title: Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse  pancreatic beta cells.
abstract: OBJECTIVE
  Sirtuin 6 (SIRT6) has been implicated in ageing, DNA repair and metabolism; however, its function in pancreatic beta cells is unclear. The aim of this study is to elucidate the role of SIRT6 in pancreatic beta cells.
  
  
  METHODS
  To investigate the function of SIRT6 in pancreatic beta cells, we performed Sirt6 gene knockdown in MIN6 cells and generated pancreatic- and beta cell-specific Sirt6 knockout mice. Islet morphology and glucose-stimulated insulin secretion (GSIS) were analysed. Glycolysis and oxygen consumption rates in SIRT6-deficient beta cells were measured. Cytosolic calcium was monitored using the Fura-2-AM fluorescent probe (Invitrogen, Grand Island, NY, USA). Mitochondria were analysed by immunoblots and electron microscopy.
  
  
  RESULTS
  Sirt6 knockdown in MIN6 beta cells led to a significant decrease in GSIS. Pancreatic beta cell Sirt6 knockout mice showed a ~50% decrease in GSIS. The knockout mouse islets had lower ATP levels compared with the wild-type controls. Mitochondrial oxygen consumption rates were significantly decreased in the SIRT6-deficient beta cells. Cytosolic calcium dynamics in response to glucose or potassium chloride were attenuated in the Sirt6 knockout islets. Numbers of damaged mitochondria were increased and mitochondrial complex levels were decreased in the SIRT6-deficient islets.
  
  
  CONCLUSIONS
  These data suggest that SIRT6 is important for GSIS from pancreatic beta cells and activation of SIRT6 may be useful to improve insulin secretion in diabetes.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS1021D, Indianapolis, IN, 46202, USA.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS1021D, Indianapolis, IN, 46202, USA.
authors.forename: Gaihong
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS1021D, Indianapolis, IN, 46202, USA.
authors.forename: Rongya
authors.initials: R
authors.lastname: Tao
authors.affiliation: Richard Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Tatsuyoshi
authors.initials: T
authors.lastname: Kono
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tersey
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS1021D, Indianapolis, IN, 46202, USA.|Richard Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.affiliation: Richard Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA.|Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS1021D, Indianapolis, IN, 46202, USA. xcdong@iu.edu.
authors.forename: X Charlie
authors.initials: XC
authors.lastname: Dong
mesh_terms: D000375:Aging; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003433:Crosses, Genetic; D004260:DNA Repair; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006019:Glycolysis; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D010101:Oxygen Consumption; D037761:Sirtuins / Q000235:genetics* / Q000502:physiology*
chemical_list: D007328:Insulin; C501860:Sirt6 protein, mouse; D037761:Sirtuins; D005947:Glucose; D010100:Oxygen; D002118:Calcium