The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.
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We thank M. Godes and C. Gramm for technical assistance, R. Pasquier and B. Szlyk for islet isolation and animal husbandry, G. Weir (Joslin Diabetes Center, Boston, MA) for antibody to glucokinase, B. Spiegelman, B. Malynn, M. Vander Heiden, A. Schinzel, J. Labelle, G. Verdine, F. Bernal, A. Saghatelian, A.-M. Richards and G. Yaney for helpful discussion and E. Smith for manuscript preparation. N.N.D. and L.D.W. are recipients of the Burroughs Wellcome Fund Career Award in Biomedical Sciences. This work was supported by US National Institute of Health grants K01CA10659 (N.N.D.), 5R01CA50239 and 5R01DK68781 (S.J.K.), 5K08HL074049 (L.D.W.) and by Charles E. Culpeper Scholarship in Medical Science (L.D.W.).
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Danial, N., Walensky, L., Zhang, CY. et al. Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14, 144–153 (2008). https://doi.org/10.1038/nm1717
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