insulin secretion. RoGFP2-Orp1 was more sensitive than HyPer to H 2 O 2 (response at 2-5 vs. 10 μM) and less pH-sensitive. Under control conditions, stimulation with glucose reduced mitochondrial roGFP2-Orp1 oxidation without affecting cytosolic roGFP2-Orp1 and HyPer fluorescence ratios, except for the pH-dependent effects on HyPer. However, stimulation with glucose decreased the oxidation of both cytosolic probes by 15 μM exogenous H 2 O 2 . The glucose effects were not affected by overexpression of catalase, mitochondrial catalase, or superoxide dismutase 1 and 2. They followed the increase in NAD(P)H autofluorescence, were maximal at 5 mM glucose in the cytosol and 10 mM glucose in the mitochondria, and were partly mimicked by the other nutrients. Exogenous H 2 O 2 (1-15 μM) did not affect insulin secretion. By contrast, menadione (1-5 μM) did not increase basal insulin secretion but reduced the stimulation of insulin secretion by 20 mM glucose. Subcellular changes in β cell H 2 O 2 levels are better monitored with roGFP2-Orp1 than HyPer/SypHer. Nutrients acutely lower mitochondrial H 2 O 2 levels in β cells and promote degradation of exogenously supplied H 2 O 2 in both cytosolic and mitochondrial compartments. The GSIS occurs independently of a detectable increase in β cell cytosolic or mitochondrial H 2 O 2 levels. Antioxid. Redox Signal. 00, 000-000.

Dulaglutide (LY-2189265) for the treatment of type 2 diabetes.

PubMed

Scheen, André J

2016-01-01

Dulaglutide is a new once-weekly glucagon-like peptide-1 receptor agonist for the management of hyperglycemia in adult patients with type 2 diabetes. It stimulates dose-dependent insulin secretion and reduces glucagon secretion, both in a glucose-dependent manner. Efficacy on blood glucose control and safety were demonstrated in the large AWARD program in type 2 diabetic patients treated with diet, metformin, dual oral therapy or insulin lispro with or without metformin, confirming findings of pilot studies in Caucasian patients and data in Japanese patients. Dulaglutide 1.5 mg once weekly was superior to metformin, sitagliptin, insulin glargine and exenatide twice daily, and non-inferior to liraglutide 1.8 mg once daily regarding the reduction in glycated hemoglobin. A modest but significant weight loss was consistently observed. Most frequent adverse events were transient and generally mild gastrointestinal disturbances. Clinical outcomes of dulaglutide will not be known until the large prospective cardiovascular outcome trial REWIND is complete.

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.

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

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

Douillet, Christelle; Currier, Jenna; Saunders, Jesse

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} ormore » 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 insulin secretion by arsenite, MAs{sup III} or DMAs{sup III} is reversible. ► Thus, pancreatic β-cells may be primary targets for chronic exposure to arsenic.« less

Essential roles of insulin, AMPK signaling and lysyl and prolyl hydroxylases in the biosynthesis and multimerization of adiponectin.

PubMed

Zhang, Lin; Li, Ming-Ming; Corcoran, Marie; Zhang, Shaoping; Cooper, Garth J S

2015-01-05

Post-translational modifications (PTMs) of the adiponectin molecule are essential for its full bioactivity, and defects in PTMs leading to its defective production and multimerization have been linked to the mechanisms of insulin resistance, obesity, and type-2 diabetes. Here we observed that, in differentiated 3T3-L1 adipocytes, decreased insulin signaling caused by blocking of insulin receptors (InsR) with an anti-InsR blocking antibody, increased rates of adiponectin secretion, whereas concomitant elevations in insulin levels counteracted this effect. Adenosine monophosphate-activated protein kinase (AMPK) signaling regulated adiponectin production by modulating the expression of adiponectin receptors, the secretion of adiponectin, and eventually the expression of adiponectin itself. We found that lysyl hydroxylases (LHs) and prolyl hydroxylases (PHs) were expressed in white-adipose tissue of ob/ob mice, wherein LH3 levels were increased compared with controls. In differentiated 3T3-L1 adipocytes, both non-specific inhibition of LHs and PHs by dipyridyl, and specific inhibition of LHs by minoxidil and of P4H with ethyl-3,4-dihydroxybenzoate, caused significant suppression of adiponectin production, more particularly of the higher-order isoforms. Transient gene knock-down of LH3 (Plod3) caused a suppressive effect, especially on the high molecular-weight (HMW) isoforms. These data indicate that PHs and LHs are both required for physiological adiponectin production and in particular are essential for the formation/secretion of the HMW isoforms. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Biotin enhances ATP synthesis in pancreatic islets of the rat, resulting in reinforcement of glucose-induced insulin secretion.

PubMed

Sone, Hideyuki; Sasaki, Yuka; Komai, Michio; Toyomizu, Masaaki; Kagawa, Yasuo; Furukawa, Yuji

2004-02-13

Previous studies showed that biotin enhanced glucose-induced insulin secretion. Changes in the cytosolic ATP/ADP ratio in the pancreatic islets participate in the regulation of insulin secretion by glucose. In the present study we investigated whether biotin regulates the cytosolic ATP/ADP ratio in glucose-stimulated islets. When islets were stimulated with glucose plus biotin, the ATP/ADP ratio increased to approximately 160% of the ATP/ADP ratio in islets stimulated with glucose alone. The rate of glucose oxidation, assessed by CO(2) production, was also about 2-fold higher in islets treated with biotin. These increasing effects of biotin were proportional to the effects seen in insulin secretion. There are no previous reports of vitamins, such as biotin, directly affecting ATP synthesis. Our data indicate that biotin enhances ATP synthesis in islets following the increased rate of substrate oxidation in mitochondria and that, as a consequence of these events, glucose-induced insulin release is reinforced by biotin.

Antibodies against glutamic acid decarboxylase and indices of insulin resistance and insulin secretion in nondiabetic adults: a cross-sectional study

PubMed Central

Mendivil, Carlos O; Toloza, Freddy JK; Ricardo-Silgado, Maria L; Morales-Álvarez, Martha C; Mantilla-Rivas, Jose O; Pinzón-Cortés, Jairo A; Lemus, Hernán N

2017-01-01

Background Autoimmunity against insulin-producing beta cells from pancreatic islets is a common phenomenon in type 1 diabetes and latent autoimmune diabetes in adults. Some reports have also related beta-cell autoimmunity to insulin resistance (IR) in type 2 diabetes. However, the extent to which autoimmunity against components of beta cells is present and relates to IR and insulin secretion in nondiabetic adults is uncertain. Aim To explore the association between antibodies against glutamic acid decarboxylase (GADA), a major antigen from beta cells, and indices of whole-body IR and beta-cell capacity/insulin secretion in adults who do not have diabetes. Methods We studied 81 adults of both sexes aged 30–70, without known diabetes or any autoimmune disease. Participants underwent an oral glucose tolerance test (OGTT) with determination of plasma glucose and insulin at 0, 30, 60, 90, and 120 minutes. From these results we calculated indices of insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] and incremental area under the insulin curve [iAUCins]) and insulin secretion (corrected insulin response at 30 minutes and HOMA beta-cell%). GADAs were measured in fasting plasma using immunoenzymatic methods. Results We found an overall prevalence of GADA positivity of 21.3%, without differences by sex and no correlation with age. GADA titers did not change monotonically across quartiles of any of the IR or insulin secretion indices studies. GADA did not correlate linearly with fasting IR expressed as HOMA-IR (Spearman’s r=−0.18, p=0.10) or postabsorptive IR expressed as iAUCins (r=−0.15, p=0.18), but did show a trend toward a negative correlation with insulin secretory capacity expressed by the HOMA-beta cell% index (r=−0.20, p=0.07). Hemoglobin A1c, body mass index, and waist circumference were not associated with GADA titers. Conclusion GADA positivity is frequent and likely related to impaired beta-cell function among adults without known diabetes. PMID:28507444

[The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

PubMed

Escalada, Francisco Javier

2014-01-01

The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia.

PubMed

Roth Flach, Rachel J; Danai, Laura V; DiStefano, Marina T; Kelly, Mark; Menendez, Lorena Garcia; Jurczyk, Agata; Sharma, Rohit B; Jung, Dae Young; Kim, Jong Hun; Kim, Jason K; Bortell, Rita; Alonso, Laura C; Czech, Michael P

2016-07-29

Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced β cell mass, fewer proliferating β cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from β cells in mice. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Effect of disruption of actin filaments by Clostridium botulinum C2 toxin on insulin secretion in HIT-T15 cells and pancreatic islets.

PubMed Central

Li, G; Rungger-Brändle, E; Just, I; Jonas, J C; Aktories, K; Wollheim, C B

1994-01-01

To examine their role in insulin secretion, actin filaments (AFs) were disrupted by Clostridium botulinum C2 toxin that ADP-ribosylates G-actin. Ribosylation also prevents polymerization of G-actin to F-actin and inhibits AF assembly by capping the fast-growing end of F-actin. Pretreatment of HIT-T15 cells with the toxin inhibited stimulated insulin secretion in a time- and dose-dependent manner. The toxin did not affect cellular insulin content or nonstimulated secretion. In static incubation, toxin treatment caused 45-50% inhibition of secretion induced by nutrients alone (10 mM glucose + 5 mM glutamine + 5 mM leucine) or combined with bombesin (phospholipase C-activator) and 20% reduction of that potentiated by forskolin (stimulator of adenylyl cyclase). In perifusion, the stimulated secretion during the first phase was marginally diminished, whereas the second phase was inhibited by approximately 80%. Pretreatment of HIT cells with wartmannin, a myosin light chain kinase inhibitor, caused a similar pattern of inhibition of the biphasic insulin release as C2 toxin. Nutrient metabolism and bombesin-evoked rise in cytosolic free Ca2+ were not affected by C2 toxin, indicating that nutrient recognition and the coupling between receptor activation and second messenger generation was not changed. In the toxin-treated cells, the AF web beneath the plasma membrane and the diffuse cytoplasmic F-actin fibers disappeared, as shown both by staining with an antibody against G- and F-actin and by staining F-actin with fluorescent phallacidin. C2 toxin dose-dependently reduced cellular F-actin content. Stimulation of insulin secretion was not associated with changes in F-actin content and organization. Treatment of cells with cytochalasin E and B, which shorten AFs, inhibited the stimulated insulin release by 30-50% although differing in their effects on F-actin content. In contrast to HIT-T15 cells, insulin secretion was potentiated in isolated rat islets after disruption of microfilaments with C2 toxin, most notably during the first phase. This effect was, however, diminished, and the second phase became slightly inhibited when the islets were degranulated. These results indicate an important role for AFs in insulin secretion. In the poorly granulated HIT-T15 cells actin-myosin interactions may participate in the recruitment of secretory granules to the releasable pool. In native islet beta-cells the predominant function of AFs appears to be the limitation of the access of granules to the plasma membrane. Images PMID:7865885

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 ...

A common variant upstream of the PAX6 gene influences islet function in man.

PubMed

Ahlqvist, E; Turrini, F; Lang, S T; Taneera, J; Zhou, Y; Almgren, P; Hansson, O; Isomaa, B; Tuomi, T; Eriksson, K; Eriksson, J G; Lyssenko, V; Groop, L

2012-01-01

Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man. A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets. rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication) = 0.02, p (all) = 0.0008) and HOMA-insulin resistance (p (replication) = 0.02, p (all) = 0.001) as well as a lower fasting proinsulin/insulin ratio (p (all) = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro. A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.

Reduced β-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance.

PubMed

Sheikh, Saba; Gudipaty, Lalitha; De Leon, Diva D; Hadjiliadis, Denis; Kubrak, Christina; Rosenfeld, Nora K; Nyirjesy, Sarah C; Peleckis, Amy J; Malik, Saloni; Stefanovski, Darko; Cuchel, Marina; Rubenstein, Ronald C; Kelly, Andrea; Rickels, Michael R

2017-01-01

Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined β-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic-sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide, and glucagon responses compared with PS-CF and normal control subjects, indicating reduced β-cell secretory capacity and α-cell function. Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. These findings indicate that despite "normal" glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early-phase insulin secretion, which with decreased incretin responses likely leads to the early development of postprandial hyperglycemia in CF. © 2017 by the American Diabetes Association.

A two year observational study of nicotinamide and intensive insulin therapy in patients with recent onset type 1 diabetes mellitus.

PubMed

Crinó, A; Schiaffini, R; Ciampalini, P; Suraci, M C; Manfrini, S; Visalli, N; Matteoli, M C; Patera, P; Buzzetti, R; Guglielmi, C; Spera, S; Costanza, F; Fioriti, E; Pitocco, D; Pozzilli, P

2005-08-01

A number of trials have evaluated residual beta-cell function in patients with recent onset type 1 diabetes mellitus (DM1) treated with nicotinamide in addition to intensive insulin therapy (IIT). In most studies, only a slight decline of C-peptide secretion was observed 12 months after diagnosis; however, no data is available on C-peptide secretion and metabolic control in patients continuing nicotinamide and IIT for up to 2 years after diagnosis. We retrospectively analysed data from 25 patients (mean age 14.7 years +/- 5 SD) with DM1 in whom nicotinamide at a dose of 25 mg/kg b. wt. was added from diagnosis (< 4 weeks) to IIT (three injections of regular insulin at meals + one NPH at bed time) and continued for up to 2 years after diagnosis. Data were also analysed from patients (n = 27) in whom IIT was introduced at diagnosis and who were similarly followed for 2 years. Baseline C-peptide as well as insulin dose and HbA1c levels were evaluated at 12 and 24 months after diagnosis. In the course of the follow-up, patients on nicotinamide + IIT or IIT alone did not significantly differ in terms of C-peptide secretion (values at 24 months in the two groups were 0.19 +/- 0.24 nM vs 0.19 +/- 0.13 nM, respectively). Insulin requirement (0.6 +/- 0.3 U/kg/day vs 0.7 +/- 0.2 U/kg/day at 24 months, respectively) did not differ between the two groups. However, HbA1c was significantly lower 2 years after diagnosis in patients treated with nicotinamide + IIT (6.09 +/- 0.9% vs 6.98 +/- 0.9%, respectively, p < 0.01). No adverse effects were observed in patients receiving nicotinamide for 2 years. Implementation of IIT with the addition of nicotinamide at diagnosis continued for 2 years improves metabolic control as assessed by HbA1c. In both nicotinamide and control patients, no decline in C-peptide was detected 2 years after diagnosis, indicating that IIT preserves C-peptide secretion. We conclude that nicotinamide + IIT at diagnosis of DM1 prolonged for up to 2 years can be recommended, but longer follow-up is required to determine whether nicotinamide should be continued beyond this period.

Physiology of the endocrine pancreas.

PubMed

Engelking, L R

1997-11-01

The endocrine pancreas is composed of nests of cells called the islets of Langerhans, which comprise only about 20% of pancreatic cell mass and secrete insulin, glucagon, somatostatin, and pancreatic polypeptide. Insulin is anabolic, increasing storage of glucose, fatty acids and amino acids, while glucagon namely stimulates hepatic glycogenolysis, gluconeogenesis, and ketogenesis. Somatostatin acts as a paracrine agent to inhibit both insulin and glucagon release, and, therefore, to modulate their output. This article explores factors controlling release of these hormones, as well as the way in which they affect fuel metabolism in the whole animal.

Induction of pancreatic duct cells of neonatal rats into insulin-producing cells with fetal bovine serum: A natural protocol and its use for patch clamp experiments

PubMed Central

Leng, San-Hua; Lu, Fu-Er

2005-01-01

AIM: To induce the pancreatic duct cells into endocrine cells with a new natural protocol for electrophysiological study. METHODS: The pancreatic duct cells of neonatal rats were isolated, cultured and induced into endocrine cells with 15% fetal bovine serum for a period of 20 d. During this period, insulin secretion, MTT value, and morphological change of neonatal and adult pancreatic islet cells were comparatively investigated. Pancreatic β-cells were identified by morphological and electrophysiological characteristics, while ATP sensitive potassium channels (KATP), voltage-dependent potassium channels (KV), and voltage-dependent calcium channels (KCA) in β-cells were identified by patch clamp technique. RESULTS: After incubation with fetal bovine serum, the neonatal duct cells budded out, changed from duct-like cells into islet clusters. In the first 4 d, MTT value and insulin secretion increased slowly (MTT value from 0.024±0.003 to 0.028±0.003, insulin secretion from 2.6±0.6 to 3.1±0.8 mIU/L). Then MTT value and insulin secretion increased quickly from d 5 to d 10 (MTT value from 0.028±0.003 to 0.052±0.008, insulin secretion from 3.1±0.8 to 18.3±2.6 mIU/L), then reached high plateau (MTT value >0.052±0.008, insulin secretion >18.3±2.6 mIU/L). In contrast, for the isolated adult pancreatic islet cells, both insulin release and MTT value were stable in the first 4 d (MTT value from 0.029±0.01 to 0.031±0.011, insulin secretion from 13.9±3.1 to 14.3±3.3 mIU/L), but afterwards they reduced gradually (MTT value <0.031±0.011, insulin secretion <8.2±1.5 mIU/L), and the pancreatic islet cells became dispersed, broken or atrophied correspondingly. The differentiated neonatal cells were identified as pancreatic islet cells by dithizone staining method, and pancreatic β-cells were further identified by both morphological features and electrophysiological characteristics, i.e. the existence of recording currents from KATP, KV, and KCA. CONCLUSION: Islet cells differentiated from neonatal pancreatic duct cells with the new natural protocol are more advantageous in performing patch clamp study over the isolated adult pancreatic islet cells. PMID:16437601

Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: results from the TULIP study.

PubMed

Schmid, Vera; Wagner, Robert; Sailer, Corinna; Fritsche, Louise; Kantartzis, Konstantinos; Peter, Andreas; Heni, Martin; Häring, Hans-Ulrich; Stefan, Norbert; Fritsche, Andreas

2017-12-01

Lifestyle intervention is effective to prevent type 2 diabetes. However, a considerable long-term non-response occurs to a standard lifestyle intervention. We investigated which risk phenotypes at baseline and their changes during the lifestyle intervention predict long-term glycaemic non-response to the intervention. Of 300 participants at high risk for type 2 diabetes who participated in a 24 month lifestyle intervention with diet modification and increased physical activity, 190 participants could be re-examined after 8.7 ± 1.6 years. All individuals underwent a five-point 75 g OGTT and measurements of body fat compartments and liver fat content with MRI and spectroscopy at baseline, 9 and 24 months during the lifestyle intervention, and at long-term follow-up. Fasting proinsulin to insulin conversion (PI/I ratio) and insulin sensitivity and secretion were calculated from the OGTT. Non-response to lifestyle intervention was defined as no decrease in glycaemia, i.e. no decrease in AUC for glucose at 0-120 min during OGTT (AUCglucose 0-120 min ). Before the lifestyle intervention, 56% of participants had normal glucose regulation and 44% individuals had impaired fasting glucose and/or impaired glucose tolerance. At long-term follow-up, 11% had developed diabetes. Multivariable regression analysis with adjustment for age, sex, BMI and change in BMI during the lifestyle intervention revealed that baseline insulin secretion and insulin sensitivity, as well as change in insulin sensitivity during the lifestyle intervention, predicted long-term glycaemic control after 9 years. In addition, increased hepatic lipid content as well as impaired fasting proinsulin conversion at baseline were newly detected phenotypes that independently predicted long-term glycaemic control. Increased hepatic lipid content and impaired proinsulin conversion are new predictors, independent of change in body weight, for non-response to lifestyle intervention in addition to the confirmed factors, impaired insulin secretion and insulin sensitivity.

Tocotrienols Stimulate Insulin Secretion of Rat Pancreatic Isolated Islets in a Dynamic Culture.

PubMed

Chia, Ling L; Jantan, Ibrahim; Chua, Kien H

2017-01-01

Tocotrienols (T3) are the naturally occurring vitamin E derivatives that possess antioxidant properties and therapeutic potential in diabetic complications. The bioactivities of the derivatives are determined by the number and arrangement of methyl substitution on the structure. The objective of this study was to determine the effects of T3 derivatives, σ-T3, γ-T3 and α-T3 on insulin secretion of rat pancreatic islets in a dynamic culture. Pancreatic islets isolated from male Wistar rats were treated with T3 for 1 h at 37°C in a microfluidic system with continuous operation that provided a stable cell culture environment. Glucose (2.8 mM and 16.7 mM, as basal and stimulant, respectively) and potassium chloride (KCl) (30 mM) were added to the treatment in calcium free medium. The supernatant was collected for insulin measurements. Short-term exposure (1 h) of σ-T3 to β cells in the stimulant glucose condition significantly potentiated insulin secretion in a dose-dependent manner. γ-T3 and α-T3 also displayed dosedependent effect but were less effective in the activation of insulin secretion. Essentially, KCl, a pancreatic β cell membrane depolarizing agent, added into the treatment further enhanced the insulin secretion of σ-T3, γ-T3 and α-T3 with ED50 values of 504, 511 and 588 µM, respectively. The findings suggest the potential of σ-T3 in regulating glucose-stimulated insulin secretion (GSIS) in response to the intracellular calcium especially in the presence of KCl. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Regulation of insulin secretion from islets of Langerhans rendered permeable by electric discharge

PubMed Central

Yaseen, M. Adel; Pedley, Kevin C.; Howell, Simon L.

1982-01-01

1. High-voltage electric discharge has been used to increase the permeability of B-cells of isolated islets of Langerhans to facilitate studies of the effects of normally impermeable substances on insulin secretion. 2. The application of an intense electric field increased the [14C]sucrose space of the islets from 37.8±3.1% to 86.2±5.2% of their total volume as assessed by 3H2O content. The cells remained permeable for at least 40min. 3. Ultrastructural studies showed no deleterious changes in the structure of the B-cells after discharge. 4. Insulin secretion from normal islets was unaffected by increasing the medium [Ca2+] from 10nm to 10μm. In the islets that had been rendered permeable by discharge, insulin secretion was significantly increased under these conditions, without any alteration in the release of lactate dehydrogenase, a cytoplasmic marker enzyme. 5. Studies of the dynamics of insulin release during perifusion showed that the response to increased (10μm) Ca2+ concentration was rapid and sustained over a period of at least 13min. 6. Secretion responses to Ca2+ in perifusion established that maximum release in permeabilized islets occurs at approx. 1μm-Ca2+ and half-maximum release occurs at approx. 0.6μm-Ca2+. 7. The study of the effect of agents that interfere with the microtubular microfilamentous system in B-cells using a perifusion system revealed that cytochalasin B caused a considerable increase, whereas vinblastine sulphate caused a significant inhibition, in insulin release in response to 1μm-Ca2+. 8. This technique should facilitate the study of the role of normally impermeable ions and metabolic intermediates in the regulation of insulin secretion. ImagesPLATE 1 PMID:6751326

Chronic Consumption of Sweeteners and Its Effect on Glycaemia, Cytokines, Hormones, and Lymphocytes of GALT in CD1 Mice

PubMed Central

Ramírez-Durán, Ninfa

2018-01-01

Background The consumption of sweeteners has increased in recent years, being used to control body weight and blood glucose. However, they can cause increased appetite, modification of immune function, and secretion of hormones in the GALT. Objective To assess the effect of chronic sweetener consumption on glycaemia, cytokines, hormones, and GALT lymphocytes in CD1 mice. Material and Methods 72 CD1 mice divided into 3 groups were used: (a) baseline, (b) middle, and (c) final. Groups (b) and (c) were divided into 4 subgroups: (i) Control, (ii) Sucrose, (iii) Sucralose, and (iv) Stevia. The following were determined: body weight, hormones (GIP, insulin, and leptin), lymphocytes CD3+T cells and CD19+B cells, IgA+ plasma cells, and cytokines (IL-4, IL-5, IFN-γ, and TNF-α). Results Sucralose reduces secretion of GIP and glycaemia but does not modify insulin concentration, increases body weight, and reduces food intake. Stevia increases the secretion of GIP, insulin, leptin, body weight, and glycaemia but keeps food consumption normal. Sucralose and Stevia showed a higher percentage of CD3+T cells, CD19+B cells, and IgA+ plasma cells in Peyer's patches, but only Stevia in lamina propria. Conclusion Sweeteners modulate the hormonal response of cytokines and the proliferation of lymphocytes in the intestinal mucosa. PMID:29854725

Reduction of diffusion barriers in isolated rat islets improves survival, but not insulin secretion or transplantation outcome

PubMed Central

Janette Williams, S; Huang, Han-Hung; Kover, Karen; Moore, Wayne; Berkland, Cory; Singh, Milind; Smirnova, Irina V; MacGregor, Ronal

2010-01-01

For people with type 1 diabetes and severe hypoglycemic unawareness, islet transplants offer hope for improving the quality of life. However, islet cell death occurs quickly during or after transplantation, requiring large quantities of islets per transplant. The purpose of this study was to determine whether poor function demonstrated in large islets was a result of diffusion barriers and if removing those barriers could improve function and transplantation outcomes. Islets were isolated from male DA rats and measured for cell viability, islet survival, glucose diffusion and insulin secretion. Modeling of diffusion barriers was completed using dynamic partial differential equations for a sphere. Core cell death occurred in 100% of the large islets (diameter >150 µm), resulting in poor survival within 7 days after isolation. In contrast, small islets (diameter <100 µm) exhibited good survival rates in culture (91%). Glucose diffusion into islets was tracked with 2-NBDG; 4.2 µm/min in small islets and 2.8 µm/min in large islets. 2-NBDG never permeated to the core cells of islets larger than 150 µm diameter. Reducing the diffusion barrier in large islets improved their immediate and long-term viability in culture. However, reduction of the diffusion barrier in large islets failed to improve their inferior in vitro insulin secretion compared to small islets, and did not return glucose control to diabetic animals following transplantation. Thus, diffusion barriers lead to low viability and poor survival for large islets, but are not solely responsible for the inferior insulin secretion or poor transplantation outcomes of large versus small islets. PMID:20885858

Exogenous glucocorticoids and a high-fat diet cause severe hyperglycemia and hyperinsulinemia and limit islet glucose responsiveness in young male Sprague-Dawley rats.

PubMed

Beaudry, Jacqueline L; D'souza, Anna M; Teich, Trevor; Tsushima, Robert; Riddell, Michael C

2013-09-01

Corticosterone (CORT) and other glucocorticoids cause peripheral insulin resistance and compensatory increases in β-cell mass. A prolonged high-fat diet (HFD) induces insulin resistance and impairs β-cell insulin secretion. This study examined islet adaptive capacity in rats treated with CORT and a HFD. Male Sprague-Dawley rats (age ∼6 weeks) were given exogenous CORT (400 mg/rat) or wax (placebo) implants and placed on a HFD (60% calories from fat) or standard diet (SD) for 2 weeks (N = 10 per group). CORT-HFD rats developed fasting hyperglycemia (>11 mM) and hyperinsulinemia (∼5-fold higher than controls) and were 15-fold more insulin resistant than placebo-SD rats by the end of ∼2 weeks (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR] levels, 15.08 ± 1.64 vs 1.0 ± 0.12, P < .05). Pancreatic β-cell function, as measured by HOMA-β, was lower in the CORT-HFD group as compared to the CORT-SD group (1.64 ± 0.22 vs 3.72 ± 0.64, P < .001) as well as acute insulin response (0.25 ± 0.22 vs 1.68 ± 0.41, P < .05). Moreover, β- and α-cell mass were 2.6- and 1.6-fold higher, respectively, in CORT-HFD animals compared to controls (both P < .05). CORT treatment increased p-protein kinase C-α content in SD but not HFD-fed rats, suggesting that a HFD may lower insulin secretory capacity via impaired glucose sensing. Isolated islets from CORT-HFD animals secreted more insulin in both low and high glucose conditions; however, total insulin content was relatively depleted after glucose challenge. Thus, CORT and HFD, synergistically not independently, act to promote severe insulin resistance, which overwhelms islet adaptive capacity, thereby resulting in overt hyperglycemia.

Hepatic glucose sensing is required to preserve β cell glucose competence

PubMed Central

Seyer, Pascal; Vallois, David; Poitry-Yamate, Carole; Schütz, Frédéric; Metref, Salima; Tarussio, David; Maechler, Pierre; Staels, Bart; Lanz, Bernard; Grueter, Rolf; Decaris, Julie; Turner, Scott; da Costa, Anabela; Preitner, Frédéric; Minehira, Kaori; Foretz, Marc; Thorens, Bernard

2013-01-01

Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr–/– mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link. PMID:23549084

Role of the Transcription Factor Sox4 in Insulin Secretion and Impaired Glucose Tolerance

PubMed Central

Goldsworthy, Michelle; Hugill, Alison; Freeman, Helen; Horner, Emma; Shimomura, Kenju; Bogani, Debora; Pieles, Guido; Mijat, Vesna; Arkell, Ruth; Bhattacharya, Shoumo; Ashcroft, Frances M.; Cox, Roger D.

