LAUSR

SIRT3 is a mitochondrial deacetylase that is necessary for insulin-stimulated muscle glucose uptake (MGU) in the setting of overnutrition, and its action is redox state-dependent (NAD/NADH). Energy stress induced by AICAR administration increases muscle insulin action and glucose uptake while enhancing the control of redox state. We hypothesized that acute energy stress would exacerbate the impairment in insulin-stimulated MGU in high fat-fed (HF) SIRT3 KO mice. To test this hypothesis, HF SIRT3 KO and WT littermates underwent 4h of either AICAR (1mg/kg/min) to induce an energetic stress or saline infusion followed by hyperinsulinemic (4mU/kg/min) euglycemic clamps. Experiments were conducted one week post jugular vein and carotid artery catheterization. Insulin clamps were combined with [3-3H] glucose to measure glucose fluxes and 2[14C]deoxyglucose to assess an index of MGU. AICAR significantly improved insulin sensitivity of liver, but not muscle of HF WT mice. Saline-SIRT3 KO mice were more insulin resistant than saline-WT mice, as glucose infusion rate (GIR) and MGU were reduced by ~50%. AICAR completely abolished the added insulin resistance in SIRT3 KO mice as GIR was similar to AICAR-WT. Consistent with this, AICAR increased muscle insulin-stimulated MGU in the SIRT3 KO mice to levels observed in WT mice. Results show that energy stress induced by AICAR infusion was sufficient to circumvent the defect in insulin-stimulated glucose uptake induced by SIRT3 KO, possibly by rescuing redox handling in skeletal muscle. Disclosure L. Lantier: None. C.C. Hughey: None. D. Wasserman: None. Funding National Institutes of Health (DK54902)