SIRT1 activation ameliorates hyperglycaemia by inducing a torpor-like state in an obese mouse model of type 2 diabetes

Diabetologia. 2015 Apr;58(4):819-27. doi: 10.1007/s00125-014-3485-4. Epub 2015 Jan 7.

Abstract

Aims/hypothesis: 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/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-like Proteins
  • Anilides / pharmacology*
  • Animals
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Disease Models, Animal
  • Enzyme Activation
  • Enzyme Activators / pharmacology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Insulin / blood
  • Insulin Resistance
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Male
  • Mice, Mutant Strains
  • Obesity / blood
  • Obesity / drug therapy*
  • Obesity / enzymology
  • Obesity / genetics
  • Obesity / physiopathology
  • Peptide Hormones / metabolism
  • Signal Transduction / drug effects
  • Sirtuin 1 / metabolism*
  • Thiazoles / pharmacology*
  • Time Factors
  • Torpor / drug effects*

Substances

  • ANGPTL8 protein, mouse
  • Angiopoietin-like Proteins
  • Anilides
  • Blood Glucose
  • Enzyme Activators
  • Hypoglycemic Agents
  • Insulin
  • Peptide Hormones
  • SRT3025
  • Thiazoles
  • Sirt1 protein, mouse
  • Sirtuin 1