title: SIRT1 activation ameliorates hyperglycaemia by inducing a torpor-like state in an obese mouse model of type 2 diabetes.
abstract: OBJECTIVE
  Nutrient overabundance and diminished physical activity underlie the epidemic of obesity and its consequences of insulin resistance and type 2 diabetes. These same phenomena, obesity and insulin resistance, are also observed in mammals as they ready themselves for the nutrient deprivation of winter, yet their plasma glucose does not rise. Given the role of silent information regulator 2 (Sir2) and its mammalian orthologue, Sirt1, in survival and life extension during energy deprivation, we hypothesised that enhancing its activity may reduce the insensible energy loss engendered by hyperglycaemia and glycosuria.
  
  
  METHODS
  At 8 weeks of age, db/db and db/m mice were randomised to receive the SIRT1 activator SRT3025 milled in chow (3.18 g/kg) or regular chow and followed for a further 12 weeks.
  
  
  RESULTS
  When compared with vehicle, SIRT1 activation greatly improved glycaemic control, augmented plasma insulin concentrations, increased pancreatic islet beta cell mass and elevated hepatic expression of the beta cell growth factor, betatrophin in db/db mice. Despite the dramatic reduction in hyperglycaemia, db/db mice displayed worsening insulin resistance, diminished physical activity and further weight gain. These findings along with reduced food intake and reduction in body temperature resembled torpor and hibernation. By contrast, SIRT1 activation conferred only minimal changes in non-diabetic db/m mice.
  
  
  CONCLUSIONS
  While reducing hyperglycaemia and promoting beta cell expansion, enhancing the activity of SIRT1 facilitates a phenotypic change in a db/db mouse model of diabetes to one that more closely resembles the physiological state of torpor or hibernation.
authors.affiliation: Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, 61 Queen Street East, Toronto, ON, Canada, M5C 2T2, richard.gilbert@utoronto.ca.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Advani
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: David M
authors.initials: DM
authors.lastname: Kepecs
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008817:Mice, Mutant Strains; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D036361:Peptide Hormones / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D064348:Torpor / Q000187:drug effects*
chemical_list: C000595899:ANGPTL8 protein, mouse; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D000813:Anilides; D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D036361:Peptide Hormones; C000601293:SRT3025; D013844:Thiazoles; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1