P2Y Purinergic Potentiation of Glucose-Induced Insulin Secretion and Pancreatic Beta-Cell Metabolism

  1. A. Farret1,
  2. M. Vignaud1,
  3. S. Dietz2,
  4. J. Vignon1,
  5. P. Petit1 and
  6. R. Gross1
  1. 1Center for Pharmacology and Health Biotechnology, CNRS UMR 5160, Montpellier, France
  2. 2Innodia, Montpellier, France
  1. Address correspondence and reprint requests to Dr. René Gross, Centre de Pharmacologie et Biotechnologie pour la Santé, CNRS UMR 5160, Faculté de Médecine, Institut de Biologie, 4 Boulevard Henri IV, CS89508, 34960 Montpellier Cedex 2, France. E-mail: gross{at}univ-montp1.fr

Abstract

Purine nucleotides and their analogs increase insulin secretion through activation of pancreatic β-cell P2Y receptors. The present study aimed at determining the role of glucose metabolism in the response to P2Y agonists and whether ATP-activated K+ channels (KATP channels) are involved in this response. The experiments were performed in the rat isolated pancreas, perfused with a Krebs-bicarbonate buffer supplemented with 2 g/l bovine serum albumin under dynamic glucose conditions from 5 mmol/l baseline to 11 mmol/l. ADPβS (0.5 μmol/l) was selected as a stable and selective P2Y agonist. This compound, ineffective on the 5 mmol/l glucose background, induced a significant threefold increase in insulin release triggered by the glucose challenge. The effect of ADPβS was markedly reduced (P < 0.001) in the presence of an inhibitor of glucose metabolism. In addition to glucose, the ADP analog also amplified the β-cell insulin response to 15 mmol/l methyl pyruvate (P < 0.05), but it was ineffective on the insulin response to 2.5 mmol/l methyl succinate. A nonmetabolic stimulus was applied using tolbutamide (185 μmol/l). Insulin secretion induced by the KATP channel blocker was strongly reinforced by ADPβS (P < 0.001), which prompted us to check a possible interplay of KATP channels in the effect of ADPβS. In the presence of diazoxide 250 μmol/l and 21 mmol/l KCl, ADPβS still amplified the second phase of glucose-induced insulin secretion (P < 0.001). We conclude that P2Y receptor activation is able to promote insulin secretion through a mechanism, involving β-cell metabolism and a rise in intracellular calcium; this effect does not result from a direct inhibitory effect on KATP channels.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted May 13, 2004.
    • Received March 18, 2004.
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