Mechanism of free fatty acid-induced insulin resistance in humans

To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18±0.02 mM [mean±SEM]; control) or high (1.93±0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (~ 5.2 mM) hyperinsulinemic (~ 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be ~ 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a ~ 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to ~ 50% of control values (4.0±1.0 vs. 9.3±1.6 μmol/[kg · min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at ~ 1.5 h (195±25 vs. control: 237±26 μM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an ~ 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation