The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion

The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion Patrick E. MacDonald 1 , Wasim El-kholy 1 , Michael J. Riedel 2 , Anne Marie F. Salapatek 1 , Peter E. Light 2 and Michael B. Wheeler 1 1 Departments of Medicine and Physiology, University of Toronto, Toronto, Ontar...

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Published in:Diabetes (New York, N.Y.) Vol. 51; no. suppl 3; pp. S434 - S442
Main Authors: MacDonald, Patrick E, El-Kholy, Wasim, Riedel, Michael J, Salapatek, Anne Marie F, Light, Peter E, Wheeler, Michael B
Format: Journal Article
Language:English
Published: United States American Diabetes Association 01-12-2002
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Summary:The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion Patrick E. MacDonald 1 , Wasim El-kholy 1 , Michael J. Riedel 2 , Anne Marie F. Salapatek 1 , Peter E. Light 2 and Michael B. Wheeler 1 1 Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada 2 Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada Abstract The physiological effects of glucagon-like peptide-1 (GLP-1) are of immense interest because of the potential clinical relevance of this peptide. Produced in intestinal L-cells through posttranslational processing of the proglucagon gene, GLP-1 is released from the gut in response to nutrient ingestion. Peripherally, GLP-1 is known to affect gut motility, inhibit gastric acid secretion, and inhibit glucagon secretion. In the central nervous system, GLP-1 induces satiety, leading to reduced weight gain. In the pancreas, GLP-1 is now known to induce expansion of insulin-secreting β-cell mass, in addition to its most well-characterized effect: the augmentation of glucose-stimulated insulin secretion. GLP-1 is believed to enhance insulin secretion through mechanisms involving the regulation of ion channels (including ATP-sensitive K + channels, voltage-dependent Ca 2+ channels, voltage-dependent K + channels, and nonselective cation channels) and by the regulation of intracellular energy homeostasis and exocytosis. The present article will focus principally on the mechanisms proposed to underlie the glucose dependence of GLP-1’s insulinotropic effect. Footnotes Address correspondence and reprint requests to Michael B. Wheeler, Department of Physiology, University of Toronto, 1 Kings College Circle, Toronto, ON, Canada, M5S 1A8. E-mail: michael.wheeler{at}utoronto.ca . Received for publication 18 March 2002 and accepted in revised form 17 May 2002. AKAP, A-kinase anchoring protein; [Ca 2+ ] i , intracellular concentration of Ca 2+ ; CICR, Ca 2+ -induced Ca 2+ release; CNS, central nervous system; cPKA, catalytic subunit of protein kinase A; DP-IV, dipeptidyl-peptidase IV; ERK, extracellular signal-related kinase; GEF-II, guanine nucleotide exchange factor II; GI, gastrointestinal; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; GSIS, glucose-stimulated insulin secretion; HSL, hormone-sensitive lipase; IP 3 , inositol triphosphate; K ATP, ATP-sensitive K + channel; K Ca , Ca 2+ -sensitive voltage-dependent K + channel; K v , voltage-dependent K + channel; MAPK, mitogen-activated protein kinase; NSCC, nonspecific cation channel; PDX-1, pancreatic duodenal homeobox-1; PI3-K, phophatidylinositol 3-kinase; PKA, protein kinase A; PKCζ, protein kinase Cζ; P o , open probability; SU, sulfonylurea; VDCC, voltage-dependent Ca 2+ channel. The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris. DIABETES
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ISSN:0012-1797
1939-327X
DOI:10.2337/diabetes.51.2007.S434