Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans

Abstract

To examine the fate of insulin across the liver bed, biosynthetic human insulin was infused in increasing amounts in six healthy men. Trapping of insulin by the liver was determined by means of the hepatic venous catheter technique. To minimize any possible error in the estimation of insulin removal as a result of endogenous insulin, pancreatic insulin secretion was suppressed by intravenous administration of somatostatin (500 μg/h). Infusion rates of human insulin were 30, 60, and 150 pmol/m 2 · min (corresponding to 0.25, 0.5, and 1.25 U/m 2 · h) for 70 minutes each. Steady-state insulin levels were within the physiologic range, ie, 69 ± 2, 135 ± 3, and 342 ± 10 pmol/L, respectively. Euglycemia was maintained throughout the study by a variable glucose infusion. The output of C-peptide from the splanchnic bed was reduced by somatostatin by about 90%, indicating that endogenous insulin production only minimally contributed to total insulin levels achieved during infusion of exogenous human insulin. Fractional extraction of insulin by the liver (63 ± 6%, 71 ± 4%, and 74 ± 5%) and hepatic insulin clearance (201 ± 19, 235 ± 23, and 245 ± 29 mL/m 2 · min) did not differ significantly during the three insulin infusion studies. The hepatic uptake of insulin rose with increasing insulin infusion rates, constituting 40% to 60% of total-body insulin removal. No change in the total metabolic clearance rate of insulin was observed between the groups (451 ± 8 mL/m 2 · min). To study the extraction rate of C-peptide by the liver, porcine C-peptide was also infused at the same increasing rates. The failure to detect any concentration gradient of the porcine C-peptide across the splanchnic bed indicates that C-peptide is not extracted by the liver in humans. The results obtained in both studies validate our previously reported data on endogenous secretion and hepatic handling of insulin derived from calculations of splanchnic output of C-peptide and insulin.