期刊
NATURE MEDICINE
卷 14, 期 2, 页码 144-153出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1717
关键词
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资金
- NCI NIH HHS [K01 CA106596, K01CA10659, K01 CA106596-02, 5R01CA50239, K01 CA106596-03, K01 CA106596-04, K01 CA106596-01, R01 CA050239] Funding Source: Medline
- NHLBI NIH HHS [K08 HL074049, 5K08HL074049] Funding Source: Medline
- NICHD NIH HHS [P30 HD018655] Funding Source: Medline
- NIDDK NIH HHS [5R01DK68781, U24 DK059635, R01 DK040936, R01 DK068781] Funding Source: Medline
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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