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

Hepatology. 1998 Jul;28(1):141-9. doi: 10.1002/hep.510280119.


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 (6,6-2H2-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 microg/24 h) designed to continuously reduce 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 approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Eating / physiology
  • Female
  • Glucose / metabolism
  • Glycogen Synthase / metabolism
  • Hormones / blood
  • Hormones / therapeutic use*
  • Humans
  • Hyperinsulinism / blood*
  • Hyperinsulinism / drug therapy*
  • Insulin / physiology*
  • Insulin Resistance / physiology*
  • Liver / metabolism
  • Liver Cirrhosis / physiopathology*
  • Male
  • Middle Aged
  • Octreotide / therapeutic use*
  • Oxidation-Reduction
  • Reference Values
  • Time Factors


  • Hormones
  • Insulin
  • Glycogen Synthase
  • Glucose
  • Octreotide