SRT2104, a Novel Small Molecule SIRT1 Activator Ameliorates Insulin Resistance and Promotes Glucose Utilization Measured under a Hyperinsulinemic-Euglycemic Clamp by Enhancing Both Glycolysis and Carbohydrate Oxidation in Mice Fed a High Fat Diet
Abstract Number: 1007-P
Authors: YONG QI, MEGHAN L. DAVIS, ELDEN O. LAINEZ, ANGELA M. COTE, MARC O. JOHNSON, DAVID J. GAGNE, GEORGE P. VLASUK, JAMES L. ELLIS, VIPIN SURI
Institutions: Cambridge, MA
Results: The NAD-dependent protein deacetylase SIRT1 integrates multiple aspects of metabolic regulation. Over-expression of SIRT1 in transgenic mice confers protection from high fat diet induced obesity (DIO), improves insulin sensitivity and reduces hepatic steatosis. Small molecule activators of SIRT1 also produce similar metabolic benefits in DIO mice. We report here that oral administration of the highly selective small molecule SIRT1 activator SRT2104, to DIO mice led to reduced body weight and hepatic steatosis and improved insulin sensitivity. The reduction in body weight was due to increased basal metabolic rate through an increase in both fatty acid and carbohydrate oxidation. To understand the mechanisms underlying improved insulin sensitivity, a hyperinsulinemic-euglycemic clamp was performed. SRT2104 enhanced insulin stimulated glucose infusion rate by 52.7% (p<0.05) and rate of glucose disposal by 15.4% (p<0.05). SRT2104 increased insulin stimulated glucose uptake in several tissues including muscle, heart and brown adipose tissue. In addition, SRT2104 increased insulin mediated suppression of hepatic glucose production (33.4±4.4 vs. 13.1±3.4% in control) (HGP, p<0.05) with no effect on basal HGP. Further dissection of glucose utilization pathways revealed that SRT2104 caused an increase in glycolysis as well as a decrease in glycogen synthesis. Molecular analysis of insulin signaling pathways in muscle showed increased insulin stimulated phosphorylation of insulin receptor, Akt, and GSK-3β in SRT2104 treated animals. Taken together, our data provides direct evidence that pharmacological activation of SIRT1 improves insulin sensitivity and promotes glucose utilization via increasing both glycolysis and carbohydrate oxidation and strongly support SIRT1 activation as a novel therapeutic strategy to improve both metabolic function and glucose homeostasis for the treatment of Type 2 Diabetes.