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A BAD Role in Insulin Release

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Science Signaling  12 Feb 2008:
Vol. 1, Issue 6, pp. ec52
DOI: 10.1126/stke.16ec52

Because both loss-of-function (Bad−/−) and gain-of-function (Bad3SA) mutations in the apoptotic function of BAD produce the same metabolic defects in mice, Danial et al. investigated the role of the Bcl-2 proapoptotic family member BAD in insulin secretion from pancreatic β cells. Bad−/− mice and isolated islets from these mice exhibited decreased insulin secretion in response to either hyperglycemia (in vivo) or exogenous glucose despite having similar total intracellular pools of releasable insulin (in culture). Application of secretagogues that stimulated insulin secretion at different points in the pathway suggested that the defect in secretion occurred at the level of glucose and glucokinase (upstream of activation of mitochondrial respiration). BAD interacted with glucokinase and, compared with wild-type islets, Bad−/− islets showed decreased glucokinase activity and required greater concentrations of glucose to stimulate the same amount of insulin release. The defective secretion appeared to be due to decreased mitochondrial respiration in response to glucose, which is required to produce the increase in the ATP/ADP ratio that regulates the KATP channel. The secretion defect was not corrected by reconstituting the knockout cells with either a BAD mutant that failed to interact with its antiapoptotic target proteins or with a mutant that constitutively interacts with these same target proteins. Thus, the secretory function of BAD does not appear to involve its role in regulating the activity of antiapoptotic proteins directly. Application of cell-permeable helix-stabilized BH3 domains based on BAD, or phosphorylated or phosphorylation mimics of this domain, to Bad−/− islet cells restored glucose-stimulated insulin secretion. (Note that when the BH3 domain of BAD is phosphorylated, it does not interact with the antiapoptotic proteins Bcl-2 and Bcl-XL.) Application of these cell-permeable BAD BH3 peptides to INS-1 cells stimulated glucokinase activity, and the peptides could be crosslinked to glucokinase, suggesting a direct interaction. Mutation of the residues that were necessary for BAD to restore glucose-stimulated insulin secretion in the Bad−/− cells in the BAD BH3 cell-permeable peptides resulted in peptides that failed to bind glucokinase. Thus, signals that stimulate the phosphorylation of BAD, which frequently also stimulate cell survival, appear to trigger a shift in the function of BAD from a mediator of apoptosis to a stimulator of cellular metabolism, which has important implications for both the increase in islet cell mass and insulin secretion in response to demand.

N. N. Danial, L. D. Walensky, C.-Y. Zhang, C. S. Choi, J. K. Fisher, A. J. A. Molina, S. R. Datta, K. L. Pitter, G. H. Bird, J. D. Wikstrom, J. T. Deeney, K. Robertson, J. Morash, A. Kulkarni, S. Neschen, S. Kim, M. E. Greenberg, B. E. Corkey, O. S. Shirihai, G. I. Shulman, B. B. Lowell, S. J. Korsmeyer, Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat. Med. 14, 144-153 (2008). [PubMed]

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