Deletion of GPR40 Impairs Glucose-Induced Insulin Secretion In Vivo in Mice Without Affecting Intracellular Fuel Metabolism in Islets
- Thierry Alquier1,2,
- Marie-Line Peyot1,
- Martin G. Latour1,
- Melkam Kebede1,2,
- Christina M. Sorensen3,
- Stephane Gesta4,
- C. Ronald Kahn4,
- Richard D. Smith3,
- Thomas L. Jetton5,
- Thomas O. Metz3,
- Marc Prentki1,6 and
- Vincent Poitout1,2
- 1Montréal Diabetes Research Center, Research Centre of the Montréal University Hospital, University of Montréal, Montréal, QC, Canada;
- 2Department of Medicine, University of Montréal, Montréal, QC, Canada;
- 3Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington;
- 4Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts;
- 5Division of Endocrinology, Diabetes, and Metabolism, University of Vermont College of Medicine, Burlington, Vermont;
- 6Department of Nutrition, University of Montréal, Montréal, QC, Canada.
- Corresponding author: Vincent Poitout, vincent.poitout{at}umontreal.ca.
Abstract
OBJECTIVE The G-protein–coupled receptor GPR40 mediates fatty acid potentiation of glucose-stimulated insulin secretion, but its contribution to insulin secretion in vivo and mechanisms of action remain uncertain. This study was aimed to ascertain whether GPR40 controls insulin secretion in vivo and modulates intracellular fuel metabolism in islets.
RESEARCH DESIGN AND METHODS Insulin secretion and sensitivity were assessed in GPR40 knockout mice and their wild-type littermates by hyperglycemic clamps and hyperinsulinemic euglycemic clamps, respectively. Transcriptomic analysis, metabolic studies, and lipid profiling were used to ascertain whether GPR40 modulates intracellular fuel metabolism in islets.
RESULTS Both glucose- and arginine-stimulated insulin secretion in vivo were decreased by ∼60% in GPR40 knockout fasted and fed mice, without changes in insulin sensitivity. Neither gene expression profiles nor intracellular metabolism of glucose and palmitate in isolated islets were affected by GPR40 deletion. Lipid profiling of isolated islets revealed that the increase in triglyceride and decrease in lyso-phosphatidylethanolamine species in response to palmitate in vitro was similar in wild-type and knockout islets. In contrast, the increase in intracellular inositol phosphate levels observed in wild-type islets in response to fatty acids in vitro was absent in knockout islets.
CONCLUSIONS These results indicate that deletion of GPR40 impairs insulin secretion in vivo not only in response to fatty acids but also to glucose and arginine, without altering intracellular fuel metabolism in islets, via a mechanism that may involve the generation of inositol phosphates downstream of GPR40 activation.
Footnotes
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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.
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- Received March 9, 2009.
- Accepted August 6, 2009.
- © 2009 American Diabetes Association
