Kinetics of glucose metabolism in relation to insulin concentrations in patients with alcoholic cirrhosis and in healthy persons.

To characterize the insulin resistance in alcoholic cirrhosis we determined in vivo insulin-glucose disposal dose-response relationships in 6 patients with alcoholic cirrhosis of varying severity and in 6 control subjects, using the glucose-insulin clamp technique. Each subject was infused sequentially with insulin at rates of 0.5, 1.0, 2.0, and 10 mU/min X kg, each rate for 2 h. Euglycemia was maintained by a continuous servo-adjusted glucose infusion. The amount of glucose infused during the last 40 min of each 2-h period, corrected for accumulation in the glucose space, reflects overall net glucose metabolism. The dose-response curves demonstrated saturation kinetics. Lineweaver-Burk plots were consistently convex, rejecting a simple Michaelis-Menten relationship, but were linear when accommodated to allosterism with two active sites. The calculated affinity constant (i.e., the concentration of insulin leading to half-maximum glucose metabolism) of patients with cirrhosis was higher than that of normal controls (104 +/- 30 vs. 32 +/- 3 mU/L, mean +/- SD). In addition the maximum rate of glucose metabolism was significantly lower than that of normals (53 +/- 9 vs. 72 +/- 16 mumol/min X kg). We conclude that, in patients with alcoholic cirrhosis, insulin resistance is caused both by a marked decrease in sensitivity to insulin and a decreased maximum effect of insulin, indicating a combined receptor-postreceptor defect as the underlying cause.