The Fatty Acid Receptor GPR40 Plays a Role in Insulin Secretion In Vivo After High-Fat Feeding

The Fatty Acid Receptor GPR40 Plays a Role in Insulin Secretion In Vivo After High-Fat Feeding Melkam Kebede 1 2 , Thierry Alquier 1 2 , Martin G. Latour 1 , Meriem Semache 1 , Caroline Tremblay 1 and Vincent Poitout 1 2 3 1 Montréal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Canada 2 Department of Medicine, University of Montréal, Montréal, Canada 3 Department of Biochemistry, University of Montréal, Montréal, Canada Corresponding author: Vincent Poitout, vincent.poitout{at}umontreal.ca Abstract OBJECTIVE— The G-protein–coupled receptor GPR40 is expressed in pancreatic β-cells and is activated by long-chain fatty acids. Gene deletion studies have shown that GPR40 mediates, at least in part, fatty acid–amplification of glucose-induced insulin secretion (GSIS) but is not implicated in GSIS itself. However, the role of GPR40 in the long-term effects of fatty acids on insulin secretion remains controversial. This study aimed to test the hypothesis that GPR40 plays a role in insulin secretion after high-fat feeding. RESEARCH DESIGN AND METHODS— GPR40 knockout (KO) mice on a C57BL/6 background and their wild-type (WT) littermates were fed a high-fat diet (HFD) for 11 weeks. Glucose tolerance, insulin tolerance, and insulin secretion in response to glucose and Intralipid were assessed during the course of the diet period. RESULTS— GPR40 KO mice had fasting hyperglycemia. They became as obese, glucose intolerant, and insulin resistant as their WT littermates given HFD and developed a similar degree of liver steatosis. Their fasting blood glucose levels increased earlier than those of control mice during the course of the HFD. The remarkable increase in insulin secretory responses to intravenous glucose and Intralipid seen in WT mice after HFD was of much lower magnitude in GPR40 KO mice. CONCLUSIONS— GPR40 plays a role not only in fatty acid modulation of insulin secretion, but also in GSIS after high-fat feeding. These observations raise doubts on the validity of a therapeutic approach based on GPR40 antagonism for the treatment of type 2 diabetes. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 16 June 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in