title: Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients.
abstract: OBJECTIVE
  Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes.
  
  
  METHODS
  We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells.
  
  
  RESULTS
  SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on pro-inflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β.
  
  
  CONCLUSIONS
  Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.
authors: Centre for Diabetes, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK. p.w.caton@qmul.ac.uk
authors: P W
authors: PW
authors: Caton
authors: S J
authors: SJ
authors: Richardson
authors: J
authors: J
authors: Kieswich
authors: M
authors: M
authors: Bugliani
authors: M L
authors: ML
authors: Holland
authors: P
authors: P
authors: Marchetti
authors: N G
authors: NG
authors: Morgan
authors: M M
authors: MM
authors: Yaqoob
authors: M J
authors: MJ
authors: Holness
authors: M C
authors: MC
authors: Sugden
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D016207:Cytokines; D007328:Insulin; D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; C466093:SIRT3 protein, human; D056566:Sirtuin 3
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