Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice

Kathryn A. Moynihan, Andrew A. Grimm, Marie M. Plueger, Ernesto Bernal-Mizrachi, Eric Ford, Corentin Cras-Méneur, M. Alan Permutt, Shin Ichiro Imai

Research output: Contribution to journalArticle

473 Scopus citations

Abstract

Sir2 NAD-dependent deacetylases connect transcription, metabolism, and aging. Increasing the dosage or activity of Sir2 extends life span in yeast, worms, and flies and promotes fat mobilization and glucose production in mammalian cells. Here we show that increased dosage of Sirt1, the mammalian Sir2 ortholog, in pancreatic β cells improves glucose tolerance and enhances insulin secretion in response to glucose in beta cell-specific Sirt1-overexpressing (BESTO) transgenic mice. This phenotype is maintained as BESTO mice age. Pancreatic perfusion experiments further demonstrate that Sirt1 enhances insulin secretion in response to glucose and KCl. Microarray analyses of β cell lines reveal that Sirt1 regulates genes involved in insulin secretion, including uncoupling protein 2 (Ucp2). Isolated BESTO islets also have reduced Ucp2, increased ATP production, and enhanced insulin secretion during glucose and KCl stimulation. These findings establish the importance of Sirt1 in β cell function in vivo and suggest therapeutic interventions for type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)105-117
Number of pages13
JournalCell Metabolism
Volume2
Issue number2
DOIs
StatePublished - Aug 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Moynihan, K. A., Grimm, A. A., Plueger, M. M., Bernal-Mizrachi, E., Ford, E., Cras-Méneur, C., Permutt, M. A., & Imai, S. I. (2005). Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice. Cell Metabolism, 2(2), 105-117. https://doi.org/10.1016/j.cmet.2005.07.001