2008-01-01

OBJECTIVES— To identify, map, clone, and functionally validate a novel mouse model for impaired glucose tolerance and insulin secretion. RESEARCH DESIGN AND METHODS— Haploinsufficiency of the insulin receptor and associated mild insulin resistance has been used to sensitize an N-ethyl-N-nitrosourea (ENU) screen to identify novel mutations resulting in impaired glucose tolerance and diabetes. The new impaired glucose tolerance 4 (IGT4) model was selected using an intraperitoneal glucose tolerance test and inheritance of the phenotype confirmed by generation of backcross progeny. Segregation of the phenotype was correlated with genotype information to map the location of the gene and candidates sequenced for mutations. The function of the SRY-related high mobility group (HMG)-box 4 (Sox4) gene in insulin secretion was tested using another ENU allele and by small interfering RNA silencing in insulinoma cells. RESULTS— We describe two allelic autosomal dominant mutations in the highly conserved HMG box of the transcription factor Sox4. Previously associated with pancreas development, Sox4 mutations in the adult mouse result in an insulin secretory defect, which exhibits impaired glucose tolerance in association with insulin receptor+/−–induced insulin resistance. Elimination of the Sox4 transcript in INS1 and Min6 cells resulted in the abolition of glucose-stimulated insulin release similar to that observed for silencing of the key metabolic enzyme glucokinase. Intracellular calcium measurements in treated cells indicate that this defect lies downstream of the ATP-sensitive K+ channel (KATP channel) and calcium influx. CONCLUSIONS— IGT4 represents a novel digenic model of insulin resistance coupled with an insulin secretory defect. The Sox4 gene has a role in insulin secretion in the adult β-cell downstream of the KATP channel. PMID:18477811

Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron-like apoptosis.

PubMed

Zheng, Ya-Li; Hu, Ya-Fang; Zhang, Aiping; Wang, Wei; Li, Bo; Amin, Niranjana; Grant, Philip; Pant, Harish C

2010-12-15

Cdk5 activity has been implicated in brain development and the regulation of many neuronal processes. Recently, the expression of p35 and Cdk5 activity has been reported in pancreatic beta cells. Decreased Cdk5 activity enhanced glucose-stimulated insulin secretion. This suggests that Cdk5 may play an important role in the regulation of insulin secretion. To further understand how Cdk5 regulates insulin secretion in glucose-stimulated pancreatic β cells, we first confirmed the presence of a low level of p35 in pancreatic Min6 cells. Next, in a time-course experiment in high glucose (25 mM) we showed that endogenous p35 increased gradually accompanied by a 3-fold increase in Cdk5 activity by 16 h. Insulin secretion, however, doubled after 2 h followed by progressive downregulation, negatively correlated with Cdk5 activity. On the other hand, overexpression of p35 in these cells resulted in more than a three-fold increase in Cdk5 activity within 2 h coupled to a 50% reduction in insulin secretion in both high and low (3 mM) glucose. Most significantly, cells overexpressing p35, treated with high glucose for 4 h, showed induction of p25, the p35-derived truncated fragment which hyperactivates Cdk5 in neurons. As a result, insulin secretion was inhibited and cells became apoptotic. Roscovitine or co-infection of dominant negative Cdk5 (dnCdk5) with p35 increased insulin secretion and inhibited apoptosis. These results suggest that the model for deregulation and hyperactivation of Cdk5 in neurodegeneration may apply to the pathology seen in type 2 diabetes (T2DM). It is consistent with the view that Alzheimer's disease and T2DM are linked metabolically and pathologically by Cdk5 in a number of ways. Copyright © 2010. Published by Elsevier B.V.

Inadequate vitamin D status: does it contribute to the disorders comprising syndrome 'X'?

PubMed

Boucher, B J

1998-04-01

Environmental factors are important in the aetiology of glucose intolerance, type II diabetes and IHD. The lack of vitamin D, which is necessary for adequate insulin secretion, relates demographically to increased risk of myocardial infarction. These disorders are connected, degenerative vascular disease increasing with glucose intolerance and diabetes and, with its risk factors, comprising syndrome 'X'. Evidence is presented suggesting that vitamin D deficiency may be an avoidable risk factor for syndrome 'X', adding another preventative measure to current recommendations which are aimed at reducing the worldwide epidemic of these disorders. Experimentally, vitamin D deficiency progressively reduces insulin secretion; glucose intolerance follows and becomes irreversible. Relationships between vitamin D status, glucose tolerance and 30 min insulin secretion during oral glucose tolerance tests are reported in British Asians; insulin secretion, but not glycaemia, improving with short-term supplementation. Studies showing reduction in blood pressure and in risk of heart attack and diabetes with exercise (usually outdoor), rarely consider the role of vitamin D status. Glycaemia and insulin secretion in elderly European men, however, relate to vitamin D status, independent of season or physical activity. Prolonged supplementation can improve glycaemia. Hypertension improves with vitamin D treatment with or without initial deficiency. Vitamin D status and climate are reviewed as risk factors for myocardial infarction; the risk reducing with altitude despite increasing cold. Glycaemia and fibrinogenaemia improve with insulin secretion increases in summer. Variation in vitamin D requirements could arise from genetic differences in vitamin D processing since bone density can vary with vitamin D-receptor genotype. Vitamin D receptors are present in islet beta cells and we report insulin secretion in healthy Asians differing profoundly with the Apa I genotype, being independent of vitamin D status. Those at risk of vitamin D deficiency include the elderly, those living indoors or having a covered-up style of dress, especially dark-skinned immigrants, and pregnant women, and these are groups recognized as being at increased risk of diabetes.

[Effects of triterpenoid from Psidium guajava leaves ursolic acid on proliferation, differentiation of 3T3-L1 preadipocyte and insulin resistance].

PubMed

Lin, Juan-Na; Kuang, Qiao-Ting; Ye, Kai-He; Ye, Chun-Ling; Huang, Yi; Zhang, Xiao-Qi; Ye, Wen-Cai

2013-08-01

To investigate the influences of triterpenoid from Psidium guajava Leaves (ursolic acid) on the proliferation, differentiation of 3T3-L1 preadipocyte, and its possible mechanism treat for insulin resistance. 3T3-L1 preadipocyte was cultured in vitro. After adding ursolic acid to the culture medium for 48h, the cell viability was tested by MTT assay. Induced for 6 days, the lipid accumulation of adipocyte was measured by Oil Red O staining. The insulin resistant cell model was established with Dexamethasone. Cellular glucose uptake was determined with GOD-POD assays and FFA concentration was determined at the time of 48h. Secreted adiponectin were measured by ELISA. The protein levels of PPARgamma and PTP1B in insulin resistant adipocyte were measured by Western Blotting. Compared with medium control group, 30, 100 micromol/L ursolic acid could increase its proliferation and differentiation significantly (P < 0.05 or P < 0.01). Compared with the model group, ursolic acid at 100 micromol/L could enhance cellular glucose uptake of insulin resistant adipocyte significantly both in basic and insulin stimulation state (P < 0.01), while ursolic acid at 30 micromol/L could already enhance its glucose uptake significantly (P < 0.05), and could already decrease its FFA production significantly (P < 0.05). Ursolic acid at 30 micromol/L could increase the secretion of adiponectin on insulin resistant adipocyte significantly (P < 0.05), up-regulate the expression of PPARgamma protein (P < 0.05), but showed no effect on the PTP1B protein expression (P > 0.05). Ursolic acid can improve the proliferation and differentiation of 3T3-L1 preadipocyte, enhance cellular glucose uptake, inhibit the production of FFA, promote the secretion of adiponectin insulin resistant adipocyte, its mechanism may be related to upregulating the expression of PPARgamma protein.

Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.

PubMed

Vora, J; Bain, S C; Damci, T; Dzida, G; Hollander, P; Meneghini, L F; Ross, S A

2013-02-01

Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Over-expression of ZnT7 increases insulin synthesis and secretion in pancreatic beta-cells by promoting insulin gene transcription

USDA-ARS?s Scientific Manuscript database

The mechanism by which zinc regulates insulin synthesis and secretion in pancreatic beta-cells is still unclear. Cellular zinc homeostasis is largely maintained by zinc transporters and intracellular zinc binding proteins. In this study, we demonstrated that zinc transporter 7 (ZnT7, Slc30a7) was co...

Leptin as a Marker of Body Fat and Hyperinsulinemia in College Students

ERIC Educational Resources Information Center

Kempf, Angela M.; Strother, Myra L.; Li, Chaoyang; Kaur, Harsohena; Huang, Terry T-K.

2006-01-01

Little is known about obesity and insulin resistance in college students. Leptin is a hormone secreted by fat cells and has been shown to strongly correlate with both obesity and insulin resistance in children and adults. We investigated associations of leptin with insulin secretion and action in 119 normal-weight students aged 18-24 years. Leptin…

Heterogeneous Contribution of Insulin Sensitivity and Secretion Defects to Gestational Diabetes Mellitus

PubMed Central

Powe, Camille E.; Allard, Catherine; Battista, Marie-Claude; Doyon, Myriam; Bouchard, Luigi; Ecker, Jeffrey L.; Perron, Patrice; Florez, Jose C.; Thadhani, Ravi

2016-01-01

OBJECTIVE To characterize physiologic subtypes of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS Insulin sensitivity and secretion were estimated in 809 women at 24–30 weeks' gestation, using oral glucose tolerance test–based indices. In women with GDM (8.3%), defects in insulin sensitivity or secretion were defined below the 25th percentile in women with normal glucose tolerance (NGT). GDM subtypes were defined based on the defect(s) present. RESULTS Relative to women with NGT, women with predominant insulin sensitivity defects (51% of GDM) had higher BMI and fasting glucose, larger infants (birth weight z score 0.57 [−0.01 to 1.37] vs. 0.03 [−0.53 to 0.52], P = 0.001), and greater risk of GDM-associated adverse outcomes (57.6 vs. 28.2%, P = 0.003); differences were independent of BMI. Women with predominant insulin secretion defects (30% of GDM) had BMI, fasting glucose, infant birth weights, and risk of adverse outcomes similar to those in women with NGT. CONCLUSIONS Heterogeneity of physiologic processes underlying hyperglycemia exists among women with GDM. GDM with impaired insulin sensitivity confers a greater risk of adverse outcomes. PMID:27208340

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

Heart, Emma; Palo, Meridith; Womack, Trayce

Pancreatic β-cells release insulin in response to elevation of glucose from basal (4–7 mM) to stimulatory (8–16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H{sub 2}O{sub 2}), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H{sub 2}O{sub 2} inhibit insulin secretion. Menadione, which produces H{sub 2}O{sub 2} via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cellmore » line, and primary rodent islets. Menadione-dependent redox cycling and resulting H{sub 2}O{sub 2} production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1–10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H{sub 2}O{sub 2} formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H{sub 2}O{sub 2} and menadione on insulin secretion. -- Highlights: ► Menadione stimulation or inhibition of insulin secretion is dependent upon applied glucose levels. ► Menadione-dependent H{sub 2}O{sub 2} production is proportional to applied glucose levels. ► Quinone-mediated redox cycling is dependent on glycolysis.« less

Physical exercise introduced after weaning enhances pancreatic islet responsiveness to glucose and potentiating agents in adult MSG-obese rats.

PubMed

Ribeiro, R A; Bonfleur, M L; Vanzela, E C; Zotti, A I; Scomparin, D X; Boschero, A C; Balbo, S L

2014-08-01

Physical exercise represents an alternative way to prevent and/or ameliorate chronic metabolic diseases. Disruption of sympathetic nervous system (SNS) activity contributes to adiposity in obese subjects. Here, we verified the preventive effect of swimming training upon adiposity, adrenal catecholamine storage, and pancreatic islet function in obese monosodium glutamate (MSG)-treated rats. Male neonatal Wistar rats received MSG (4 mg/g body weight) during the first 5 days of life and, at weaning, half of the rats were submitted to swimming training, 30 min/day, 3 days a week, until 90 days of age (exercised rats: MSGex). Half of the rats were used as controls (sedentary group, MSGsd). Exercise training (ET) decreased insulinemia and fat deposition in MSGex, and increased adrenal catecholamine content, compared with MSGsd rats. Insulinemia during the ivGTT was lower in MSGex rats, despite a lack of difference in glycemia. Swimming training enhanced insulin release in islets challenged by 2.8-8.3 mmol/l glucose, whereas, at supraphysiological glucose concentrations (11.1-16.7 mmol/l), MSGex islets secreted less insulin than MSGsd. No differences in insulin secretion were observed following l-arginine (Arg) or K(+) stimuli. In contrast, islets from MSGex rats secreted more insulin when exposed to carbachol (100 μmol/l), forskolin (10 μmol/l), or IBMX (1 mmol/l) at 8.3 mmol/l glucose. Additionally, MSGex islets presented a better epinephrine inhibition upon insulin release. These results demonstrate that ET prevented the onset of obesity in MSG rats, probably by enhancing adrenal catecholamine levels. ET ameliorates islet responsiveness to several compounds, as well as insulin peripheral action. © Georg Thieme Verlag KG Stuttgart · New York.

Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity.

PubMed

Cui, Ju; Pang, Jing; Lin, Ya-Jun; Gong, Huan; Wang, Zhen-He; Li, Yun-Xuan; Li, Jin; Wang, Zai; Jiang, Ping; Dai, Da-Peng; Li, Jian; Cai, Jian-Ping; Huang, Jian-Dong; Zhang, Tie-Mei

2017-06-01

Recent studies have shown that KIF5B (conventional kinesin heavy chain) mediates glucose transporter type 4 translocation and adiponectin secretion in 3T3-L1 adipocytes, suggesting an involvement of KIF5B in the homeostasis of metabolism. However, the in vivo physiologic function of KIF5B in adipose tissue remains to be determined. In this study, adipose-specific Kif5b knockout (F-K5bKO) mice were generated using the Cre-LoxP strategy. F-K5bKO mice had similar body weights to controls fed on a standard chow diet. However, F-K5bKO mice had hyperlipidemia and significant glucose intolerance and insulin resistance. Deletion of Kif5b aggravated the deleterious impact of a high-fat diet (HFD) on body weight gain, hepatosteatosis, glucose tolerance, and systematic insulin sensitivity. These changes were accompanied by impaired insulin signaling, decreased secretion of adiponectin, and increased serum levels of leptin and proinflammatory adipokines. F-K5bKO mice fed on an HFD exhibited lower energy expenditure and thermogenic dysfunction as a result of whitening of brown adipose due to decreased mitochondria biogenesis and down-regulation of key thermogenic gene expression. In conclusion, selective deletion of Kif5b in adipose tissue exacerbates HFD-induced obesity and its associated metabolic disorders, partly through a decrease in energy expenditure, dysregulation of adipokine secretion, and insulin signaling.-Cui, J., Pang, J., Lin, Y.-J., Gong, H., Wang, Z.-H., Li, Y.-X., Li, J., Wang, Z., Jiang, P., Dai, D.-P., Li, J., Cai, J.-P., Huang, J.-D., Zhang, T.-M. Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity. © FASEB.

Maternal high-fat diet intensifies the metabolic response to stress in male rat offspring.

PubMed

Karbaschi, Roxana; Zardooz, Homeira; Khodagholi, Fariba; Dargahi, Leila; Salimi, Mina; Rashidi, FatemehSadat

2017-01-01

The mother's consumption of high-fat food can affect glucose metabolism and the hypothalamic-pituitary-adrenal axis responsiveness in the offspring and potentially affect the metabolic responses to stress as well. This study examines the effect of maternal high-fat diet on the expression of pancreatic glucose transporter 2 and the secretion of insulin in response to stress in offspring. Female rats were randomly divided into normal and high-fat diet groups and were fed in accordance with their given diets from pre-pregnancy to the end of lactation. The offspring were divided into control (NC and HFC) and stress (NS and HFS) groups based on their mothers' diet and exposure to stress in adulthood. After the two-week stress induction period was over, an intraperitoneal glucose tolerance test (IPGTT) was performed and plasma glucose and insulin levels were assessed. The pancreas was then removed for measuring insulin secretion from the isolated islets as well as glucose transporter 2 mRNA expression and protein levels. According to the results obtained, plasma corticosterone concentrations increased significantly on days 1 and 14 of the stress induction period and were lower on the last day compared to on the first day. In both the NS and HFS groups, stress reduced plasma insulin concentration in the IPGTT without changing the plasma glucose concentration, suggesting an increased insulin sensitivity in the NS and HFS groups, although more markedly in the latter. Stress reduced insulin secretion (at high glucose concentrations) and increased glucose transporter 2 mRNA and protein expression, especially in the HFS group. Mothers' high-fat diet appears to intensify the stress response by changing the programming of the neuroendocrine system in the offspring.

Investigation of intracellular signalling cascades mediating stimulatory effect of a Gymnema sylvestre extract on insulin secretion from isolated mouse and human islets of Langerhans.

PubMed

Al-Romaiyan, A; Liu, B; Docherty, R; Huang, G-C; Amiel, S; Persaud, S J; Jones, P M

2012-12-01

Traditional plant-based remedies such as Gymnema sylvestre (GS) extracts have been used to treat diabetes mellitus for many centuries. We have shown previously that a novel GS extract, OSA®, has a direct effect on insulin secretion but its mode of action has not been studied in detail Thus this study investigated the possible underlying mechanism(s) by which OSA® exerts its action. The effects of OSA® on [Ca(2+)]i and K(+) conductances were assessed by Ca(2+) microfluorimetry and electrophysiology in dispersed mouse islets and MIN6 β-cells, respectively. Isolated mouse (from 20 to 25 mice) and human (from 3 donors) islets, and MIN6 β-cells, were used to investigate whether the stimulatory effect of OSA® on insulin secretion was dependent on the presence of extracellular calcium and protein kinase activation. OSA ®-induced insulin secretion from mouse islets and MIN6 β-cells was inhibited by nifedipine, a voltage-gated Ca(2+) channel blocker, and by the removal of extracellular Ca(2+), respectively. OSA® did not affect the activities of KATP channels or voltage-dependent K(+) channels in MIN6 β-cells but it caused an increase in intracellular Ca(2+) ([Ca(2+)]i) concentrations in Fura-2-loaded mouse islet cells. The insulin secretagogue effect of OSA® was dependent, in part, on protein kinase activation since incubating mouse or human islets with staurosporine, a general protein kinase inhibitor, resulted in partial inhibition of OSA®-induced insulin secretion. Experiments using permeabilized, Ca(2+)-clamped MIN6 β-cells revealed a Ca(2+)-independent component action of OSA® at a late stage in the stimulus-response coupling pathway. OSA®-induced insulin secretion was unexpectedly associated with a decrease in intracellular cAMP levels. These data indicate that the GS isolate OSA® stimulates insulin secretion from mouse and human islets in vitro, at least in part as a consequence of Ca(2+) influx and protein kinase activation. © 2012 Blackwell Publishing Ltd.

Recombinant Incretin-Secreting Microbe Improves Metabolic Dysfunction in High-Fat Diet Fed Rodents.

PubMed

Ryan, Paul M; Patterson, Elaine; Kent, Robert M; Stack, Helena; O'Connor, Paula M; Murphy, Kiera; Peterson, Veronica L; Mandal, Rupasri; Wishart, David S; Dinan, Timothy G; Cryan, John F; Seeley, Randy J; Stanton, Catherine; Ross, R Paul

2017-10-19

The gut hormone glucagon-like peptide (GLP)-1 and its analogues represent a new generation of anti-diabetic drugs, which have also demonstrated propensity to modulate host lipid metabolism. Despite this, drugs of this nature are currently limited to intramuscular administration routes due to intestinal degradation. The aim of this study was to design a recombinant microbial delivery vector for a GLP-1 analogue and assess the efficacy of the therapeutic in improving host glucose, lipid and cholesterol metabolism in diet induced obese rodents. Diet-induced obese animals received either Lactobacillus paracasei NFBC 338 transformed to express a long-acting analogue of GLP-1 or the isogenic control microbe which solely harbored the pNZ44 plasmid. Short-term GLP-1 microbe intervention in rats reduced serum low-density lipoprotein cholesterol, triglycerides and triglyceride-rich lipoprotein cholesterol substantially. Conversely, extended GLP-1 microbe intervention improved glucose-dependent insulin secretion, glucose metabolism and cholesterol metabolism, compared to the high-fat control group. Interestingly, the microbe significantly attenuated the adiposity associated with the model and altered the serum lipidome, independently of GLP-1 secretion. These data indicate that recombinant incretin-secreting microbes may offer a novel and safe means of managing cholesterol metabolism and diet induced dyslipidaemia, as well as insulin sensitivity in metabolic dysfunction.

Low-fat versus low-carbohydrate weight reduction diets: effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial.

PubMed

Bradley, Una; Spence, Michelle; Courtney, C Hamish; McKinley, Michelle C; Ennis, Cieran N; McCance, David R; McEneny, Jane; Bell, Patrick M; Young, Ian S; Hunter, Steven J

2009-12-01

Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction. We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean +/- SD] BMI 33.6 +/- 3.7 kg/m(2), aged 39 +/- 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured. Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance-related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group. This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.

The Ia-2β intronic miRNA, miR-153, is a negative regulator of insulin and dopamine secretion through its effect on the Cacna1c gene in mice.

PubMed

Xu, Huanyu; Abuhatzira, Liron; Carmona, Gilberto N; Vadrevu, Suryakiran; Satin, Leslie S; Notkins, Abner L

2015-10-01

miR-153 is an intronic miRNA embedded in the genes that encode IA-2 (also known as PTPRN) and IA-2β (also known as PTPRN2). Islet antigen (IA)-2 and IA-2β are major autoantigens in type 1 diabetes and are important transmembrane proteins in dense core and synaptic vesicles. miR-153 and its host genes are co-regulated in pancreas and brain. The present experiments were initiated to decipher the regulatory network between miR-153 and its host gene Ia-2β (also known as Ptprn2). Insulin secretion was determined by ELISA. Identification of miRNA targets was assessed using luciferase assays and by quantitative real-time PCR and western blots in vitro and in vivo. Target protector was also employed to evaluate miRNA target function. Functional studies revealed that miR-153 mimic suppresses both glucose- and potassium-induced insulin secretion (GSIS and PSIS, respectively), whereas miR-153 inhibitor enhances both GSIS and PSIS. A similar effect on dopamine secretion also was observed. Using miRNA target prediction software, we found that miR-153 is predicted to target the 3'UTR region of the calcium channel gene, Cacna1c. Further studies confirmed that Cacna1c mRNA and protein are downregulated by miR-153 mimics and upregulated by miR-153 inhibitors in insulin-secreting freshly isolated mouse islets, in the insulin-secreting mouse cell line MIN6 and in the dopamine-secreting cell line PC12. miR-153 is a negative regulator of both insulin and dopamine secretion through its effect on Cacna1c expression, which suggests that IA-2β and miR-153 have opposite functional effects on the secretory pathway.

Incretin hormone receptors are required for normal beta cell development and function in female mice.

PubMed

Omar, Bilal; Ahlkvist, Linda; Yamada, Yuchiro; Seino, Yutaka; Ahrén, Bo

2016-05-01

The incretin hormones, glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), potentiate insulin secretion and are responsible for the majority of insulin secretion that occurs after a meal. They may also, however, have a fundamental role in pancreatic beta cell development and function, independently of their role in potentiating insulin secretion after a meal. This has led to observations that a loss of GIP or GLP-1 action affects normal beta cell function, however each one of the incretin hormones may compensate when the action of the other is lost and therefore the overall impact of the incretin hormones on beta cell function is not known. We therefore utilized a mouse line deficient in both the GLP-1 and GIP receptor genes, the double incretin receptor knockout (DIRKO), to determine the consequences of a lifelong, complete lack of incretin hormone action on beta cell function, in vivo, in intact animals. We found that DIRKO mice displayed impaired glucose tolerance and insulin secretion in response to both oral glucose and mixed meal tolerance tests compared to wild-type mice. Assessment of beta cell function using the hyperglycemic clamp technique revealed an 80% decrease in first phase insulin response in DIRKO mice, but a normal second phase insulin secretion. A similar decline was seen when wild-type mice were given acute intravenous injection of glucose together with the GLP-1 receptor antagonist Ex9-39. Ex vivo assessments of the pancreas revealed significantly fewer islets in the pancreata of DIRKO mice despite no differences in total pancreatic mass. Insulin secretion from isolated islets of DIRKO mice was impaired to a similar extent to that seen during the hyperglycemic clamp. Insulin secretion in wild-type islets was impaired by acute treatment with Ex9-39 to a similar extent as the in vivo intravenous glucose tolerance tests. In conclusion, a loss of the action of both incretin hormones results in direct impairment of beta cell function both in vivo and in vitro in a process that appears to be independent of the intestinally secreted incretin hormones. We therefore conclude that the incretin hormones together significantly impact both beta-cell function and beta-cell development. Copyright © 2016. Published by Elsevier Inc.

Hospital protocols for targeted glycemic control: Development, implementation, and models for cost justification.

PubMed

Magee, Michelle F

2007-05-15

Evolving elements of best practices for providing targeted glycemic control in the hospital setting, clinical performance measurement, basal-bolus plus correction-dose insulin regimens, components of standardized subcutaneous (s.c.) insulin order sets, and strategies for implementation and cost justification of glycemic control initiatives are discussed. Best practices for targeted glycemic control should address accurate documentation of hyperglycemia, initial patient assessment, management plan, target blood glucose range, blood glucose monitoring frequency, maintenance of glycemic control, criteria for glucose management consultations, and standardized insulin order sets and protocols. Establishing clinical performance measures, including desirable processes and outcomes, can help ensure the success of targeted hospital glycemic control initiatives. The basal-bolus plus correction-dose regimen for insulin administration will be used to mimic the normal physiologic pattern of endogenous insulin secretion. Standardized insulin order sets and protocols are being used to minimize the risk of error in insulin therapy. Components of standardized s.c. insulin order sets include specification of the hyperglycemia diagnosis, finger stick blood glucose monitoring frequency and timing, target blood glucose concentration range, cutoff values for excessively high or low blood glucose concentrations that warrant alerting the physician, basal and prandial or nutritional (i.e., bolus) insulin, correction doses, hypoglycemia treatment, and perioperative or procedural dosage adjustments. The endorsement of hospital administrators and key physician and nursing leaders is needed for glycemic control initiatives. Initiatives may be cost justified on the basis of the billings for clinical diabetes management services and/or the return- on-investment accrued to reductions in hospital length of stay, readmissions, and accurate documentation and coding of unrecognized or uncontrolled diabetes, and diabetes complications. Standardized insulin order sets and protocols may minimize risk of insulin errors. The endorsement of these protocols by administrators, physicians, nurses, and pharmacists is also needed for success.

Early-phase prandial insulin secretion: its role in the pathogenesis of type 2 diabetes mellitus and its modulation by repaglinide.

PubMed

Owens, D R; Cozma, L S; Luzio, S D

2002-12-01

The major contributory factor to increasing hyperglycaemia in established Type 2 diabetes mellitus (T2DM) appears to be the progressive delay and attenuation of the prandial insulin response. An important consequence of this derangement is that hepatic glucose production is no longer suppressed during times of prandial glucose intake. Together with a relative impairment in the rate of peripheral glucose disposal, this leads to supra-physiological plasma glucose excursions, which may damage the vasculature. An obvious therapeutic strategy, therefore, would be to increase insulin availability when most needed--in the early prandial phase. In experiments with exogenous insulin interventions, peak post-prandial blood glucose increments were curtailed without undue increases in total insulin exposure. However, available evidence suggests that the sulphonylurea glibenclamide does not effectively alter early-phase prandial insulin release but predominately increases late-phase and basal insulin output, thus incurring the risk of hypoglycaemia. The novel insulin secretagogue repaglinide, by contrast, augments early-phase prandial insulin secretion when taken before meals, as shown by studies in non-diabetic people and patients with newly diagnosed, previously untreated T2DM. Repaglinide exerts its greatest effect on the insulin secretion rate during the first 30 min after a meal is started, thereby going some way to restoring the early insulin secretion curve seen after a meal in non-diabetic people. No residual secretagogue activity is seen 4 hr after taking a single dose of up to 2 mg. Prandial glucose regulation with repaglinide could be associated with lower post-prandial glucose excursions and less risk of post-prandial hypoglycaemia than glibenclamide.

