title: Galphaz negatively regulates insulin secretion and glucose clearance.
abstract: Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein Gz (Galphaz). Clues to one potential function recently emerged with the finding that activation of Galphaz 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 Galphaz knock-out mouse model was utilized to determine whether Galphaz 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 Galphaz-null and wild-type mice. There was also no difference between the insulin sensitivity of Galphaz-null mice and wild-type controls, as measured by insulin tolerance tests. Galphaz-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 Galphaz-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from Galphaz-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in Galphaz-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in Galphaz-null islets in the absence of exogenous stimulation. These findings indicate that Galphaz may be a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes.
authors: Department of Pharmacology, and The Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27710-3813, USA.
authors: Michelle E
authors: ME
authors: Kimple
authors: Jamie W
authors: JW
authors: Joseph
authors: Candice L
authors: CL
authors: Bailey
authors: Patrick T
authors: PT
authors: Fueger
authors: Ian A
authors: IA
authors: Hendry
authors: Christopher B
authors: CB
authors: Newgard
authors: Patrick J
authors: PJ
authors: Casey
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013549:Sweetening Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D007328:Insulin; D013549:Sweetening Agents; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005947:Glucose