Insulin resistance in cirrhosis: Prolonged reduction of hyperinsulinemia normalizes insulin sensitivity

Insulin resistance is present in nearly all patients with cirrhosis, but its etiology remains unknown. Chronic hyperinsulinemia has been suspected as a potential candidate, and we therefore tested the hypothesis that, in cirrhosis, prolonged reduction of the hyperinsulinemia restores insulin sensitivity. Whole-body insulin sensitivity (euglycemic insulin-clamp technique), glucose turnover (6,6-H-2(2)-glucose isotope dilution); glucose oxidation (indirect calorimetry), non-oxidative glucose disposal, and fractional glycogen synthase activity in muscle (biopsies) were measured in eight clinically stable patients with cirrhosis before and at the end of a 4-day continuous subcutaneous infusion of the somatostatin-analogue octreotide (200 mu g/24 h) designed to continuously;educe plasma insulin levels. Baseline data were compared with results obtained in healthy individuals matched for sex, age, and weight (n = 8), During the baseline (pre-octreotide) study, patients demonstrated a significant decrease in insulin-mediated glucose uptake compared with controls (5.75 +/- 0.21 vs. 7.98 +/- 0.84 mg/kg/min; P <.03), which was entirely accounted for by an impairment in non-oxidative glucose disposal (P <.04). Four-day infusion of octreotide to cirrhotic patients: 1) reduced postabsorptive and meal-stimulated plasma insulin levels by approximate to 35% to 45% without significantly affecting glucose tolerance; 2) did not significantly alter plasma free fatty acids' (FFA), growth hormone, and glucagon levels in the postabsorptive state and during the meal test; :3) normalized insulin-mediated whole-body glucose disposal (7.63 +/- 0.72 mg/kg/min post-octreotide; P = not significant vs. control). Restoration of insulin-mediated glucose utilization was entirely caused by normalization of non-oxidative glucose disposal; 4) was associated with a considerably more pronounced stimulation by insulin of the fractional glycogen synthase.in muscle compared with pre-octreotide results (increment above baseline pre: 0.035 +/- 0.010 vs. post: 0.060 +/- 0.023 nmol/min/mg protein; P <.04), Fractional glycogen activity significantly correlated with non-oxidative glucose disposal during insulin infusion (r =.69; P <.03), Prolonged reduction of hyperinsulinemia for 96 hours in cirrhotic patients normalizes insulin-mediated glucose uptake and glycogen synthesis in muscle. We conclude that chronic hyperinsulinemia causes insulin resistance in cirrhosis.