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.

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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.

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SummaryAdult male fatty and lean rats of Zucker strain were given access ad libitum to either a single nutritionally complete diet, or a self selection regime with separate sources of three macronutrients, protein (casein), fat (hydrogenated coconut oil), and carbohydrate (sucrose). Animals on the single diet were fed on a powdered stock diet, and then switched to the self-selection regime. Energy intake on the self-selection regime was the same as that for the single diet condition in both fatty and lean rats. Fatty rats consumed 45% more energy than did their lean littermates. Further, fatty rats selected 47.0% of their total calories as protein, 30.1% as fat, and 22.9% as carbohydrate. The respective per centages for lean rats were 56.1, 13.0 and 30.9. In lean rats, the injection of insulin (10U/kg) or 2-deoxy-D-glucose (500mg/kg, 2DG) failed to increase energy intake, but increased carbohydrate intake 2 times by attenuating protein intake. Also in fatty rats, insulin did not increase energy intake, but it did increase carbohydrate by 50% by attenuating fat intake. 2DG decreased energy intake by attenuating carbohydrate and fat intakes in fatty rats. Fatty rats were slightly less hypoglycemic to insulin, but more hyperglycemic to 2DG than lean rats. These different self-selec tion patterns of fatty rats seemed to be associated with their endocrine, metabolic, and behavioral abnormalities.