Premium
Insulin resistance in cirrhosis: Prolonged reduction of hyperinsulinemia normalizes insulin sensitivity
Author(s) -
Petrides Alexander S.,
Stanley Timmye,
Matthews Dwight E.,
Vogt Christoph,
Bush Andrew J.,
Lambeth Helen
Publication year - 1998
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510280119
Subject(s) - medicine , endocrinology , hyperinsulinemia , insulin , insulin resistance , octreotide , glucagon , somatostatin , glucose clamp technique , cirrhosis , pancreatic hormone
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‐ 2 H 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 μg/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 ≈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.