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 (6,6-2H2-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.
Petrides
A S
AS
Department of Medicine and Gastroenterology, Academic Hospital of the Ruhr University, Bochum, Germany.
Stanley
T
T
Matthews
D E
DE
Vogt
C
C
Bush
A J
AJ
Lambeth
H
H
D004435:Eating / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006728:Hormones / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood* / Q000188:drug therapy*; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D012016:Reference Values; D013997:Time Factors
D006728:Hormones; D007328:Insulin; D006006:Glycogen Synthase; D005947:Glucose; D015282:Octreotide