The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding.
OBJECTIVE
The G-protein-coupled receptor GPR40 is expressed in pancreatic beta-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 METHOD 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.
Montréal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Canada
Melkam
M
Kebede
Thierry
T
Alquier
Martin G
MG
Latour
Meriem
M
Semache
Caroline
C
Tremblay
Vincent
V
Poitout
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology*; D004435:Eating / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology; D006943:Hyperglycemia / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D004041:Dietary Fats; D005227:Fatty Acids; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled