As. Petrides et al., INSULIN-RESISTANCE IN CIRRHOSIS - PROLONGED REDUCTION OF HYPERINSULINEMIA NORMALIZES INSULIN SENSITIVITY, Hepatology, 28(1), 1998, pp. 141-149
Insulin resistance is present in nearly all patients with cirrhosis, b
ut its etiology remains unknown. Chronic hyperinsulinemia has been sus
pected as a potential candidate, and we therefore tested the hypothesi
s that, in cirrhosis, prolonged reduction of the hyperinsulinemia rest
ores insulin sensitivity. Whole-body insulin sensitivity (euglycemic i
nsulin-clamp technique), glucose turnover (6,6-H-2(2)-glucose isotope
dilution); glucose oxidation (indirect calorimetry), non-oxidative glu
cose disposal, and fractional glycogen synthase activity in muscle (bi
opsies) were measured in eight clinically stable patients with cirrhos
is before and at the end of a 4-day continuous subcutaneous infusion o
f the somatostatin-analogue octreotide (200 mu g/24 h) designed to con
tinuously;educe plasma insulin levels. Baseline data were compared wit
h results obtained in healthy individuals matched for sex, age, and we
ight (n = 8), During the baseline (pre-octreotide) study, patients dem
onstrated a significant decrease in insulin-mediated glucose uptake co
mpared with controls (5.75 +/- 0.21 vs. 7.98 +/- 0.84 mg/kg/min; P <.0
3), which was entirely accounted for by an impairment in non-oxidative
glucose disposal (P <.04). Four-day infusion of octreotide to cirrhot
ic patients: 1) reduced postabsorptive and meal-stimulated plasma insu
lin levels by approximate to 35% to 45% without significantly affectin
g glucose tolerance; 2) did not significantly alter plasma free fatty
acids' (FFA), growth hormone, and glucagon levels in the postabsorptiv
e state and during the meal test; :3) normalized insulin-mediated whol
e-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 gluc
ose disposal; 4) was associated with a considerably more pronounced st
imulation by insulin of the fractional glycogen synthase.in muscle com
pared with pre-octreotide results (increment above baseline pre: 0.035
+/- 0.010 vs. post: 0.060 +/- 0.023 nmol/min/mg protein; P <.04), Fra
ctional glycogen activity significantly correlated with non-oxidative
glucose disposal during insulin infusion (r =.69; P <.03), Prolonged r
eduction of hyperinsulinemia for 96 hours in cirrhotic patients normal
izes insulin-mediated glucose uptake and glycogen synthesis in muscle.
We conclude that chronic hyperinsulinemia causes insulin resistance i
n cirrhosis.