The Effect of Zinc-Crystallized Glucagon-Like Peptide-1 on Insulin Secretion of Macroencapsulated Pancreatic Islets

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.

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Minireview: Dopaminergic Regulation of Insulin Secretion from the Pancreatic Islet

Molecular Endocrinology ◽

10.1210/me.2013-1083 ◽

2013 ◽

Vol 27 (8) ◽

pp. 1198-1207 ◽

Cited By ~ 41

Author(s):

Alessandro Ustione ◽

David W. Piston ◽

Paul E. Harris

Keyword(s):

Insulin Secretion ◽

Pancreatic Islets ◽

Dopaminergic Neurons ◽

Feedback Loop ◽

Β Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion ◽

Dopaminergic Regulation ◽

Physiologic Role

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.

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Equine glucagon-like peptide-1 receptor physiology

PeerJ ◽

10.7717/peerj.4316 ◽

2018 ◽

Vol 6 ◽

pp. e4316 ◽

Cited By ~ 5

Author(s):

Murad H. Kheder ◽

Simon R. Bailey ◽

Kevin J. Dudley ◽

Martin N. Sillence ◽

Melody A. de Laat

Keyword(s):

Insulin Secretion ◽

Pancreatic Islets ◽

Insulin Response ◽

Synthetic Analogue ◽

Isolated Pancreatic Islets ◽

Novel Approach ◽

Insulin Dysregulation ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Background Equine metabolic syndrome (EMS) is associated with insulin dysregulation, which often manifests as post-prandial hyperinsulinemia. Circulating concentrations of the incretin hormone, glucagon-like peptide-1 (GLP-1) correlate with an increased insulin response to carbohydrate intake in animals with EMS. However, little is known about the equine GLP-1 receptor (eGLP-1R), or whether GLP-1 concentrations can be manipulated. The objectives were to determine (1) the tissue localisation of the eGLP-1R, (2) the GLP-1 secretory capacity of equine intestine in response to glucose and (3) whether GLP-1 stimulated insulin secretion from isolated pancreatic islets can be attenuated. Methods Archived and abattoir-sourced tissues from healthy horses were used. Reverse transcriptase PCR was used to determine the tissue distribution of the eGLP-1R gene, with immunohistochemical confirmation of its pancreatic location. The GLP-1 secretion from intestinal explants in response to 4 and 12 mM glucose was quantified in vitro. Pancreatic islets were freshly isolated to assess the insulin secretory response to GLP-1 agonism and antagonism in vitro, using concentration-response experiments. Results The eGLP-1R gene is widely distributed in horses (pancreas, heart, liver, kidney, duodenum, digital lamellae, tongue and gluteal skeletal muscle). Within the pancreas the eGLP-1R was immunolocalised to the pancreatic islets. Insulin secretion from pancreatic islets was concentration-dependent with human GLP-1, but not the synthetic analogue exendin-4. The GLP-1R antagonist exendin 9-39 (1 nM) reduced (P = 0.08) insulin secretion by 27%. Discussion The distribution of the eGLP-1R across a range of tissues indicates that it may have functions beyond insulin release. The ability to reduce insulin secretion, and therefore hyperinsulinemia, through eGLP-1R antagonism is a promising and novel approach to managing equine insulin dysregulation.

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Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

Experimental and Therapeutic Medicine ◽

10.3892/etm.2017.5136 ◽

2017 ◽

Cited By ~ 2

Author(s):

Bo Pang ◽

Sungjoon Kim ◽

Daiqing Li ◽

Zejun Ma ◽

Bei Sun ◽

...

Keyword(s):

Insulin Secretion ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Melastatin ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Transient Receptor ◽

Glucose Stimulated Insulin Secretion

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Stimulation of Insulin Secretion by a Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist in Rodent and Human Islets.

10.1210/endo-meetings.2010.part1.p10.p1-479 ◽

2010 ◽

pp. P1-479-P1-479

Author(s):

KW Sloop ◽

FS Willard ◽

MB Brenner ◽

J Ficorilli ◽

K Valasek ◽

...

Keyword(s):

Insulin Secretion ◽

Small Molecule ◽

Receptor Agonist ◽

Human Islets ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Stimulation Of

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

Journal of Clinical Investigation ◽

10.1172/jci25764 ◽

2005 ◽

Vol 115 (12) ◽

pp. 3554-3563 ◽

Cited By ~ 208

Author(s):

C. Knauf

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Glycogen Storage ◽

Hepatic Glycogen ◽

Muscle Insulin Resistance ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

Experimental Diabetes Research ◽

10.1155/2011/604989 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Minglin Pan ◽

Guang Yang ◽

Xiuli Cui ◽

Shao-Nian Yang

Keyword(s):

Insulin Secretion ◽

Insulin Release ◽

Adrenergic Agonist ◽

Signaling Systems ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion ◽

Insulin Secretory Response ◽

Adrenergic Activation ◽

Gi Proteins

The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1) receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX-) sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

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