EFFECT OF INCREASED FREE FATTY-ACID SUPPLY ON GLUCOSE-METABOLISM AND SKELETAL-MUSCLE GLYCOGEN-SYNTHASE ACTIVITY IN NORMAL MAN

1. Experimental elevation of plasma non-esterified fatty acid concentrations has been postulated to decrease insulin-stimulated glucose oxidation and storage rates. Possible mechanisms were examined by measuring skeletal muscle glycogen synthase activity and muscle glycogen content before and during hyperinsulinaemia while fasting plasma non-esterified fatty acid levels were maintained. 2. Fasting plasma non-esterified fatty acid levels were maintained in seven healthy male subjects by infusion of 20% (w/v) Intralipid (1 ml/min) for 120 min before and during a 240 min hyperinsulinaemic euglycaemic clamp (100 m-units h-1 kg-1) combined with indirect calorimetry. On the control day, 0.154 mol/l NaCl was infused. Vastus lateralis muscle biopsy was performed before and at the end of the insulin infusion. 3. On the Intralipid study day serum triacylglycerol (2.24 +/- 0.20 versus 0.67 +/- 0.10 mmol/l), plasma non-esterified fatty acid (395 +/- 13 versus 51 +/- 1-mu-mol/l), blood glycerol (152 +/- 2 versus 11 +/- 1-mu-mol/l) and blood 3-hydroxybutyrate clamp levels [mean (95% confidence interval)] [81 (64-104) versus 4 (3-5) mu-mol/l] were all significantly higher (all P < 0.001) than on the control study day. Lipid oxidation rates were also elevated (1.07 +/- 0.07 versus 0.27 +/- 0.08 mg min-1 kg-1, P < 0.001). During the clamp with Intralipid infusion, insulin-stimulated whole-body glucose disposal decreased by 28% (from 8.53 +/- 0.77 to 6.17 +/- 0.71 mg min-1 kg-1, P < 0.005). This was the result of a 48% decrease in glucose oxidation (3.77 +/- 0.32 to 1.95 +/- 0.21 mg min-1 kg-1, P < 0.001), with no significant change in non-oxidative glucose disposal (4.76 +/- 0.49 to 4.22 +/- 0.57 mg min-1 kg-1, not significant). 4. Basal and insulin-stimulated glycogen synthase activities (13.1 +/- 1.9 versus 11.4 +/- 2.3% and 30.8 +/- 2.3 versus 27.6 +/- 4.5%, respectively) were unaffected by the increased plasma non-esterified fatty acid levels. Similarly, basal (36.1 +/- 2.7 versus 37.2 +/- 1.4-mu-mol/g) and stimulated (40.0 +/- 0.6 versus 37.6 +/- 4.4-mu-mol/g) muscle glycogen levels were unaltered. Insulin-stimulated hexokinase activity was also not affected (0.52 +/- 0.08 versus 0.60 +/- 0.08 units/g wet weight). 5. Maintenance of plasma non-esterified fatty acid levels at fasting values resulted in an increase in lipid oxidation and was associated with a decrease in insulin-stimulated whole-body glucose uptake and glucose oxidation rates, but no change in non-oxidative glucose disposal. Increased plasma non-esterified fatty acid levels did not appear to have a direct inhibitory effect on glycogen synthase activity or storage of glucose as glycogen at these insulin levels.