Repaglinide--prandial glucose regulator: a new class of oral antidiabetic drugs.

PubMed

Owens, D R

1998-01-01

The highest demand on insulin secretion occurs in connection with meals. In normal people, following a meal, the insulin secretion increases rapidly, reaching peak concentration in the blood within an hour. The mealtime insulin response in patients with Type 2 diabetes is blunted and delayed, whereas basal levels often remain within the normal range (albeit at elevated fasting glucose levels). Restoration of the insulin secretion pattern at mealtimes (prandial phase)--without stimulating insulin secretion in the 'postabsorptive' phase--is the rationale for the development of 'prandial glucose regulators', drugs that are characterized by a very rapid onset and short duration of action in stimulating insulin secretion. Repaglinide, a carbamoylmethyl benzoic acid (CMBA) derivative is the first such compound, which recently has become available for clinical use. Repaglinide is very rapidly absorbed (t(max) less than 1 hour) with a t1/2 of less than one hour. Furthermore, repaglinide is inactivated in the liver and more than 90% excreted via the bile. The implications of tailoring repaglinide treatment to meals were examined in a study where repaglinide was dosed either morning and evening, or with each main meal (i.e. breakfast, lunch, dinner), with the total daily dose of repaglinide being identical. The mealtime dosing caused a significant improvement in both fasting and 24-hour glucose profiles, as well as a significant decrease in HbA1c. In other studies, repaglinide caused a decrease of 5.8 mmol x l(-1) in peak postprandial glucose levels, and a decrease of 3.1 mmol x l(-1) in fasting levels with a reduction in HbA1c of 1.8% compared with placebo. In comparative studies with either sulphonylurea or metformin, repaglinide caused similar or improved control (i.e. HbA1c, mean glucose levels) and the drug was well tolerated (e.g. reported gastrointestinal side-effects were more than halved when patients were switched from metformin to repaglinide). A hallmark of repaglinide treatment is that this medication follows the eating pattern, and not vice versa. Hence the risk of developing severe hypoglycaemia (BG < or = 2.5 mmol x l(-1)) in connection with flexible lifestyles should be reduced. This concept was examined in a study in which patients well controlled on repaglinide skipped their lunch on one occasion. When a meal (i.e. lunch) was skipped--so was the repaglinide dose, whereas in the comparative group on glibenclamide the recommended morning and evening doses were taken. Twenty-four per cent of the patients in the glibenclamide group developed severe hypoglycaemia, whereas no hypoglycaemic events occurred in the group receiving repaglinide. However, in long-term studies the overall prevalence of hypoglycaemia was similar to that found with other insulin secretagogues. In summary, current evidence shows that the concept of prandial glucose regulation offers good long-term glycaemic control combined with a low risk of severe hypoglycaemia with missed meals. The concept should meet the needs of Type 2 diabetic patients, allowing flexibility in their lifestyle.

Galanin inhibits caerulein-stimulated pancreatic amylase secretion via cholinergic nerves and insulin.

PubMed

Barreto, Savio G; Woods, Charmaine M; Carati, Colin J; Schloithe, Ann C; Jaya, Surendra R; Toouli, James; Saccone, Gino T P

2009-08-01

Pancreatic exocrine secretion is affected by galanin, but the mechanisms involved are unclear. We aimed to determine the effect and elucidate the mechanism of action of exogenous galanin on basal and stimulated pancreatic amylase secretion in vitro. The effect of galanin on basal-, carbachol-, and caerulein-stimulated amylase secretion from isolated murine pancreatic lobules was measured. Carbachol and caerulein concentration-response relationships were established. Lobules were coincubated with galanin (10(-12) M to 10(-7) M), carbachol (10(-6) M), or caerulein (10(-10) M). Lobules were preincubated with atropine (10(-5) M), tetrodotoxin (10(-5) M), hexamethonium (10(-5) M), or diazoxide (10(-7) M and 10(-4) M) for 30 min followed by incubation with caerulein (10(-10) M) alone or combined with galanin (10(-12) M). Amylase secretion was expressed as percent of total lobular amylase. Immunohistochemical studies used the antigen retrieval technique and antisera for galanin receptor (GALR) 1, 2, and 3. Carbachol and caerulein stimulated amylase secretion in a concentration-dependent manner with maximal responses of two- and 1.7-fold over control evoked at 10(-6) M and 10(-10) M, respectively. Galanin (10(-12) M) completely inhibited caerulein-stimulated amylase secretion but had no effect on carbachol-stimulated or basal secretion. Atropine and tetrodotoxin pretreatment abolished the caerulein-stimulated amylase secretion, whereas hexamethonium had no significant effect. Diazoxide significantly reduced caerulein-stimulated amylase secretion by approximately 80%. Galanin did not affect caerulein-stimulated amylase secretion in the presence of hexamethonium or diazoxide. Glucose-stimulated amylase secretion was also inhibited by galanin. Immunohistochemistry revealed islet cells labeled for GALR2. These data suggest that galanin may modulate caerulein-stimulated amylase secretion by acting on cholinergic nerves and/or islet cells possibly via GALR2 to regulate insulin release.

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

Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin Secretion through Myeloid Cell Retinoic Acid Production.

PubMed

Dalmas, Elise; Lehmann, Frank M; Dror, Erez; Wueest, Stephan; Thienel, Constanze; Borsigova, Marcela; Stawiski, Marc; Traunecker, Emmanuel; Lucchini, Fabrizio C; Dapito, Dianne H; Kallert, Sandra M; Guigas, Bruno; Pattou, Francois; Kerr-Conte, Julie; Maechler, Pierre; Girard, Jean-Philippe; Konrad, Daniel; Wolfrum, Christian; Böni-Schnetzler, Marianne; Finke, Daniela; Donath, Marc Y

2017-11-21

Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion. Copyright © 2017 Elsevier Inc. All rights reserved.

Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP

PubMed Central

Elliott, Amicia D.; Ustione, Alessandro

2014-01-01

The dysregulation of glucose-inhibited glucagon secretion from the pancreatic islet α-cell is a critical component of diabetes pathology and metabolic disease. We show a previously uncharacterized [Ca2+]i-independent mechanism of glucagon suppression in human and murine pancreatic islets whereby cAMP and PKA signaling are decreased. This decrease is driven by the combination of somatostatin, which inhibits adenylyl cyclase production of cAMP via the Gαi subunit of the SSTR2, and insulin, which acts via its receptor to activate phosphodiesterase 3B and degrade cytosolic cAMP. Our data indicate that both somatostatin and insulin signaling are required to suppress cAMP/PKA and glucagon secretion from both human and murine α-cells, and the combination of these two signaling mechanisms is sufficient to reduce glucagon secretion from isolated α-cells as well as islets. Thus, we conclude that somatostatin and insulin together are critical paracrine mediators of glucose-inhibited glucagon secretion and function by lowering cAMP/PKA signaling with increasing glucose. PMID:25406263

Adaptive response of rat pancreatic β-cells to insulin resistance induced by monocrotophos: Biochemical evidence.

PubMed

Nagaraju, Raju; Rajini, Padmanabhan Sharda

2016-11-01

Our previous findings clearly suggested the role of duration of exposure to monocrotophos (MCP) in the development of insulin resistance. Rats exposed chronically to MCP developed insulin resistance with hyperinsulinemia without overt diabetes. In continuation of this vital observation, we sought to delineate the biochemical mechanisms that mediate heightened pancreatic β-cell response in the wake of MCP-induced insulin resistance in rats. Adult rats were orally administered (0.9 and 1.8mg/kgb.w/d) MCP for 180days. Terminally, MCP-treated rats exhibited glucose intolerance, hyperinsulinemia, and potentiation of glucose-induced insulin secretion along with elevated levels of circulating IGF1, free fatty acids, corticosterone, and paraoxonase activity. Biochemical analysis of islet extracts revealed increased levels of insulin, malate, pyruvate and ATP with a concomitant increase in activities of cytosolic and mitochondrial enzymes that are known to facilitate insulin secretion and enhanced shuttle activities. Interestingly, islets from MCP-treated rats exhibited increased insulin secretory potential ex vivo compared to those isolated from control rats. Further, MCP-induced islet hypertrophy was associated with increased insulin-positive cells. Our study demonstrates the impact of the biological interaction between MCP and components of metabolic homeostasis on pancreatic beta cell function/s. We speculate that the heightened pancreatic beta cell function evidenced may be mediated by increased IGF1 and paraoxonase activity, which effectively counters insulin resistance induced by chronic exposure to MCP. Our findings emphasize the need for focused research to understand the confounding environmental risk factors which may modulate heightened beta cell functions in the case of organophosphorus insecticide-induced insulin resistance. Such an approach may help us to explain the sharp increase in the prevalence of type II diabetes worldwide. Copyright © 2016 Elsevier B.V. All rights reserved.

In vivo and in vitro evaluation of the effects of Urtica dioica and swimming activity on diabetic factors and pancreatic beta cells.

PubMed

Ranjbari, Abbas; Azarbayjani, Mohammad Ali; Yusof, Ashril; Halim Mokhtar, Abdul; Akbarzadeh, Samad; Ibrahim, Mohamed Yousif; Tarverdizadeh, Bahman; Farzadinia, Parviz; Hajiaghaee, Reza; Dehghan, Firouzeh

2016-03-15

Urtica dioica (UD) has been identified as a traditional herbal medicine. This study aimed to investigate the effect of UD extract and swimming activity on diabetic parameters through in vivo and in vitro experiments. Adult WKY male rats were randomly distributed in nine groups: intact control, diabetic control, diabetic + 625 mg/kg, 1.25 g/kg UD, diabetic + 100 mg/kg Metformin, diabetic + swimming, diabetic + swimming 625 mg/kg, 1.25 g/kg UD, and diabetic +100 mg/kg Metformin + swimming. The hearts of the animals were punctured, and blood samples were collected for biochemical analysis. The entire pancreas was exposed for histologic examination. The effect of UD on insulin secretion by RIN-5F cells in 6.25 or 12.5 mM glucose dose was examined. Glucose uptake by cultured L6 myotubes was determined. The serum glucose concentration decreased, the insulin resistance and insulin sensitivity significantly increased in treated groups. These changes were more pronounced in the group that received UD extract and swimming training. Regeneration and less beta cell damage of Langerhans islets were observed in the treated groups. UD treatment increased insulin secretion in the RIN-5F cells and glucose uptake in the L6 myotubes cells. Swimming exercises accompanied by consuming UD aqueous extracts effectively improved diabetic parameters, repaired pancreatic tissues in streptozotocin-induced diabetics in vivo, and increased glucose uptake or insulin in UD-treated cells in vitro.

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

Fenugreek lactone attenuates palmitate-induced apoptosis and dysfunction in pancreatic β-cells

PubMed Central

Gong, Jing; Dong, Hui; Jiang, Shu-Jun; Wang, Ding-Kun; Fang, Ke; Yang, De-Sen; Zou, Xin; Xu, Li-Jun; Wang, Kai-Fu; Lu, Fu-Er

2015-01-01

AIM: To investigate the effect of fenugreek lactone (FL) on palmitate (PA)-induced apoptosis and dysfunction in insulin secretion in pancreatic NIT-1 β-cells. METHODS: Cells were cultured in the presence or absence of FL and PA (0.25 mmol/L) for 48 h. Then, lipid droplets in NIT-1 cells were observed by oil red O staining, and the intracellular triglyceride content was measured by colorimetric assay. The insulin content in the supernatant was determined using an insulin radio-immunoassay. Oxidative stress-associated parameters, including total superoxide dismutase, glutathione peroxidase and catalase activity and malondialdehyde levels in the suspensions were also examined. The expression of upstream regulators of oxidative stress, such as protein kinase C-α (PKC-α), phospho-PKC-α and P47phox, were determined by Western blot analysis and real-time PCR. In addition, apoptosis was evaluated in NIT-1 cells by flow cytometry assays and caspase-3 viability assays. RESULTS: Our results indicated that compared to the control group, PA induced an increase in lipid accumulation and apoptosis and a decrease in insulin secretion in NIT-1 cells. Oxidative stress in NIT-1 cells was activated after 48 h of exposure to PA. However, FL reversed the above changes. These effects were accompanied by the inhibition of PKC-α, phospho-PKC-α and P47phox expression and the activation of caspase-3. CONCLUSION: FL attenuates PA-induced apoptosis and insulin secretion dysfunction in NIT-1 pancreatic β-cells. The mechanism for this action may be associated with improvements in levels of oxidative stress. PMID:26730156

Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program

PubMed Central

Florez, Jose C.; Jablonski, Kathleen A.; Kahn, Steven E.; Franks, Paul W.; Dabelea, Dana; Hamman, Richard F.; Knowler, William C.; Nathan, David M.; Altshuler, David

2008-01-01

The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over ~3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-to-diabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation. Diabetes 56: 531–536, 2007 PMID:17259403

Glucose Metabolism After Renal Transplantation

PubMed Central

Hecking, Manfred; Kainz, Alexander; Werzowa, Johannes; Haidinger, Michael; Döller, Dominik; Tura, Andrea; Karaboyas, Angelo; Hörl, Walter H.; Wolzt, Michael; Sharif, Adnan; Roden, Michael; Moro, Ermanno; Pacini, Giovanni; Port, Friedrich K.; Säemann, Marcus D.

2013-01-01

OBJECTIVE We determined prevalence, risk factors, phenotype, and pathophysiological mechanism of new-onset diabetes after transplantation (NODAT) to generate strategies for optimal pharmacological management of hyperglycemia in NODAT patients. RESEARCH DESIGN AND METHODS Retrospective cohort study comparing demographics, laboratory data, and oral glucose tolerance test (OGTT)-derived metabolic parameters from kidney transplant recipients versus subjects not receiving transplants. RESULTS Among 1,064 stable kidney transplant recipients (≥6 months posttransplantation), 113 (11%) had a history of NODAT and 132 (12%) had pretransplant diabetes. In the remaining patients, randomly assigned OGTTs showed a high prevalence of abnormal glucose metabolism (11% diabetes; 32% impaired fasting glucose, impaired glucose tolerance, or both), predominantly in older patients who received tacrolimus as the primary immunosuppressant. Compared with 1,357 nontransplant subjects, stable kidney transplant recipients had lower basal glucose, higher glycated hemoglobin, lower insulin secretion, and greater insulin sensitivity in each of the three subgroups, defined by OGTT 2-h glucose (<140, 140–199, ≥200 mg/dL). These findings were reinforced in linear spline interpolation models of insulin secretion and sensitivity (all P < 0.001) and in another regression model in which the estimated oral glucose insulin sensitivity index was substantially higher (by 79–112 mL/min m2) for transplant versus nontransplant subjects despite adjustments for age, sex, and BMI (all P < 0.001). CONCLUSIONS Glucose metabolism differs substantially between kidney transplant recipients and nontransplant controls. Because impaired insulin secretion appears to be the predominant pathophysiological feature after renal transplantation, early therapeutic interventions that preserve, maintain, or improve β-cell function are potentially beneficial in this population. PMID:23656979

TRPM channels phosphorylation as a potential bridge between old signals and novel regulatory mechanisms of insulin secretion.

PubMed

Diaz-Garcia, Carlos Manlio; Sanchez-Soto, Carmen; Hiriart, Marcia

2013-03-01

Transient receptor potential channels, especially the members of the melastatin family (TRPM), participate in insulin secretion. Some of them are substrates for protein kinases, which are involved in several neurotransmitter, incretin and hormonal signaling cascades in β cells. The functional relationships between protein kinases and TRPM channels in systems of heterologous expression and native tissues rise issues about novel regulation pathways of pancreatic β-cell excitability. The aim of the present work is to review the evidences about phosphorylation of TRPM channels in β cells and to discuss the perspectives on insulin secretion.

Cross-fostering reduces obesity induced by early exposure to monosodium glutamate in male rats.

PubMed

Miranda, Rosiane Aparecida; da Silva Franco, Claudinéia Conationi; de Oliveira, Júlio Cezar; Barella, Luiz Felipe; Tófolo, Laize Peron; Ribeiro, Tatiane Aparecida; Pavanello, Audrei; da Conceição, Ellen Paula Santos; Torrezan, Rosana; Armitage, James; Lisboa, Patrícia Cristina; de Moura, Egberto Gaspar; de Freitas Mathias, Paulo Cezar; Vieira, Elaine

2017-01-01

Maternal obesity programmes a range of metabolic disturbances for the offspring later in life. Moreover, environmental changes during the suckling period can influence offspring development. Because both periods significantly affect long-term metabolism, we aimed to study whether cross-fostering during the lactation period was sufficient to rescue a programmed obese phenotype in offspring induced by maternal obesity following monosodium L-glutamate (MSG) treatment. Obesity was induced in female Wistar rats by administering subcutaneous MSG (4 mg/g body weight) for the first 5 days of postnatal life. Control and obese female rats were mated in adulthood. The resultant pups were divided into control second generation (F 2 ) (CTLF 2 ), MSG-treated second generation (F 2 ) (MSGF 2 ), which suckled from their CTL and MSG biological dams, respectively, or CTLF 2 -CR, control offspring suckled by MSG dams and MSGF 2 -CR, MSG offspring suckled by CTL dams. At 120 days of age, fat tissue accumulation, lipid profile, hypothalamic leptin signalling, glucose tolerance, glucose-induced, and adrenergic inhibition of insulin secretion in isolated pancreatic islets were analysed. Maternal MSG-induced obesity led to an obese phenotype in male offspring, characterized by hyperinsulinaemia, hyperglycaemia, hyperleptinaemia, dyslipidaemia, and impaired leptin signalling, suggesting central leptin resistance, glucose intolerance, impaired glucose-stimulated, and adrenergic inhibition of insulin secretion. Cross-fostering normalized body weight, food intake, leptin signalling, lipid profiles, and insulinaemia, but not glucose homeostasis or insulin secretion from isolated pancreatic islets. Our findings suggest that alterations during the lactation period can mitigate the development of obesity and prevent the programming of adult diseases.

Effects of High Glucose Levels and Glycated Serum on GIP Responsiveness in the Pancreatic Beta Cell Line HIT-T15.

PubMed

Puddu, Alessandra; Sanguineti, Roberta; Montecucco, Fabrizio; Viviani, Giorgio Luciano

2015-01-01

Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone produced in the gastrointestinal tract that stimulates glucose dependent insulin secretion. Impaired incretin response has been documented in diabetic patients and was mainly related to the inability of the pancreatic beta cells to secrete insulin in response to GIP. Advanced Glycation End Products (AGEs) have been shown to play an important role in pancreatic beta cell dysfunction. The aim of this study is to investigate whether the exposure to AGEs can induce GIP resistance in the pancreatic beta cell line HIT-T15. Cells were cultured for 5 days in low (CTR) or high glucose (HG) concentration in the presence of AGEs (GS) to evaluate the expression of GIP receptor (GIPR), the intracellular signaling activated by GIP, and secretion of insulin in response to GIP. The results showed that incubation with GS alone altered intracellular GIP signaling and decreased insulin secretion as compared to CTR. GS in combination with HG reduced the expression of GIPR and PI3K and abrogated GIP-induced AKT phosphorylation and GIP-stimulated insulin secretion. In conclusion, we showed that treatment with GS is associated with the loss of the insulinotropic effect of GIP in hyperglycemic conditions.

Association of fat to lean mass ratio with metabolic dysfunction in women with polycystic ovary syndrome.

PubMed

Ezeh, Uche; Pall, Marita; Mathur, Ruchi; Azziz, Ricardo

2014-07-01

Are differences in metabolic dysfunction between polycystic ovary syndrome (PCOS) and control women related to differences in their fat to lean mass (F/L) ratio? Compared with controls of similar body mass index (BMI), women with PCOS demonstrate adverse body composition characterized by increased whole body fat relative to lean mass (i.e. a higher F/L ratio), which is associated with differences in metabolic dysfunction between the two groups. Previous studies examining body composition and insulin resistance (IR) in PCOS have yielded conflicting results. Excess total fat mass (i.e. fat mass index [fat BMI]) correlates with IR, whereas increased total lean mass (i.e. lean BMI) has been associated with higher insulin sensitivity. However, the role of the F/L ratio, which integrates the antagonistic effects of both fat and lean mass depots, on IR in PCOS, has not been investigated. We conducted a prospective cross-sectional study of 120 women between the ages of 22-44 years to study the relation of the F/L ratio with measures of insulin action and secretion in both steady and dynamic states. Sixty PCOS (by NIH, 1990 criteria) and 60 control (age, race and BMI-matched) women were prospectively studied for body composition (by bioelectrical impedance analysis [BIA]) and basal IR and insulin secretion by the homeostasis model assessment (HOMA-IR and HOMA-%β-cell function, respectively) in a tertiary care academic referral center. A subset of 12 PCOS and 12 matched control women also underwent a modified frequently sampled intravenous glucose tolerance test (FSIVGTT) to determine glucose uptake and insulin secretion in dynamic state. Our results indicate that women with PCOS demonstrated greater degrees of hyperandrogenism, and higher waist-to-hip ratio (WHR), %body fat, fat BMI, F/L, fasting insulin levels, and HOMA-IR and HOMA-%β-cell values, than controls. In models adjusted for WHR and free testosterone and diagnostic groups, fasting insulin levels, HOMA-IR, and HOMA-%beta cell function were positively related to the F/L ratio. A positive relationship was also found in both study groups between F/L and the FSIVGTT measures insulin sensitivity (Si) and acute insulin response to glucose (AIRg). The F/L tended to negatively correlate with glucose effectiveness or non-insulin-mediated glucose transport (Sg) only in PCOS women. Regional tissue sub-compartments, which have been shown to have potential independent associations with metabolic variables, cannot be determined by bioelectrical impedance analysis (BIA). The current results suggest that BIA could be used to assess F/L in place of dual energy X-ray absorptiometry (DXA) in research protocols, and that F/L could possibly be used as an alternative to WHR as a surrogate marker of metabolic dysfunction in clinical practice. This work was supported by grants R01-DK073632 and R01-HD29364 from the NIH and an endowment of the Helping Hand of Los Angeles, Inc. (to R.A.). The authors have no competing interests to declare. Not applicable.

Design and clinical pilot testing of the model-based dynamic insulin sensitivity and secretion test (DISST).

PubMed

Lotz, Thomas F; Chase, J Geoffrey; McAuley, Kirsten A; Shaw, Geoffrey M; Docherty, Paul D; Berkeley, Juliet E; Williams, Sheila M; Hann, Christopher E; Mann, Jim I

2010-11-01

Insulin resistance is a significant risk factor in the pathogenesis of type 2 diabetes. This article presents pilot study results of the dynamic insulin sensitivity and secretion test (DISST), a high-resolution, low-intensity test to diagnose insulin sensitivity (IS) and characterize pancreatic insulin secretion in response to a (small) glucose challenge. This pilot study examines the effect of glucose and insulin dose on the DISST, and tests its repeatability. DISST tests were performed on 16 subjects randomly allocated to low (5 g glucose, 0.5 U insulin), medium (10 g glucose, 1 U insulin) and high dose (20 g glucose, 2 U insulin) protocols. Two or three tests were performed on each subject a few days apart. Average variability in IS between low and medium dose was 10.3% (p=.50) and between medium and high dose 6.0% (p=.87). Geometric mean variability between tests was 6.0% (multiplicative standard deviation (MSD) 4.9%). Geometric mean variability in first phase endogenous insulin response was 6.8% (MSD 2.2%). Results were most consistent in subjects with low IS. These findings suggest that DISST may be an easily performed dynamic test to quantify IS with high resolution, especially among those with reduced IS. © 2010 Diabetes Technology Society.

Insulin-producing cells could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells

PubMed Central

2013-01-01

Objective The aim of this study was to compare the difference between insulin-producing cells (IPCs) and normal human pancreatic beta cells both in physiological function and morphological features in cellular level. Methods The levels of insulin secretion were measured by enzyme-linked immunosorbent assay. The insulin gene expression was determined by real-time quantitative polymerase chain reaction. The morphological features were detected by atomic force microscopy (AFM) and laser confocal scanning microscopy. Results IPCs and normal human pancreatic beta cells were similar to each other under the observation in AFM with the porous structure features in the cytoplasm. Both number of membrane particle size and average roughness of normal human beta cells were higher than those of IPCs. Conclusions Our results firstly revealed that the cellular ultrastructure of IPCs was closer to that of normal human pancreatic beta cells, but they still could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells. PMID:23421382

Effect of activators and inhibitors of K+ channels on insulin secretion in the amphibian pancreas.

PubMed

Francini, F; Pirotte, B; Gagliardino, J J

1997-02-01

The aim of this study was to obtain pharmacological evidence for the presence and participation of K+ channels in amphibian pancreatic islets. Pancreases from the toad Bufo arenarum were thus incubated with activators or blockers of K+ channels and the immunoreactive insulin released into the medium was measured by radioimmunoassay. Two K(+)-ATP channel openers (diazoxide and BPDZ44) inhibited; while a K(+)-ATP channel blocker (tolbutamide) and metabolizable sugars (glucose, glyceraldehyde) significantly stimulated the output of insulin. Although a nonmetabolizable sugar (galactose) failed to increase insulin release, dinitrophenol decreased the secretagogue effect of glucose. By contrast, although somatostatin and clonidine blocked the release of insulin, tetraethylammonium significantly stimulated secretion. For each compound tested, the effects on both insulin secretion and B-cell K+ channel activity were similar to those observed in the mammalian pancreas. These findings point to the existence of mammalian-like K+ channels in the B-cells of some amphibians.

The glucagon-miniglucagon interplay: a new level in the metabolic regulation.

PubMed

Bataille, Dominique; Fontés, Ghislaine; Costes, Safia; Longuet, Christine; Dalle, Stéphane

2006-07-01

Miniglucagon (glucagon 19-29) is the ultimate processing product of proglucagon, present in the glucagon-secreting granules of the alpha cells, at a close vicinity of the insulin-secreting beta cells. Co-released with glucagon and thanks to its original mode of action and its huge potency, it suppresses, inside the islet of Langerhans, the detrimental effect of glucagon on insulin secretion, while it leaves untouched the beneficial effect of glucagon on glucose competence of the beta cell. At the periphery, miniglucagon is processed at the surface of glucagon- and insulin-sensitive cells from circulating glucagon. At that level, it acts via a cellular pathway which uses initial molecular steps distinct from that of insulin which, when impaired, are involved in insulin resistence. This bypass allows miniglucagon to act as an insulin-like component, a characteristic which makes this peptide of particular interest from a pathophysiological and pharmacological point of views in understanding and treating metabolic diseases, such as the type 2 diabetes.

A Central Role for GRB10 in Regulation of Islet Function in Man

PubMed Central

Prasad B, Rashmi; Salehi, S. Albert; Almgren, Peter; Osmark, Peter; Bouatia-Naji, Nabila; Wierup, Nils; Fall, Tove; Stančáková, Alena; Barker, Adam; Lagou, Vasiliki; Osmond, Clive; Xie, Weijia; Lahti, Jari; Jackson, Anne U.; Cheng, Yu-Ching; Liu, Jie; O'Connell, Jeffrey R.; Blomstedt, Paul A.; Fadista, Joao; Alkayyali, Sami; Dayeh, Tasnim; Ahlqvist, Emma; Taneera, Jalal; Lecoeur, Cecile; Kumar, Ashish; Hansson, Ola; Hansson, Karin; Voight, Benjamin F.; Kang, Hyun Min; Levy-Marchal, Claire; Vatin, Vincent; Palotie, Aarno; Syvänen, Ann-Christine; Mari, Andrea; Weedon, Michael N.; Loos, Ruth J. F.; Ong, Ken K.; Nilsson, Peter; Isomaa, Bo; Tuomi, Tiinamaija; Wareham, Nicholas J.; Stumvoll, Michael; Widen, Elisabeth; Lakka, Timo A.; Langenberg, Claudia; Tönjes, Anke; Rauramaa, Rainer; Kuusisto, Johanna; Frayling, Timothy M.; Froguel, Philippe; Walker, Mark; Eriksson, Johan G.; Ling, Charlotte; Kovacs, Peter; Ingelsson, Erik; McCarthy, Mark I.; Shuldiner, Alan R.; Silver, Kristi D.; Laakso, Markku; Groop, Leif; Lyssenko, Valeriya

2014-01-01

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father. PMID:24699409

What couples glycolysis to mitochondrial signal generation in glucose-stimulated insulin secretion?

