Feedback inhibition of insulin secretion is altered in cirrhosis.

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/m2 X 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) microU/ml; P less than 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 less than 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. approximately 100%, and 54 +/- 4% vs. approximately 100% during the 40, 372, and 1280 mU/m2 X 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 less than 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/m2 X min; P less than 0.001). These results suggest that reduced feedback inhibition of insulin secretion may contribute to the hyperinsulinemia associated with cirrhosis.

Insulin resistance in human liver cirrhosis is not modified by porto-systemic surgical shunt.

Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinaemia. It is considered an insulin resistant state with both a receptor and a post-receptor defect of insulin activity. It would appear that reduced hepatic degradation rather than increased B-cell production is responsible for hyperinsulinaemia. The effect of surgical portosystemic shunt on insulin resistance was studied in 18 cirrhotics with impaired glucose tolerance (12 males, 6 females; mean age 46.9 +/- 0.7 years) by measuring: glucose production (3H-glucose infusion), glucose utilisation (euglycaemic clamp at approximately 100, approximately 1000 and approximately 10,000 microU/1), plasma insulin and C-peptide levels, and liver function indices (serum bilirubin, albumin, ALT, GGT) before and 2 months after surgery. Liver sorbitol clearance was also employed to measure variations in the functional liver plasma flow induced by the shunt. No significant changes were noted in: glucose production (1.94 +/- 0.17 SEM vs 1.96 +/- 0.17 mg/kg/min), glucose utilisation (metabolic clearance rate: 3.32 +/- 0.48 vs 3.42 +/- 0.43 at approximately microU/ml; 9.70 +/- 1.0 vs 9.16 +/- 0.9 at approximately 1000 microU/ml; 10.92 +/- 1.1 vs 11.07 +/- 0.8 ml/kg/min at approximately 10 000 microU/ml), fasting plasma insulin, C-peptide and C-peptide/insulin molar ratio (4.66 +/- 0.47 vs 5.50 +/- 0.54), and the liver function indices. By contrast, there was a significant decrease in functional liver plasma flow (813 +/- 34 vs 604 +/- 34 ml/min, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of insulin resistance in human liver cirrhosis. Evidence of a combined receptor and postreceptor defect.

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 microCi/min) was performed for 120 min before and during a euglycemic clamp at approximately 100, 1,000, and 10,000 microU/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 microU/ml) was significantly higher (P less than 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 less than 0.001) at approximately 100; 6.05 +/- 1.07 vs. 11.45 +/- 1.24 (P less than 0.001) at approximately 1,000; and 11.69 +/- 0.69 vs. 14.13 +/- 0.74 (P less than 0.05) at approximately 10,000 microU/ml. Mean plasma C-peptide was significantly higher in cirrhotics both basally and during the steady states (P less than 0.001); it was completely suppressed at approximately 10,000 microU/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 less than 0.001) at approximately 100 microU/ml; at approximately 1,000 microU/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 less than 0.025) in cirrhotics in all insulin concentration studies. Glucose transport values on isolated adipocytes were significantly lower in cirrhotics both basally (P less than 0.001) and at maximal insulin concentration (P less than 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.

Dietary guar gum supplementation does not modify insulin resistance in gross obesity.

Obesity is considered an insulin resistant state. Dietary guar gum supplementation is able to reduce blood glucose and plasma insulin response to a carbohydrate meal. In order to evaluate whether guar is able to reduce hyperinsulinemia and insulin resistance in gross obesity, we studied 9 obese patients, greater than 50% overweight with impaired glucose tolerance before and after 4 + 4 g/day guar for 6 weeks. Six patients repeated the treatment with 8 + 8 g/day guar after a 3-month interval. Guar was added to the usual diet in order to maintain the body weight constant. Pre-treatment and post treatment study included: total specific insulin binding on circulating monocytes; 3H-glucose infusion and euglycemic hyperinsulinemic clamp at approximately 100 microU/ml. The differences between post-treatment and pre-treatment values were not significant for any of the parameters studied. Fasting glucose production was: 2.17 +/- 0.33 SEM (pretreatment) vs 2.18 +/- 0.18 (4 + 4 g/day) vs 2.28 +/- 0.14 (8 + 8 g/day) mg/kg/min; glucose utilization was: 3.52 +/- 0.43 vs 3.22 +/- 0.44 vs 3.49 +/- 0.63 mg/kg/min; total specific insulin binding was: 2.80 +/- 0.20 vs 2.75 +/- 0.25 vs 2.78 +/- 0.31%; body weight was: 101.4 +/- 5.4 vs 100.2 +/- 6.2 vs 100.5 +/- 7.0 kg. These results indicate that dietary guar gum supplementation per se is unable to reduce insulin resistance in gross obesity if overweight is maintained constant.