Direct and indirect effects of amino acids on hepatic glucose metabolism in humans

Aim/hypothesis. The study was designed to examine the contribution of direct (substrate-mediated) and indirect (hormone-mediated) effects of amino acids on hepatic glucose metabolism in healthy men. Methods. The protocols were: (i) CON+S (n=7): control conditions with somatostatin to inhibit endogenous hormone release resulting in fasting plasma concentrations of amino acids, insulin (similar to28 pmol/l) and glucagon (similar to65 ng/l), (ii) AA+S (n=7): amino acid infusion-fasting insulinaemia-fasting glucagonaemia, (iii) GLUC+S (n=6): fasting amino acids-fasting insulinaemia-hyperglucagonaemia (similar to99 ng/l) and (iv) AA-S (n=5): amino acid infusion without somatostatin resulting in amino acid-induced hyperinsulinaemia (similar to61 pmol/l)-hyperglucagonaemia (similar to147 ng/l). Net glycogenolysis was calculated from liver glycogen concentrations using C-13 nuclear magnetic resonance spectroscopy. Total gluconeogenesis (GNG) was calculated by subtracting net glycogenolysis from endogenous glucose production (EGP) which was measured with [6,6-H-2(2)]glucose. Net GNG was assessed with the (H2O)-H-2 method. Results. During AA+S and GLUC+S, plasma glucose increased by about 50% (p<0.01) due to a comparable rise in EGP. This was associated with a 53-% (p<0.05) and a 65% increase (p<0.01) of total and net GNG during AA+S, whereas net glycogenolysis rose by 70% (p<0.001) during GLUC+S. During AA-S, plasma glucose remained unchanged despite nearly-doubled (p<0.01) total GNG. Conclusion/interpretation. Conditions of postprandial amino acid elevation stimulate secretion of insulin and glucagon without affecting glycaemia despite markedly increased gluconeogenesis. Impaired insulin secretion unmasks the direct gluconeogenic effect of amino acids and increases plasma glucose.