325-OR: ß-Arrestin 1 Regulates Glucagon-Like Peptide-1 Receptor Mediated Insulin Secretion in a Ligand-Dependent Manner

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 325-OR
Author(s):  
JONATHAN D. DOUROS ◽  
KYLE SLOOP ◽  
JONATHAN CAMPBELL ◽  
DAVID D’ALESSIO
Keyword(s):  
Insulin Secretion ◽  
Dependent Manner ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Ingestion of coffee polyphenols increases postprandial release of the active glucagon-like peptide-1 (GLP-1(7–36)) amide in C57BL/6J mice

2015 ◽  
Vol 4 ◽  
Author(s):  
Yoshie Fujii ◽  
Noriko Osaki ◽  
Tadashi Hase ◽  
Akira Shimotoyodome
Keyword(s):  
Insulin Secretion ◽  
Human Subjects ◽  
Coffee Consumption ◽  
Epidemiological Studies ◽  
Diabetes Risk ◽  
Dependent Manner ◽  
Diabetes In Animals ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Dose Dependent

AbstractThe widespread prevalence of diabetes, caused by impaired insulin secretion and insulin resistance, is now a worldwide health problem. Glucagon-like peptide 1 (GLP-1) is a major intestinal hormone that stimulates glucose-induced insulin secretion from β cells. Prolonged activation of the GLP-1 signal has been shown to attenuate diabetes in animals and human subjects. Therefore, GLP-1 secretagogues are attractive targets for the treatment of diabetes. Recent epidemiological studies have reported that an increase in daily coffee consumption lowers diabetes risk. The present study examined the hypothesis that the reduction in diabetes risk associated with coffee consumption may be mediated by the stimulation of GLP-1 release by coffee polyphenol extract (CPE). GLP-1 secretion by human enteroendocrine NCI-H716 cells was augmented in a dose-dependent manner by the addition of CPE, and was compatible with the increase in observed active GLP-1(7–36) amide levels in the portal blood after administration with CPE alone in mice. CPE increased intracellular cyclic AMP (cAMP) levels in a dose-dependent manner, but this was not mediated by G protein-coupled receptor 119 (GPR119). The oral administration of CPE increased diet (starch and glyceryl trioleate)-induced active GLP-1 secretion and decreased glucose-dependent insulinotropic polypeptide release. Although CPE administration did not affect diet-induced insulin secretion, it decreased postprandial hyperglycaemia, which indicates that higher GLP-1 levels after the ingestion of CPE may improve insulin sensitivity. We conclude that dietary coffee polyphenols augment gut-derived active GLP-1 secretion via the cAMP-dependent pathway, which may contribute to the reduced risk of type 2 diabetes associated with daily coffee consumption.

scholarly journals Actions of glucagon-like peptide-1 on KATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide

2006 ◽  
Vol 190 (3) ◽  
pp. 889-896 ◽  
Author(s):  
Neville H McClenaghan ◽  
Peter R Flatt ◽  
Andrew J Ball
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Channel Dependent ◽  
Releasing Effect ◽  
Independent Effects

This study examined the effects of glucagon-like peptide-1 (GLP-1) on insulin secretion alone and in combination with sulphonylureas or nateglinide, with particular attention to KATP channel-independent insulin secretion. In depolarised cells, GLP-1 significantly augmented glucose-induced KATP channel-independent insulin secretion in a glucose concentration-dependent manner. GLP-1 similarly augmented the KATP channel-independent insulin-releasing effects of tolbutamide, glibenclamide or nateglinide. Downregulation of protein kinase A (PKA)- or protein kinase C (PKC)-signalling pathways in culture revealed that the KATP channel-independent effects of sulphonylureas or nateglinide were critically dependent upon intact PKA and PKC signalling. In contrast, GLP-1 exhibited a reduced but still significant insulin-releasing effect following PKA and PKC downregulation, indicating that GLP-1 can modulate KATP channel-independent insulin secretion by protein kinase-dependent and -independent mechanisms. The synergistic insulin-releasing effects of combinatorial GLP-1 and sulphonylurea/nateglinide were lost following PKA- or PKC-desensitisation, despite GLP-1 retaining an insulin-releasing effect, demonstrating that GLP-1 can induce insulin release under conditions where sulphonylureas and nateglinide are no longer effective. Our results provide new insights into the mechanisms of action of GLP-1, and further highlight the promise of GLP-1 or similarly acting analogues alone or in combination with sulphonylureas or meglitinide drugs in type 2 diabetes therapy.

