G Alpha(Z) 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 G(z) (G alpha(z)). Clues to one potential function recently emerged with the finding that activation of G alpha(z) inhibits glucose-stimulated insulin secretion in an insulinoma cell line (Kimple, M. E., Nixon, A. B., Kelly, P., Bailey, C. L., Young, K. H., Fields, T. A., and Casey, P. J. ( 2005) J. Biol. Chem. 280, 31708-31713). To extend this study in vivo, a G alpha(z) knock-out mouse model was utilized to determine whether G alpha(z) 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 G alpha(z)-null and wild-type mice. There was also no difference between the insulin sensitivity of G alpha(z)-null mice and wildtype controls, as measured by insulin tolerance tests. G alpha(z)-null mice did, however, display increased plasma insulin concentrations and a corresponding increase in glucose clearance following intraperitoneal and oral glucose challenge as compared with wild-type controls. The increased plasma insulin observed in G alpha(z)-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from G alpha(z)-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in G alpha(z)-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in G alpha(z)-null islets in the absence of exogenous stimulation. These findings indicate that G alpha(z) may be a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes.