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.

Differing effects of pancreas-kidney transplantation with systemic versus portal venous drainage on cholesteryl ester transfer in IDDM subjects.

OBJECTIVE: Cholesteryl ester transfer (CET) is accelerated in patients with IDDM treated with conventional (subcutaneous) insulin therapy (CIT) and a number of other disorders associated with premature cardiovascular disease. We have shown that in IDDM this disturbance is closely linked to iatrogenic hyperinsulinemia (HI), because it was reversed when insulin was administered by the intraportal (i.p.) route. In this study, we sought to determine whether HI after successful pancreas-kidney transplantation (PKT) has the same adverse effect on CET. RESEARCH DESIGN AND METHODS: CET was measured by both mass and isotopic assays and compared in two groups of euglycemic non-insulin-requiring IDDM PKT patients with either systemically draining allografts and persistent HI or grafts with portal vein anastomoses that were normoinsulinemic (PK-P). A third group of eight nondiabetic kidney transplant (KT) patients receiving the same immunosuppressive drugs served as control subjects. RESULTS: CET in pancreas-kidney transplantation subjects with systemic venous drainage (PK-S) was increased (P < 0.001) to the same level we have reported previously in IDDM patients receiving CIT and was significantly higher (P < 0.001) than in those subjects with PK-P. CET in the PK-P group did not differ from that of the KT control patients. CONCLUSIONS: CET is affected by variations in systemic insulin levels in pancreas transplant patients with allografts that have differing venous drainage. Because high systemic insulin levels are linked to the activation of (ET, euglycemic HI IDDM pancreas allograft recipients may continue to be at high risk for macrovascular complications.