scholarly journals Coingestion of Acylglycerols Differentially Affects Glucose-Induced Insulin Secretion via Glucose-Dependent Insulinotropic Polypeptide in C57BL/6J Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2118-2126 ◽  
Author(s):  
Akira Shimotoyodome ◽  
Daisuke Fukuoka ◽  
Junko Suzuki ◽  
Yoshie Fujii ◽  
Tomohito Mizuno ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Dietary Fat ◽  
Energy Homeostasis ◽  
Insulin Response ◽  
Postprandial Blood Glucose ◽  
Dependent Manner ◽  
Nutrient Metabolism ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Chylomicron Formation

The precise role of fat in postprandial glycemia and insulinemia has not been thoroughly researched because postprandial blood glucose and concurrent insulin secretion are largely assumed to be proportional to carbohydrate intake. Recent studies have suggested that dietary fat differentially regulates the postprandial insulin response. To explore this, we examined the effects of coadministered fat on glucose-induced glycemia and insulinemia in C57BL/6J mice. The insulin response to glucose was augmented by the addition of glycerol trioleate (TO) in a dose-dependent manner, which was associated with enhanced glucose transport from the circulation to muscle and adipose tissues. To investigate the mechanism underlying fat-induced hyperinsulinemia, we examined the release of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1. TO increased GIP secretion, whereas glucagon-like peptide-1 secretion was unaffected. TO-induced hyperinsulinemia was significantly attenuated by the pretreatment of mice with a specific GIP antagonist. Diacylglycerol (DAG) promoted lower postprandial GIP and triglyceride responses and, when ingested with glucose, a lower insulin response compared with triacylglycerol of a similar fatty acid composition. Pluronic L-81, an inhibitor of chylomicron formation, reduced not only the triglyceride response but also TO-induced GIP secretion, indicating that the lower GIP response after DAG ingestion may be associated with retarded chylomicron formation in the small intestine. We conclude that dietary fat augments glucose-induced insulinemia via gut-derived GIP and, thereby, influences postprandial nutrient metabolism in mice. DAG promotes a lower GIP and thereby reduced insulin responses compared with triacylglycerol, which may differentially influence postprandial energy homeostasis.

Glucagon-like peptide-1 induces a cAMP-dependent increase of [Na+]i associated with insulin secretion in pancreatic β-cells

2003 ◽  
Vol 285 (5) ◽  
pp. E1001-E1009 ◽  
Author(s):  
Yoshikazu Miura ◽  
Hisao Matsui
Keyword(s):  
Insulin Secretion ◽  
Adenylate Cyclase ◽  
Islet Cells ◽  
Free Calcium ◽  
Dependent Manner ◽  
Intracellular Free Calcium Concentration ◽  
Free Calcium Concentration ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) elevates the intracellular free calcium concentration ([Ca2+]i) and insulin secretion in a Na+-dependent manner. To investigate a possible role of Na ion in the action of GLP-1 on pancreatic islet cells, we measured the glucose-and GLP-1-induced intracellular Na+ concentration ([Na+]i), [Ca2+]i, and insulin secretion in hamster islet cells in various concentrations of Na+. The [Na+]i and [Ca2+]i were monitored in islet cells loaded with sodium-binding benzofuran isophthalate and fura 2, respectively. In the presence of 135 mM Na+ and 8 mM glucose, GLP-1 (10 nM) strongly increased the [Na+]i, [Ca2+]i, and insulin secretion. In the presence of 13.5 mM Na+, both glucose and GLP-1 increased neither the [Na+]i nor the [Ca2+]i. In a Na+-free medium, GLP-1 and glucose did not increase the [Na+]i. SQ-22536, an inhibitor of adenylate cyclase, and H-89, an inhibitor of PKA, incompletely inhibited the response. In the presence of both 8 mM glucose and H-89, 8-pCPT-2′-O-Me-cAMP, a PKA-independent cAMP analog, increased the insulin secretion and the [Na+]i. Therefore, we conclude that GLP-1 increases the cAMP level via activation of adenylate cyclase, which augments the membrane Na+ permeability through PKA-dependent and PKA-independent mechanisms, thereby increasing the [Ca2+]i and promoting insulin secretion from hamster islet cells.

scholarly journals Insulin secretion defects in liver cirrhosis can be reversed by glucagon-like peptide-1

