Article abstract
Nature Medicine 14, 144 - 153 (2008)
Published online: 27 January 2008 | doi:10.1038/nm1717
Dual role of proapoptotic BAD in insulin secretion and beta cell survival
Nika N Danial1,2,3, Loren D Walensky2,3,4,5, Chen-Yu Zhang6, Cheol Soo Choi7,8, Jill K Fisher1,2,3, Anthony J A Molina9, Sandeep Robert Datta10,13, Kenneth L Pitter2,3,4,5, Gregory H Bird2,3,4,5, Jakob D Wikstrom9, Jude T Deeney11, Kirsten Robertson1,2,3, Joel Morash2,3,4,5, Ameya Kulkarni7,8, Susanne Neschen7,8, Sheene Kim7,8, Michael E Greenberg10, Barbara E Corkey11, Orian S Shirihai9, Gerald I Shulman7,8, Bradford B Lowell12 & Stanley J Korsmeyer1,7
Abstract
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.
- Department of Pathology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Division of Hematology/Oncology, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
- Howard Hughes Medical Institute, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
- Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
- Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA.
- Neurobiology Program, Department of Neurology, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
- Obesity Research Center, Evans Department of Medicine, 650 Albany Street, Boston Medical Center, Boston, Massachusetts 02118, USA.
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
- Current address: Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, 701 West 168th Street, New York, New York 10032, USA.
Correspondence to: Nika N Danial1,2,3 e-mail: nika_danial@dfci.harvard.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosisNature Letters to Editor (21 Aug 2003)
Engineering physiologically regulated insulin secretion in non-β cells by expressing glucagon-like peptide 1 receptorGene Therapy Research Article
See all 15 matches for Research
