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

  1. Patrick E. MacDonald1,
  2. Wasim El-kholy1,
  3. Michael J. Riedel2,
  4. Anne Marie F. Salapatek1,
  5. Peter E. Light2 and
  6. Michael B. Wheeler1
  1. 1Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada
  2. 2Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada


    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 Ca2+ 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.


    • 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}

      Received for publication 18 March 2002 and accepted in revised form 17 May 2002.

      AKAP, A-kinase anchoring protein; [Ca2+]i, intracellular concentration of Ca2+; CICR, Ca2+-induced Ca2+ 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; IP3, inositol triphosphate; KATP, ATP-sensitive K+ channel; KCa, Ca2+-sensitive voltage-dependent K+ channel; Kv, 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; Po, open probability; SU, sulfonylurea; VDCC, voltage-dependent Ca2+ channel.

      The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.

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