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Beneficial metabolic effects of conditional activation of Gq signaling in pancreatic β‐cells

Like other cell types, pancreatic β‐cells express a multitude of G‐protein‐coupled receptors (GPCRs) which are linked to different functional classes of heterotrimeric G proteins, including G proteins of the Gq family. To examine the regulation of β‐cell function by Gq in vivo, we generated transgenic mice that expressed a Gq‐coupled designer receptor in β‐cells only (β‐Rq mice). This designer receptor could only be activated by an exogenously administered ligand, clozapine‐N‐oxide (CNO), an otherwise pharmacologically inert compound. CNO injection experiments showed that acute activation of β‐cell Gq signaling led to enhanced insulin release and greatly improved glucose tolerance. Chronic CNO treatment of β‐Rq mice caused elevated serum insulin and decreased blood glucose levels, increases in pancreatic insulin content and β‐cell mass, and enhanced expression of several genes important for β‐cell function and maintenance, including IRS‐2, Pdx1, MafA, NeuroD1, and Ngn3. Strikingly, chronic CNO treatment of β‐Rq mice also greatly ameliorated the symptoms of streptozotocin‐induced diabetes. These observations suggest that agents that can promote signaling through β‐cell Gq could become clinically useful as antidiabetic drugs.