It is currently appreciated that both insulin resistance and beta-cell dysfunction are early and essential events in the development of type 2 diabetes. Our current knowledge of factors that influence beta-cell function is lacking, despite research in this field having been conducted for several decades. To this end, we have recently shown that the heterotrimeric G-protein alpha-subunit, G{alpha}z, modulates an endogenous signaling pathway that is inhibitory to glucose-stimulated insulin secretion in an insulinoma cell line [Kimple et al. (2005) J Biol Chem 280:31708]. These results led to the hypothesis that loss of G{alpha}z activity would result in increased insulin secretion and improved beta-cell function in vivo, possibly protecting against the development of type 2 diabetes. In support of this hypothesis, we have performed preliminary experiments in which G{alpha}z-null mice, when compared to wild-type littermate controls, display increased plasma insulin concentrations and correspondingly decreased blood glucose levels during glucose tolerance tests. Furthermore, the increased plasma insulin levels observed in G{alpha}z-null mice are likely a direct result of enhanced insulin secretion, as pancreatic islets isolated from G{alpha}z-null mice exhibit significantly higher glucose-stimulated insulin secretion than those from wild-type mice. To further address our hypothesis, and our understanding of the role of G{alpha}z signaling in insulin secretion and islet cell function, we propose the following Specific Aims: (1) to delineate the signaling pathways upstream and downstream of G{alpha}z that are important for its inhibition of insulin secretion, (2) to determine at which step in the stimulated secretion process G{alpha}z is acting, and (3) to determine whether loss of G{alpha}z is protective against the development of diabetes, both age-induced and high-fat diet-induced. The results of these studies are expected to yield important new insights into the regulation of insulin secretion and beta- cell function at a molecular level, and may point to G{alpha}z as a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes. Relevance: This proposal aims to delineate the specific pathways by which a protein involved in the regulation of insulin secretion functions. How much insulin is secreted into the blood is one determinant of blood glucose levels;therefore, this project has direct relevance to diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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Duke University
Schools of Medicine
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Kimple, Michelle E; Neuman, Joshua C; Linnemann, Amelia K et al. (2014) Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes. Exp Mol Med 46:e102
Neuman, Joshua C; Truchan, Nathan A; Joseph, Jamie W et al. (2014) A method for mouse pancreatic islet isolation and intracellular cAMP determination. J Vis Exp :e50374
Kimple, Michelle E; Keller, Mark P; Rabaglia, Mary R et al. (2013) Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes 62:1904-12
Neuman, Joshua C; Kimple, Michelle E (2013) The EP3 Receptor: Exploring a New Target for Type 2 Diabetes Therapeutics. J Endocrinol Diabetes Obes 1:
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Kimple, Michelle E; Moss, Jennifer B; Brar, Harpreet K et al. (2012) Deletion of G?Z protein protects against diet-induced glucose intolerance via expansion of ?-cell mass. J Biol Chem 287:20344-55
Kelly, Patrick; Bailey, Candice L; Fueger, Patrick T et al. (2010) Rap1 promotes multiple pancreatic islet cell functions and signals through mammalian target of rapamycin complex 1 to enhance proliferation. J Biol Chem 285:15777-85