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.