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J. Biol. Chem., Vol. 283, Issue 8, 4560-4567, February 22, 2008

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G_z Negatively Regulates Insulin Secretion and Glucose Clearance^*

Michelle E. Kimple, Jamie W. Joseph, Candice L. Bailey, Patrick T. Fueger, Ian A. Hendry^¶, Christopher B. Newgard^||, and Patrick J. Casey^||1

From the Departments of Pharmacology and Cancer Biology and ^||Biochemistry and Biophysics, and The Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27710 and the ^¶Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 0200 Australia

Relatively little is known about the in vivo functions of the subunit of the heterotrimeric G protein G_z (G_z). Clues to one potential function recently emerged with the finding that activation of G_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_z knock-out mouse model was utilized to determine whether G_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_z-null and wild-type mice. There was also no difference between the insulin sensitivity of G_z-null mice and wild-type controls, as measured by insulin tolerance tests. G_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_z-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from G_z-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in G_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_z-null islets in the absence of exogenous stimulation. These findings indicate that G_z may be a potential new target for therapeutics aimed at ameliorating β-cell dysfunction in Type 2 diabetes.

Received for publication, August 6, 2007 , and in revised form, December 10, 2007.

^* This work was supported by National Institutes of Health Grants DK67799 (to M. E. K.), DK42583 (to C. B. N.), and GM55717 (to P. J. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Duke University Medical Center, Box 3813, Durham, NC 27710-3813. Tel.: 919-613-8613; Fax: 919-613-8642; E-mail: casey006{at}mc.duke.edu.

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