Mechanism of insulin resistance in human liver cirrhosis

Insulin resistance in liver cirrhosis may depend on either reduced sensitivity (receptor defect) and/or reduced response to insulin (postreceptor defect). To clarify the mechanism of such resistance, a [³H]glucose infusion (0.2 μCi/min) was performed for 120 min before and during a euglycemic clamp at ~100, 1,000, and 10,000 μU/ml steady state plasma insulin concentration in 18 compensated cirrhotics with portal hypertension and impaired glucose tolerance, and 18 healthy volunteers with no family history of diabetes, matched for sex, age, and weight. Mean fasting plasma insulin (29.2±3.4 SEM vs. 14.8±1.1 μU/ml) was significantly higher (P<0.001) in cirrhotics, while fasting plasma glucose was much the same in the two groups. Glucose use (milligrams per kilogram per minute) was significantly lower in cirrhotics at all three steady state plasma insulin levels: 3.04±0.34 vs. 7.72±0.61 (P<0.001) at ~100; 6.05±1.07 vs. 11.45±1.24 (P<0.001) at ~1,000; and 11.69±0.69 vs. 14.13±0.74 (P<0.05) at ~10,000 μU/ml. Mean plasma C-peptide was significantly higher in cirrhotics both basally and during the steady states (P<0.001); it was completely suppressed at ~10,000 μU/ml in controls and only 57.5% of the baseline in cirrhotics. Endogenous glucose production (milligrams per kilogram per minute) was much the same in the two groups in the fasting state and almost entirely suppressed in the controls (0.10±0.05 vs. 0.48±0.11, P<0.001) at ~100 μU/ml; at ~ 1,000 μU/ml a residual glucose production, 0.07±0.05, was observed in the cirrhotics only. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro in six cirrhotics and six controls. Insulin binding to circulating monocytes and isolated adipocytes was significantly lower (P<0.025) in cirrhotics in all insulin concentration studies. Glucose transport values on isolated adipocytes were significantly lower in cirrhotics both basally (P<0.001) and at maximal insulin concentration (P<0.05). These results suggest that insulin resistance in human cirrhosis is more dependent on depressed peripheral glucose use than on increased endogenous glucose production, and that a combined receptor and postreceptor defect in insulin action on target cells seems to be present.