To elucidate the relative contribution of parenchymal liver damage and spontaneous portal-systemic shunting to the reduction of peripheral insulin degradation rate and the decrease in plasma concentrations of three branched chain amino acids (valine, leucine, and isoleucine), plasma insulin, C-peptide, and amino acid concentrations were measured during oral glucose tolerance tests in 17 patients with liver cirrhosis, 10 with idiopathic portal hypertension, 5 hospitalized controls, and normal subjects. None of the patients had evidence of hepatic encephalopathy. Patients with idiopathic portal hypertension had histologically minimum hepatic fibrosis in spite of the existence of extensive exophageal varices. The molar ratio between plasma concentrations of C-peptide and insulin was significantly decreased in patients with cirrhosis, but not in those with idiopathic portal hypertension. In both patients with cirrhosis and idiopathic portal hypertension, the three branched chain amino acid levels were significantly decreased and the molar ratio between the concentrations of the three branched chain amino acids and two aromatic amino acids (tyrosine and phenylalanine) were markedly reduced. These results suggest that spontaneous portal-systemic shunting does not primarily contribute to the reduced degradation of insulin, but has a close relationship with the decrease in branched chain amino acid levels and in the molar ratio of plasma amino acids. In addition, the present data indicate that decreased branched chain amino acid levels in patients with cirrhosis is not merely ascribed to hyperinsulinemia and that the decrease in the molar ratio of plasma amino acids is not specific to the presence of hepatic encephalopathy.