Mechanisms of Hyperinsulinemia and Hyperglucagonemia after Liver Transplantation

Abstract These studies were undertaken to evaluate the mechanisms for changes in plasma insulin and glucagon levels observed post-liver transplantation. Two groups of pigs were studied: a control group ( n = 8) underwent laparotomy and catheter placement in the carotid artery and portal and hepatic veins. Hepatic blood flow was measured by ultrasonic flow probes placed around the hepatic artery and portal vein. An experimental group ( n = 8) underwent orthotopic liver transplantation and similar instrumentation. On Day 1 after surgery, an estimate of insulin and glucagon secretion and hepatic extraction was determined using arteriovenous difference techniques. Serum assays were performed for markers of hepatic and renal function. Plasma insulin levels of the transplanted pigs were higher in the carotid artery (4 ± 1 μU/ml vs 7 ± 1 μU/ml), but not in the hepatic vein (5 ± 1 μU/ml vs 7 ± 1 μU/ml) and in the portal vein (10 ± 2 μU/ml vs 12 ± 2 μU/ml). Arterial plasma C-peptide was significantly greater in the transplanted group (0.23 ± 0.02 ng/ml vs 0.42 ± 0.03 ng/ml); however, the molar ratio of C-peptide and insulin was not different between the two groups (3.6 ± 0.9 vs 3.4 ± 0.4). Plasma glucagon levels of the transplanted pigs were significantly elevated in the carotid artery (111 ± 11 pg/ml vs 323 ± 65 pg/ml), portal vein (221 ± 27 pg/ml vs 495 ± 69 pg/ml), and hepatic vein (142 ± 15 pg/ml vs 395 ± 58 pg/ml). The estimate of pancreatic secretion of insulin (115 ± 28 μU/kg·min) vs 71 ± 21 μU/kg·min) and glucagon (2.0 ± 0.4 ng/kg·min vs 2.7 ± 0.7 ng/kg·min) and the fractional hepatic extraction rate of insulin (35 ± 8% vs 32 ± 5%) were not different between the two groups. However, the hepatic fractional extraction rate of glucagon was significantly decreased in the transplanted group (25 ± 5% vs 11 ± 3%). Therefore, the hyperglucagonemia observed 24 hr following liver transplantation is partly due to reduced hepatic fractional extraction of glucagon while the hyperinsulinemia is mainly due to the nonhepatic clearance of insulin. We speculate that decreased renal function may contribute to the hyperinsulinemia, elevated C-peptide concentrations, and hyperglucagonemia.