The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding

Abstract

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.

FIG. 1.

Fasting blood glucose levels of GPR40 KO and WT mice before (A) and during (B) feeding a high-fat (HF) or regular diet (RD). *P < 0.05.

FIG. 2.

A: Glucose levels during oral glucose tolerance tests (OGTTs) after 8 weeks of HFD; n = 10–11 mice per group. B: Glucose levels during intraperitoneal insulin tolerance tests (IPITTs) after 9 weeks of HFD; n = 8–10 mice per group. C: Oil Red O staining of liver sections of KO and WT mice fed regular diet (RD) or HFD. Images are representative of 3–4 animals in each group. (Please see http://dx.doi.org/10.2337/db08-0553 for a high-quality digital representation of this figure.)

FIG. 3.

A and B: Insulin levels in response to intravenous glucose after 10 weeks of regular diet (RD) (A) or HFD (B). C and D: Area under the curve (AUC) for insulin over the first 10 min (C) and from 10–60 min (D) following glucose injection. Values are expressed as means ± SE of 8–10 mice per group. E and F: Insulin levels in response to intravenous Intralipid after 11 weeks of regular diet (E) or HFD (F). G and H: Area under the curve for insulin for the first 10 min (G) and from 10–60 min (H) following Intralipid injection. Values are expressed as means ± SE of 6–8 mice per group. *P < 0.

FIG. 3.

A and B: Insulin levels in response to intravenous glucose after 10 weeks of regular diet (RD) (A) or HFD (B). C and D: Area under the curve (AUC) for insulin over the first 10 min (C) and from 10–60 min (D) following glucose injection. Values are expressed as means ± SE of 8–10 mice per group. E and F: Insulin levels in response to intravenous Intralipid after 11 weeks of regular diet (E) or HFD (F). G and H: Area under the curve for insulin for the first 10 min (G) and from 10–60 min (H) following Intralipid injection. Values are expressed as means ± SE of 6–8 mice per group. *P < 0.