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

Abstract

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.

Superior beta cell proliferation, function and gene expression in a subpopulation of rat islets identified by high blood perfusion

“…Grx-1 mediates NADPH-dependent stimulation of calcium-dependent insulin secretion [35]. Gpr40 mediates fatty acid potentiation of glucose-stimulated insulin secretion [36] and can, when overexpressed, augment glucosestimulated insulin secretion [37], possibly by increasing intracellular inositol phosphate levels [38]. Gpr40 was upregulated in the more highly blood-perfused islets, potentially contributing to the superior function found in these islets.…”

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

“…This in turn raises the possibility that FFA1 is responsible for both acute insulinotropic effects but also development of diabetes after long term ingestion of CLAs, two observations that have been made in various clinical studies with oral CLA supplementation (8, 13). So far, FFA1 has been consistently involved in mediating the acute stimulatory effects of various long chain fatty acids on insulin secretion (15,16,21,32,44,45), but it has also been implicated in potential deleterious effects of fatty acids on ␤-cell function (27,38,44), albeit the latter aspect is considered as rather controversial (27,38). Nevertheless, these aspects are of prime importance to antidiabetic drug discovery because a potential contribution of FFA1 to ␤-cell dysfunction would disqualify FFA1 agonists as novel type 2 diabetes drugs.…”

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…Recently, a line of mice over-expressing GPR40 under the control of an insulin-promoter have been developed [70] and these animals displayed improved oral glucose tolerance as well as enhanced glucose-and fatty-acid stimulated insulin secretion compared to wild type mice. Interestingly, these animals were resistant to the detrimental effects of a high fat diet and, when the transgene was expressed against a genetic background predisposing to type 2 diabetes, enhanced insulin secretion was observed.…”