There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A₁ adenosine receptor agonist which inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high fat (HF) diet in rodents. HF diet feeding to rats for 2 weeks caused a significant increase in insulin, FFA and triglycerides (TG) concentrations as compared to rats fed chow. CVT-3619 (1 mg/kg) caused a time dependent decrease in fasting insulin, FFA and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response whereas glucose response was not different to an oral glucose tolerance test (OGTT). Treatment with CVT-3619 for 2 weeks resulted in significant lowering of FFA, TG and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 weeks. Glucose infusion rate (GIR) was decreased significantly in HF mice as compared to chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly (p<0.01) increased GIR to values to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA, TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.