A growing body of evidence indicates that mitochondrial physiology is important in both glucose-stimulated insulin release and survival of beta-cells. This evolving body of literature raises an important question: How do mitochondria function as coupling agents for insulin secretion and survival? In preliminary studies, we have shown that the pro-apoptotic protein BAD, a member of the BCL-2 family of cell death regulators, resides in a mitochondria-tethered glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. We have shown moreover that Bad-null mice display defect in glucose-stimulated insulin secretion and oxidative metabolism of glucose. The objective of the studies proposed in this application is to test the hypothesis that BAD plays a dual role in beta-cells;it regulates insulin secretion through its effects on aerobic metabolism and it modulates apoptosis through engaging other BCL-2 family members. This hypothesis gives rise to testable predictions that we propose to address using both genetics and chemistry. There are two specific aims:
Aim 1 tests the prediction that, the two distinctive functions of BAD in insulin secretion and apoptosis are specified by selective structural motifs and/or post translational modifications. This prediction will be tested using mutational analysis combined with genetic reconstitution assays. These studies will be integrated with examination of mitochondrial function to identify the metabolic determinants of BAD's role in insulin release. As a complementary approach to this structure-function analysis, we will employ novel cell permeable BAD peptido-mimetic compounds (BAD SAHBs) as chemical tools to further dissect the role of BAD in glucose metabolism and insulin secretion in beta-cells.
Aim 2 tests the prediction that the metabolic and apoptotic functions of BAD are physiologically relevant to ?-cell dysfunction in diabetes. We will use several available Bad genetic models, including knockout mice and knockin animals, to genetically test the contribution of BAD to ?-cell function and survival in two well defined models of type 2 diabetes, namely the high fat diet-induced model of diabetes and the leptin insensitive db/db genetic model. The studies described in this proposal may lead to identification of a new therapeutic target in diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Appel, Michael C
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Dana-Farber Cancer Institute
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Ljubicic, Sanda; Polak, Klaudia; Fu, Accalia et al. (2015) Phospho-BAD BH3 mimicry protects ? cells and restores functional ? cell mass in diabetes. Cell Rep 10:497-504
Giménez-Cassina, Alfredo; Danial, Nika N (2015) Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins. Trends Endocrinol Metab 26:165-75
Lo, James C; Ljubicic, Sanda; Leibiger, Barbara et al. (2014) Adipsin is an adipokine that improves ? cell function in diabetes. Cell 158:41-53
Giménez-Cassina, Alfredo; Garcia-Haro, Luisa; Choi, Cheol Soo et al. (2014) Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab 19:272-84
Szlyk, Benjamin; Braun, Craig R; Ljubicic, Sanda et al. (2014) A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat Struct Mol Biol 21:36-42
Fu, Suneng; Fan, Jason; Blanco, Joshua et al. (2012) Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting. PLoS Genet 8:e1002902
Osundiji, Mayowa A; Godes, Marina L; Evans, Mark L et al. (2011) BAD modulates counterregulatory responses to hypoglycemia and protective glucoprivic feeding. PLoS One 6:e28016
Tinoco, Arthur D; Kim, Yun-Gon; Tagore, Debarati M et al. (2011) A peptidomics strategy to elucidate the proteolytic pathways that inactivate peptide hormones. Biochemistry 50:2213-22