TY - JOUR
T1 - Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice
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
N1 - Funding Information:
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 We also thank Irving Boime for encouragement, Laura Bordone and Leonard Guarente for sharing unpublished results, and members of the Imai and Permutt laboratories for their help and discussions.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.).
PY - 2005/8
Y1 - 2005/8
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.
UR - http://www.scopus.com/inward/record.url?scp=25144454432&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2005.07.001
DO - 10.1016/j.cmet.2005.07.001
M3 - Article
C2 - 16098828
AN - SCOPUS:25144454432
SN - 1550-4131
VL - 2
SP - 105
EP - 117
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -