The effect of chronic physiologic hyperglucagonemia on basal and insulin-mediated glucose metabolism was evaluated in normal subjects, using the euglycemic insulin clamp technique (+50, +100, and +500 μU/ml). After glucagon infusion fasting glucose increased from 76 ± 4 to 93 ± 2 mg/dl and hepatic glucose production (HGP) rose from 1.96 ± 0.08 to 2.25 ± 0.08 mg/kg·min (P < 0.001). Basal glucose oxidation after glucagon increased (P < 0.05) and correlated inversely with decreased free fatty acid concentrations (r = -0.94; P < 0.01) and decreased lipid oxidation (r = 0.75; P < 0.01). Suppression of HGP and stimulation of total glucose disposal were impaired at each insulin step after glucagon (P < 0.05-0.01). The reduction in insulin-mediated glucose uptake was entirely due to diminished non-oxidative glucose utilization. Glucagon infusion also caused a decrease in basal lipid oxidation and an enhanced ability of insulin to inhibit lipid oxidation and augment lipid synthesis. These results suggest that hyperglucagonemia may contribute to the disturbances in glucose and lipid metabolism in some diabetic patients.
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