GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo.
Long-chain fatty acids amplify insulin secretion from the pancreatic beta-cell. The G-protein-coupled receptor GPR40 is specifically expressed in beta-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 approximately 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 Galpha(q/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.
Latour
Martin G
MG
Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Technopole Angus, 2901 Rachel Est, Montréal, QC, H1W 4A4 Canada.
Alquier
Thierry
T
Oseid
Elizabeth
E
Tremblay
Caroline
C
Jetton
Thomas L
TL
Luo
Jian
J
Lin
Daniel C-H
DC
Poitout
Vincent
V
D000818:Animals; D002478:Cells, Cultured; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D005217:Fat Emulsions, Intravenous; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D006493:Heparin; D005947:Glucose