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Background: In vivo glucose uptake occurs via two mechanisms, namely insulin-mediated glucose uptake(IMGU) and non-insulin-mediated glucose up- take(NIMGU). NIMGU accaunts for about 70~85% of postabsorptive glucose uptake. Despite many studies, it is still controversial how an increase in lipolysis affects glucose metabolism in man. More specifically, the effect of free fatty acid(FFA) on NIMGU has not been exanuned. Method: Two-step(euglycemia-hyperglycemia) glucose clamp techique with [3-H]-glucose infusion was performed in 6 normal men. Each man was studied twice, with(test experiement) and without (control experiment) the administration of lipid and heparin at an interval of at least 4 weeks in random order. The subjects received an insulin infusion at 1.1 pmol/kg. min in conjuction with the infusion of somatostatin(step 1, 153 nmol/h; step 2, 458 nmol/h). Result: Plasma glucose levels during step 1 were 5.4+0.1 mmol/L(control experiment), 5.4+0.1 mmol/ L(test experiment), and were raised to 14.7+0.2 mmol/L, 14.6+0.1 mmol/L, respectively, during step 2. Plasma insulin levels during step 1 were 56+4 pmol/L(control experiment), 52+4 pmol/L(test experiment), and were 65+3 pmol/L, 62+4 pmol/L, respectively, during step 2. In control experiment, plasma FFA levels were 0.24+0.02 mmol/L during step 1 and 0.11+0.01 mmol/L during step 2. In test experiment, plasma FFA levels increased signifi- cantly to 1.08+0.06 mmol/L during step 1 and 1.01 +0.04 mmol/L during step 2, respectively(p<0.01). Glucose infusion rate(GIR) to increase glucose con- centrations to the desired levels were 7.7+0.8 pnol/ kg,min during step 1 and 29.7+3.7 pmol/kg.min during step 2 in control experiment. In test experi- ment, GIR decreawd significantly to 3.8+0.9 pmol/ kg.min during step 1 and 20.7+1.2 pmol/kg.min during step 2, respectively(p<0.05). There was no significant difference between NIMGU, estimated by the difference between glucose disapperance rate of step 1 and step 2 of lipid infusion test experiment and that of control experiment. Conclusion: These results showed that artificial elevation of plasma FFA levels led to a state of insulin resistance, however, the change of FFA level did not influence NIMGU in man.