U.S. Department of Energy

Pacific Northwest National Laboratory

Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets.

TitleDeletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets.
Publication TypeJournal Article
Year of Publication2009
AuthorsAlquier T, Peyot M-L, Latour MG, Kebede M, Sorensen CM, Gesta S, C Kahn R, Smith RD, Jetton TL, Metz TO, Prentki M, Poitout V
JournalDiabetes
KeywordsAdipose Tissue, Animals, Arachidonic Acid, Arginine, Fatty Acids, Gene Expression Profiling, Glucose, Inositol Phosphates, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Lipids, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, G-Protein-Coupled
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 approximately 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.

DOI10.2337/db09-0362
Alternate JournalDiabetes
PubMed ID19720802
PubMed Central IDPMC2768167
Grant List86545 / / Canadian Institutes of Health Research / Canada
R33 DK070146-04 / DK / NIDDK NIH HHS / United States
| Pacific Northwest National Laboratory