Feedback Inhibition of Isulin Secretion is Altered in Cirrhosis*

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Abstract
Hyperinsulinemia in human cirrhosis is generally considered an expression of reduced hepatic insulin degradation. To determine whether hyperinsulinemia may also depend on an altered feedback inhibition of insulin secretion, we performed euglycemic hyperinsulinemic clamp studies, infusing 40, 372, or 1280 mU/m(2)-min biosynthetic human insulin in 30 compensated cirrhotic patients with portal hypertension and impaired glucose tolerance and 25 normal subjects, matched for age, sex, and weight. Mean fasting plasma insulin was significantly higher in cirrhotic patients [26.1 ± 2.3 vs. 12.4 ± 0.6 (±SE) μU/ml; P < 0.001], while fasting plasma glucose levels were similar in the 2 groups. The mean plasma C-peptide level was significantly higher in cirrhotic patients, both basally (2.7± 0.1 vs. 1.7 ± 0.1 ng/ml; P < 0.001) and during the clamp studies. Suppression of C-peptide at 120 min of the clamp was significantly less in cirrhotic patients (37 ± 7% vs. 79 ± 4%, 52 ± 9% vs. ∼100%, and 54 ± 4% vs ∼100% during the 40, 372, and 1280 mU/m(2)-min insulin infusions, respectively). The fasting C-peptide to insulin molar ratio was significantly lower in cirrhotic patients (5.4 ± 0.3 vs. 6.4 ± 0.3; P < 0.005). The MCR of insulin at the three steady states was not significantly different between the 2 groups, whereas the basal systemic delivery rate of insulin was significantly higher in cirrhotic patients (14.7 ± 1.7 vs. 6.5 ± 0.4 mU/m(2)· min; P < 0.001). These results suggest that reduced feedback inhibition of insulin secretion may contribute to the hyperinsulinemia associated with cirrhosis.