Cited by 314Pancreatic function and diabetesCell death mechanisms and regulationEndoplasmic Reticulum Stress and Disease

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

Open access
Danial, Nika N, Walensky, Loren D, Zhang, Chen-Yu, Choi, Cheol Soo, Fisher, Jill K, Molina, Anthony J A, Datta, Sandeep Robert, Pitter, Kenneth L +14 more·2008·Nature Medicine

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.

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Crossref · 10.1038/nm1717

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Authors
Danial, N. N., Walensky, L. D., Zhang, C.-Y., Choi, C. S., Fisher, J. K., Molina, A. J. A., Datta, S. R., Pitter, K. L., Bird, G. H., Wikstrom, J. D., Deeney, J. T., Robertson, K., Morash, J., Kulkarni, A., Neschen, S., Kim, S., Greenberg, M. E., Corkey, B. E., Shirihai, O. S., Shulman, G. I., Lowell, B. B., & Korsmeyer, S. J.
Affiliations
  • Harvard University (US)
  • Boston Children's Hospital (US)
  • State Key Laboratory of Pharmaceutical Biotechnology (CN)
  • Howard Hughes Medical Institute (US)
  • Tufts University (US)
  • Boston Medical Center (US)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
Danial, Nika N
Venue
Nature Medicine
Published
2008-01-27
Volume
14
Issue
2
Pages
144-153
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2158213282
Cited by
307
References
52
Citations by year
2026: 3 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 5 · 2021: 13 · 2020: 17 · 2019: 12 · 2018: 13 · 2017: 13 · 2016: 17 · 2015: 23 · 2014: 19 · 2013: 22 · 2012: 18
FWCI
38.39
Type
journal article
Language
en
Open access
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (K08HL074049)
  • National Cancer Institute (K01CA10659, R01CA050239, 5R01CA50239, K01CA106596)
  • National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK68781, R01DK068781, R01DK040936, U24DK059635)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
Bad, Bcl-2 family proteins, glucose-stimulated insulin secretion, beta-cell survival, glucokinase, mitochondrial respiration, beta-cell mass, high-fat feeding, islets, apoptosis
MeSH terms
Insulin Secretion, Amino Acid Sequence, Animals, Blood Glucose, Calcium, Cell Count, Cell Survival, Diet, Glucokinase, Glucose, Humans, Hydrocarbons, Insulin, Models, Genetic, Molecular Sequence Data, Peptides, Phosphoserine, Protein Structure, Tertiary, Insulin-Secreting Cells, bcl-Associated Death Protein, Mice, Membrane Potential, Mitochondrial

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