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

Diabetologia. 2003 Jul;46(7):917-25. doi: 10.1007/s00125-003-1129-1. Epub 2003 Jun 18.


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 (approximately 28 pmol/l) and glucagon (approximately 65 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 (approximately 99 ng/l) and (iv) AA-S (n=5): amino acid infusion without somatostatin resulting in amino acid-induced hyperinsulinaemia (approximately 61 pmol/l)-hyperglucagonaemia (approximately 147 ng/l). Net glycogenolysis was calculated from liver glycogen concentrations using (13)C nuclear magnetic resonance spectroscopy. Total gluconeogenesis (GNG) was calculated by subtracting net glycogenolysis from endogenous glucose production (EGP) which was measured with [6,6-(2)H(2)]glucose. Net GNG was assessed with the (2)H(2)O 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acids / blood
  • Amino Acids / pharmacology*
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Carbon Isotopes
  • Energy Intake
  • Gluconeogenesis / drug effects
  • Glucose / metabolism*
  • Humans
  • Kinetics
  • Liver / drug effects
  • Liver / metabolism*
  • Magnetic Resonance Spectroscopy
  • Male
  • Reference Values
  • Somatostatin / pharmacology


  • Amino Acids
  • Blood Glucose
  • Carbon Isotopes
  • Somatostatin
  • Glucose