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PMID: 18223655 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Dual role of proapoptotic BAD in insulin secretion and beta cell survival.

Nature medicine ·Vol. 14 ·No. 2 ·2008-02-00 ·Pages 144-53

Danial NN, Walensky LD, Zhang CY, Choi CS, Fisher JK, Molina AJ, Datta SR, Pitter KL, Bird GH, Wikstrom JD, Deeney JT, Robertson K, Morash J, Kulkarni A, Neschen S, Kim S, Greenberg ME, Corkey BE, Shirihai OS, Shulman GI, Lowell BB, Korsmeyer SJ

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.

MeSH Terms
Amino Acid Sequence Animals Blood Glucose Calcium/metabolism Cell Count Cell Survival/drug effects Diet Glucokinase/metabolism Glucose/pharmacology Humans Hydrocarbons/pharmacology Insulin/metabolism Insulin Secretion Insulin-Secreting Cells/cytology,drug effects,enzymology,metabolism Membrane Potential, Mitochondrial/drug effects Mice Models, Genetic Molecular Sequence Data Peptides/pharmacology Phosphoserine/metabolism Protein Structure, Tertiary bcl-Associated Death Protein/chemistry,deficiency,metabolism
Chemicals
Blood Glucose Hydrocarbons Insulin Peptides bcl-Associated Death Protein Phosphoserine Glucokinase Glucose Calcium
Authors & Affiliations
22 authors, click to expand affiliations / ORCID
Danial Nika N
Department of Pathology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA. [email protected]
Walensky Loren D
Zhang Chen-Yu
Choi Cheol Soo
Fisher Jill K
Molina Anthony J A
Datta Sandeep Robert
Pitter Kenneth L
Bird Gregory H
Wikstrom Jakob D
Deeney Jude T
Robertson Kirsten
Morash Joel
Kulkarni Ameya
Neschen Susanne
Kim Sheene
Greenberg Michael E
Corkey Barbara E
Shirihai Orian S
Shulman Gerald I
Lowell Bradford B
Korsmeyer Stanley J
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm1717
Email
[email protected]
Published
2008-02-00
Epub
2008-00-27
Pages
144-53
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC3918232
Subset
IM
Grants
NCI NIH HHS · K01 CA106596-04 · United States
NCI NIH HHS · K01 CA106596-03 · United States
NIDDK NIH HHS · 5R01DK68781 · United States
NIDDK NIH HHS · U24 DK059635 · United States
NIDDK NIH HHS · R01 DK040936 · United States
NHLBI NIH HHS · K08 HL074049 · United States
NCI NIH HHS · K01 CA106596-01 · United States
NCI NIH HHS · R01 CA050239 · United States
NIDDK NIH HHS · R01 DK068781 · United States
NCI NIH HHS · K01 CA106596 · United States
NCI NIH HHS · 5R01CA50239 · United States
NICHD NIH HHS · P30 HD018655 · United States
NHLBI NIH HHS · 5K08HL074049 · United States
NCI NIH HHS · K01CA10659 · United States
NCI NIH HHS · K01 CA106596-02 · United States
External Links
PubMed source DOI: 10.1038/nm1717 PMC Full Text View journal details
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