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Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients.

Authors: Caton, PW  Richardson, SJ  Kieswich, J  Bugliani, M  Holland, ML  Marchetti, P  Morgan, NG  Yaqoob, MM  Holness, MJ  Sugden, MC 
Citation: Caton PW, etal., Diabetologia. 2013 May;56(5):1068-77. doi: 10.1007/s00125-013-2851-y. Epub 2013 Feb 9.
Pubmed: (View Article at PubMed) PMID:23397292
DOI: Full-text: DOI:10.1007/s00125-013-2851-y

AIMS/HYPOTHESIS: 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 IL1beta and TNFalpha. 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 IL1beta. CONCLUSIONS/INTERPRETATION: 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 IL1beta synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.

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CRRD Object Information
CRRD ID: 9586042
Created: 2014-09-25
Species: All species
Last Modified: 2014-09-25
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.