Overexpression of GPR40 in Pancreatic ��-Cells Augments Glucose-Stimulated Insulin Secretion and Improves Glucose Tolerance in Normal and Diabetic Mice

OBJECTIVE

GPR40 is a G protein–coupled receptor regulating free fatty acid–induced insulin secretion. We generated transgenic mice overexpressing the hGPR40 gene under control of the mouse insulin II promoter and used them to examine the role of GPR40 in the regulation of insulin secretion and glucose homeostasis.

RESEARCH DESIGN AND METHODS

Normal (C57BL/6J) and diabetic (KK) mice overexpressing the hGPR40 gene under control of the insulin II promoter were generated, and their glucose metabolism and islet function were analyzed.

RESULTS

In comparison with nontransgenic littermates, hGPR40 transgenic mice exhibited improved oral glucose tolerance with an increase in insulin secretion. Although islet morphologic analysis showed no obvious differences between hGPR40 transgenic and nontransgenic mice, isolated islets from hGPR40 transgenic mice had enhanced insulin secretion in response to high glucose (16 mmol/l) compared with those from nontransgenic mice, and they both had similar low glucose (3 mmol/l)-stimulated insulin secretion. In addition, hGPR40 transgenic islets significantly increased insulin secretion against a naturally occurring agonist palmitate in the presence of 11 mmol/l glucose. hGPR40 transgenic mice were also found to be resistant to high-fat diet–induced glucose intolerance, and hGPR40 transgenic mice harboring KK background showed augmented insulin secretion and improved oral glucose tolerance compared with nontransgenic littermates.

CONCLUSIONS

Our results suggest that GPR40 may have a role in regulating glucose-stimulated insulin secretion and plasma glucose levels in vivo and that pharmacological activation of GPR40 may provide a novel insulin secretagogue beneficial for the treatment of type 2 diabetes.Free fatty acids (FFAs) serve not only as nutrients but also as cell signaling mediators (1), and they are implicated in several metabolic disorders, including diabetes. Elevated circulating FFAs cause insulin resistance and impair glucose metabolism in liver, muscle, adipose tissue, and pancreatic β-cells (2). In pancreatic β-cells, prolonged exposure to elevated levels of fatty acids together with high levels of glucose impairs β-cell function (3,4) and induces cell death (5). In contrast to the toxic effects that accompany chronic exposure, in acute treatment FFAs play an essential role to amplify glucose-stimulated insulin secretion (6,7).GPR40 was identified as a receptor for medium- and long-chain FFAs and is preferentially expressed at high levels in rodent primary β-cells, β-cell lines (8–11), and human islets (12,13). Several reports have shown that GPR40 is mainly coupled with Gα_q/Gα₁₁, which activates phosholipase C (PLC), resulting in the formation of inositol 1,4,5-triphosphate and induction of calcium release from endoplasmic reticulum (11,14–16). In fact, FFAs increase intracellular calcium concentration via GPR40 and lead to glucose-dependent augmentation of insulin secretion (8–11,15,17).Although several studies have shown the important role of GPR40 in FFA-induced insulin secretion, the involvement of GPR40 in FFA-induced lipotoxicity in β-cells remains controversial. Steneberg et al. (18) reported that overexpression of GPR40 in β-cells under the control of insulin promoter factor 1 (IPF-1)/pancreatic and duodenal homeobox factor 1 (PDX-1) promoter lead to β-cell dysfunction, hypoinsulinemia, and diabetes. In contrast, studies of GPR40 knockout mice showed that GPR40 did not play a role in the mechanism by which chronic treatment with fatty acids impaired insulin secretion (19,20). Furthermore, both acute and chronic treatment by small-molecule agonists of GPR40 caused enhancement of glucose-stimulated insulin secretion and improved glucose tolerance (20–22). Together, these reports suggested that a GPR40 agonist might not be harmful to β-cells but, in fact, may prove beneficial for the treatment of type 2 diabetes.To clarify the function of GPR40 in pancreatic β-cells more extensively, we generated transgenic mice overexpressing the human GPR40 (hGPR40) gene under control of the insulin II promoter and examined the role of GPR40 in the regulation of insulin secretion and glucose homeostasis. We found that hGPR40 transgenic mice displayed improved glucose tolerance with augmented insulin secretion both in regular and high-fat–diet feeding conditions. Moreover, even when insulin resistance was reinforced in diabetic KK mice, overexpression of hGPR40 in this background also improved glucose tolerance with increasing insulin secretion. Thus, our findings indicated that GPR40 has a role in regulating glucose-stimulated insulin secretion and plasma glucose levels in vivo, and they supported the concept that GPR40 agonists might be effective insulin secretagogues for the treatment of type 2 diabetes.