MECHANISM OF FREE FATTY ACID-INDUCED INSULIN-RESISTANCE IN HUMANS

To examine the mechanism by which lipids cause insulin resistance in h umans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous C-13 and P-31 nuclear magn etic resonance spectroscopy in nine healthy subjects in the presence o f low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.0 4 mM; lipid infusion) plasma free fatty acid levels under euglycemic ( similar to 5.2 mM) hyperinsulinemic (similar to 400 pM) clamp conditio ns for 6 h, During the initial 3.5 h of the clamp the rate of whole-bo dy glucose uptake was not affected by lipid infusion, but it then decr eased continuously to be similar to 46% of control values after 6 h (P < 0.00001), Augmented lipid oxidation was accompanied by a similar to 40% reduction of oxidative glucose metabolism starting during the thi rd hour of lipid infusion (P < 0.05), Rates of muscle glycogen synthes is were similar during the first 3 h of lipid and control infusion, bu t thereafter decreased to similar to 50% of control values (4.0 +/- 1. 0 vs, 9.3 +/- 1.6 mu mol/[kg . min], P < 0.05), Reduction of muscle gl ycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at similar to 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mu M; P < 0.01), Therefo re in contrast to the originally postulated mechanism in which free fa tty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these res ults demonstrate that free fatty acids induce insulin resistance in hu mans by initial inhibition of glucose transport/phosphorylation which is then followed by an similar to 50% reduction in both the rate of mu scle glycogen synthesis and glucose oxidation.