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To examine the influence of elevated free fatty acid (FFA) levels on hepatic glucose production (HGP) and oxidative and nonoxidative pathways of glucose metabolism, 12 healthy subjects participated in two euglycemic insulin-clamp studies performed with and without infusion of Intralipid plus heparin. To elucidate the role of skeletal muscle in this putative interaction, we performed muscle biopsies for the measurement of activities of glycogen synthase (GS), pyruvate dehydrogenase (PDH), and carnitine palmitoyltransferase (CPT). Infusion of Intralipid plus heparin caused an increase in plasma FFA concentrations and rate of lipid oxidation (measured by indirect calorimetry) that was not inhibited by insulin. Suppression of HGP by insulin was impaired by elevated plasma FFA levels. Furthermore, the increase in plasma FFA was associated with a 20% reduction in total glucose metabolism (P < 0.01), which was completely accounted for by a reduction in the rate of glucose oxidation. Although the fractional activity of GS was increased by insulin, elevation of plasma FFA had no influence on this key enzyme of glycogen synthesis. In addition, the activities of PDH and CPT were uninfluenced by the elevation of FFA, suggesting that oxidative processes in skeletal muscle were not a major target for the operative glucose-fatty acid cycle under the current conditions. Taken together, the data indicate that the interaction between FFA and glucose metabolism also involves impaired suppression of HGP by insulin.

Peripheral hyperinsulinaemia is the cause of metabolic changes that might contribute to the high incidence of macrovascular disease in patients with diabetes mellitus. In order to test this hypothesis muscle biopsies from 12 Type 2 diabetic patients and 14 age and sex matched non-diabetic patients, undergoing minor surgery, were obtained. The diabetic patients had significantly elevated fasting serum insulin (0.29 +/- 0.05 vs 0.06 +/- 0.03 nmol-1) and glucose (8.3 +/- 1.5 vs 4.6 +/- 0.5 mmol-1) and HbA1 levels (8.4 +/- 0.4 vs 5.0 +/- 0.2 per cent). The fasting and 2-h postprandial C-peptide levels were 0.99 +/- 0.25 vs 0.39 +/- 0.12 and 3.12 +/- 0.75 vs 1.09 +/- 0.34 nmol/l, respectively. The diabetic patients showed a marked elevation of triglyceride in the striated muscle biopsies compared to the non-diabetic controls (290 +/- 52 vs 48 +/- 6 mumol/g wet weight, p less than 0.001). Moreover, the activities of glucose-6-phosphate dehydrogenase (0.25 +/- 0.03 vs 0.13 +/- 0.01 U/g wet weight) and malic enzyme (0.15 +/- 0.01 vs 0.05 +/- 0.01 U/g wet weight), necessary for lipid synthesis, were significantly increased (both p less than 0.001) in the diabetic patients while the glycolytic enzymes, hexokinase (0.65 +/- 0.09 vs 1.82 +/- 0.11 U/g wet weight), pyruvate kinase (7.3 +/- 0.9 vs 13.2 +/- 0.9 U/g wet weight), phosphofructokinase (1.3 +/- 0.2 vs 2.6 +/- 0.2 U/g wet weight), and alpha-glycerophosphate dehydrogenase (7.3 +/- 0.5 vs 12.5 +/- 0.7 U/g wet weight) were decreased (all p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

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