PubMed

Ishihara, H; Wollheim, C B

2000-05-01

Pancreatic islet beta-cells are poised to generate metabolic messengers in the mitochondria that link glucose metabolism to insulin exocytosis. This is accomplished through the tight coupling of glycolysis to mitochondrial activation. The messenger molecules ATP and glutamate are produced after the metabolism of glycolysis-derived pyruvate in the mitochondria. The entry of monocarboxylates such as pyruvate into the beta cell is limited, explaining why overexpression of monocarboxylate transporters unravels pyruvate-stimulated insulin secretion. NADH generated by glycolysis is efficiently reoxidized by highly active mitochondrial shuttles rather than by lactate dehydrogenase. Overexpression of this enzyme does not alter glucose-stimulated insulin secretion, suggesting that NADH availability restricts the conversion of pyruvate to lactate in the beta cell. These metabolic features permit the fuel function of glucose to be extended to the generation of signaling molecules, which increases cytosolic Ca2+ and promotes insulin exocytosis.

Chronic Glucose Exposure Systematically Shifts the Oscillatory Threshold of Mouse Islets: Experimental Evidence for an Early Intrinsic Mechanism of Compensation for Hyperglycemia

PubMed Central

Glynn, Eric; Thompson, Benjamin; Vadrevu, Suryakiran; Lu, Shusheng; Kennedy, Robert T.; Ha, Joon; Sherman, Arthur

2016-01-01

Mouse islets exhibit glucose-dependent oscillations in electrical activity, intracellular Ca2+ and insulin secretion. We developed a mathematical model in which a left shift in glucose threshold helps compensate for insulin resistance. To test this experimentally, we exposed isolated mouse islets to varying glucose concentrations overnight and monitored their glucose sensitivity the next day by measuring intracellular Ca2+, electrical activity, and insulin secretion. Glucose sensitivity of all oscillation modes was increased when overnight glucose was greater than 2.8mM. To determine whether threshold shifts were a direct effect of glucose or involved secreted insulin, the KATP opener diazoxide (Dz) was coapplied with glucose to inhibit insulin secretion. The addition of Dz or the insulin receptor antagonist s961 increased islet glucose sensitivity, whereas the KATP blocker tolbutamide tended to reduce it. This suggests insulin and glucose have opposing actions on the islet glucose threshold. To test the hypothesis that the threshold shifts were due to changes in plasma membrane KATP channels, we measured cell KATP conductance, which was confirmed to be reduced by high glucose pretreatment and further reduced by Dz. Finally, treatment of INS-1 cells with glucose and Dz overnight reduced high affinity sulfonylurea receptor (SUR1) trafficking to the plasma membrane vs glucose alone, consistent with insulin increasing KATP conductance by altering channel number. The results support a role for metabolically regulated KATP channels in the maintenance of glucose homeostasis. PMID:26697721

Obesity-induced diabetes in mouse strains treated with gold thioglucose: a novel animal model for studying β-cell dysfunction.

PubMed

Karasawa, Hiroshi; Takaishi, Kiyosumi; Kumagae, Yoshihiro

2011-03-01

An obesity-induced diabetes model using genetically normal mouse strains would be invaluable but remains to be established. One reason is that several normal mouse strains are resistant to high-fat diet-induced obesity. In the present study, we show the effectiveness of gold thioglucose (GTG) in inducing hyperphagia and severe obesity in mice, and demonstrate the development of obesity-induced diabetes in genetically normal mouse strains. GTG treated DBA/2, C57BLKs, and BDF1 mice gained weight rapidly and exhibited significant increases in nonfasting plasma glucose levels 8-12 weeks after GTG treatment. These mice showed significantly impaired insulin secretion, particularly in the early phase after glucose load, and reduced insulin content in pancreatic islets. Interestingly, GTG treated C57BL/6 mice did not become diabetic and retained normal early insulin secretion and islet insulin content despite being as severely obese and insulin resistant as the other mice. These results suggest that the pathogenesis of obesity-induced diabetes in GTG-treated mice is attributable to the inability of their pancreatic β-cells to secrete enough insulin to compensate for insulin resistance. Mice developing obesity-induced diabetes after GTG treatment might be a valuable tool for investigating obesity-induced diabetes. Furthermore, comparing the genetic backgrounds of mice with different susceptibilities to diabetes may lead to the identification of novel genetic factors influencing the ability of pancreatic β-cells to secrete insulin.

Energy metabolism in the liver.

PubMed

Rui, Liangyou

2014-01-01

The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low-density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β-oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases. © 2014 American Physiological Society.

Energy Metabolism in the Liver

PubMed Central

Rui, Liangyou

2014-01-01

The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and cholesterol esters in hepatocytes, and these complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as VLDL particles. In the fasted state, the liver secretes glucose through both breakdown of glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). During pronged fasting, hepatic gluconeogenesis is the primary source of endogenous glucose production. Fasting also promotes lipolysis in adipose tissue to release nonesterified fatty acids which are converted into ketone bodies in the liver though mitochondrial β oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis, but suppresses gluconeogenesis; glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases (NAFLD). PMID:24692138

A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans.

PubMed

MacDonald, Patrick E; De Marinis, Yang Zhang; Ramracheya, Reshma; Salehi, Albert; Ma, Xiaosong; Johnson, Paul R V; Cox, Roger; Eliasson, Lena; Rorsman, Patrik

2007-06-01

Glucagon, secreted from pancreatic islet alpha cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring beta cells, or to an intrinsic glucose sensing by the alpha cells themselves. We examined hormone secretion and Ca(2+) responses of alpha and beta cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn(2+) signalling was blocked, but was reversed by low concentrations (1-20 muM) of the ATP-sensitive K(+) (KATP) channel opener diazoxide, which had no effect on insulin release or beta cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 muM). Higher diazoxide concentrations (>/=30 muM) decreased glucagon and insulin secretion, and alpha- and beta-cell Ca(2+) responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (<1 muM) stimulated glucagon secretion, whereas high concentrations (>10 muM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na(+) (TTX) and N-type Ca(2+) channels (omega-conotoxin), but not L-type Ca(2+) channels (nifedipine), prevented glucagon secretion. Both the N-type Ca(2+) channels and alpha-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an alpha-cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.

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.

Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency

PubMed Central

Arnold, Amy C.; Garland, Emily M.; Celedonio, Jorge E.; Raj, Satish R.; Abumrad, Naji N.; Biaggioni, Italo; Robertson, David; Luther, James M.

2017-01-01

Context: Dopamine β-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown. Case Description: We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (−32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 μU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis. Conclusions: We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism. PMID:27778639

Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency.

PubMed

Arnold, Amy C; Garland, Emily M; Celedonio, Jorge E; Raj, Satish R; Abumrad, Naji N; Biaggioni, Italo; Robertson, David; Luther, James M; Shibao, Cyndya A

2017-01-01

Dopamine β-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown. We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (-32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 μU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis. We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism. Copyright © 2017 by the Endocrine Society

Age-Related Mitochondrial DNA Depletion and the Impact on Pancreatic Beta Cell Function

PubMed Central

Nile, Donna L.; Brown, Audrey E.; Kumaheri, Meutia A.; Blair, Helen R.; Heggie, Alison; Miwa, Satomi; Cree, Lynsey M.; Payne, Brendan; Chinnery, Patrick F.; Brown, Louise; Gunn, David A.; Walker, Mark

2014-01-01

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes. PMID:25532126

Mechanisms of Action of GLP-1 in the Pancreas

PubMed Central

Doyle, Máire E.; Egan, Josephine M.

2007-01-01

Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans PMID:17306374

Age-related mitochondrial DNA depletion and the impact on pancreatic Beta cell function.

PubMed

Nile, Donna L; Brown, Audrey E; Kumaheri, Meutia A; Blair, Helen R; Heggie, Alison; Miwa, Satomi; Cree, Lynsey M; Payne, Brendan; Chinnery, Patrick F; Brown, Louise; Gunn, David A; Walker, Mark

2014-01-01

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.

[The correlation between serum uric acid level and early-phase insulin secretion in subjects with normal glucose regulation].

PubMed

Lu, L; Zheng, F P; Li, H

2016-05-01

To investigate the correlation between serum uric acid (SUA) level and early-phase insulin secretion in subjects with normal glucose regulation (NGR). Totally 367 community NGR residents confirmed by a 75g oral glucose tolerance test were enrolled. The insulin resistance index (HOMA-IR) and the early-phase insulin secretion index after a glucose load (ΔI30/ΔG30) were used to estimate the insulin sensitivity and the early-phase insulin secretion, respectively. The subjects were divided into 4 groups according to the SUA level quartiles. Differences in early-phase insulin levels, ΔI30/ΔG30, and HOMA-IR were compared among the 4 groups. Age, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting insulin (FINS), 30 minutes postprandial insulin(30 minINS), 2 hours postprandial insulin(2hINS), HOMA-IR and TG levels increased across the rising categories of SUA levels, while the HDL-C was decreased across the SUA groups (P<0.01). The SUA level was positively correlated with age(r=0.157, P<0.01), BMI(r=0.262, P<0.01), waist circumference(r=0.372, P<0.01), systolic blood pressure(r=0.200, P<0.01), diastolic blood pressure(r=0.254, P<0.01), 30 minutes postprandial plasma glucose(r=0.118, P=0.023), FINS(r=0.249, P<0.01), 30minINS(r=0.189, P<0.01), 2hINS(r=0.206, P<0.01), glycosylated hemoglobin(HbA1c, r=0.106, P=0.042), HOMA-IR(r=0.244, P<0.01), TG(r=0.350, P<0.01), ΔI30/ΔG30(r=0.144, P<0.01), and negatively correlated with HDL-C level(r=-0.321, P<0.01). Multiple stepwise regression analysis showed that SUA(β=0.292, P<0.01) and HOMA-IR(β=29.821, P<0.01) were positively associated with ΔI30/ΔG30. SUA level is closely related with the early-phase insulin secretion in NGR subjects.

Genetic markers of insulin sensitivity and insulin secretion are associated with spontaneous postnatal growth and response to growth hormone treatment in short SGA children: the North European SGA Study (NESGAS).

PubMed

Jensen, Rikke Beck; Thankamony, Ajay; Day, Felix; Scott, Robert A; Langenberg, Claudia; Kirk, Jeremy; Donaldson, Malcolm; Ivarsson, Sten-A; Söder, Olle; Roche, Edna; Hoey, Hilary; Juul, Anders; Ong, Ken K; Dunger, David B

2015-03-01

The wide heterogeneity in the early growth and metabolism of children born small for gestational age (SGA), both before and during GH therapy, may reflect common genetic variations related to insulin secretion or sensitivity. Combined multiallele single nucleotide polymorphism scores with known associations with insulin sensitivity or insulin secretion were analyzed for their relationships with spontaneous postnatal growth and first-year responses to GH therapy in 96 short SGA children. The insulin sensitivity allele score (GS-InSens) was positively associated with spontaneous postnatal weight gain (regression coefficient [B]: 0.12 SD scores per allele; 95% confidence interval [CI], 0.01-0.23; P = .03) and also in response to GH therapy with first-year height velocity (B: 0.18 cm/y per allele; 95% CI, 0.02-0.35; P = .03) and change in IGF-1 (B: 0.17 SD scores per allele; 95% CI, 0.00-0.32; P = .03). The association with first-year height velocity was independent of reported predictors of response to GH therapy (adjusted P = .04). The insulin secretion allele score (GS-InSec) was positively associated with spontaneous postnatal height gain (B: 0.15; 95% CI, 0.01-0.30; P = .03) and disposition index both before (B: 0.02; 95% CI, 0.00-0.04; P = .04) and after 1 year of GH therapy (B: 0.03; 95% CI, 0.01-0.05; P = .002), but not with growth and IGF-1 responses to GH therapy. Neither of the allele scores was associated with size at birth. Genetic allele scores indicative of insulin sensitivity and insulin secretion were associated with spontaneous postnatal growth and responses to GH therapy in short SGA children. Further pharmacogenetic studies may support the rationale for adjuvant therapies by informing the mechanisms of treatment response.

Addition of n-3 fatty acids to a 4-hour lipid infusion does not affect insulin sensitivity, insulin secretion, or markers of oxidative stress in subjects with type 2 diabetes mellitus.

PubMed

Mostad, Ingrid L; Bjerve, Kristian S; Basu, Samar; Sutton, Pauline; Frayn, Keith N; Grill, Valdemar

2009-12-01

Fatty acids (FA) can impair glucose metabolism to a varying degree depending on time of exposure and also of type of FA. Here we tested for acute effects of marine n-3 FA on insulin sensitivity, insulin secretion, energy metabolism, and oxidative stress. This was a randomized, double-blind, crossover study in 11 subjects with type 2 diabetes mellitus. A 4-hour lipid infusion (Intralipid [Fresenius Kabi, Halden, Norway], total of 384 mL) was compared with a similar lipid infusion partly replaced by Omegaven (Fresenius Kabi) that contributed a median of 0.1 g fish oil per kilogram body weight, amounting to 0.04 g/kg of marine n-3 FA. Insulin sensitivity was assessed by isoglycemic hyperinsulinemic clamps; insulin secretion (measured after the clamps), by C-peptide glucagon tests; and energy metabolism, by indirect calorimetry. Infusion of Omegaven increased the proportion of n-3 FA in plasma nonesterified fatty acids (NEFA) compared with Intralipid alone (20:5n-3: median, 1.5% [interquartile range, 0.6%] vs -0.2% [0.2%], P = .001; 22:6n-3: 0.8% [0.4%] vs -0.7% [0.2%], P = .001). However, glucose utilization was not affected; neither was insulin secretion or total energy production (P = .966, .210, and .423, respectively, for the differences between the lipid clamps). Omegaven tended to lower oxidation of fat (P = .062) compared with Intralipid only, correlating with the rise in individual n-3 NEFA (r = 0.627, P = .039). The effects of clamping on phospholipid FA composition, leptin, adiponectin, or F(2)-isoprostane concentrations were not affected by Omegaven. Enrichment of NEFA with n-3 FA during a 4-hour infusion of Intralipid failed to affect insulin sensitivity, insulin secretion, or markers of oxidative stress in subjects with type 2 diabetes mellitus.

Insulin Resistance and Mitochondrial Dysfunction.

PubMed

Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

2017-01-01

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

Microtubules negatively regulate insulin secretion in pancreatic β cells

PubMed Central

Zhu, Xiaodong; Hu, Ruiying; Brissova, Marcela; Stein, Roland W.; Powers, Alvin C.; Gu, Guoqiang; Kaverina, Irina

2015-01-01

Summary For glucose-stimulated insulin secretion (GSIS) insulin granules have to be localized close to the plasma membrane. The role of microtubule-dependent transport in granule positioning and GSIS has been debated. Here, we report that microtubules, counterintuitively, restrict granule availability for secretion. In β cells, microtubules originate at the Golgi and form a dense non-radial meshwork. Non-directional transport along these microtubules limits granule dwelling at the cell periphery, restricting granule availability for secretion. High glucose destabilizes microtubules, decreasing their density; such local microtubule depolymerization is necessary for GSIS, likely because granule withdrawal from the cell periphery becomes inefficient. Consistently, microtubule depolymerization by nocodazole blocks granule withdrawal, increases their concentration at exocytic sites, and dramatically enhances GSIS in vitro and in mice. Furthermore, glucose-driven MT destabilization is balanced by new microtubule formation, which likely prevents over-secretion. Importantly, microtubule density is greater in dysfunctional β cells of diabetic mice. PMID:26418295

Mathematical model of the glucose-insulin regulatory system: From the bursting electrical activity in pancreatic β-cells to the glucose dynamics in the whole body

NASA Astrophysics Data System (ADS)

Han, Kyungreem; Kang, Hyuk; Choi, M. Y.; Kim, Jinwoong; Lee, Myung-Shik

2012-10-01

A theoretical approach to the glucose-insulin regulatory system is presented. By means of integrated mathematical modeling and extensive numerical simulations, we probe the cell-level dynamics of the membrane potential, intracellular Ca2+ concentration, and insulin secretion in pancreatic β-cells, together with the whole-body level glucose-insulin dynamics in the liver, brain, muscle, and adipose tissues. In particular, the three oscillatory modes of insulin secretion are reproduced successfully. Such comprehensive mathematical modeling may provide a theoretical basis for the simultaneous assessment of the β-cell function and insulin resistance in clinical examination.

Swimming training prevents metabolic imprinting induced by hypernutrition during lactation.

PubMed

Fischer, Stefani Valeria; Capriglioni Cancian, Cláudia Regina; Montes, Elisangela Gueiber; de Carvalho Leite, Nayara; Grassiolli, Sabrina

2015-02-01

Reduction in litter size during lactation induces hypernutrition of the offspring culminating with altered metabolic programming during adult life. Overnourished rats present alterations in the endocrine pancreas and major predisposition to the development of type 2 diabetes. Our study evaluated the impact of swimming training on insulin secretion control in overnourished rats. At postnatal day 3 male rat pup litters were redistributed randomly into Small Litters (SL, 3 pups) or Normal Litters (NL, 9 pups) to induce early overfeeding during lactation. Both groups were subjected to swimming training (3 times/week/30 min) post-weaning (21 days) for 72 days. At 92 days of life pancreatic islets were isolated using collagenase technique and incubated with glucose in the presence or absence of acetylcholine (Ach, 0.1-1000 μM) or glucagon-like peptide 1 (GLP1, 10 nM). Adipose tissue depots (white and brown) and endocrine pancreas samples were examined by histological analysis. Food intake and body weight were measured. Blood biochemical parameters were also evaluated. Swimming training prevented metabolic program alteration by hypernutrition during lactation. Exercise reduced obesity and hyperglycemia in overnourished rats. Pancreatic islets isolated from overnourished rats showed a reduction in glucose-induced insulin secretion and cholinergic responses while the insulinotropic action of GLP1 was increased. Physical training effectively restored glucose-induced insulin secretion and GLP1-stimulated action in pancreatic islets from overnourished rats. However, swimming training did not correct the weak cholinergic response in pancreatic islets isolated from overnourished rats. Swimming training avoids obesity development, corrects glucose-induced insulin secretion, as well as, GLP1 insulinotropic response in overnourished rats. Copyright © 2014 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

The relationship between insulin secretion, the insulin-like growth factor axis and growth in children with cystic fibrosis.

PubMed

Ripa, Paulus; Robertson, Ian; Cowley, David; Harris, Margaret; Masters, I Brent; Cotterill, Andrew M

2002-03-01

Cystic fibrosis-related diabetes mellitus (CFRD) is an increasingly common complication of cystic fibrosis. CFRD is preceded by a progressive decline in insulin secretion but there is no accepted definition of the prediabetic state in CFRD. This prediabetic state appears to have adverse effects on clinical status, nutrition and lung function, but there is no direct evidence that the impaired glucose homeostasis is the cause of these deteriorations. This study examined the prevalence of glucose intolerance and impaired insulin secretion in a population of children with CF without CFRD. Severe CF lung disease is often associated with poor weight gain and slower growth but the mechanism for this is still unclear. The relationships between the current state of glucose homeostasis, insulin secretion and the insulin-like growth factor axis, height velocity, nutrition status and lung function were therefore studied. Eighteen children with cystic fibrosis aged 9.5-15 years had oral glucose tolerance tests and 14 of these also had intravenous glucose tolerance tests (four refused). Blood samples were collected for insulin, C-peptide, glucose, HbA1c, insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-1 and IGFBP-3. Data on height, weight, puberty status, clinical score (Shwachman score) and lung function were recorded. Height velocity, height and weight standard deviation scores (SDS) were calculated using WHO/CDC data. The mean height SDS (-0.52 +/- 0.17) was less than the normal population (P = 0.007) and the mean height velocity was 4.6 +/- 0.5 cm/year, 39% with a height velocity less than the third percentile for age. The weight SDS and body mass index (BMI) were similar to the normal population. Four children had impaired glucose tolerance. The first-phase insulin response (FPIR) was below the first percentile of normal population values in nine (65%). Impaired FPIR or impaired glucose tolerance did not correlate with the Shwachman score, nutritional status or pulmonary function. There was a significant positive correlation between insulin secretion (area under the curve) and height velocity (P = 0.001) and serum IGFBP-3 levels (P = 0.001). Impaired glucose tolerance was present in 20% of children with cystic fibrosis. Impaired insulin secretion was common (65%) even in children with normal glucose tolerance. The mean height SDS for the group was low and the height velocity was abnormally slow in 39%, yet nutritional status as measured by BMI was appropriate for age. Relative insulin deficiency rather than nutritional deprivation or poor clinical status thus appears to be implicated in the poor linear growth of these children with relatively stable lung disease. This was a small study and firm conclusions on this chronic suppurative disease as to the cause of poor growth are not possible. The causes of poor growth are likely to be complex; nevertheless, the apparent decrease in insulin secretion combined with the expected increased demands on insulin production during pubertal growth raises the question as to whether insulin therapy should be considered in children with cystic fibrosis before the onset of cystic fibrosis-related diabetes mellitus.

Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein*

PubMed Central

Chen, Qing; Lu, Mingjian; Monks, Bobby R.; Birnbaum, Morris J.

2016-01-01

Diabetes is accompanied by dysregulation of glucose, lipid, and protein metabolism. In recent years, much effort has been spent on understanding how insulin regulates glucose and lipid metabolism, whereas the effect of insulin on protein metabolism has received less attention. In diabetes, hepatic production of serum albumin decreases, and it has been long established that insulin positively controls albumin gene expression. In this study, we used a genetic approach in mice to identify the mechanism by which insulin regulates albumin gene transcription. Albumin expression was decreased significantly in livers with insulin signaling disrupted by ablation of the insulin receptor or Akt. Concomitant deletion of Forkhead Box O1 (Foxo1) in these livers rescued the decreased albumin secretion. Furthermore, activation of Foxo1 in the liver is sufficient to suppress albumin expression. These results suggest that Foxo1 acts as a repressor of albumin expression. PMID:26668316

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.

Uncoupling protein-2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS-1E cells and in diabetic mouse islets

PubMed Central

Liu, Limei; Liu, Jian; Gao, Yuansheng; Yu, Xiaoxing; Xu, Gang; Huang, Yu

2014-01-01

BACKGROUND AND PURPOSE Uncoupling protein-2 (UCP2) may regulate glucose-stimulated insulin secretion. The current study investigated the effects of berberine, an alkaloid found in many medicinal plants, on oxidative stress and insulin secretion through restoration of UCP2 expression in high glucose (HG)-treated INS-1E cells and rat islets or in db/db mouse islets. EXPERIMENTAL APPROACH Mouse and rat pancreatic islets were isolated. Nitrotyrosine, superoxide dismutase (SOD)-1 and UCP2 expression and AMPK phosphorylation were examined by Western blotting. Insulin secretion was measured by elisa. Mitochondrial reactive oxygen species (ROS) production was detected by confocal microscopy. KEY RESULTS Incubation of INS-1E cells and rat islets with HG (30 mmol·L−1; 8 h) elevated nitrotyrosine level, reduced SOD-1 and UCP2 expression and AMPK phosphorylation, and inhibited glucose-stimulated insulin secretion. HG also increased mitochondrial ROS in INS-1E cells. Co-treatment with berberine inhibited such effects. The AMPK inhibitor compound C, the UCP2 inhibitor genipin and adenovirus ucp2 shRNA inhibited these protective effects of berberine. Furthermore, compound C normalized berberine-stimulated UCP2 expression but genipin did not affect AMPK phosphorylation. Islets from db/db mice exhibited elevated nitrotyrosine levels, reduced expression of SOD-1 and UCP2 and AMPK phosphorylation, and decreased insulin secretion compared with those from db/m+ mice. Berberine also improved these defects in diabetic islets and genipin blocked the effects of berberine. CONCLUSIONS AND IMPLICATIONS Berberine inhibited oxidative stress and restored insulin secretion in HG-treated INS-IE cells and diabetic mouse islets by activating AMPK and UCP2. UCP2 is an important signalling molecule in mediating anti-diabetic effects of berberine. PMID:24588674

Uncoupling protein-2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS-1E cells and in diabetic mouse islets.

PubMed

Liu, Limei; Liu, Jian; Gao, Yuansheng; Yu, Xiaoxing; Xu, Gang; Huang, Yu

2014-07-01

Uncoupling protein-2 (UCP2) may regulate glucose-stimulated insulin secretion. The current study investigated the effects of berberine, an alkaloid found in many medicinal plants, on oxidative stress and insulin secretion through restoration of UCP2 expression in high glucose (HG)-treated INS-1E cells and rat islets or in db/db mouse islets. Mouse and rat pancreatic islets were isolated. Nitrotyrosine, superoxide dismutase (SOD)-1 and UCP2 expression and AMPK phosphorylation were examined by Western blotting. Insulin secretion was measured by ELISA. Mitochondrial reactive oxygen species (ROS) production was detected by confocal microscopy. Incubation of INS-1E cells and rat islets with HG (30 mmol·L(-1); 8 h) elevated nitrotyrosine level, reduced SOD-1 and UCP2 expression and AMPK phosphorylation, and inhibited glucose-stimulated insulin secretion. HG also increased mitochondrial ROS in INS-1E cells. Co-treatment with berberine inhibited such effects. The AMPK inhibitor compound C, the UCP2 inhibitor genipin and adenovirus ucp2 shRNA inhibited these protective effects of berberine. Furthermore, compound C normalized berberine-stimulated UCP2 expression but genipin did not affect AMPK phosphorylation. Islets from db/db mice exhibited elevated nitrotyrosine levels, reduced expression of SOD-1 and UCP2 and AMPK phosphorylation, and decreased insulin secretion compared with those from db/m(+) mice. Berberine also improved these defects in diabetic islets and genipin blocked the effects of berberine. Berberine inhibited oxidative stress and restored insulin secretion in HG-treated INS-IE cells and diabetic mouse islets by activating AMPK and UCP2. UCP2 is an important signalling molecule in mediating anti-diabetic effects of berberine. © 2014 The British Pharmacological Society.

Impact of incretin on early-phase insulin secretion and glucose excursion.

PubMed

Shen, Jie; Chen, Zhi; Chen, Chaofeng; Zhu, Xiao; Han, Yajuan

2013-10-01

This study investigated the impact of incretin on early-phase insulin secretion and glucose excursion. The normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) groups included 16, 8, and 19 subjects, respectively. Subjects underwent continuous glucose monitoring for 3 days, followed by an oral glucose tolerance test. Plasma glucose, insulin, glucagon, total glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-l (GLP-1) levels were measured at 30-min increments for 2 h after glucose intake. Differences with P < 0.05 were considered statistically significant. The area under the curve (AUC) of total GIP (120-min GIP-AUC) of the T2DM group was significantly lower than those of the NGT and IGT groups. The 120-min GLP-1-AUC of the NGT group was significantly larger than those of the T2DM and IGT groups. The early-phase insulin secretion index (ΔI30/ΔG30) of the T2DM group was significantly lower than those of the NGT and IGT groups. Mean amplitudes of glycemic excursions (MAGEs) went in the order of NGT < IGT < T2DM (P < 0.01, IGT vs. NGT; P < 0.001, T2DM vs. IGT). The 120-min GIP-AUC was negatively correlated with MAGE (r = -0.464), but uncorrelated with ΔI30/ΔG30. The 120-min GLP-1-AUC was positively correlated with ΔI30/ΔG30 (r = 0.580), but negatively correlated with MAGE (r = -0.606). Incretin may ameliorate glucose excursions, and GLP-1 may exert them by promoting early-phase insulin secretion. No correlation was observed between GIP secretion and early-phase insulin secretion.

Exocrine cell-derived microparticles in response to lipopolysaccharide promote endocrine dysfunction in cystic fibrosis.

