Overexpression of GPR40 in Pancreatic  -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.

Free Fatty Acid Receptors FFAR1 and GPR120 as Novel Therapeutic Targets for Metabolic Disorders

“…In contrast, impairment of β‐cell function was observed in FFAR1 overexpressing transgenic mice, indicating that FFAR1 expression is regulated by the insulin promoter factor 1/pancreatic and duodenal homeobox 1 promoter 24. Also, a line of mice has been developed that overexpresses FFAR1 under the control of an insulin promoter, and their phenotypic characterization showed that FFAR1 could partly mediate GSIS 31. These results suggest that FFAR1 might contribute to the mechanism related to obesity and metabolic disorders.…”

GPR40‐induced insulin secretion by the novel agonist TAK‐875: first clinical findings in patients with type 2 diabetes

“…G protein-coupled receptor 40 [GPR40, also known as free fatty acid receptor 1 (FFAR1)] [8] is highly expressed in pancreatic β-cells and activated by long-chain free fatty acids (FFAs) [9,10]. FFAs are an important energy source, and they also act as signalling molecules for modulating insulin secretion [11][12][13].…”

“…FFAs are an important energy source, and they also act as signalling molecules for modulating insulin secretion [11][12][13]. Most of the insulinotropic effects of FFAs appear to be mediated through GPR40, since GPR40specific small interfering RNA and antisense oligonucleotides inhibit fatty acid-induced insulin secretion [9][10][11][12][13][14]. It has been postulated that FFAs interact with GPR40 with a resultant increase in cytosolic Ca 2+ via phospholipase C and L-type Ca 2+ channels [15,16].…”

“…For example, GPR40 played an important role in regulating glucose-stimulated insulin secretion and glucose homeostasis in a long-term study involving normal and diabetic mice [10] and, over an extended period, it improved insulin secretory responses to FFAs and glucose tolerance in mice fed high fat original article DIABETES, OBESITY AND METABOLISM diets [17]. For example, GPR40 played an important role in regulating glucose-stimulated insulin secretion and glucose homeostasis in a long-term study involving normal and diabetic mice [10] and, over an extended period, it improved insulin secretory responses to FFAs and glucose tolerance in mice fed high fat original article DIABETES, OBESITY AND METABOLISM diets [17].…”

Discovery of a series of 2-(pyridinyl)pyrimidines as potent antagonists of GPR40

“…However, both of these claims have been countered. [7][8][9][10][11] It has been shown recently that human islets cultured long term in the presence of a GPR40 antagonist (ANT203, Fig. 1) showed a 40 number of beneficial effects, including inhibition of the detrimental effects of palmitate on glucose stimulated insulin secretion and insulin content, 12 although perhaps contrary results have also been described.…”