2000 ◽  
Vol 164 (1) ◽  
pp. 13-19 ◽  
Author(s):  
EG Siegel ◽  
A Seidenstucker ◽  
B Gallwitz ◽  
F Schmitz ◽  
A Reinecke-Luthge ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Liver Cirrhosis ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Dependent Manner ◽  
Isolated Pancreatic Islets ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Liver cirrhosis is often accompanied by a disturbed carbohydrate metabolism similar to type 2 diabetes. To investigate the severity of the defect in insulin secretion in this form of diabetes, we measured insulin release from isolated pancreatic islets of rats with CCl(4)-phenobarbital-induced liver cirrhosis. Cirrhosis was confirmed by clinical signs, elevated liver enzymes and histology. Fasting venous plasma glucose concentrations were equal in rats with liver cirrhosis and in controls. Plasma insulin and glucagon concentrations were significantly greater (P<0.01) in cirrhotic rats than in control animals. Glucose (16.7 mM)-induced stimulation of insulin release from pancreatic islets revealed a twofold increase in control and cirrhotic rats. Basal and stimulated insulin secretion, however, were significantly lower in cirrhotic animals. The incretin hormone, glucagon-like peptide-1 (GLP-1), has therapeutic potential for the treatment of type 2 diabetes. Therefore, islets from control and cirrhotic animals were incubated with GLP-1 in concentrations from 10(-)(11) to 10(-)(6) M. GLP-1 stimulated insulin release in a concentration-dependent manner. In islets from cirrhotic rats, basal and stimulated insulin secretion was blunted compared with controls. These data show that the hyperinsulinemia observed in liver cirrhosis is not due to an increase of insulin secretion from islets, but could be explained by decreased hepatic clearance of insulin. GLP-1 may ameliorate diabetes in patients with liver cirrhosis.

Human Sperm Express the Receptor for Glucagon-like Peptide-1 (GLP-1), Which Affects Sperm Function and Metabolism

Endocrinology ◽  
2020 ◽  
Vol 161 (4) ◽  
Author(s):  
Vittoria Rago ◽  
Daniela De Rose ◽  
Marta Santoro ◽  
Salvatore Panza ◽  
Rocco Malivindi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Human Sperm ◽  
Dependent Manner ◽  
Stimulatory Action ◽  
Peripheral Tissues ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Acyl Coenzyme A ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Dose Response Study

Abstract Aim Glucagon-like peptide-1 (GLP-1) produces pleiotropic effects binding to the GLP-1 receptor (GLP1-R), potentiating insulin secretion in the pancreas. GLP1-R is expressed in peripheral tissues and evidence for its role in reproduction has come from knockout mice, although the relationship between GLP-1 and male fertility needs to be clarified. Given that human sperm is an insulin-sensitive and insulin-secreting cell, we hypothesized that the GLP-1/GLP1-R axis may be expressed and functional in these cells. Results and discussion We revealed the presence of GLP1-R by Western blotting and immunofluorescence analyses. Because Exendin-4 (Ex-4) displays similar functional properties to native GLP-1, we used this agonist to perform a dose-response study on progressive motility and cholesterol efflux, showing that 300 pM Ex-4 was the most effective treatment. These actions are mediated by GLP1-R and independent from sperm-secreted insulin. The exposure to Ex-4 fueled phosphatidylinositol-3-kinase (PI3K)/AKT signaling and was reversed by H89, indicating a protein kinase A (PKA)-dependence of GLP-1/GLP1-R signaling. It emerged that in sperm, insulin secretion regulated by Ex-4 did not occur in a strictly glucose-dependent manner. A stimulatory action of Ex-4/GLP1-R on lactate dehydrogenase and glucose-6-phosphate dehydrogenase (G6PDH) activities was observed. Ex-4/GLP1-R decreased triglycerides content concomitantly to enhanced lipase and acyl-coenzyme A (acyl-CoA) dehydrogenase activities, addressing a lipolytic effect. Conclusion Collectively, we discovered that human sperm is a new GLP1 incretin target, broadening our knowledge about the effects of the GLP1-R agonist in the male reproductive field. Further findings in humans should be conducted in the future to confirm it and to improve the translational aspect of this study.

scholarly journals Nutrient consumption-dependent association of a glucagon-like peptide-1 receptor gene polymorphism with insulin secretion