PubMed

Constantinescu, Andrei Alexandru; Gleizes, Céline; Alhosin, Mahmoud; Yala, Elhassan; Zobairi, Fatiha; Leclercq, Alexandre; Stoian, Gheorghe; Mitrea, Ioan Liviu; Prévost, Gilles; Toti, Florence; Kessler, Laurence

2014-03-01

Diabetes in cystic fibrosis (CF) is a result of exocrine pancreas alteration followed by endocrine dysfunction at a later stage. Microparticles (MPs) are plasma membrane fragments shed from stimulated or damaged cells that act as cellular effectors. Our aim was to identify a new form of interaction between exocrine and endocrine pancreatic cells mediated by exocrine MPs, in the context of recurrent infection in CF. MPs from either human exocrine CFTRΔF508-mutated (CFPAC-1) cells or exocrine normal pancreatic (PANC-1) cells were collected after treatment by LPS from Pseudomonas aeruginosa and applied to rat endocrine normal insulin-secreting RIN-m5F cells. MP membrane integration in target cells was established by confocal microscopy and flow cytometry using PKH26 lipid probe. Apoptosis, lysosomal activity, insulin secretion were measured after 18 h. MP-mediated NF-κB activation was measured in HEK-Blue reporter cells by SEAP reporter gene system and in RIN-m5F cells by Western blot. In endocrine normal cells, CFTR inhibition was achieved using Inhibitor-172. Compared to PANC-1, MPs from CFPAC-1 significantly reduced insulin secretion and lysosomal activity in RIN-m5F. MPs induced NF-κB activation by increasing the level of IκB phosphorylation. Moreover, the inhibition of NF-κB activation using specific inhibitors was associated with a restored insulin secretion. Interestingly, CFTR inhibition in normal RIN-m5F cells promoted apoptosis and decreased insulin secretion. During recurrent infections associated with CF, exocrine MPs may contribute to endocrine cell dysfunction via NF-κB pathways. Membrane CFTR dysfunction is associated with decreased insulin secretion. © 2013. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. All rights reserved.

LXRalpha activation perturbs hepatic insulin signaling and stimulates production of apolipoprotein B-containing lipoproteins.

PubMed

Basciano, Heather; Miller, Abigale; Baker, Chris; Naples, Mark; Adeli, Khosrow

2009-08-01

Liver X receptor-alpha (LXRalpha) is considered a master regulator of hepatic lipid metabolism; however, little is known about the link between LXR activation, hepatic insulin signaling, and very low-density lipoprotein (VLDL)-apolipoprotein B (apoB) assembly and secretion. Here, we examined the effect of LXRalpha activation on hepatic insulin signaling and apoB-lipoprotein production. In vivo activation of LXRalpha for 7 days using a synthetic LXR agonist, TO901317, in hamsters led to increased plasma triglyceride (TG; 3.6-fold compared with vehicle-treated controls, P = 0.006), apoB (54%, P < 0.0001), and VLDL-TG (eightfold increase compared with vehicle). As expected, LXR stimulation activated maturation of sterol response element binding protein-1c (SREBP-1c) as well as the SREBP-1c target genes steroyl CoA desaturase (SCD) and fatty acid synthase (FAS). Metabolic pulse-chase labeling experiments in primary hamster hepatocytes showed increased stability and secretion of newly synthesized apoB following LXR activation. Microsomal triglyceride transfer protein (MTP) mRNA and protein were unchanged, however, likely because of the relatively short period of treatment and long half-life of MTP mRNA. Examination of hepatic insulin-signaling molecules revealed LXR-mediated reductions in insulin receptor (IR)beta subunit mass (39%, P = 0.014) and insulin receptor substrate (IRS)-1 tyrosine phosphorylation (24%, P = 0.023), as well as increases in protein tyrosine phosphatase (PTP)1B (29%, P < 0.001) protein mass. In contrast to IRS-1, a twofold increase in IRS-2 mass (228%, P = 0.0037) and a threefold increase in IRS-2 tyrosine phosphorylation (321%, P = 0.012) were observed. In conclusion, LXR activation dysregulates hepatic insulin signaling and leads to a considerable increase in the number of circulating TG-rich VLDL-apoB particles, likely due to enhanced hepatic assembly and secretion of apoB-containing lipoproteins.

Different downstream signalling of CCK1 receptors regulates distinct functions of CCK in pancreatic beta cells.

PubMed

Ning, Shang-lei; Zheng, Wen-shuai; Su, Jing; Liang, Nan; Li, Hui; Zhang, Dao-lai; Liu, Chun-hua; Dong, Jun-hong; Zhang, Zheng-kui; Cui, Min; Hu, Qiao-Xia; Chen, Chao-chao; Liu, Chang-hong; Wang, Chuan; Pang, Qi; Chen, Yu-xin; Yu, Xiao; Sun, Jin-peng

2015-11-01

Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined. Apoptosis in pancreatic beta cell apoptosis was evaluated using Hoechst-33342 staining, TUNEL assays and Annexin-V-FITC/PI staining. Insulin secretion and second messenger production were monitored using ELISAs. Protein and phospho-protein levels were determined by Western blotting. A glucose tolerance test was carried out to examine the functions of CCK-8s in streptozotocin-induced diabetic mice. The sulfated carboxy-terminal octapeptide CCK26-33 amide (CCK-8s) activated CCK1 receptors and induced accumulation of both IP3 and cAMP. Whereas Gq -PLC-IP3 signalling was required for the CCK-8s-induced insulin secretion under low-glucose conditions, Gs -PKA/Epac signalling contributed more strongly to the CCK-8s-mediated insulin secretion in high-glucose conditions. CCK-8s also promoted formation of the CCK1 receptor/β-arrestin-1 complex in pancreatic beta cells. Using β-arrestin-1 knockout mice, we demonstrated that β-arrestin-1 is a key mediator of both CCK-8s-mediated insulin secretion and of its the protective effect against apoptosis in pancreatic beta cells. The anti-apoptotic effects of β-arrestin-1 occurred through cytoplasmic late-phase ERK activation, which activates the 90-kDa ribosomal S6 kinase-phospho-Bcl-2-family protein pathway. Knowledge of different CCK1 receptor-activated downstream signalling pathways in the regulation of distinct functions of pancreatic beta cells could be used to identify biased CCK1 receptor ligands for the development of new anti-diabetic drugs. © 2015 The British Pharmacological Society.

The effect of oral and intravenous dextrose on C-peptide secretion in ponies.

PubMed

de Laat, M A; van Haeften, J J; Sillence, M N

2016-02-01

Managing equine hyperinsulinemia is crucial for preventing laminitis, but our understanding of the mechanisms involved in insulin dysregulation in this species is incomplete. C-peptide is co-secreted with insulin but is resistant to hepatic metabolism and can be used to study insulin dysregulation. This study examined C-peptide secretion in serial blood samples collected after oral and i.v. dextrose (0.75 g/kg) administration to 9 ponies (BCS, 7.1 ± 0.5). The ponies were designated as hyperinsulinemic (HI) or normoinsulinemic (NI) responders before the study, using oral glucose tests and fasted glucose-to-insulin ratios, and responses were compared between the 2 groups. C-peptide concentrations increased ( < 0.01) rapidly from fasted levels after both oral and i.v. dextrose, with similar area under the concentration-time curve (AUC) for both tests and a significant correlation with AUC. The AUC was similar in HI and NI ponies after i.v. dextrose, indicating similar pancreatic capacity for both groups. However, for oral dextrose, the AUC and the AUC were markedly higher ( < 0.05) in the HI ponies, indicating a greater secretion rate of these peptides. Slower insulin clearance might have also contributed to the larger AUC in HI ponies, but this hypothesis requires further investigation with specific measures of hepatic insulin clearance.

The potent insulin secretagogue effect of betulinic acid is mediated by potassium and chloride channels.

PubMed

Gomes Castro, Allisson Jhonatan; Cazarolli, Luisa Helena; Bretanha, Lizandra C; Sulis, Paola Miranda; Rey Padilla, Diana Patricia; Aragón Novoa, Diana Marcela; Dambrós, Betina Fernanda; Pizzolatti, Moacir G; Mena Barreto Silva, Fátima Regina

2018-06-15

Betulinic acid (BA) has been described as an insulin secretagogue which may explain its potent antihyperglycemic effect; however, the exact role of BA as an insulinogenic agent is not clear. The aim of this study was to investigate the mechanism of BA on calcium influx and static insulin secretion in pancreatic islets isolated from euglycemic rats. We found that BA triggers calcium influx by a mechanism dependent on ATP-dependent potassium channels and L-type voltage-dependent calcium channels. Additionally, the voltage-dependent and calcium-dependent chloride channels are also involved in the mechanism of BA, probably due to an indirect stimulation of calcium entry and increased intracellular calcium. Additionally, the downstream activation of PKC, which is necessary for the effect of BA on calcium influx, is involved in the full stimulatory response of the triterpene. BA stimulated the static secretion of insulin in pancreatic islets, indicating that the abrupt calcium influx may be a key step in its secretagogue effect. As such, BA stimulates insulin secretion through the activation of electrophysiological mechanisms, such as the closure of potassium channels and opening of calcium and chloride channels, inducing cellular depolarization associated with metabolic-biochemical effects, in turn activating PKC and ensuring the secretion of insulin. Copyright © 2018 Elsevier Inc. All rights reserved.

Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells

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

Shi, Xiaoli; Xiong, Xiaokan; Dai, Zhe

2015-12-04

Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLXmore » increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes. - Highlights: • TLX overexpression in MIN6 cell causes significant expression changes of 225 genes. • TLX overexpression promotes MIN6 cell proliferation and decreases cell apoptosis. • TLX overexpression does not cause impairment of insulin secretion.« less

Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism

PubMed Central

Cochran, Blake J.; Hou, Liming; Manavalan, Anil Paul Chirackal; Moore, Benjamin M.; Tabet, Fatiha; Sultana, Afroza; Cuesta Torres, Luisa; Tang, Shudi; Shrestha, Sudichhya; Senanayake, Praween; Patel, Mili; Ryder, William J.; Bongers, Andre; Maraninchi, Marie; Wasinger, Valerie C.; Westerterp, Marit; Tall, Alan R.; Barter, Philip J.

2016-01-01

Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes. PMID:27702832

1,5-anhydroglucitol is associated with early-phase insulin secretion in chinese patients with newly diagnosed type 2 diabetes mellitus.

PubMed

Ma, Xiaojing; Hao, Yaping; Hu, Xiang; Luo, Yuqi; Deng, Zixuan; Zhou, Jian; Bao, Yuqian; Jia, Weiping

2015-05-01

The goal of the present study was to explore the correlations of 1,5-anhydroglucitol (l,5-AG), glycated hemoglobin (HbA1c), and glycated albumin (GA) with insulin sensitivity and secretion. In total, 302 patients with newly diagnosed type 2 diabetes mellitus (166 men, 136 women) were enrolled in this study. The homeostasis model assessment for insulin resistance (HOMA-IR) and homeostasis model assessment for β-cell function (HOMA-β) were calculated to determine the basal insulin sensitivity and secretion. The insulinogenic index (IGI) was used to evaluate early-phase insulin secretion. 1,5-AG and GA were assayed via the enzymatic method, and HbA1c was detected by high-pressure liquid chromatography. Among all 302 subjects, the serum 1,5-AG level was 13.1±7.2 μg/mL, and the HbA1c and GA levels [median (interquartile range)] were 6.7% (6.2-7.3%) and 17.7% (16.0-19.5%), respectively. Increased 1,5-AG quartiles were accompanied by trends toward a decreased HOMA-IR and an increased HOMA-β and IGI (for all trends, P<0.001). 1,5-AG was negatively associated with HOMA-IR (r=-0.200, P<0.001) and positively associated with HOMA-β and IGI (r=0.210 and 0.413, respectively; both P<0.001). 1,5-AG was independently related to HOMA-IR and HOMA-β and exhibited an independent positive association with IGI (standardized β=0.242, P<0.001). Additionally, both HbA1c and GA were independently correlated with HOMA-IR and HOMA-β. 1,5-AG is not only correlated with basal insulin sensitivity and secretion, but also closely associated with early-phase insulin secretion in Chinese patients with newly diagnosed type 2 diabetes mellitus.

L-rhamnose as a source of colonic propionate inhibits insulin secretion but does not influence measures of appetite or food intake.

PubMed

Darzi, Julia; Frost, Gary S; Swann, Jonathan R; Costabile, Adele; Robertson, M Denise

2016-03-01

Activation of free fatty acid receptor (FFAR)2 and FFAR3 via colonic short-chain fatty acids, particularly propionate, are postulated to explain observed inverse associations between dietary fiber intake and body weight. Propionate is reported as the predominant colonic fermentation product from l-rhamnose, a natural monosaccharide that resists digestion and absorption reaching the colon intact, while effects of long-chain inulin on appetite have not been extensively investigated. In this single-blind randomized crossover study, healthy unrestrained eaters (n = 13) ingested 25.5 g/d l-rhamnose, 22.4 g/d inulin or no supplement (control) alongside a standardized breakfast and lunch, following a 6-d run-in to investigate if appetite was inhibited. Postprandial qualitative appetite, breath hydrogen, and plasma glucose, insulin, triglycerides and non-esterified fatty acids were assessed for 420 min, then an ad libitum meal was provided. Significant treatment x time effects were found for postprandial insulin (P = 0.009) and non-esterified fatty acids (P = 0.046) with a significantly lower insulin response for l-rhamnose (P = 0.023) than control. No differences between treatments were found for quantitative and qualitative appetite measures, although significant treatment x time effects for meal desire (P = 0.008) and desire to eat sweet (P = 0.036) were found. Breath hydrogen was significantly higher with inulin (P = 0.001) and l-rhamnose (P = 0.009) than control, indicating colonic fermentation. These findings suggest l-rhamnose may inhibit postprandial insulin secretion, however neither l-rhamnose or inulin influenced appetite. Copyright © 2015 Elsevier Ltd. All rights reserved.

Glycolytic and mitochondrial metabolism in pancreatic islets from MSG-treated obese rats subjected to swimming training.

PubMed

Leite, Nayara de Carvalho; Ferreira, Thiago Rentz; Rickli, Sarah; Borck, Patricia Cristine; Mathias, Paulo Cezar de Freitas; Emilio, Henriette Rosa de Oliveira; Grassiolli, Sabrina

2013-01-01

Obese rats obtained by neonatal monosodium glutamate (MSG) administration present insulin hypersecretion. The metabolic mechanism by which glucose catabolism is coupled to insulin secretion in the pancreatic β-cells from MSG-treated rats is understood. The purpose of this study was to evaluate glucose metabolism in pancreatic islets from MSG-treated rats subjected to swimming training. MSG-treated and control (CON) rats swam for 30 minutes (3 times/week) over a period of 10 weeks. Pancreatic islets were isolated and incubated with glucose in the presence of glycolytic or mitochondrial inhibitors. Swimming training attenuated fat pad accumulation, avoiding changes in the plasma levels of lipids, glucose and insulin in MSG-treated rats. Adipocyte and islet hypertrophy observed in MSG-treated rats were attenuated by exercise. Pancreatic islets from MSG-treated obese rats also showed insulin hypersecretion, greater glucose transporter 2 (GLUT2) expression, increased glycolytic flux and reduced mitochondrial complex III activity. Swimming training attenuated islet hypertrophy and normalised GLUT2 expression, contributing to a reduction in the glucose responsiveness of pancreatic islets from MSG-treated rats without altering glycolytic flux. However, physical training increased the activity of mitochondrial complex III in pancreatic islets from MSG-treated rats without a subsequent increase in glucose-induced insulin secretion. Copyright © 2013 S. Karger AG, Basel.

Insulin and Metformin Regulate Circulating and Adipose Tissue Chemerin

PubMed Central

Tan, Bee K.; Chen, Jing; Farhatullah, Syed; Adya, Raghu; Kaur, Jaspreet; Heutling, Dennis; Lewandowski, Krzysztof C.; O'Hare, J. Paul; Lehnert, Hendrik; Randeva, Harpal S.

2009-01-01

OBJECTIVE To assess chemerin levels and regulation in sera and adipose tissue from women with polycystic ovary syndrome (PCOS) and matched control subjects. RESEARCH DESIGN AND METHODS Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of chemerin. Serum chemerin was measured by enzyme-linked immunosorbent assay. We investigated the in vivo effects of insulin on serum chemerin levels via a prolonged insulin-glucose infusion. Ex vivo effects of insulin, metformin, and steroid hormones on adipose tissue chemerin protein production and secretion into conditioned media were assessed by Western blotting and enzyme-linked immunosorbent assay, respectively. RESULTS Serum chemerin, subcutaneous, and omental adipose tissue chemerin were significantly higher in women with PCOS (n = 14; P < 0.05, P < 0.01). Hyperinsulinemic induction in human subjects significantly increased serum chemerin levels (n = 6; P < 0.05, P < 0.01). In adipose tissue explants, insulin significantly increased (n = 6; P < 0.05, P < 0.01) whereas metformin significantly decreased (n = 6; P < 0.05, P < 0.01) chemerin protein production and secretion into conditioned media, respectively. After 6 months of metformin treatment, there was a significant decrease in serum chemerin (n = 21; P < 0.01). Importantly, changes in homeostasis model assessment–insulin resistance were predictive of changes in serum chemerin (P = 0.046). CONCLUSIONS Serum and adipose tissue chemerin levels are increased in women with PCOS and are upregulated by insulin. Metformin treatment decreases serum chemerin in these women. PMID:19502420

Hypoglycemic effects of date seed extract. Possible mechanism of action, and potential therapeutic implications.

PubMed

El Fouhil, Ahmed F; Ahmed, Aly M; Atteya, Muhammad; Mohamed, Raeesa A; Moustafa, Amr S; Al-Roalle, Ali H; Darwish, Hasem H

2013-11-01

To investigate the possible mechanism, by which an extract from date seeds exert its hypoglycemic effect. This study was performed at the Anatomy Department, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia from May to December 2012. Eighty rats were divided into 4 groups. Group 1 received no treatment. Group 2 received daily ingestions of 10 ml of date seed extract for 8 weeks. Animals of groups 3 and 4 were made diabetic by streptozotocin injection, and were given daily subcutaneous injections of 3 IU/day of insulin for 8 weeks. Group 4 received, in addition, daily ingestions of 10 ml of seed extracts. Rats were sacrificed, and the sera were separated for estimation of serum C-peptide levels. Pancreatic tissues were processed for histological study of the islet cells, immunohistochemical study for insulin secretion and image analysis for insulin quantification. Mean serum C-peptide level was significantly higher in group 4 compared to group 3. Pancreatic islets from rats of group 3 showed weak immunoreactivity for insulin, while those of group 4 showed strong immunoreactivity in some hypertrophied beta cells. Immunopositive cells were detected in the wall of interlobular ducts and in centroacinar cells of pancreas only in group 4. Quantification of insulin immunoreactivity showed a marked reduction in islet size and extent of insulin immunoreactivity in diabetic compared to control groups. Date seed extracts may stimulate endogenous insulin secretion through extra-islet sources.

Endocannabinoid regulation of β-cell functions: implications for glycaemic control and diabetes.

PubMed

Jourdan, T; Godlewski, G; Kunos, G

2016-06-01

Visceral obesity is a major risk factor for the development of insulin resistance which can progress to overt type 2 diabetes (T2D) with loss of β-cell function and, ultimately, loss of β-cells. Insulin secretion by β-cells of the pancreatic islets is tightly coupled to blood glucose concentration and modulated by a large number of blood-borne or locally released mediators, including endocannabinoids. Obesity and its complications, including T2D, are associated with increased activity of the endocannabinoid/CB1 receptor (CB1 R) system, as indicated by the therapeutic effects of CB1 R antagonists. Similar beneficial effects of CB1 R antagonists with limited brain penetrance indicate the important role of CB1 R in peripheral tissues, including the endocrine pancreas. Pancreatic β-cells express all of the components of the endocannabinoid system, and endocannabinoids modulate their function via both autocrine and paracrine mechanisms, which influence basal and glucose-induced insulin secretion and also affect β-cell proliferation and survival. The present brief review will survey available information on the modulation of these processes by endocannabinoids and their receptors, with an attempt to assess the contribution of such effects to glycaemic control in T2D and insulin resistance. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

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

Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice.

PubMed

Ma, Xiaojun; Lin, Yuezhen; Lin, Ligen; Qin, Guijun; Pereira, Fred A; Haymond, Morey W; Butte, Nancy F; Sun, Yuxiang

2012-08-01

The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ob mice (Ghsr(-/-):ob/ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ob mice upregulated negative β-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive β-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic β-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ob mice did not affect the islet size; the average islet size of Ghsr(-/-):ob/ob mice is similar to that of ob/ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway.

Comparison of β-Cell Function Between Overweight/Obese Adults and Adolescents Across the Spectrum of Glycemia.

PubMed

Chen, Melinda E; Chandramouli, Aaditya G; Considine, Robert V; Hannon, Tamara S; Mather, Kieren J

2018-02-01

Type 2 diabetes is a growing health problem among both adults and adolescents. To better understand the differences in the pathogenesis of diabetes between these groups, we examined differences in β-cell function along the spectrum of glucose tolerance. We evaluated 89 adults and 50 adolescents with normal glucose tolerance (NGT), dysglycemia, or type 2 diabetes. Oral glucose tolerance test results were used for C-peptide and insulin/glucose minimal modeling. Model-derived and direct measures of insulin secretion and insulin sensitivity were compared across glycemic stages and between age-groups at each stage. In adolescents with dysglycemia, there was marked insulin resistance (insulin sensitivity index: adolescents, median [interquartile range] 1.8 [1.1-2.4] × 10 -4 ; adults, 5.0 [2.3-9.9]; P = 0.01). The nature of β-cell dysfunction across stages of dysglycemia differed between the groups. We observed higher levels of secretion among adolescents than adults (total insulin secretion: NGT, 143 [103-284] × 10 -9 /min adolescent vs. 106 [71-127], P = 0.001); adults showed stepwise impairments in static insulin secretion (NGT, 7.5 [4.0-10.3] × 10 -9 /min; dysglycemia, 5.0 [2.3-9.9]; type 2 diabetes, 0.7 [0.1-2.45]; P = 0.003), whereas adolescents showed diabetes-related impairment in dynamic secretion (NGT, 1,905 [1,630-3,913] × 10 -9 ; dysglycemia, 2,703 [1,323-3,637]; type 2 diabetes, 1,189 [269-1,410]; P = 0.001). Adults and adolescents differ in the underlying defects leading to dysglycemia, and in the nature of β-cell dysfunction across stages of dysglycemia. These results may suggest different approaches to diabetes prevention in youths versus adults. © 2017 by the American Diabetes Association.

[The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

PubMed

Escalada, Francisco Javier

2014-09-01

The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes.

PubMed

Moran, A; Phillips, J; Milla, C

2001-10-01

Insulin and glucose levels in response to premeal insulin lispro or repaglinide were evaluated in adult patients with cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia. Seven patients with CFRD were fed 1,000-kcal liquid mixed meals. Three study conditions were administered in random order on separate mornings: 1) no premeal diabetes medication, 2) insulin lispro, 0.1 unit/kg body wt premeal and 3) repaglinide 1 mg premeal. Glucose and insulin levels were measured every 20 min for 5 h. Fasting insulin and glucose levels were normal in patients with CFRD, but the peak glucose level was elevated. Insulin lispro significantly decreased the peak glucose level (P = 0.0004) and the 2-h (P = 0.001) and 5-h (P < 0.0001) glucose area under the curve (AUC). Repaglinide significantly decreased the 5-h glucose AUC (P = 0.03). Neither drug completely normalized cystic fibrosis glucose excursion at the doses used for this study. Insulin lispro significantly increased the 5-h insulin AUC (P = 0.04). In response to subcutaneous insulin lispro, postprandial glucose excursion was significantly diminished and insulin secretion was enhanced compared with a control meal in which no medication was given to patients with CFRD. The oral agent repaglinide resulted in lesser corrections in these parameters. Neither drug completely normalized glucose or insulin levels, suggesting that the doses chosen for this study were suboptimal. Placebo-controlled longitudinal studies comparing the effectiveness of repaglinide and insulin on glucose metabolic control as well as overall nutrition and body weight are needed to help determine optimal medical treatment of CFRD.

Quantifying Insulin Sensitivity and Entero-Insular Responsiveness to Hyper- and Hypoglycemia in Ferrets

PubMed Central

Sui, Hongshu; Yi, Yaling; Yao, Jianrong; Liang, Bo; Sun, Xingshen; Hu, Shanming; Uc, Aliye; Nelson, Deborah J.; Ode, Katie Larson; Philipson, Louis H.; Engelhardt, John F.; Norris, Andrew W.

2014-01-01

Ferrets are an important emerging model of cystic fibrosis related diabetes. However, there is little documented experience in the use of advanced techniques to quantify aspects of diabetes pathophysiology in the ferret. Glycemic clamps are the gold standard technique to assess both insulin sensitivity and insulin secretion in humans and animal models of diabetes. We therefore sought to develop techniques for glycemic clamps in ferrets. To assess insulin sensitivity, we performed euglycemic hyperinsulinemic clamps in 5–6 week old ferrets in the anesthetized and conscious states. To assess insulin secretion, we performed hyperglycemic clamps in conscious ferrets. To evaluate responsiveness of ferret islet and entero-insular hormones to low glucose, a portion of the hyperglycemic clamps were followed by a hypoglycemic clamp. The euglycemic hyperinsulinemic clamps demonstrated insulin responsiveness in ferrets similar to that previously observed in humans and rats. The anesthetic isoflurane induced marked insulin resistance, whereas lipid emulsion induced mild insulin resistance. In conscious ferrets, glucose appearance was largely suppressed at 4 mU/kg/min insulin infusion, whereas glucose disposal was progressively increased at 4 and 20 mU/kg/min insulin. Hyperglycemic clamp induced first phase insulin secretion. Hypoglycemia induced a rapid diminishment of insulin, as well as a rise in glucagon and pancreatic polypeptide levels. The incretins GLP-1 and GIP were affected minimally by hyperglycemic and hypoglycemic clamp. These techniques will prove useful in better defining the pathophysiology in ferrets with cystic fibrosis related diabetes. PMID:24594704

Quantifying insulin sensitivity and entero-insular responsiveness to hyper- and hypoglycemia in ferrets.

PubMed

Sui, Hongshu; Yi, Yaling; Yao, Jianrong; Liang, Bo; Sun, Xingshen; Hu, Shanming; Uc, Aliye; Nelson, Deborah J; Ode, Katie Larson; Philipson, Louis H; Engelhardt, John F; Norris, Andrew W

2014-01-01

Ferrets are an important emerging model of cystic fibrosis related diabetes. However, there is little documented experience in the use of advanced techniques to quantify aspects of diabetes pathophysiology in the ferret. Glycemic clamps are the gold standard technique to assess both insulin sensitivity and insulin secretion in humans and animal models of diabetes. We therefore sought to develop techniques for glycemic clamps in ferrets. To assess insulin sensitivity, we performed euglycemic hyperinsulinemic clamps in 5-6 week old ferrets in the anesthetized and conscious states. To assess insulin secretion, we performed hyperglycemic clamps in conscious ferrets. To evaluate responsiveness of ferret islet and entero-insular hormones to low glucose, a portion of the hyperglycemic clamps were followed by a hypoglycemic clamp. The euglycemic hyperinsulinemic clamps demonstrated insulin responsiveness in ferrets similar to that previously observed in humans and rats. The anesthetic isoflurane induced marked insulin resistance, whereas lipid emulsion induced mild insulin resistance. In conscious ferrets, glucose appearance was largely suppressed at 4 mU/kg/min insulin infusion, whereas glucose disposal was progressively increased at 4 and 20 mU/kg/min insulin. Hyperglycemic clamp induced first phase insulin secretion. Hypoglycemia induced a rapid diminishment of insulin, as well as a rise in glucagon and pancreatic polypeptide levels. The incretins GLP-1 and GIP were affected minimally by hyperglycemic and hypoglycemic clamp. These techniques will prove useful in better defining the pathophysiology in ferrets with cystic fibrosis related diabetes.

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

PubMed

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

2017-08-07

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

May maternal lifestyle have an impact on neonatal glucose levels?

PubMed

Hoirisch-Clapauch, Silvia; Porto, Maria Amelia S; Nardi, Antonio E

2016-02-01

Neonatal glucose levels correlate negatively with umbilical cord levels of C-peptide, a polypeptide secreted with insulin. In other words, neonatal hypoglycemia results from excessive insulin secretion from fetal/neonatal beta cells. Given that insulin causes fat to be stored rather than to be used for energy, one would expect that chronic hyperinsulinemia would result in large-for-gestational-age neonates. The finding that many small-for-gestational-age neonates have hypoglycemia suggests that the stimulus for insulin production occurs close to delivery. We postulated that a potent stimulation of maternal insulin production close to delivery would also provide a potent stimulus for fetal and neonatal insulin production, causing neonatal hypoglycemia. This study has evaluated 155 mothers with markers of excessive insulin production (such as acanthosis or grade III obesity), or with situations characterized by increased insulin requirements (such as an invasive bacterial infection or use of systemic corticosteroid within a week before delivery; or sedentariness or high-carbohydrate intake within 24h before delivery) and their 158 neonates who were screened for glycemic levels at 1, 2 and 4h after birth. The minimum glucose level was correlated to the maternal parameters, and to classical predictors of neonatal hypoglycemia, such as low-birth weight and preterm delivery. The only independent predictors were sedentariness and high-carbohydrate intake within 24h before delivery. The risk of neonatal hypoglycemia increased five-fold with sedentariness, 11-fold with high-carbohydrate intake, and 329-fold with both risk factors. The risk of neonatal hypoglycemia seems to be highly influenced by maternal lifestyle within 24h before delivery. Controlled randomized trials may help determine whether a controlled carbohydrate diet combined with regular physical activity close to delivery can prevent neonatal hypoglycemia and all its severe complications to the newborn. Copyright © 2015 Elsevier Ltd. All rights reserved.

