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


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.
Alquier
Thierry
T
Montréal Diabetes Research Center, Research Centre of the Montréal University Hospital, University of Montréal, Montréal, QC, Canada.
Peyot
Marie-Line
ML
Latour
Martin G
MG
Kebede
Melkam
M
Sorensen
Christina M
CM
Gesta
Stephane
S
Ronald Kahn
C
C
Smith
Richard D
RD
Jetton
Thomas L
TL
Metz
Thomas O
TO
Prentki
Marc
M
Poitout
Vincent
V
D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D020869:Gene Expression Profiling; D005947:Glucose / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008055:Lipids / Q000302:isolation & purification / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics*
D005227:Fatty Acids; C473036:Ffar1 protein, mouse; D007295:Inositol Phosphates; D007328:Insulin; D008055:Lipids; D043562:Receptors, G-Protein-Coupled; D016718:Arachidonic Acid; D001120:Arginine; D005947:Glucose