Selective activation of Gq signaling in pancreatic beta cells in vivo improves beta cell function and whole body glucose homeostasis

Thursday, October 11, 2012 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center, Building 45	NIDDK	ENDOC-8

* FARE Award Winner

Authors

• S Jain
• IR Azua
• M White
• JM Guettier
• J Wess

Abstract

Pancreatic beta cells express many GPCRs which are linked to different functional classes of heterotrimeric G proteins including Gq. In order to be able to selectively stimulate beta-cell Gq signaling in vivo, we generated transgenic mice that expressed a Gq-coupled designer GPCR (Rq) in pancreatic beta-cells only (b-Rq mice). Importantly, this designer receptor can only be activated by clozapine-N-oxide (CNO), an otherwise pharmacologically inert compound. Prolonged activation of beta-cell Gq signalling by chronic CNO treatment of b-Rq mice was associated with elevated serum insulin and decreased blood glucose levels, increased pancreatic insulin content, increased beta-cell mass and rate of beta-cell proliferation, and elevated expression of several genes important for the maintenance of beta-cell function and mass, including IRS-2 and the transcription factors Pdx1, MafA, NeuroD1 and Ngn3. Chronic activation also protected b-Rq mice against hyperglycemia and glucose intolerance induced by consumption of a high-fat diet or treatment with low doses of streptozotocin. Studies with b-Rq-mice lacking IRS2 strongly suggested that IRS2 plays a central role in mediating the beneficial metabolic effects resulting from prolonged activation of beta-cell Gq signalling. These results suggest that agents aimed at enhancing Gq signaling in pancreatic beta-cells could become clinically useful as antidiabetic drugs.

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