Glucagon-Like Peptide 1 Recruits Muscle Microvasculature and Improves Insulin’s Metabolic Action in the Presence of Insulin Resistance

PubMed Central

Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J.

2014-01-01

Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin’s metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy. PMID:24658303

Insulin treatment partially prevents cognitive and hippocampal alterations as well as glucocorticoid dysregulation in early-onset insulin-deficient diabetic rats.

PubMed

Marissal-Arvy, Nathalie; Campas, Marie-Neige; Semont, Audrey; Ducroix-Crepy, Céline; Beauvieux, Marie-Christine; Brossaud, Julie; Corcuff, Jean-Benoit; Helbling, Jean-Christophe; Vancassel, Sylvie; Bouzier-Sore, Anne-Karine; Touyarot, Katia; Ferreira, Guillaume; Barat, Pascal; Moisan, Marie-Pierre

2018-04-17

The diagnosis of Type 1 Diabetes (T1D) in ever younger children led us to question the impact of insulin deficiency or chronic hyperglycemia on cerebral development and memory performances. Here, we sought abnormalities in these traits in a model of streptozotocin-induced diabetes in juvenile rats treated or not by insulin. We made the assumption that such alterations would be related, at least in part, to excessive glucocorticoid exposition in hippocampal neurons. We have compared 3 groups of juvenile rats: controls, untreated diabetics and insulin-treated diabetics. Diabetes was induced by streptozotocin (65 mg/kg IP/day, 2 consecutive days), at postnatal days 21 and 22 and a subcutaneous pellet delivering 2 U of insulin/day was implanted in treated diabetic rats 3 days later. Three weeks after diabetes induction, cognitive performances (Y maze, object location and recognition tests), in vivo brain structure (brain volume and water diffusion by structural magnetic resonance imaging), and hippocampal neurogenesis (immunohistochemical labeling) measurements were undertaken. Corticosterone levels were evaluated in plasma under basal and stress conditions, and within hippocampus together with 11β-dehydrocorticosterone to assess 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. The comparison of the three experimental groups revealed that, compared to controls, untreated diabetic rats showed decreased cognitive performances in Y-maze and object location test (p < 0.05), decreased brain and hippocampal microstructure (p < 0.05), and decreased maturation and survival of hippocampal newborn neurons (p < 0.05). These alterations were associated with increased plasma corticosterone at the baseline nadir of its secretion (p < 0.001) and during the recovery phase following a restraint stress (p < 0.001), as well as increased hippocampal corticosterone levels (p < 0.01) and 11β-HSD1 activity (p < 0.05). As untreated diabetic rats, insulin-treated diabetic rats displayed decreased brain volume and water diffusion (p < 0.05 compared to controls) and intermediate memory performances and hippocampal neurogenesis (p value not significant compared to either controls or untreated diabetics). Moreover, they were similar to controls for basal plasma and hippocampal corticosterone and 11β-HSD1 activity but show increased plasma corticosterone during the recovery phase following a restraint stress similar to untreated diabetics (p < 0.001 compared to controls). Thus, insulin did not completely prevent several hippocampal-dependent behavioral and structural alterations induced by diabetes in juvenile rats which may relate to the higher cognitive difficulties encountered in T1D children compared to non-diabetic controls. Although insulin restored basal corticosterone and 11β-HSD1 activity (in hippocampus and plasma), the negative feedback regulation of corticosterone secretion after stress was still impaired in insulin-treated diabetic rats. Further characterization of insulin control on glucocorticoid regulation and availability within hippocampus is awaited. Copyright © 2018 Elsevier Ltd. All rights reserved.

Efficacy and Safety of Insulin Glargine 300 U/mL versus 100 U/mL in Diabetes Mellitus: A Comprehensive Review of the Literature

PubMed Central

2018-01-01

To achieve good metabolic control in diabetes and maintain it in the long term, a combination of changes in lifestyle and pharmacological treatment is necessary. The need for insulin depends upon the balance between insulin secretion and insulin resistance. Insulin is considered the most effective glucose-lowering therapy available and is required by people with type 1 diabetes mellitus to control their blood glucose levels; yet, many people with type 2 diabetes mellitus will also eventually require insulin therapy, due to the progressive nature of the disease. A variety of long-acting insulins is currently used for basal insulin therapy (such as insulin glargine, degludec, and detemir), each having sufficient pharmacodynamic and pharmacokinetic profiles to afford lower intrapatient variability and an extended duration of action. The new glargine-300 formulation was developed to have a flatter and more extended time-action profile than the original glargine-100, and these characteristics may translate into more stable and sustained glycemic control over a 24 h dosing interval. The objective of this comprehensive review was to summarize the available evidence on the clinical efficacy and safety of glargine-300 versus glargine-100 from the EDITION clinical trial program, in patients with type 1 and type 2 diabetes mellitus. PMID:29619381

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

PubMed

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

2018-01-01

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

Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion.

PubMed

Ramaswamy, S; Grace, C; Mattei, A A; Siemienowicz, K; Brownlee, W; MacCallum, J; McNeilly, A S; Duncan, W C; Rae, M T

2016-06-06

Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells.

Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion

PubMed Central

Ramaswamy, S.; Grace, C.; Mattei, A. A.; Siemienowicz, K.; Brownlee, W.; MacCallum, J.; McNeilly, A. S.; Duncan, W. C.; Rae, M. T.

2016-01-01

Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells. PMID:27265420

Impaired glucose metabolism in subjects with the Williams-Beuren syndrome: A five-year follow-up cohort study

PubMed Central

Lunati, Maria Elena; Bedeschi, Maria Francesca; Resi, Veronica; Grancini, Valeria; Palmieri, Eva; Salera, Simona; Lalatta, Faustina; Pugliese, Giuseppe

2017-01-01

Objective The Williams-Beuren syndrome (WS) is associated with impaired glucose metabolism (IGM) early in adulthood. However, the pathophysiology of IGM remains poorly defined, due to the lack of longitudinal studies investigating the contribution of β-cell dysfunction and impaired insulin sensitivity. This study aimed at assessing incidence of IGM and the underlying mechanisms in WS adults. Methods This observational, longitudinal (5-year), cohort study enrolled thirty-one consecutive WS subjects attending a tertiary referral center. An oral glucose tolerance test (OGTT) was performed yearly and used to classify patients as normal or IGM, including impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and diabetes mellitus (DM), and to calculate surrogate measures of insulin secretion and/or sensitivity. Results IGM patients were 18 (58.1%, three DM) at baseline and 19 (61.3%, five DM) at end-of-follow-up. However, 13 individuals changed category of glucose homeostasis in both directions during follow-up (8 progressors, 5 regressors) and 18 did not (8 non-progressors, 10 non-regressors). New cases of IGM and DM were 11.1 and 2.53 per 100 persons-year, respectively, and were treated non-pharmacologically. In the whole cohort and, to a higher extent, in progressors, indices of early-phase insulin secretion and insulin sensitivity decreased significantly from baseline to end-of-follow-up, with concurrent reduction of the oral disposition index and insulin secretion-sensitivity index-2 (ISSI-2), compensating insulin secretion for the level of insulin resistance. No baseline measure independently predicted progression, which correlated with change from baseline in ISSI-2. Compared with patients with normal glucose homeostasis, IGT subjects had impaired insulin sensitivity, whereas insulin secretion was reduced only in those with IFG+IGT or DM. Conclusions IGM incidence is high in young adults with WS, suggesting the need of early screening and timed intervention. As in classical type 2 diabetes, impaired insulin sensitivity and β-cell dysfunction contribute, in this sequence, to progression to IGM and DM. PMID:29053727

Improvement of glycaemic control and elevation of C-peptide following a diet free of dairy products in an insulin-treated, patient with type 2 diabetes with ulcerative colitis.

PubMed

Tandeter, Howard

2009-01-01

An insulin-treated patient with type 2 diabetes mellitus started a diet free of dairy products. Unexpectedly, she developed episodes of hypoglycaemia, without any change in her usual medication (insulin NPH at bedtime and Metformin). Laboratory tests showed an improvement of endogenous insulin secretion as demonstrated by the induction of hypoglycaemia and the elevation to normalisation of C-peptide levels. The patient was rechallenged with dairy products, leading to the lowering of the C-peptide levels back to abnormal levels, and an increase in HBA1C levels. The findings in our patient contrast with the insulinotropic effect of milk in healthy subjects described in the literature. The two main "milk debates" on the relation between milk (or its components) and diabetes are presented. Further observations will be needed to clarify the question of whether a diet free of dairy products can improve glycaemic control in other insulin-treated patients with type 2 diabetes.

Pancreatic Islet Responses to Metabolic Trauma

PubMed Central

Burke, Susan J.; Karlstad, Michael D.; Collier, J. Jason

2016-01-01

Carbohydrate, lipid, and protein metabolism are largely controlled by the interplay of various hormones, which includes those secreted by the pancreatic islets of Langerhans. While typically representing only 1–2% of the total pancreatic mass, the islets have a remarkable ability to adapt to disparate situations demanding a change in hormone release, such as peripheral insulin resistance. There are many different routes to the onset of insulin resistance, including obesity, lipodystrophy, glucocorticoid excess, and the chronic usage of atypical anti-psychotic drugs. All of these situations are coupled to an increase in pancreatic islet size, often with a corresponding increase in insulin production. These adaptive responses within the islets are ultimately intended to maintain glycemic control and to promote macronutrient homeostasis during times of stress. Herein, we review the consequences of specific metabolic trauma that lead to insulin resistance and the corresponding adaptive alterations within the pancreatic islets. PMID:26974425

Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

PubMed

Viscarra, Jose A; Rodriguez, Ruben; Vazquez-Medina, Jose Pablo; Lee, Andrew; Tift, Michael S; Tavoni, Stephen K; Crocker, Daniel E; Ortiz, Rudy M

2013-08-01

Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation.

Insulin analogs with improved pharmacokinetic profiles.

PubMed

Brange; Vølund

1999-02-01

The aim of insulin replacement therapy is to normalize blood glucose in order to reduce the complications of diabetes. The pharmacokinetics of the traditional insulin preparations, however, do not match the profiles of physiological insulin secretion. The introduction of the rDNA technology 20 years ago opened new ways to create insulin analogs with altered properties. Fast-acting analogs are based on the idea that an insulin with less tendency to self-association than human insulin would be more readily absorbed into the systemic circulation. Protracted-acting analogs have been created to mimic the slow, steady rate of insulin secretion in the fasting state. The present paper provides a historical review of the efforts to change the physicochemical and pharmacological properties of insulin in order to improve insulin therapy. The available clinical studies of the new insulins are surveyed and show, together with modeling results, that new strategies for optimal basal-bolus treatment are required for utilization of the new fast-acting analogs.

Variation of glucose tolerance in adult patients with cystic fibrosis: What is the potential contribution of insulin sensitivity?

PubMed

Boudreau, Valérie; Coriati, Adèle; Hammana, Imane; Ziai, Sophie; Desjardins, Katherine; Berthiaume, Yves; Rabasa-Lhoret, Rémi

2016-11-01

Reduced insulin secretion is a key factor to explain high prevalence of glucose intolerance in patients with cystic fibrosis (CF). However, the role of insulin sensitivity remains unclear. The aim of this study is to investigate the association of insulin secretion and sensitivity with the evolution of glucose tolerance. A total of 152 patients without known diabetes from the Montreal CF cohort underwent two 2-h oral glucose tolerance tests (OGTT) at baseline and again after 21.2±5.5months. Pulmonary function and anthropometric measurements were also collected at each visit. At both visits, based on their OGTT results, patients were categorized in glucose tolerance groups (normal glucose tolerance, impaired glucose tolerance or CF-related diabetes) and stratified in 3 groups according to the variation of their glucose tolerance: stable, improved or deteriorated. At baseline, patients in the deteriorated group had a better sensitivity to insulin than those in the improved group (P=0.029). At follow-up glucose tolerance remained stable in 55.3%, improved in 14.5% and deteriorated in 30.3% of patients. During follow-up, insulin secretion remained stable in all 3 groups. While insulin sensitivity remained stable in patients without changes in glucose tolerance it worsened in patients who deteriorated glucose tolerance (P<0.001) and improved in patients who improved their glucose tolerance (P=0.003). In a context of significantly reduced insulin secretion, variations of insulin sensitivity are associated with variations of glucose tolerance in adult patients with CF. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Long-term consumption of fermented soybean-derived Chungkookjang enhances insulinotropic action unlike soybeans in 90% pancreatectomized diabetic rats.

PubMed

Kwon, Dae Young; Jang, Jin Sun; Hong, Sang Mee; Lee, Ji Eun; Sung, So Ra; Park, Hye Ryeo; Park, Sunmin

2007-02-01

We previously reported that Chungkookjang (CKJ), fermented unsalted soybeans, exhibited better anti-diabetic action than cooked soybeans (CSB) in vitro, but its effectiveness and mechanism have not been studied in vivo. We investigated whether CKJ modulated insulin resistance, insulin secretion, and pancreatic beta-cell growth and survival in 90% pancreatectomized (Px) diabetic rats. The Px rats weighing 201 +/- 12 g were divided into four groups and fed for 8 weeks with a CSB diet, a CKJ diet, a casein diet, or a casein diet plus rosiglitazone (20 mg/kg body weight/day). With the exception of protein sources and contents of isoflavonoid aglycones and glycosides, the composition of the diets was made identical by adding soybean oil and cellulose to a casein diet. At the end of the experimental periods, hyperglycemic clamp was performed in conscious, unstressed and overnight fasted Px rats to measure insulin secretion capacity. Insulin/IGF-1 signaling was measured by immunoblotting in isolated islets from the treated rats, and beta-cell mass, proliferation and apoptosis were also determined by immunohistochemistry. After 8-week administration, CSB did not modulate glucose-stimulated insulin secretion, but surprisingly, CKJ enhanced insulin secretion. In addition, CKJ potentiated insulin/IGF-1 signaling in islets via the induction of insulin receptor substrate-2 expression, leading to increasing pancreatic duodenal homeobox-1, insulin promoter transcription factor. In parallel with the enhancement of the signaling, CKJ elevated pancreatic beta-cell hyperplasia by increasing its proliferation and decreasing apoptosis, whereas CSB did not. Based on these results, the fermentation of soybeans predominantly with Bacillus subtilis generated isoflavonoid aglycones and small peptides, which improved insulinotropic action in islets of type 2 diabetic rats. Overall, the anti-diabetic action of CKJ was superior to CSB in type 2 diabetic rats.

The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates.

PubMed

Tsonkova, Violeta Georgieva; Sand, Fredrik Wolfhagen; Wolf, Xenia Asbæk; Grunnet, Lars Groth; Kirstine Ringgaard, Anna; Ingvorsen, Camilla; Winkel, Louise; Kalisz, Mark; Dalgaard, Kevin; Bruun, Christine; Fels, Johannes Josef; Helgstrand, Charlotte; Hastrup, Sven; Öberg, Fredrik Kryh; Vernet, Erik; Sandrini, Michael Paolo Bastner; Shaw, Allan Christian; Jessen, Carsten; Grønborg, Mads; Hald, Jacob; Willenbrock, Hanni; Madsen, Dennis; Wernersson, Rasmus; Hansson, Lena; Jensen, Jan Nygaard; Plesner, Annette; Alanentalo, Tomas; Petersen, Maja Borup Kjær; Grapin-Botton, Anne; Honoré, Christian; Ahnfelt-Rønne, Jonas; Hecksher-Sørensen, Jacob; Ravassard, Philippe; Madsen, Ole D; Rescan, Claude; Frogne, Thomas

2018-02-01

To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates. EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation. Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins. Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate. By screening of various proteins and peptides, we found Bombesin (BB) receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP) to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation. ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST) was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion. Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated insulin secretion capabilities. The cell line has an active cytokine induced caspase 3/7 apoptotic pathway and is responsive to ER stress initiation factors. The cells' ability to proliferate can be further increased by already known compounds as well as by novel peptides and proteins. Based on its robust performance during the functionality assessment assays, the EndoC-βH1 cell line was successfully used as a screening platform for identification of novel anti-diabetic drug candidates. Copyright © 2017 Novo Nordisk A/S. Published by Elsevier GmbH.. All rights reserved.

Evaluation of long-term treatment effect in a type 1 diabetes intervention trial: differences after stimulation with glucagon or a mixed meal.

PubMed

Pozzilli, Paolo; Raz, Itamar; Peled, Dana; Elias, Dana; Avron, Ann; Tamir, Merana; Eren, Rachel; Dagan, Shlomo; Cohen, Irun R

2014-01-01

Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes. A recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson's correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (AUC). The absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74-0.9). However, the correlations between the AUC were much weaker (r = 0.39-0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4-11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose. Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.

Expression of sulfonylurea receptors in rat taste buds.

PubMed

Liu, Dian-Xin; Liu, Xiao-Min; Zhou, Li-Hong; Feng, Xiao-Hong; Zhang, Xiao-Juan

2011-07-01

To test the possibility that a fast-onset promoting agent repaglinide may initiate prandial insulin secretion through the mechanism of cephalic-phase insulin release, we explored the expression and distribution character of sulfonylurea receptors in rat taste buds. Twenty male Wistar rats aged 10 weeks old were killed after general anesthesia. The circumvallate papillae, fungiform papillae and pancreas tissues were separately collected. Immunohistochemical staining was used to detect the expression and distribution of sulfonylurea receptor 1 (SUR1) or sulfonylurea receptor 2 (SUR2) in rat taste buds. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to analyze the expression of SUR1 or SUR2 mRNA. The pancreatic tissues from the same rat were used as positive control. This is the first study to report that SUR1 is uniquely expressed in the taste buds of fungiform papillae of each rat tongue, while the expression of SUR1 or SUR2 was not detected in the taste buds of circumvallate papillae. SUR1 is selectively expressed in rat taste buds, and its distribution pattern may be functionally relevant, suggesting that the rapid insulin secretion-promoting effect of repaglinide may be exerted through the cephalic-phase secretion pathway mediated by taste buds. Copyright © 2010 Elsevier GmbH. All rights reserved.

Ectopic expression of syncollin in INS-1 beta-cells sorts it into granules and impairs regulated secretion.

PubMed

Li, Jingsong; Luo, Ruihua; Hooi, Shing Chuan; Ruga, Pilar; Zhang, Jiping; Meda, Paolo; Li, GuoDong

2005-03-22

Syncollin was first demonstrated to be a protein capable of affecting granule fusion in a cell-free system, but later studies revealed its luminal localization in zymogen granules. To determine its possible role in exocytosis in the intact cell, syncollin and a truncated form of the protein (lacking the N-terminal hydrophobic domain) were stably transfected in insulin-secreting INS-1 cells since these well-studied exocytotic cells appear not to express the protein per se. Studies by subcellular fractionation analysis, double immunofluorescence staining, and electron microscopy examination revealed that transfection of syncollin produced strong signals in the insulin secretory granules, whereas the product from transfecting the truncated syncollin was predominantly associated with the Golgi apparatus and to a lesser degree with the endoplasmic reticulum. The expressed products were associated with membranes and not the soluble fractions in either cytoplasm or the lumens of organelles. Importantly, insulin release stimulated by various secretagogues was severely impaired in cells expressing syncollin, but not affected by expressing truncated syncollin. Transfection of syncollin appeared not to impede insulin biosynthesis and processing, since cellular contents of proinsulin and insulin and the number of secretory granules were not altered. In addition, the early signals (membrane depolarization and Ca(2+) responses) for regulated insulin secretion were unaffected. These findings indicate that syncollin may be targeted to insulin secretory granules specifically and impair regulated secretion at a distal stage.

Circulating 25-hydroxyvitamin D and insulin resistance in older adults: The Cardiovascular Health Study

PubMed Central

Danziger, John; Biggs, Mary L.; Niemi, Matt; Ix, Joachim H.; Kizer, Jorge R.; Djoussé, Luc; de Boer, Ian H.; Siscovick, David S.; Kestenbaum, Bryan; Mukamal, Kenneth J.

2014-01-01

Background Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear. Objective To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults. Methods and Results Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992–1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996–1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95%CI (−0.17, −0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis. Conclusions Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors. PMID:23987236

Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study

PubMed Central

Ganna, Andrea; Brandmaier, Stefan; Broeckling, Corey D.; Prenni, Jessica E.; Wang-Sattler, Rui; Peters, Annette; Strauch, Konstantin; Meitinger, Thomas; Giedraitis, Vilmantas; Ärnlöv, Johan; Berne, Christian; Gieger, Christian; Ripatti, Samuli; Lind, Lars; Sundström, Johan; Ingelsson, Erik

2016-01-01

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining “gold standard” measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development. PMID:27768686

Characterisation of the insulinotropic activity of an aqueous extract of Gymnema sylvestre in mouse beta-cells and human islets of Langerhans.

PubMed

Liu, Bo; Asare-Anane, Henry; Al-Romaiyan, Altaf; Huang, Guocai; Amiel, Stephanie A; Jones, Peter M; Persaud, Shanta J

2009-01-01

Leaves of the Gymnema sylvestre (GS) plant have been used to treat diabetes mellitus for millennia, but the previously documented insulin secretagogue effects of GS extracts in vitro may be non-physiological through damage to the beta-cells. We have now examined the effects of a novel GS extract (termed OSA) on insulin secretion from the MIN6 beta-cell line and isolated human islets of Langerhans. Insulin secretion from MIN6 cells was stimulated by OSA in a concentration-dependent manner, with low concentrations (0.06-0.25 mg/ml) having no deleterious effects on MIN6 cell viability, while higher concentrations (> or = 0.5 mg/ml) caused increased Trypan blue uptake. OSA increased beta-cell Ca2+ levels, an effect that was mediated by Ca2+ influx through voltage-operated calcium channels. OSA also reversibly stimulated insulin secretion from isolated human islets and its insulin secretagogue effects in MIN6 cells and human islets were partially dependent on the presence of extracellular Ca2+. These data indicate that low concentrations of the GS isolate OSA stimulate insulin secretion in vitro, at least in part as a consequence of Ca2+ influx, without compromising beta-cell viability. Identification of the component of the OSA extract that stimulates regulated insulin exocytosis, and further investigation of its mode(s) of action, may provide promising lead targets for Type 2 diabetes therapy. 2009 S. Karger AG, Basel.

Saxagliptin Upregulates Nesfatin-1 Secretion and Ameliorates Insulin Resistance and Metabolic Profiles in Type 2 Diabetes Mellitus.

PubMed

Chen, Kuanlin; Zhuo, Tiejun; Wang, Jian; Mei, Qing

2018-06-18

Saxagliptin as one of dipeptidyl peptidase-4 (DPP-4) inhibitors can effectively improve glycaemic control in type 2 diabetes mellitus, and nesfatin-1 is regarded as a very important factor in regulating feeding behavior and energy homeostasis. In this trial, we observed the effect of saxagliptin on regulating nesfatin-1 secretion and ameliorating insulin resistance and metabolic profiles in type 2 diabetes mellitus. One hundred two type 2 diabetes participants (M/F = 48/54) were investigated. Fifty-one (M/F = 24/27) of them as the treatment group were treated with oral glucose-lowering agents including saxagliptin, the other 51 (M/F = 24/27) as the control group were treated with oral glucose-lowering agents excluding any DPP-4 inhibitors. The parameters of serum nesfatin-1, C-peptide, homeostasis model assessment-β (HOMA-β) function, HOMA insulin resistance (HOMA-IR), glycosylated hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), body mass index (BMI), and blood pressure (BP) at baseline, month 3, 6, and 12 were observed and compared respectively. Saxagliptin significantly upregulated nesfatin-1 secretion (P < 0.001 at 3-, 6-, and 12-months vs. baseline), increased serum C-peptide (P < 0.05, 0.001, and 0.001 at 3-, 6-, and 12-months vs. baseline), improved HOMA-IR and function of HOMA-β (P < 0.001 at 3-, 6-, and 12-months vs. baseline) and metabolic profiles (P < 0.001 with HbA1c at 3-, 6- and 12-months; P < 0.001 with LDL-C at 6- and 12-months; P < 0.001 and 0.01 with HDL-C at 6- and 12-months vs. baseline), declined BMI (P < 0.05 at 6- and 12-months vs. baseline) and BP (P < 0.001 with systolic BP (SBP), and mean BP at 6- and 12-months, P < 0.01 with diastolic BP at 6- and 12-months vs. baseline). Saxagliptin could upregulate nesfatin-1 secretion and ameliorate insulin resistance and metabolic profiles in type 2 diabetes mellitus. Saxagliptin had the potential to play fundamental by upregulating nesfatin-1 secretion besides lowering glucose by inhibiting the degradation of glucagon-like peptide-1.

L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2.

PubMed

Nakatsu, Daiki; Horiuchi, Yuta; Kano, Fumi; Noguchi, Yoshiyuki; Sugawara, Taichi; Takamoto, Iseki; Kubota, Naoto; Kadowaki, Takashi; Murata, Masayuki

2015-03-10

Increase in the concentration of plasma L-cysteine is closely associated with defective insulin secretion from pancreatic β-cells, which results in type 2 diabetes (T2D). In this study, we investigated the effects of prolonged L-cysteine treatment on glucose-stimulated insulin secretion (GSIS) from mouse insulinoma 6 (MIN6) cells and from mouse pancreatic islets, and found that the treatment reversibly inhibited glucose-induced ATP production and resulting GSIS without affecting proinsulin and insulin synthesis. Comprehensive metabolic analyses using capillary electrophoresis time-of-flight mass spectrometry showed that prolonged L-cysteine treatment decreased the levels of pyruvate and its downstream metabolites. In addition, methyl pyruvate, a membrane-permeable form of pyruvate, rescued L-cysteine-induced inhibition of GSIS. Based on these results, we found that both in vitro and in MIN6 cells, L-cysteine specifically inhibited the activity of pyruvate kinase muscle isoform 2 (PKM2), an isoform of pyruvate kinases that catalyze the conversion of phosphoenolpyruvate to pyruvate. L-cysteine also induced PKM2 subunit dissociation (tetramers to dimers/monomers) in cells, which resulted in impaired glucose-induced ATP production for GSIS. DASA-10 (NCGC00181061, a substituted N,N'-diarylsulfonamide), a specific activator for PKM2, restored the tetramer formation and the activity of PKM2, glucose-induced ATP production, and biphasic insulin secretion in L-cysteine-treated cells. Collectively, our results demonstrate that impaired insulin secretion due to exposure to L-cysteine resulted from its direct binding and inactivation of PKM2 and suggest that PKM2 is a potential therapeutic target for T2D.

Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.

