The study investigates the mechanism by which lipids cause insulin resistance in humans. Nine healthy subjects underwent euglycemic-hyperinsulinemic clamps with low (0.18 mM) and high (1.93 mM) plasma free fatty acid (FFA) levels for 6 hours. During the initial 3.5 hours, whole-body glucose uptake was not affected by FFA infusion, but it decreased continuously to 46% of control values after 6 hours. Augmented lipid oxidation led to a 40% reduction in oxidative glucose metabolism starting at the third hour of FFA infusion. Muscle glycogen synthesis rates were similar during the first 3 hours but decreased to 50% of control values thereafter. Muscle glucose-6-phosphate concentrations fell at around 1.5 hours, indicating a reduction in muscle glycogen synthesis. These findings suggest that FFA-induced insulin resistance in humans involves initial inhibition of glucose transport and phosphorylation, followed by a significant reduction in muscle glycogen synthesis and glucose oxidation. This mechanism differs from the classical model proposed by Randle et al., which attributes insulin resistance to the initial inhibition of pyruvate dehydrogenase. The study highlights the importance of altered intramuscular FFA metabolism in the pathogenesis of insulin resistance in patients with non-insulin-dependent diabetes mellitus (NIDDM).The study investigates the mechanism by which lipids cause insulin resistance in humans. Nine healthy subjects underwent euglycemic-hyperinsulinemic clamps with low (0.18 mM) and high (1.93 mM) plasma free fatty acid (FFA) levels for 6 hours. During the initial 3.5 hours, whole-body glucose uptake was not affected by FFA infusion, but it decreased continuously to 46% of control values after 6 hours. Augmented lipid oxidation led to a 40% reduction in oxidative glucose metabolism starting at the third hour of FFA infusion. Muscle glycogen synthesis rates were similar during the first 3 hours but decreased to 50% of control values thereafter. Muscle glucose-6-phosphate concentrations fell at around 1.5 hours, indicating a reduction in muscle glycogen synthesis. These findings suggest that FFA-induced insulin resistance in humans involves initial inhibition of glucose transport and phosphorylation, followed by a significant reduction in muscle glycogen synthesis and glucose oxidation. This mechanism differs from the classical model proposed by Randle et al., which attributes insulin resistance to the initial inhibition of pyruvate dehydrogenase. The study highlights the importance of altered intramuscular FFA metabolism in the pathogenesis of insulin resistance in patients with non-insulin-dependent diabetes mellitus (NIDDM).