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

Nika N Danial1, Loren D Walensky, Chen-Yu Zhang

  • 1Department of Pathology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA. nika_danial@dfci.harvard.edu

Nature Medicine
|January 29, 2008
PubMed

Insights

The proapoptotic protein BAD plays a key role in glucose-stimulated insulin secretion by beta cells, with its BH3 domain crucial for this function. Targeting phosphorylated BAD BH3 mimetics may restore beta cell function and regulate beta cell mass.

Area of Science:

  • Molecular Biology
  • Cellular Metabolism
  • Endocrinology

Background:

  • The BCL-2 family member BAD is known for its proapoptotic role.
  • BAD interacts with glucokinase, influencing glucose-driven mitochondrial respiration.

Purpose of the Study:

  • To investigate the physiological role of BAD in glucose-stimulated insulin secretion (GSIS) by beta cells.
  • To explore the therapeutic potential of targeting BAD's BH3 domain for metabolic disorders.

Main Methods:

  • Genetic studies in beta cells to assess BAD's function in GSIS.
  • Utilizing cell-permeable, hydrocarbon-stapled BAD BH3 helices as pharmacological tools.
  • Assessing mitochondrial respiration and insulin secretion in BAD-deficient islets.

Main Results:

  • Genetic evidence confirms BAD's crucial role in GSIS, dependent on BH3 sequence phosphorylation.
  • Phosphorylated BAD BH3 mimetics restored mitochondrial respiration and corrected insulin secretion in deficient islets.
  • BAD was found to regulate beta cell mass adaptation during high-fat feeding.

Conclusions:

  • BAD possesses bifunctional activities, regulating both beta cell survival and insulin secretion.
  • The BAD BH3 domain has an alternative function in regulating glucose metabolism and insulin release.
  • Phosphorylated BAD BH3 mimetics represent a potential therapeutic strategy for enhancing beta cell function.

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