PubMed Central

Zhou, Y P; Grill, V E

1994-01-01

We tested effects of long-term exposure of pancreatic islets to free fatty acids (FFA) in vitro on B cell function. Islets isolated from male Sprague-Dawley rats were exposed to palmitate (0.125 or 0.25 mM), oleate (0.125 mM), or octanoate (2.0 mM) during culture. Insulin responses were subsequently tested in the absence of FFA. After a 48-h exposure to FFA, insulin secretion during basal glucose (3.3 mM) was several-fold increased. However, during stimulation with 27 mM glucose, secretion was inhibited by 30-50% and proinsulin biosynthesis by 30-40%. Total protein synthesis was similarly affected. Conversely, previous palmitate did not impair alpha-ketoisocaproic acid (5 mM)-induced insulin release. Induction and reversibility of the inhibitory effect on glucose-induced insulin secretion required between 6 and 24 h. Addition of the carnitine palmitoyltransferase I inhibitor etomoxir (1 microM) partially reversed (by > 50%) FFA-associated decrease in secretory as well as proinsulin biosynthetic responses to 27 mM glucose. The inhibitory effect of previous palmitate was similar when co-culture was performed with 5.5, 11, or 27 mM glucose. Exposure to palmitate or oleate reduced the production of 14CO2 from D-[U-14C]glucose, and of 14CO2 from D-[3,4-14C]-glucose, both effects being reversed by etomoxir. Conclusions: long-term exposure to FFA inhibits glucose-induced insulin secretion and biosynthesis probably through a glucose fatty acid cycle. PMID:8113418

BAG3 regulates formation of the SNARE complex and insulin secretion

PubMed Central

Iorio, V; Festa, M; Rosati, A; Hahne, M; Tiberti, C; Capunzo, M; De Laurenzi, V; Turco, M C

2015-01-01

Insulin release in response to glucose stimulation requires exocytosis of insulin-containing granules. Glucose stimulation of beta cells leads to focal adhesion kinase (FAK) phosphorylation, which acts on the Rho family proteins (Rho, Rac and Cdc42) that direct F-actin remodeling. This process requires docking and fusion of secretory vesicles to the release sites at the plasma membrane and is a complex mechanism that is mediated by SNAREs. This transiently disrupts the F-actin barrier and allows the redistribution of the insulin-containing granules to more peripheral regions of the β cell, hence facilitating insulin secretion. In this manuscript, we show for the first time that BAG3 plays an important role in this process. We show that BAG3 downregulation results in increased insulin secretion in response to glucose stimulation and in disruption of the F-actin network. Moreover, we show that BAG3 binds to SNAP-25 and syntaxin-1, two components of the t-SNARE complex preventing the interaction between SNAP-25 and syntaxin-1. Upon glucose stimulation BAG3 is phosphorylated by FAK and dissociates from SNAP-25 allowing the formation of the SNARE complex, destabilization of the F-actin network and insulin release. PMID:25766323

Effects of a westernized lifestyle on the association between fasting serum nonesterified fatty acids and insulin secretion in Japanese men.

PubMed

Kamei, Nozomu; Yamane, Kiminori; Nakanishi, Shuhei; Ishida, Kazufumi; Ohtaki, Megu; Okubo, Masamichi; Kohno, Nobuoki

2005-06-01

The effects of the prolonged elevation of nonesterified fatty acid (NEFA) levels on insulin secretion have been controversial and thought to be sex-specific. To investigate the association between a westernized lifestyle and the effects of NEFA on insulin secretion in Japanese men, we examined 67 nondiabetic Japanese-American men and 220 nondiabetic native Japanese men who underwent a 75-g oral glucose tolerance test (OGTT). Most Japanese Americans we surveyed are genetically identical to Japanese living in Japan, but their lifestyle is more westernized. Sets of multiple regression analyses were performed to evaluate the relationship between the sum of the immunoreactive insulin (IRI) levels during the OGTT ((Sigma)IRI) and clinical parameters. Japanese Americans had higher levels of fasting IRI, (Sigma)IRI, and a higher insulin resistance index (homeostasis model assessment for insulin resistance [HOMA-IR]) than native Japanese, whereas there were no significant differences in fasting NEFA and triglyceride levels. A multiple regression analysis adjusted for age, fasting triglycerides, and body mass index (BMI) demonstrated that the fasting NEFA level was an independent determinant of the (Sigma)IRI only in Japanese-American men ( P = .001), but not in native Japanese men ( P = .054). Even when HOMA-IR was included in models instead of BMI, the NEFA level was a significant variable of (Sigma)IRI only in Japanese Americans ( P < .001), and not in native Japanese ( P = .098). In addition, a multiple regression analysis adjusted for age, fasting triglycerides, and BMI demonstrated that the fasting NEFA level was the only independent determinant of (Sigma)C-peptide in Japanese-American men ( P = .041). In conclusion, NEFA seems to be associated with insulin secretion independent of obesity or HOMA-IR. A westernized lifestyle may increase the effects of serum fasting NEFA levels on total insulin secretion after a glucose load in Japanese men.

A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats

PubMed Central

Hoelmkjaer, Kirsten M.; Wewer Albrechtsen, Nicolai J.; Holst, Jens J.; Cronin, Anna M.; Nielsen, Dorte H.; Mandrup-Poulsen, Thomas; Bjornvad, Charlotte R.

2016-01-01

Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats. PMID:27136422

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis.

PubMed

McClain, D A; Abraham, D; Rogers, J; Brady, R; Gault, P; Ajioka, R; Kushner, J P

2006-07-01

The prevalence and mechanisms of diabetes in hereditary haemochromatosis are not known. We therefore measured glucose tolerance, insulin secretory capacity and insulin sensitivity in adults with haemochromatosis. Subjects recruited from referrals to a haemochromatosis clinic underwent OGTT and frequently sampled IVGTT. A chart review of former clinic patients was also performed. The prevalence of diabetes (23%) and IGT (30%) was increased in haemochromatosis compared with matched control subjects (0% diabetes and 14% IGT). Subjects with haemochromatosis and diabetes were overweight (14%) or obese (86%). The prevalence of diabetes, as determined by chart review of fasting glucose values, in subjects who had haemochromatosis and were in the 40-79 years age range was 26%. Overall, patients with haemochromatosis and control subjects had similar values for acute insulin response to glucose and insulin sensitivity. However, patients with haemochromatosis and IGT had a 68% decrease in acute insulin response to glucose (p<0.02) compared with those with NGT. They were not insulin-resistant, exhibiting instead a 62% increase in insulin sensitivity (NS). Haemochromatosis subjects with diabetes exhibited further declines in acute insulin response to glucose, insulin resistance, or both. Diabetes and IGT are common in haemochromatosis, justifying screening for diabetes and therapeutic phlebotomy. The major abnormality associated with IGT is decreased insulin secretory capacity. Diabetes is usually associated with obesity and concomitant insulin resistance.

Mechanisms Regulating Insulin Response to Intragastric Glucose in Lean and Non-Diabetic Obese Subjects: A Randomized, Double-Blind, Parallel-Group Trial

PubMed Central

Meyer-Gerspach, Anne Christin; Cajacob, Lucian; Riva, Daniele; Herzog, Raphael; Drewe, Juergen; Beglinger, Christoph; Wölnerhanssen, Bettina K.

2016-01-01

Background/Objectives The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads. Subjects/Methods The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit. A total of 12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water. Results Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin disposal (P < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (P < 0.001) in obese subjects. Conclusions It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance. Trial Registration ClinicalTrials.gov NCT01875575 PMID:26942445

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

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

Zhao, Qing; Che, Yongzhe; Li, Qiang

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

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

PubMed Central

Stark, Romana; Kibbey, Richard G.

2013-01-01

Background Plasma glucose levels are tightly regulated within a narrow physiologic range. Insulin-mediated glucose uptake by tissues must be balanced by the appearance of glucose from nutritional sources, glycogen stores, or gluconeogenesis. In this regard, a common pathway regulating both glucose clearance and appearance has not been described. The metabolism of glucose to produce ATP is generally considered to be the primary stimulus for insulin release from beta-cells. Similarly, gluconeogenesis from phosphoenolpyruvate (PEP) is believed to be the primarily pathway via the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). These models cannot adequately explain the regulation of insulin secretion or gluconeogenesis. Scope of review A metabolic sensing pathway involving mitochondrial GTP (mtGTP) and PEP synthesis by the mitochondrial isoform of PEPCK (PEPCK-M) is associated with glucose-stimulated insulin secretion from pancreatic beta-cells. Here we examine whether there is evidence for a similar mtGTP-dependent pathway involved in gluconeogenesis. In both islets and the liver, mtGTP is produced at the substrate level by the enzyme succinyl CoA synthetase (SCS-GTP) with a rate proportional to the TCA cycle. In the beta-cell PEPCK-M then hydrolyzes mtGTP in the production of PEP that, unlike mtGTP, can escape the mitochondria to generate a signal for insulin release. Similarly, PEPCK-M and mtGTP might also provide a significant source of PEP in gluconeogenic tissues for the production of glucose. This review will focus on the possibility that PEPCK-M, as a sensor for TCA cycle flux, is a key mechanism to regulate both insulin secretion and gluconeogenesis suggesting conservation of this biochemical mechanism in regulating multiple aspects of glucose homeostasis. Moreover, we propose that this mechanism may be more important for regulating insulin secretion and gluconeogenesis compared to canonical nutrient sensing pathways. Major conclusions PEPCK-M, initially believed to be absent in islets, carries a substantial metabolic flux in beta-cells. This flux is intimately involved with the coupling of glucose-stimulated insulin secretion. PEPCK-M activity may have been similarly underestimated in glucose producing tissues and could potentially be an unappreciated but important source of gluconeogenesis. General Significance The generation of PEP via PEPCK-M may occur via a metabolic sensing pathway important for regulating both insulin secretion and gluconeogenesis. PMID:24177027

Effects of endurance exercise training, metformin, and their combination on adipose tissue leptin and IL-10 secretion in OLETF rats

PubMed Central

Padilla, Jaume; Arce-Esquivel, Arturo A.; Bayless, David S.; Martin, Jeffrey S.; Leidy, Heather J.; Booth, Frank W.; Rector, R. Scott; Laughlin, M. Harold

2012-01-01

Adipose tissue inflammation plays a role in cardiovascular (CV) and metabolic diseases associated with obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The interactive effects of exercise training and metformin, two first-line T2DM treatments, on adipose tissue inflammation are not known. Using the hyperphagic, obese, insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, we tested the hypothesis that treadmill training, metformin, or a combination of these reduces the secretion of proinflammatory cytokines from adipose tissue. Compared with Long-Evans Tokushima Otsuka (LETO) control rats (L-Sed), sedentary OLETF (O-Sed) animals secreted significantly greater amounts of leptin from retroperitoneal adipose tissue. Conversely, secretion of interleukin (IL)-10 by O-Sed adipose tissue was lower than that in L-Sed animals. Examination of leptin and IL-10 secretion from adipose tissue in OLETF groups treated with endurance exercise training (O-EndEx), metformin treatment (O-Met), and a combination of these (O-E+M) from 20 to 32 wk of age indicated that 1) leptin secretion from adipose tissue was reduced in O-Met and O-E+M, but not O-EndEx animals; 2) adipose tissue IL-10 secretion was increased in O-EndEx and O-E+M but not in O-Met animals; and 3) only the combined treatment (O-E+M) displayed both a reduction in leptin secretion and an increase in IL-10 secretion. Leptin and IL-10 concentrations in adipose tissue–conditioned buffers were correlated with their plasma concentrations, adipocyte diameters, and total adiposity. Overall, this study indicates that exercise training and metformin have additive influences on adipose tissue secretion and plasma concentrations of leptin and IL-10. PMID:23019312

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

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

Vaca, Pilar; Berna, Genoveva; Araujo, Raquel

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.more » 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.« less

Modulation of natriuretic peptide receptors in human adipose tissue: molecular mechanisms behind the "natriuretic handicap" in morbidly obese patients.

PubMed

Gentili, Alessandra; Frangione, Maria Rosaria; Albini, Elisa; Vacca, Carmine; Ricci, Maria Anastasia; De Vuono, Stefano; Boni, Marcello; Rondelli, Fabio; Rotelli, Luciana; Lupattelli, Graziana; Orabona, Ciriana

2017-08-01

The B-type natriuretic peptide (BNP) hormone plays a crucial role in the regulation of cardiovascular and energy homeostasis. Obesity is associated with low circulating levels of BNP, a condition known as "natriuretic handicap." Recent evidences suggest an altered expression of BNP receptors-both the signaling natriuretic peptide receptors (NPR)-A and the clearance NPR-C receptor-in adipose tissue (AT) as one of the putative causes of natriuretic handicap. The current study aims at clarifying the molecular mechanisms behind the natriuretic handicap, focusing on NPR modulation in the AT of obese and control subjects. The study enrolled 34 obese and 20 control subjects undergoing bariatric or abdominal surgery, respectively. The main clinical and biochemical parameters, including circulating BNP, were assessed. In visceral (VAT) and subcutaneous AT (SAT) samples, collected during surgery, the adipocytes and stromal vascular fraction (SVF) expression of NPR-A and NPR-C and the SVF secretion of interleukin 6 (IL-6) were determined. Both VAT and SAT from obese patients expressed a lower NPR-A/NPR-C ratio in adipocytes and the SVF secreted a higher level of IL-6, compared with the controls. Moreover, NPR-A/NPR-C ratio expressed by VAT and SAT adipocytes negatively correlated with body mass index, insulin, the Homeostasis Model Assessment of Insulin resistance, and IL-6 secreted by SVF, and the expression of the clearance receptor NPR-C, in both the VAT and SAT adipocytes, showed a negative correlation with circulating BNP. Overall, insulin resistance/hyperinsulinemia and AT inflammation (ie, high level of IL-6) are the major determinants of the lower NPR-A/NPR-C ratio in adipocytes, thus contributing to the natriuretic handicap in obese subjects. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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

2011-07-01

The glucagon-like peptide-1 mimetic exenatide has a glucose-dependent insulinotropic effect, and it is effective in controlling blood glucose (BG) with minimal side effects in people with type 2 diabetes. Exenatide also delays gastric emptying, increases satiety, and improves β-cell function. We studied the effect of exenatide on insulin secretion during euglycemia and hyperglycemia in cats. Nine young, healthy, neutered, purpose-bred cats were used in a randomized, cross-over design. BG concentrations during an oral glucose tolerance test were determined in these cats previously. Two isoglycemic glucose clamps (mimicking the BG concentration during the oral glucose tolerance test) were performed in each cat on separate days, one without prior treatment (IGC) and the second with exenatide (1 μg/kg) injected subcutaneously 2 h before (ExIGC). BG, insulin, and exenatide concentrations were measured, and glucose infusion rates were recorded and compared in paired tests between the two experiments. After exenatide injection, insulin serum concentrations increased significantly (2.4-fold; range 1.0- to 9.2-fold; P = 0.004) within 15 min. This was followed by a mild decrease in BG concentration and a return of insulin concentration to baseline despite a continuous increase in serum exenatide concentrations. Insulin area under the curve (AUC) during ExIGC was significantly higher than insulin AUC during IGC (AUC ratio, 2.0 ± 0.4; P = 0.03). Total glucose infused was not significantly different between IGC and ExIGC. Exenatide was detectable in plasma at 15 min after injection. The mean exenatide concentration peaked at 45 min and then returned to baseline by 75 min. Exenatide was still detectable in the serum of three of five cats 8 h after injection. No adverse reactions to exenatide were observed. In conclusion, exenatide affects insulin secretion in cats in a glucose-dependent manner, similar to its effect in other species. Although this effect was not accompanied by a greater ability to dispose of an intravenous glucose infusion, other potentially beneficial effects of exenatide on pancreatic β cells, mainly increasing their proliferation and survival, should be investigated in cats. Copyright © 2011 Elsevier Inc. All rights reserved.

Depressive symptoms, antidepressant medication use, and insulin resistance: the PPP-Botnia Study.

PubMed

Pyykkönen, Antti-Jussi; Räikkönen, Katri; Tuomi, Tiinamaija; Eriksson, Johan G; Groop, Leif; Isomaa, Bo

2011-12-01

Although insulin resistance (IR) may underlie associations between depressive symptoms and diabetes, previous findings have been contradictory. We examined whether depressive symptoms associate with IR and insulin secretion, and, additionally, whether antidepressant medication use may modulate such associations. A total of 4,419 individuals underwent an oral glucose tolerance test (OGTT). Participants with previously or newly diagnosed diabetes are excluded from this sample. The homeostasis model assessment of IR (HOMA-IR) and corrected insulin response (CIR) were calculated. Depressive symptoms and antidepressant medication use were self-reported. After controlling for confounding factors, depressive symptoms were associated with higher fasting and 30-min insulin during the OGTT and higher HOMA-IR but not CIR. Antidepressant medication use failed to modify these associations. Depressive symptoms are associated with IR but not with changes in insulin response when corrected for IR in individuals without previously or newly diagnosed diabetes.

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

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

Sekiya, Motohiro; Yahagi, Naoya, E-mail: nyahagi-tky@umin.ac.jp; Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655

2009-09-25

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

Association of fat to lean mass ratio with metabolic dysfunction in women with polycystic ovary syndrome

PubMed Central

Ezeh, Uche; Pall, Marita; Mathur, Ruchi; Azziz, Ricardo

2014-01-01

STUDY QUESTION Are differences in metabolic dysfunction between polycystic ovary syndrome (PCOS) and control women related to differences in their fat to lean mass (F/L) ratio? SUMMARY ANSWER Compared with controls of similar body mass index (BMI), women with PCOS demonstrate adverse body composition characterized by increased whole body fat relative to lean mass (i.e. a higher F/L ratio), which is associated with differences in metabolic dysfunction between the two groups. WHAT IS KNOWN ALREADY Previous studies examining body composition and insulin resistance (IR) in PCOS have yielded conflicting results. Excess total fat mass (i.e. fat mass index [fat BMI]) correlates with IR, whereas increased total lean mass (i.e. lean BMI) has been associated with higher insulin sensitivity. However, the role of the F/L ratio, which integrates the antagonistic effects of both fat and lean mass depots, on IR in PCOS, has not been investigated. STUDY DESIGN, SIZE, DURATION We conducted a prospective cross-sectional study of 120 women between the ages of 22–44 years to study the relation of the F/L ratio with measures of insulin action and secretion in both steady and dynamic states. PARTICIPANTS/MATERIALS, SETTING, METHODS Sixty PCOS (by NIH, 1990 criteria) and 60 control (age, race and BMI-matched) women were prospectively studied for body composition (by bioelectrical impedance analysis [BIA]) and basal IR and insulin secretion by the homeostasis model assessment (HOMA-IR and HOMA-%β-cell function, respectively) in a tertiary care academic referral center. A subset of 12 PCOS and 12 matched control women also underwent a modified frequently sampled intravenous glucose tolerance test (FSIVGTT) to determine glucose uptake and insulin secretion in dynamic state. MAIN RESULTS AND THE ROLE OF CHANCE Our results indicate that women with PCOS demonstrated greater degrees of hyperandrogenism, and higher waist-to-hip ratio (WHR), %body fat, fat BMI, F/L, fasting insulin levels, and HOMA-IR and HOMA-%β-cell values, than controls. In models adjusted for WHR and free testosterone and diagnostic groups, fasting insulin levels, HOMA-IR, and HOMA-%beta cell function were positively related to the F/L ratio. A positive relationship was also found in both study groups between F/L and the FSIVGTT measures insulin sensitivity (Si) and acute insulin response to glucose (AIRg). The F/L tended to negatively correlate with glucose effectiveness or non-insulin-mediated glucose transport (Sg) only in PCOS women. LIMITATIONS, REASONS FOR CAUTION Regional tissue sub-compartments, which have been shown to have potential independent associations with metabolic variables, cannot be determined by bioelectrical impedance analysis (BIA). WIDER IMPLICATIONS OF THE FINDINGS The current results suggest that BIA could be used to assess F/L in place of dual energy X-ray absorptiometry (DXA) in research protocols, and that F/L could possibly be used as an alternative to WHR as a surrogate marker of metabolic dysfunction in clinical practice. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants R01-DK073632 and R01-HD29364 from the NIH and an endowment of the Helping Hand of Los Angeles, Inc. (to R.A.). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER Not applicable. PMID:24813197

Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells.

PubMed

Olofsson, Charlotta S; Göpel, Sven O; Barg, Sebastian; Galvanovskis, Juris; Ma, Xiaosong; Salehi, Albert; Rorsman, Patrik; Eliasson, Lena

2002-05-01

A readily releasable pool (RRP) of granules has been proposed to underlie the first phase of insulin secretion. In the present study we combined electron microscopy, insulin secretion measurements and recordings of cell capacitance in an attempt to define this pool ultrastructurally. Mouse pancreatic B-cells contain approximately 9,000 granules, of which 7% are docked below the plasma membrane. The number of docked granules was reduced by 30% (200 granules) during 10 min stimulation with high K+. This stimulus depolarized the cell to -10 mV, elevated cytosolic [Ca2+] ([Ca2+](i)) from a basal concentration of 130 nM to a peak of 1.3 microM and released 0.5 ng insulin/islet, corresponding to 200-300 granules/cell. The Ca2+ transient decayed towards the prestimulatory concentration within approximately 200 s, presumably reflecting Ca2+ channel inactivation. Renewed stimulation with high K+ failed to stimulate insulin secretion when applied in the absence of glucose. The size of the RRP, derived from the insulin measurements, is similar to that estimated from the increase in cell capacitance elicited by photolytic release of caged Ca2+. We propose that the RRP represents a subset of the docked pool of granules and that replenishment of RRP can be accounted for largely by chemical modification of granules already in place or situated close to the plasma membrane.

A novel extract of Gymnema sylvestre improves glucose tolerance in vivo and stimulates insulin secretion and synthesis in vitro.

PubMed

Al-Romaiyan, A; King, A J; Persaud, S J; Jones, P M

2013-07-01

Herbal medicines, especially plant-derived extracts, have been used to treat Type 2 diabetes mellitus (T2DM) for many centuries, and offer the potential of cheap and readily available alternatives to conventional pharmaceuticals in developing countries. Extracts of Gymnema sylvestre (GS) have anti-diabetic activities and have been used as a folk medicine in India for centuries. We have investigated the effects of a novel high molecular weight GS extract termed OSA® on glucose tolerance in insulin-resistant ob/ob mice, and on insulin secretion and synthesis by isolated mouse islets. Single administration of OSA® (500 mg/kg) to ob/ob mice 30 min before an intraperitoneal glucose load improved their abnormal glucose tolerance. In vitro studies indicated that OSA® (0.25 mg/ml) initiated rapid and reversible increases in insulin secretion from isolated mouse islets at substimulatory (2 mM) and stimulatory (20 mM) glucose concentrations. In addition, prolonged treatment (24-48 h) of mouse islets with OSA® elevated the expression of preproinsulin mRNA and maintained the total insulin content of mouse islets in the presence of stimulated insulin secretion. These effects of OSA® are consistent with its potential use as a therapy for the hyperglycemia associated with obesity-related T2DM. Copyright © 2012 John Wiley & Sons, Ltd.

Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism.

PubMed

Shimodahira, Makiko; Fujimoto, Shimpei; Mukai, Eri; Nakamura, Yasuhiko; Nishi, Yuichi; Sasaki, Mayumi; Sato, Yuichi; Sato, Hiroki; Hosokawa, Masaya; Nagashima, Kazuaki; Seino, Yutaka; Inagaki, Nobuya

2010-01-01

Rapamycin, an immunosuppressant used in human transplantation, impairs beta-cell function, but the mechanism is unclear. Chronic (24 h) exposure to rapamycin concentration dependently suppressed 16.7 mM glucose-induced insulin release from islets (1.65+/-0.06, 30 nM rapamycin versus 2.35+/-0.11 ng/islet per 30 min, control, n=30, P<0.01) without affecting insulin and DNA contents. Rapamycin also decreased alpha-ketoisocaproate-induced insulin release, suggesting reduced mitochondrial carbohydrate metabolism. ATP content in the presence of 16.7 mM glucose was significantly reduced in rapamycin-treated islets (13.42+/-0.47, rapamycin versus 16.04+/-0.46 pmol/islet, control, n=30, P<0.01). Glucose oxidation, which indicates the velocity of metabolism in the Krebs cycle, was decreased by rapamycin in the presence of 16.7 mM glucose (30.1+/-2.7, rapamycin versus 42.2+/-3.3 pmol/islet per 90 min, control, n=9, P<0.01). Immunoblotting revealed that the expression of complex I, III, IV, and V was not affected by rapamycin. Mitochondrial ATP production indicated that the respiratory chain downstream of complex II was not affected, but that carbohydrate metabolism in the Krebs cycle was reduced by rapamycin. Analysis of enzymes in the Krebs cycle revealed that activity of alpha-ketoglutarate dehydrogenase (KGDH), which catalyzes one of the slowest reactions in the Krebs cycle, was reduced by rapamycin (10.08+/-0.82, rapamycin versus 13.82+/-0.84 nmol/mg mitochondrial protein per min, control, n=5, P<0.01). Considered together, these findings indicate that rapamycin suppresses high glucose-induced insulin secretion from pancreatic islets by reducing mitochondrial ATP production through suppression of carbohydrate metabolism in the Krebs cycle, together with reduced KGDH activity.

The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas.

PubMed Central

Wiggins, D; Gibbons, G F

1992-01-01

In hepatocyte cultures maintained in the absence of extracellular fatty acids, at least 70% of the secreted very-low-density lipoprotein (VLDL) triacylglycerol was derived via lipolysis of intracellular triacylglycerol. This proportion was unchanged when the cells were exposed for 24 h to insulin or glucagon, hormones which decreased the overall secretion of intracellular triacylglycerol, or to chloroquine or tolbutamide, agents which inhibit lysosomal lipolysis. The rate of intracellular lipolysis was 2-3-fold greater than that required to maintain the observed rate of triacylglycerol secretion. Most of the fatty acids released were returned to the intracellular pool. Neither insulin nor glucagon had any significant effect on the overall lipolysis and re-esterification of intracellular triacylglycerol. In these cases a greater proportion of the released fatty acids re-entered the cellular pool, rather than being recruited for VLDL assembly. Tolbutamide inhibited intracellular lipolysis, but suppressed VLDL secretion to a greater extent. 3,5-Dimethylpyrazole did not affect lipolysis or VLDL secretion. The increased secretion of VLDL triacylglycerol observed after exposure of cells to insulin for 3 days was not accompanied by an increased rate of intracellular lipolysis. However, a larger proportion of the triacylglycerol secreted under these conditions may not have undergone prior lipolysis. PMID:1599431

Low molecular weight compounds from Zoanthus sociatus impair insulin secretion via Ca(+2) influx blockade and cause glucose intolerance in vivo.

PubMed

Diaz-Garcia, Carlos Manlio; Sanchez-Soto, Carmen; Fuentes-Silva, Deyanira; Leon-Pinzon, Carolina; Dominguez-Perez, Dany; Varela, Carlos; Rodriguez-Romero, Adela; Castañeda, Olga; Hiriart, Marcia

2012-02-01

Cnidarians comprise a taxon with a high biodiversity of cytolitic, neurotoxic and cardiotoxic compounds, which have not been studied on insulin release. We tested the effect of a crude extract of Zoanthus sociatus (Ellis, 1767) and the low molecular weight fraction of this extract on insulin secretion in isolated rat β-cells and also in a glucose tolerance test in vivo. We observed that the extract inhibited insulin release by reducing the amount secreted by individual β-cells and also by silencing a fraction of the secreting population. This effect coincided with a diminished rise of intracellular Ca(+2) in response to high glucose and high K+ -induced depolarization. Moreover intraperitoneal administration of the low molecular weight fraction produced glucose intolerance in adult rats. The active fraction exhibited molecular weights similar to the neurotoxins described in the phylum. Our results broaden the toxic effects of cnidarian venoms and show evidence of potential modulators of voltage-gated Ca(+2) channels in this group. Copyright © 2011 Elsevier Ltd. All rights reserved.

A 3D cell culture system: separation distance between INS-1 cell and endothelial cell monolayers co-cultured in fibrin influences INS-1 cells insulin secretion.

PubMed

Sabra, Georges; Vermette, Patrick

2013-02-01

The aim of this study was to develop an in vitro cell culture system allowing studying the effect of separation distance between monolayers of rat insulinoma cells (INS-1) and human umbilical vein endothelial cells (HUVEC) co-cultured in fibrin over INS-1 cell insulin secretion. For this purpose, a three-dimensional (3D) cell culture chamber was designed, built using micro-fabrication techniques and validated. The co-culture was successfully carried out and the effect on INS-1 cell insulin secretion was investigated. After 48 and 72 h, INS-1 cells co-cultured with HUVEC separated by a distance of 100 µm revealed enhanced insulin secretion compared to INS-1 cells cultured alone or co-cultured with HUVEC monolayers separated by a distance of 200 µm. These results illustrate the importance of the separation distance between two cell niches for cell culture design and the possibility to further enhance the endocrine function of beta cells when this factor is considered. Copyright © 2012 Wiley Periodicals, Inc.

[Changes in the secretion of somatotropin and insulin in hyperthyroidism].