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuki Nishiya ◽  
Makoto Daimon ◽  
Satoru Mizushiri ◽  
Hiroshi Murakami ◽  
Jutaro Tanabe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Gene Polymorphism ◽  
Life Style ◽  
Significant Risk ◽  
Dependent Manner ◽  
Model Assessment ◽  
Dietary History ◽  
Nutrient Consumption ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Since type 2 diabetes (DM) is a life-style related disease, life-style should be considered when association between genetic factors and DM are examined. However, most studies did not examine genetic associations in consideration with lifestyle. Glucagon-like peptide-1 (GLP-1) receptor (GLP1R) mediates the insulinotropic action of GLP-1 in β-cells. We here examined the association while taking into consideration of interactions between the gene polymorphism and various nutrient factors. Participants from the population-based Iwaki study of Japanese subjects held in 2014–2017 with information on nutritional intake evaluated by self-administered dietary history questionnaire, and GLP1R genotype (rs3765467: A/G), were included (n = 1,560). Although not significant, insulin secretion indices assessed by homeostasis model assessment of β-cell function (HOMA-β) in subjects with the GG genotype tended to be lower than in those with the AA+AG genotypes in most groups stratified into tertiles based on daily nutrient consumptions (high, middle, and low). Stratification also showed that the GG genotype was a significant risk for decreased insulin secretion (HOMA-β ≤ 30) even after adjustment for multiple factors (age, body mass index, alcohol consumption), but only in the highest tertiles of energy, protein and carbohydrate consumption in men [odds ratios (95% confidence interval) 3.95 (1.03–15.1), 15.83 (1.58–158.9), and 4.23 (1.10–11.2), respectively]. A polymorphism of the GLP1R gene was associated with decreased insulin secretion in a nutrient consumption-dependent manner in Japanese men, indicating an interaction between GLP1R and nutritional factors in the pathophysiology of DM.

scholarly journals Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide stimulate release of substance P from TRPV1- and TRPA1-expressing sensory nerves

2020 ◽  
Vol 319 (1) ◽  
pp. G23-G35 ◽  
Author(s):  
Fahima Mayer ◽  
Amanda L. Gunawan ◽  
Patrick Tso ◽  
Gregory W. Aponte
Keyword(s):  
Insulin Secretion ◽  
Substance P ◽  
Blood Sugar ◽  
Sensory Neurons ◽  
Sensory Nerves ◽  
Dependent Manner ◽  
Lower Blood ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Lymphatic Fluid

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted upon eating to lower blood sugar. GLP-1 and GIP were found to induce the secretion of substance P (SP) from cultured sensory nerves. SP enhances insulin secretion. Mesenteric lymphatic fluid (MLF) also stimulates sensory neurons in a diet-dependent manner. These studies identify new actions of GLP-1 and GIP as incretins and suggest a mechanism for sensory nerves to respond to diet through MLF.

scholarly journals Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist S6 Stimulates Insulin Secretion From Rat Islets

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaohua Yang ◽  
Min Zhang ◽  
Zhihong Lu ◽  
Linping Zhi ◽  
Huan Xue ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Small Molecule ◽  
Imaging Techniques ◽  
Fluorescent Imaging ◽  
Imaging Plate ◽  
Dependent Manner ◽  
Kv Channels ◽  
Voltage Dependent ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 receptor (GLP-1R) agonist-based therapeutics for type 2 diabetes mellitus have attracted worldwide attention. However, there are challenges in the development of small molecule GLP-1R agonists owing to the complexity of ligand recognition and signal induction mechanisms. Here, we attained S6 using virtual screening and fluorescent imaging plate reader (FLIPR)-based calcium assays. The purpose of this study was to identify and characterize S6, a novel small molecule GLP-1R agonist. Data from cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI) indicated that S6 could bind potently with GLP-1R. Radioimmunoassay data showed that S6 potentiated insulin secretion in a glucose-dependent manner and the insulinotropic effect was mediated by GLP-1R. Calcium imaging techniques suggested that S6 elevated the intracellular calcium concentration [(Ca2+)i] by activating GLP-1R. In patch-clamp experiments, we demonstrated that S6 inhibited voltage-dependent K+ (Kv) channels in a GLP-1R-dependent fashion. Besides, S6 significantly prolonged action potential duration but had no effect on voltage-dependent Ca2+ channels. In summary, these findings indicate that S6 stimulates glucose-dependent insulin secretion mainly by acting on GLP-1R, inhibiting Kv channels, increasing (Ca2+)i. This study will provide direction for the screening and development of novel small-molecule agents targeting GLP-1R in the future.

Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

2013 ◽  
Vol 304 (7) ◽  
pp. E677-E685 ◽  
Author(s):  
Melissa A. Burmeister ◽  
Jennifer Ayala ◽  
Daniel J. Drucker ◽  
Julio E. Ayala
Keyword(s):  
Food Intake ◽  
Glucose Metabolism ◽  
Dependent Manner ◽  
Anorectic Effect ◽  
Dependent Inhibition ◽  
Glycolytic Inhibitor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Amp Activated Protein Kinase ◽  
Mediated Reduction

Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.

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