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

doi:10.1016/j.cmet.2005.07.001

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

Medicine, Endocrinology Division

Research output: Contribution to journal › Article › peer-review

570 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 language	English (US)
Pages (from-to)	105-117
Number of pages	13
Journal	Cell Metabolism
Volume	2
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2005.07.001
State	Published - Aug 2005

Funding

We thank Kenneth Polonsky for technical suggestions and helpful discussions about islet physiology, Laura Todt for transgene construction, Chris Welling and Mitsuru Ohsugi for help with IPGTTs and MIN6 cell culture, Sharon Travis for insulin measurements, Yiyong Zhou and Seth Crosby for help with microarray analysis, Jun-ichi Miyazaki for providing MIN6 cells and pIns-1, and David Turner for mU6pro. We also thank Irving Boime for encouragement, Laura Bordone and Leonard Guarente for sharing unpublished results, and members of the Imai and Permutt laboratories for their help and discussions. This work was supported by grants from NIA (AG024150); NIDDK through the Washington University Diabetes Research Training Center (DK20579); the National Center for Research Resources (C06 RR015502); and the Washington University Center for Aging (to S.-i.I.), the Lucille P. Markey Special Emphasis Pathway in Human Pathology (to K.A.M.), and the Glenn/AFAR Scholarship for Research in the Biology of Aging (to K.A.M. and A.A.G.).

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2005.07.001

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

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.",

author = "Moynihan, {Kathryn A.} and Grimm, {Andrew A.} and Plueger, {Marie M.} and Ernesto Bernal-Mizrachi and Eric Ford and Corentin Cras-M{\'e}neur and Permutt, {M. Alan} and Imai, {Shin Ichiro}",

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AU - Moynihan, Kathryn A.

AU - Grimm, Andrew A.

AU - Plueger, Marie M.

AU - Bernal-Mizrachi, Ernesto

AU - Ford, Eric

AU - Cras-Méneur, Corentin

AU - Permutt, M. Alan

AU - Imai, Shin Ichiro

PY - 2005/8

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N2 - 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.

AB - 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.

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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