GPR40 Is Necessary but Not Sufficient for Fatty Acid Stimulation of Insulin Secretion In Vivo

  1. Martin G. Latour1,
  2. Thierry Alquier1,
  3. Elizabeth Oseid2,
  4. Caroline Tremblay1,
  5. Thomas L. Jetton3,
  6. Jian Luo4,
  7. Daniel C.-H. Lin4 and
  8. Vincent Poitout15
  1. 1Montréal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
  2. 2Pacific Northwest Research Institute, Seattle, Washington
  3. 3Division of Endocrinology, Diabetes and Metabolism, University of Vermont College of Medicine, Burlington, Vermont
  4. 4Amgen, Inc., San Francisco, California
  5. 5Departments of Medicine, Nutrition, and Biochemistry, University of Montréal, Montréal, Quebec, Canada
  1. Address correspondence and reprint requests to Vincent Poitout, DVM, PhD, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Technopole Angus, 2901 Rachel Est, Montréal, QC, H1W 4A4 Canada. E-mail: vincent.poitout{at}umontreal.ca

Abstract

Long-chain fatty acids amplify insulin secretion from the pancreatic β-cell. The G-protein–coupled receptor GPR40 is specifically expressed in β-cells and is activated by fatty acids; however, its role in acute regulation of insulin secretion in vivo remains unclear. To this aim, we generated GPR40 knockout (KO) mice and examined glucose homeostasis, insulin secretion in response to glucose and Intralipid in vivo, and insulin secretion in vitro after short- and long-term exposure to fatty acids. Our results show that GPR40 KO mice have essentially normal glucose tolerance and insulin secretion in response to glucose. Insulin secretion in response to Intralipid was reduced by ∼50%. In isolated islets, insulin secretion in response to glucose and other secretagogues was unaltered, but fatty acid potentiation of insulin release was markedly reduced. The Gαq/11 inhibitor YM-254890 dose-dependently reduced palmitate potentiation of glucose-induced insulin secretion. Islets from GPR40 KO mice were as sensitive to fatty acid inhibition of insulin secretion upon prolonged exposure as islets from wild-type animals. We conclude that GPR40 contributes approximately half of the full acute insulin secretory response to fatty acids in mice but does not play a role in the mechanisms by which fatty acids chronically impair insulin secretion.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted December 29, 2006.
    • Received November 2, 2006.
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