Failure of ?-cells to secrete adequate insulin is essential for the development of diabetes mellitus. The long- term objectives of this grant are to elucidate the cellular mechanisms of ?-cell glucose sensing by the mitochondrial GTP (mtGTP) cycle. This grant builds on our recent studies demonstrating a key role for mtGTP directly synthesized by the TCA cycle by the GTP-specific isoform of the enzyme succinyl CoA synthetase (SCS-GTP) as a sensor of glucose metabolism. The mtGTP is trapped within the mitochondria and must convert anaplerotic metabolites into PEP by the GTP-dependent mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) that then transmits the signal to the cytosol. Therefore, understanding the mechanism of this important signal and its role in the normal physiology of insulin secretion in vivo is the focus of this grant. Specifically it will assess the role of the mtGTP cycle by: 1) using two newly generated strains of mice with the inducible ?-cell specific expression of SCS-GTP or SCS-ATP to study the impact of mtGTP synthesis on insulin secretion in vivo, 2) characterize the functional interaction of a complex formed by PEPCK-M and SCS-GTP, and 3) using a series of molecular short-circuits and leaks to assess the role of each of the components of the mtGTP cycle in insulin secretion. Based on strong preliminary data for all three aims that support an essential role for the mtGTP cycle in the regulation of glucose-stimulated insulin secretion, it is anticipated that the results of these studies will lead to important new paradigm shifting insights into the function of pancreatic ?-cells that will lead to the rational development of novel therapeutic targets for either augmenting insulin secretion or preventing ?-cell failure.

National Institute of Health (NIH)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Sato, Sheryl M
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Madiraju, Anila K; Erion, Derek M; Rahimi, Yasmeen et al. (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542-6
Stark, Romana; Guebre-Egziabher, Fitsum; Zhao, Xiaojian et al. (2014) A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis. J Biol Chem 289:7257-63
Stark, Romana; Kibbey, Richard G (2014) The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: has it been overlooked? Biochim Biophys Acta 1840:1313-30
Israelsen, William J; Dayton, Talya L; Davidson, Shawn M et al. (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397-409