PubMed

Cavagnini, F; Peracchi, M; Panerai, A E; Pinto, M

1975-06-01

Twenty hyperthyroid patients were investigated for growth hormone (GH) and immunoreactive insulin (IRI) secretion in response to insulin hypoglycaemia, arginine infusion and glucose-induced hyperglycaemia. GH response to either insulin hypoglycaemia or arginine infusion was significantly reduced in these patients compared with 20 normal subjects. Thyrotoxic patients also displayed an abnormal GH pattern after a 100 g oral glucose load: in fact, serum GH underwent a paradoxical increase in spite of abnormally high levels attained by blood glucose. IRI secretion was also clearly reduced in response to arginine infusion and moderately blunted after oral glucose. In a group of patients re-evaluated under euthyroid conditions, a fair increase of GH response to the provocative stimuli jointly with the restoration of a normal suppressibility of serum GH by glucose were noted; by contrast, no significant change of IRI response to arginine or glucose took place. Likewise, the impairment of glucose tolerance was not improved. These findings indicate that an impairment of GH and IRI secretion is present in hyperthyroidism. The possibility that a potentiation of the catecholamine effects caused by the thyroid hormones is involved in this alteration deserves consideration.

Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome.

PubMed

Moorkens, G; Berwaerts, J; Wynants, H; Abs, R

2000-07-01

Previous studies have revealed that hormonal disturbances may accompany the chronic fatigue syndrome (CFS). Changes in the secretion of the pituitary-adrenal axis have been demonstrated, as well as abnormalities in the GH-IGF-I axis. However, data have not always been well characterized and were sometimes conflicting. The small number of CFS patients investigated in earlier studies may have played a role in the interpretation of the results. Hormonal testing was performed in 73 nonobese CFS patients and nonobese 21 age-and gender-matched healthy controls. We investigated GH, ACTH and cortisol responses to insulin-induced hypoglycaemia. In a subgroup of patients arginine and clonidine stimulation for GH was also performed. Nocturnal secretion of GH, ACTH and cortisol were determined. Serum levels of IGF-I, prolactin, TSH, and free thyroxine were also measured. Visceral fat mass was assessed by CT scanning. GH response to insulin induced hypoglycaemia assessed by peak value (17.0 +/- 13.1 microg/l vs. 22. 1 +/- 9.8 microg/l; P = 0.01) and by AUC (450.0 +/- 361.3 microg/l vs. 672.3 +/- 393.0 microg/l; P = 0.002) was significantly decreased in CFS patients vs. controls. Nocturnal GH secretion assessed by GH peak value (5.4 +/- 3.7 vs. 9.0 +/- 5.1 microg/l; P = 0.44) and by AUC (34.4 +/- 20.2 vs. 67.4 +/- 43.1; P = 0.045) was also significantly impaired in CFS patients. Arginine and clonidine administration showed no differences in GH secretion between CFS patients and controls. In the CFS group, GH peak values were significantly higher after ITT than after arginine (P = 0.017) or clonidine (P = 0.001). No differences in serum IGF-I levels were found between CFS patients and controls. Except for a significantly lower nocturnal cortisol peak value, no differences were found in ACTH and cortisol secretion between CFS patients and controls. Significantly higher serum prolactin levels (7.4 +/- 4.7 microg/l vs. 4.4 +/- 1.3 microg/l; P = 0.004) and significantly higher serum TSH levels (1.6 +/- 1.0 mU/l vs. 1.0 +/- 0.4 mU/l; P = 0.011) were found in CFS patients. Serum free thyroxine was comparable in both groups. Visceral fat mass was significantly higher in CFS patients (86.6 +/- 34.9 cm2 vs. 51.5 +/- 15.7 cm2; P < 0.001). We observed a significant impairment of GH response during insulin-induced hypoglycaemia and a low nocturnal GH secretion in CFS patients. These changes did, however, not lead to different concentrations in serum IGF-I. The clinical expression of this inadequate GH secretion can thus be questioned, although the alteration in body composition may be related to this relative GH deficiency. Significantly increased prolactin and TSH levels were found when compared to controls. These findings give support to the hypothesis of a decreased dopaminergic tone in CFS. Further investigations are required in order to identify specific adaptations within the neurotransmitter system in CFS and to determine the clinical importance of the impaired GH homeostasis.

IVGTT-based simple assessment of glucose tolerance in the Zucker fatty rat: Validation against minimal models.

PubMed

Morettini, Micaela; Faelli, Emanuela; Perasso, Luisa; Fioretti, Sandro; Burattini, Laura; Ruggeri, Piero; Di Nardo, Francesco

2017-01-01

For the assessment of glucose tolerance from IVGTT data in Zucker rat, minimal model methodology is reliable but time- and money-consuming. This study aimed to validate for the first time in Zucker rat, simple surrogate indexes of insulin sensitivity and secretion against the glucose-minimal-model insulin sensitivity index (SI) and against first- (Φ1) and second-phase (Φ2) β-cell responsiveness indexes provided by C-peptide minimal model. Validation of the surrogate insulin sensitivity index (ISI) and of two sets of coupled insulin-based indexes for insulin secretion, differing from the cut-off point between phases (FPIR3-SPIR3, t = 3 min and FPIR5-SPIR5, t = 5 min), was carried out in a population of ten Zucker fatty rats (ZFR) and ten Zucker lean rats (ZLR). Considering the whole rat population (ZLR+ZFR), ISI showed a significant strong correlation with SI (Spearman's correlation coefficient, r = 0.88; P<0.001). Both FPIR3 and FPIR5 showed a significant (P<0.001) strong correlation with Φ1 (r = 0.76 and r = 0.75, respectively). Both SPIR3 and SPIR5 showed a significant (P<0.001) strong correlation with Φ2 (r = 0.85 and r = 0.83, respectively). ISI is able to detect (P<0.001) the well-recognized reduction in insulin sensitivity in ZFRs, compared to ZLRs. The insulin-based indexes of insulin secretion are able to detect in ZFRs (P<0.001) the compensatory increase of first- and second-phase secretion, associated to the insulin-resistant state. The ability of the surrogate indexes in describing glucose tolerance in the ZFRs was confirmed by the Disposition Index analysis. The model-based validation performed in the present study supports the utilization of low-cost, insulin-based indexes for the assessment of glucose tolerance in Zucker rat, reliable animal model of human metabolic syndrome.

A Plant-Based Dietary Intervention Improves Beta-Cell Function and Insulin Resistance in Overweight Adults: A 16-Week Randomized Clinical Trial.

PubMed

Kahleova, Hana; Tura, Andrea; Hill, Martin; Holubkov, Richard; Barnard, Neal D

2018-02-09

The aim of this study was to test the effect of a plant-based dietary intervention on beta-cell function in overweight adults with no history of diabetes. Participants ( n = 75) were randomized to follow a low-fat plant-based diet ( n = 38) or to make no diet changes ( n = 37) for 16 weeks. At baseline and 16 weeks, beta-cell function was quantified with a mathematical model. Using a standard meal test, insulin secretory rate was calculated by C-peptide deconvolution. The Homeostasis Model Assessment (HOMA-IR) index was used to assess insulin resistance while fasting. A marked increase in meal-stimulated insulin secretion was observed in the intervention group compared with controls (interaction between group and time, Gxt, p < 0.001). HOMA-IR index fell significantly ( p < 0.001) in the intervention group (treatment effect -1.0 (95% CI, -1.2 to -0.8); Gxt, p = 0.004). Changes in HOMA-IR correlated positively with changes in body mass index (BMI) and visceral fat volume ( r = 0.34; p = 0.009 and r = 0.42; p = 0.001, respectively). The latter remained significant after adjustment for changes in BMI ( r = 0.41; p = 0.002). Changes in glucose-induced insulin secretion correlated negatively with BMI changes ( r = -0.25; p = 0.04), but not with changes in visceral fat. Beta-cell function and insulin sensitivity were significantly improved through a low-fat plant-based diet in overweight adults.

Exercise as an intervention to improve metabolic outcomes after intrauterine growth restriction.

PubMed

Gatford, Kathryn L; Kaur, Gunveen; Falcão-Tebas, Filippe; Wadley, Glenn D; Wlodek, Mary E; Laker, Rhianna C; Ebeling, Peter R; McConell, Glenn K

2014-05-01

Individuals born after intrauterine growth restriction (IUGR) are at an increased risk of developing diabetes in their adult life. IUGR impairs β-cell function and reduces β-cell mass, thereby diminishing insulin secretion. IUGR also induces insulin resistance, with impaired insulin signaling in muscle in adult humans who were small for gestational age (SGA) and in rodent models of IUGR. There is epidemiological evidence in humans that exercise in adults can reduce the risk of metabolic disease following IUGR. However, it is not clear whether adult IUGR individuals benefit to the same extent from exercise as do normal-birth-weight individuals, as our rat studies suggest less of a benefit in those born IUGR. Importantly, however, there is some evidence from studies in rats that exercise in early life might be able to reverse or reprogram the long-term metabolic effects of IUGR. Studies are needed to address gaps in current knowledge, including determining the mechanisms involved in the reprogramming effects of early exercise in rats, whether exercise early in life or in adulthood has similar beneficial metabolic effects in larger animal models in which insulin resistance develops after IUGR. Human studies are also needed to determine whether exercise training improves insulin secretion and insulin sensitivity to the same extent in IUGR adults as in control populations. Such investigations will have implications for customizing the recommended level and timing of exercise to improve metabolic health after IUGR.

Topologically heterogeneous beta cell adaptation in response to high-fat diet in mice.

PubMed

Ellenbroek, Johanne H; Töns, Hendrica A; de Graaf, Natascha; Loomans, Cindy J; Engelse, Marten A; Vrolijk, Hans; Voshol, Peter J; Rabelink, Ton J; Carlotti, Françoise; de Koning, Eelco J

2013-01-01

Beta cells adapt to an increased insulin demand by enhancing insulin secretion via increased beta cell function and/or increased beta cell number. While morphological and functional heterogeneity between individual islets exists, it is unknown whether regional differences in beta cell adaptation occur. Therefore we investigated beta cell adaptation throughout the pancreas in a model of high-fat diet (HFD)-induced insulin resistance in mice. C57BL/6J mice were fed a HFD to induce insulin resistance, or control diet for 6 weeks. The pancreas was divided in a duodenal (DR), gastric (GR) and splenic (SR) region and taken for either histology or islet isolation. The capacity of untreated islets from the three regions to adapt in an extrapancreatic location was assessed by transplantation under the kidney capsule of streptozotocin-treated mice. SR islets showed 70% increased beta cell proliferation after HFD, whereas no significant increase was found in DR and GR islets. Furthermore, isolated SR islets showed twofold enhanced glucose-induced insulin secretion after HFD, as compared with DR and GR islets. In contrast, transplantation of islets isolated from the three regions to an extrapancreatic location in diabetic mice led to a similar decrease in hyperglycemia and no difference in beta cell proliferation. HFD-induced insulin resistance leads to topologically heterogeneous beta cell adaptation and is most prominent in the splenic region of the pancreas. This topological heterogeneity in beta cell adaptation appears to result from extrinsic factors present in the islet microenvironment.

Cdk5 inhibitory peptide (CIP) inhibits Cdk5/p25 activity induced by high glucose in pancreatic beta cells and recovers insulin secretion from p25 damage.

PubMed

Zheng, Ya-Li; Li, Congyu; Hu, Ya-Fang; Cao, Li; Wang, Hui; Li, Bo; Lu, Xiao-Hua; Bao, Li; Luo, Hong-Yan; Shukla, Varsha; Amin, Niranjana D; Pant, Harish C

2013-01-01

Cdk5/p25 hyperactivity has been demonstrated to lead to neuron apoptosis and degenerations. Chronic exposure to high glucose (HG) results in hyperactivity of Cdk5 and reduced insulin secretion. Here, we set out to determine whether abnormal upregulation of Cdk5/p25 activity may be induced in a pancreatic beta cell line, Min6 cells. We first confirmed that p25 were induced in overexpressed p35 cells treated with HG and increased time course dependence. Next, we showed that no p25 was detected under short time HG stimulation (4-12 hrs), however was detectable in the long exposure in HG cells (24 hrs and 48 hrs). Cdk5 activity in the above cells was much higher than low glucose treated cells and resulted in more than 50% inhibition of insulin secretion. We confirmed these results by overexpression of p25 in Min6 cells. As in cortical neurons, CIP, a small peptide, inhibited Cdk5/p25 activity and restored insulin secretion. The same results were detected in co-infection of dominant negative Cdk5 (DNCdk5) with p25. CIP also reduced beta cells apoptosis induced by Cdk5/p25. These studies indicate that Cdk5/p25 hyperactivation deregulates insulin secretion and induces cell death in pancreatic beta cells and suggests that CIP may serve as a therapeutic agent for type 2 diabetes.

[Factors causing damage and destruction of beta-cells of the islets of Langerhans in the pancreas].

PubMed

Anděl, Michal; Němcová, Vlasta; Pavlíková, Nela; Urbanová, Jana; Cecháková, Marie; Havlová, Andrea; Straková, Radka; Večeřová, Livia; Mandys, Václav; Kovář, Jan; Heneberg, Petr; Trnka, Jan; Polák, Jan

2014-09-01

Insulin secretion in patients with manifested diabetes mellitus tends to disappear months to decades after the diagnosis, which is a clear sign of a gradual loss of pancreatic islet beta-cells. In our sample of 30 type 2 diabetic patients, whose disease manifested between 30 and 45 years of age, about a half have retained or even increased insulin secretion 30 years later, while the other half exhibit a much diminished or lost insulin secretion. Factors that can damage or destroy beta-cells can be divided into the following groups: Metabolic factors: hyperglycemia and glucotoxicity, lipotoxicity, hypoxia, reactive oxygen species; Pharmacological factors: antimicrobial medication pentamidine, SSRI antidepressants; Factors related to impaired insulin secretion: MODY type diabetes; Environmental toxic factors: rat poison Vacor, streptozotocin, polychlorinated and polybrominated hydrocarbons; Disorders of the exocrine pancreas: tumor infiltration, fibrous infiltration, chronic pancreatitis, cystic fibrosis; Infections, inflammation, autoimmunity, viral factors: Coxsackie viruses, H1N1 influenza, enteroviruses. We are currently working on finding other factors leading to beta-cell damage, studying their effect on apoptosis and necrosis and looking for possible protective factors to prevent this damage. We our increasing knowledge about the mechanisms of beta-cell damage and destruction we come ever closer to suggest measures for their prevention. In this review we offer a brief and simplified summary of some of the findings related to this area.Key words: pancreatic islet beta-cells of Langerhans - factors damaging or destroying beta-cells - insulin secretion.

A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic β-Cells.

PubMed

Buenaventura, Teresa; Kanda, Nisha; Douzenis, Phoebe C; Jones, Ben; Bloom, Stephen R; Chabosseau, Pauline; Corrêa, Ivan R; Bosco, Domenico; Piemonti, Lorenzo; Marchetti, Piero; Johnson, Paul R; Shapiro, A M James; Rutter, Guy A; Tomas, Alejandra

2018-03-01

The glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Because endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic β-cells. We identify five (clathrin, dynamin1, AP2, sorting nexins [SNX] SNX27, and SNX1) that increase and four (huntingtin-interacting protein 1 [HIP1], HIP14, GASP-1, and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analog exendin-4. The roles of HIP1 and the endosomal SNX1 and SNX27 were further characterized in mouse and human β-cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the SNXs were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation and, in doing so, determine the overall β-cell incretin responses. We thus identify key modulators of GLP-1R trafficking and signaling that might provide novel targets to enhance insulin secretion in T2D. © 2017 by the American Diabetes Association.

Rising intracellular zinc by membrane depolarization and glucose in insulin-secreting clonal HIT-T15 beta cells.

PubMed

Slepchenko, Kira G; Li, Yang V

2012-01-01

Zinc (Zn(2+)) appears to be intimately involved in insulin metabolism since insulin secretion is correlated with zinc secretion in response to glucose stimulation, but little is known about the regulation of zinc homeostasis in pancreatic beta-cells. This study set out to identify the intracellular zinc transient by imaging free cytosolic zinc in HIT-T15 beta-cells with fluorescent zinc indicators. We observed that membrane depolarization by KCl (30-60 mM) was able to induce a rapid increase in cytosolic concentration of zinc. Multiple zinc transients of similar magnitude were elicited during repeated stimulations. The amplitude of zinc responses was not affected by the removal of extracellular calcium or zinc. However, the half-time of the rising slope was significantly slower after removing extracellular zinc with zinc chelator CaEDTA, suggesting that extracellular zinc affect the initial rising phase of zinc response. Glucose (10 mM) induced substantial and progressive increases in intracellular zinc concentration in a similar way as KCl, with variation in the onset and the duration of zinc mobilization. It is known that the depolarization of beta-cell membrane is coupled with the secretion of insulin. Rising intracellular zinc concentration may act as a critical signaling factor in insulin metabolism of pancreatic beta-cells.

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. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

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

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

Reinhardt, Florian; Schultz, Julia; Waterstradt, Rica

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

β-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion.

PubMed

Reynolds, Merrick S; Hancock, Chad R; Ray, Jason D; Kener, Kyle B; Draney, Carrie; Garland, Kevin; Hardman, Jeremy; Bikman, Benjamin T; Tessem, Jeffery S

2016-07-01

β-Cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle, and adipose. Previously, we have demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic β-cells. In this study, we examined whether Nr4a expression impacts pancreatic β-cell mitochondrial function. Here, we show that β-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3. Mitochondrial respiration in permeabilized cells was significantly decreased in β-cells lacking Nr4a1 or Nr4a3. Furthermore, respiration rates of intact cells deficient for Nr4a1 or Nr4a3 in the presence of 16 mM glucose resulted in decreased glucose mediated oxygen consumption. Consistent with this reduction in respiration, a significant decrease in glucose-stimulated insulin secretion rates is observed with deletion of Nr4a1 or Nr4a3. Interestingly, the changes in respiration and insulin secretion occur without a reduction in mitochondrial content, suggesting decreased mitochondrial function. We establish that knockdown of Nr4a1 and Nr4a3 results in decreased expression of the mitochondrial dehydrogenase subunits Idh3g and Sdhb. We demonstrate that loss of Nr4a1 and Nr4a3 impedes production of ATP and ultimately inhibits glucose-stimulated insulin secretion. These data demonstrate for the first time that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for β-cell mitochondrial function and insulin secretion. Copyright © 2016 the American Physiological Society.

Age and body weight effects on glucose and insulin tolerance in colony cats maintained since weaning on high dietary carbohydrate.

PubMed

Backus, R C; Cave, N J; Ganjam, V K; Turner, J B M; Biourge, V C

2010-12-01

High dietary carbohydrate is suggested to promote development of diabetes mellitus in cats. Glucose tolerance, insulin sensitivity, and insulin secretion were assessed in young [0.8-2.3 (median = 1.1) years, n = 13] and mature [4.0-7.0 (median 5.8) years, n = 12] sexually intact females of a large (n ≅ 700) feline colony in which only dry-type diets (35% metabolizable energy as carbohydrate) were fed from weaning. Insulin sensitivity was assessed from the 'late-phase' (60-120 min) plasma insulin response of intravenous glucose tolerance tests (IVGTTs) and from fractional change in glycaemia from baseline 15 min after an insulin bolus (0.1 U/kg, i.v.). Insulin secretion was assessed from the 'early-phase' (0-15 min) plasma insulin response of IVGTTs. Compared to the young cats, the mature cats had greater body weights [2.3-3.8 (median = 2.9) vs. 3.0-6.3 (median = 4.0) kg, p < 0.01], greater late-phase insulin responses (p < 0.05), lower insulin-induced glycaemic changes (p = 0.06), lower early-phase insulin responses (p < 0.05), and non-significantly different rates of glucose disposal. The late-phase insulin response was correlated with body weight and age (p < 0.05). When group assignments were balanced for body weight, the age-group differences and correlations became non-significant. The findings indicate that body weight gain is more likely than dry-type diets to induce the pre-diabetic conditions of insulin resistance and secretion dysfunction. © 2010 The Authors. Journal of Animal Physiology and Animal Nutrition © 2010 Blackwell Verlag GmbH.

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.

Expression characteristics of long noncoding RNA uc.322 and its effects on pancreatic islet function.

PubMed

Zhao, Xiaoqin; Rong, Can; Pan, Fenghui; Xiang, Lizhi; Wang, Xinlei; Hu, Yun

2018-06-28

Increasing evidence indicates that long noncoding RNAs (lncRNAs) perform special biological functions by regulating gene expression through multiple pathways and molecular mechanisms. The aim of this study was to explore the expression characteristics of lncRNA uc.322 in pancreatic islet cells and its effects on the secretion function of islet cells. Bioinformatics analysis was used to detect the lncRNA uc.322 sequence, location, and structural features. Expression of lncRNA uc.322 in different tissues was detected by quantitative polymerase chain reaction analyses. Quantitative polymerase chain reaction, Western blot analysis, adenosine triphosphate determination, glucose-stimulated insulin secretion, and enzyme-linked immunosorbent assay were used to evaluate the effects of lncRNA uc.322 on insulin secretion. The results showed that the full-length of lncRNA uc.322 is 224 bp and that it is highly conserved in various species. Bioinformatics analysis revealed that lncRNA uc.322 is located on chr7:122893196-122893419 (GRCH37/hg19) within the SRY-related HMG-box 6 gene exon region. Compared with other tissues, lncRNA uc.322 is highly expressed in pancreatic tissue. Upregulation of lncRNA uc.322 expression increases the insulin transcription factors pancreatic and duodenal homeobox 1 and Forkhead box O1 expression, promotes insulin secretion in the extracellular fluid of Min6 cells, and increases the adenosine triphosphate concentration. On the other hand, knockdown of lncRNA uc.322 has opposite effects on Min6 cells. Overall, this study showed that upregulation of lncRNA uc.322 in islet β-cells can increase the expression of insulin transcription factors and promote insulin secretion, and it may be a new therapeutic target for diabetes. © 2018 Wiley Periodicals, Inc.

l-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2

PubMed Central

Nakatsu, Daiki; Horiuchi, Yuta; Kano, Fumi; Noguchi, Yoshiyuki; Sugawara, Taichi; Takamoto, Iseki; Kubota, Naoto; Kadowaki, Takashi; Murata, Masayuki

2015-01-01

Increase in the concentration of plasma l-cysteine is closely associated with defective insulin secretion from pancreatic β-cells, which results in type 2 diabetes (T2D). In this study, we investigated the effects of prolonged l-cysteine treatment on glucose-stimulated insulin secretion (GSIS) from mouse insulinoma 6 (MIN6) cells and from mouse pancreatic islets, and found that the treatment reversibly inhibited glucose-induced ATP production and resulting GSIS without affecting proinsulin and insulin synthesis. Comprehensive metabolic analyses using capillary electrophoresis time-of-flight mass spectrometry showed that prolonged l-cysteine treatment decreased the levels of pyruvate and its downstream metabolites. In addition, methyl pyruvate, a membrane-permeable form of pyruvate, rescued l-cysteine–induced inhibition of GSIS. Based on these results, we found that both in vitro and in MIN6 cells, l-cysteine specifically inhibited the activity of pyruvate kinase muscle isoform 2 (PKM2), an isoform of pyruvate kinases that catalyze the conversion of phosphoenolpyruvate to pyruvate. l-cysteine also induced PKM2 subunit dissociation (tetramers to dimers/monomers) in cells, which resulted in impaired glucose-induced ATP production for GSIS. DASA-10 (NCGC00181061, a substituted N,N′-diarylsulfonamide), a specific activator for PKM2, restored the tetramer formation and the activity of PKM2, glucose-induced ATP production, and biphasic insulin secretion in l-cysteine–treated cells. Collectively, our results demonstrate that impaired insulin secretion due to exposure to l-cysteine resulted from its direct binding and inactivation of PKM2 and suggest that PKM2 is a potential therapeutic target for T2D. PMID:25713368

An ecdysteroid-inducible insulin-like growth factor-like peptide regulates adult development of the silkmoth Bombyx mori.

PubMed

Okamoto, Naoki; Yamanaka, Naoki; Satake, Honoo; Saegusa, Hironao; Kataoka, Hiroshi; Mizoguchi, Akira

2009-03-01

Insulin-like growth factors (IGFs) play essential roles in fetal and postnatal growth and development of mammals. They are secreted by a wide variety of tissues, with the liver being the major source of circulating IGFs, and regulate cell growth, differentiation and survival. IGFs share some biological activities with insulin but are secreted in distinct physiological and developmental contexts, having specific functions. Although recent analyses of invertebrate genomes have revealed the presence of multiple insulin family peptide genes in each genome, little is known about functional diversification of the gene products. Here we show that a novel insulin family peptide of the silkmoth Bombyx mori, which was purified and sequenced from the hemolymph, is more like IGFs than like insulin, in contrast to bombyxins, which are previously identified insulin-like peptides in B. mori. Expression analysis reveals that this IGF-like peptide is predominantly produced by the fat body, a functional equivalent of the vertebrate liver and adipocytes, and is massively released during pupa-adult development. Studies using in vitro tissue culture systems show that secretion of the peptide is stimulated by ecdysteroid and that the secreted peptide promotes the growth of adult-specific tissues. These observations suggest that this peptide is a Bombyx counterpart of vertebrate IGFs and that functionally IGF-like peptides may be more ubiquitous in the animal kingdom than previously thought. Our results also suggest that the known effects of ecdysteroid on insect adult development may be in part mediated by IGF-like peptides.

Co-culture of clonal beta cells with GLP-1 and glucagon-secreting cell line impacts on beta cell insulin secretion, proliferation and susceptibility to cytotoxins.

PubMed

Green, Alastair D; Vasu, Srividya; Moffett, R Charlotte; Flatt, Peter R

2016-06-01

We investigated the direct effects on insulin releasing MIN6 cells of chronic exposure to GLP-1, glucagon or a combination of both peptides secreted from GLUTag L-cell and αTC1.9 alpha-cell lines in co-culture. MIN6, GLUTag and αTC1.9 cell lines exhibited high cellular hormone content and release of insulin, GLP-1 and glucagon, respectively. Co-culture of MIN6 cells with GLUTag cells significantly increased cellular insulin content, beta-cell proliferation, insulin secretory responses to a range of established secretogogues and afforded protection against exposure cytotoxic concentrations of glucose, lipid, streptozotocin or cytokines. Benefits of co-culture of MIN6 cells with αTC1.9 alphacells were limited to enhanced beta-cell proliferation with marginal positive actions on both insulin secretion and cellular protection. In contrast, co-culture of MIN6 with GLUTag cells plus αTC1.9 cells, markedly enhanced both insulin secretory responses and protection against beta-cell toxins compared with co-culture with GLUTag cells alone. These data indicate important long-term effects of conjoint GLP-1 and glucagon exposure on beta-cell function. This illustrates the possible functional significance of alpha-cell GLP-1 production as well as direct beneficial effects of dual agonism at beta-cell GLP-1 and glucagon receptors. Copyright © 2016 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.

Effects of Exenatide Plus Rosiglitazone on β-Cell Function and Insulin Sensitivity in Subjects With Type 2 Diabetes on Metformin

PubMed Central

DeFronzo, Ralph A.; Triplitt, Curtis; Qu, Yongming; Lewis, Michelle S.; Maggs, David; Glass, Leonard C.

2010-01-01

OBJECTIVE Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on β-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin. RESEARCH DESIGN AND METHODS In this 20-week, randomized, open-label, multicenter study, participants (mean age, 56 ± 10 years; weight, 93 ± 16 kg; A1C, 7.8 ± 0.7%) continued their metformin regimen and received either EXE 10 μg b.i.d. (n = 45), ROSI 4 mg b.i.d. (n = 45), or EXE 10 μg b.i.d. + ROSI 4 mg b.i.d. (n = 47). Seventy-three participants underwent clamp procedures to quantitate insulin secretion and insulin sensitivity. RESULTS A1C declined in all groups (P < 0.05), but decreased most with EXE+ROSI (EXE+ROSI, −1.3 ± 0.1%; ROSI, −1.0 ± 0.1%, EXE, −0.9 ± 0.1%; EXE+ROSI vs. EXE or ROSI, P < 0.05). ROSI resulted in weight gain, while EXE and EXE+ROSI resulted in weight loss (EXE, −2.8 ± 0.5 kg; EXE+ROSI, −1.2 ± 0.5 kg; ROSI, + 1.5 ± 0.5 kg; P < 0.05 between and within all groups). At week 20, 1st and 2nd phase insulin secretion was significantly higher in EXE and EXE+ROSI versus ROSI (both P < 0.05). Insulin sensitivity (M value) was significantly higher in EXE+ROSI versus EXE (P = 0.014). CONCLUSIONS Therapy with EXE+ROSI offset the weight gain observed with ROSI and elicited an additive effect on glycemic control with significant improvements in β-cell function and insulin sensitivity. PMID:20107105