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Mol Cell Endocrinol. 2010 Aug 30;325(1-2):18-25. doi: 10.1016/j.mce.2010.04.014. Epub 2010 Apr 21.

GPR40 is partially required for insulin secretion following activation of beta3-adrenergic receptors.

Author information

1
Department of Biological Sciences, sanofi-aventis, 1041 Route 202-206, Bridgewater, NJ 08807, USA. zhen.pang@sanofi-aventis.com

Abstract

The free fatty acid (FFA) receptor GPR40, expressed by pancreatic beta-cells, may be responsible for insulin release following beta(3) adrenoceptor (Adrb3) activation. To test this hypothesis, we first studied the effects of Adrb3 agonists SR58611A and CL316,243 in GPR40 knockout (GPR40(-/-)) mice. Both drugs increased blood FFA levels in wild-type (GPR40(+/+)) and GPR40(-/-) mice, indicating that lipolysis is not GPR40-dependent. However, the magnitude of the insulin response after agonist treatment was decreased by approximately 50% in GPR40(-/-) mice. Analysis of the time-course revealed that the change in FFAs (5-10 min post-treatment) in response to SR58611A preceded insulin secretion (10-15 min post-treatment). While reduced by agonist treatment, glucose levels in GPR40(-/-) mice remained significantly higher than in GPR40(+/+) mice. Energy expenditure, food intake, or body weight was not affected in GPR40(-/-) mice, whereas SR58611A increased energy metabolism. Furthermore, CL316,243 did not potentiate glucose-stimulated insulin secretion in isolated mouse islets or activate a cAMP reporter in transgenic mice. Our data indicate that insulin secretion, a secondary event following stimulation of Adrb3 receptors, is partially mediated by GPR40 and suggest that GPR40 is integral to the anti-diabetes effects of Adrb3 agonists.

PMID:
20416356
DOI:
10.1016/j.mce.2010.04.014
[Indexed for MEDLINE]

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