Glucose intolerance, hyperinsulinemia, peripheral insulin resistance and hyperglucagonemia are common in patients with advanced liver disease. These abnormalities in the plasma levels of the pancreatic hormones, insulin and glucagon have been thought to be responsible, at least in part, for the abnormal plasma ratio of branched-chain amino acids to aromatic amino acids. To evaluate this issue, plasma levels of glucose, insulin, glucagon, C-peptide and the branched-chain and aromatic amino acids were measured before and serially after orthotopic liver transplantation in 9 humans and 5 dogs. The abnormal plasma amino acid levels rapidly improved and achieved normal levels following orthotopic liver transplantation. Insulin levels also became normal following orthotopic liver transplantation, despite enhanced insulin secretion documented by an even further increased level of C-peptide. In contrast, the baseline abnormal plasma glucagon levels which are commonly seen in cirrhotics became even more abnormal following orthotopic liver transplantation. Despite this progressive increase in the abnormally elevated plasma glucagon levels, plasma amino acid levels, both branched-chain and aromatic, became normal. These data demonstrate that before and after orthotopic liver transplantation, there is: (i) no relationship between the changes in the plasma levels of glucagon and changes observed in the plasma level of amino acids; and (ii) plasma insulin and amino acid levels change in the same direction. In addition, these changes in plasma insulin and amino acid levels following orthotopic liver transplantation occur despite enhanced secretion of insulin evidenced by the progressive increase in plasma levels of C-peptide.