Negatively regulates insulin secretion and glucose clearance *

Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein Gz (Gαz). Clues to one potential function recently emerged with the finding that activation of Gαz inhibits glucosestimulated insulin secretion (GSIS) in an insulinoma cell line [Kimple et al. (2005) J Biol Chem 280:31708]. To extend this study in vivo, a Gαz knock-out mouse model was utilized to determine whether Gαz function plays a role in the inhibition of insulin secretion. No differences were discovered in the gross morphology of the pancreatic islets, or in the islet DNA, protein, or insulin content, between Gαz-null and wild-type mice. There was also no difference between the insulin sensitivity of Gαz-null mice and wild-type controls, as measured by insulin tolerance tests. Gαz-null mice did, however, display increased plasma insulin concentrations and a corresponding increase in glucose clearance following intraperitoneal and oral glucose challenge as compared to wild-type controls. The increased plasma insulin observed in Gαz-null mice is likely a direct result of enhanced insulin secretion, as pancreatic islets isolated from Gαz-null mice exhibited significantly higher GSIS than those of wild-type mice. Finally, the increased insulin secretion observed in Gαz-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in Gαznull islets in the absence of exogenous stimulation. These findings indicate that Gαz may be a potential new target for therapeutics aimed at ameliorating β-cell dysfunction in Type 2 diabetes.