Abstract： Objective To investigate the effects of tumor necrosis factor-alpha (TNF-α) on insulin sensitivity and glucose-lipid metabolism in TNF-α-induced IR mice. Methods Male C57BL/6J mice were given an intraperitoneal injection of TNF-α (H group,6μg/kg; M group,3μg/kg; L group,1μg/kg;twice daily) and saline (NC group) for 7 days. The plasma glucose and insulin were assayed during intravenous glucose tolerance test (IVGTT) and hyperinsulinemic-euglycemic clamp combined with 3-[3H] glucose as a tracer was carried out. Results After TNF-α treatment,fasting blood glucose (FBG),plasma insulin and free fatty acids (FFA) were significantly elevated in H group compared with NC,L and M groups (P<0.01 and P<0.05,respectively). There was a lower glucose tolerance in H group versus other three groups during IVGTT. The insulin release by glucose stimulation was higher in H group versus NC and L groups (P<0.01 and P<0.05). Basal glucose disappearance rate (GDR) and hepatic glucose production (HGP) were significantly increased in H group compared with NC group (P<0.01). During the steady-state of clamp,plasma insulin levels were significantly increased in H group versus NC group (341.7±17.7 vs 84.7±5.5mU/L,P<0.01). The suppressive effect of insulin on FFA was significantly blunted in H group compared with NC group (0.82±0.03 vs 0.43±0.07mmol/L,P<0.01). Steady-state glucose infusion rate (GIR) was significantly decreased in H group compared with NC group (39.1±2.3 vs 54.2±2.2 mg·kg-1·min-1,P<0.01). Although GDR was increased in both group,but it was still lower in H group than in control group(47.9±0.8 vs 53.9±2.0 mg.kg-1.min-1,P<0.01).As compared with baseline,HGP in the controls was almost completely suppressed during steady state of clamp,but in H group suppressed by approximately 41%. Conclusions High-dose TNF-α treatment induces the abnormality of glucose-lipid metabolism and the insulin resistance of hepatic and peripheral tissue in mice