Enhanced Secretion of Glucagon-Like Peptide 1 by Biguanide Compounds

Biochem Biophys Res Commun. 2002 Nov 15;298(5):779-84. doi: 10.1016/s0006-291x(02)02565-2.


Metformin was reported to increase plasma active glucagon-like peptide-1 (GLP-1) in humans. There are two possible mechanisms for this effect: (1) metformin inhibits dipeptidyl peptidase IV (DPPIV), an enzyme degrading GLP-1, and (2) metformin enhances GLP-1 secretion. To elucidate the mechanism(s), we examined (1) IC(50) of metformin for DPPIV inhibition, (2) plasma active GLP-1 changes after oral biguanide (metformin, phenformin, and buformin) treatment in fasting DPPIV-deficient F344/DuCrj rats, and (3) plasma intact GLP-1 excursions after oral administration of metformin and/or valine-pyrrolidide, a DPPIV inhibitor, in fasting DPPIV-positive F344/Jcl rats. Our in vitro assay showed that metformin at up to 30mM has no inhibitory activity towards porcine or rat DPPIV. Metformin treatment (30, 100, and 300mg/kg) increased plasma active GLP-1 levels dose-dependently in DPPIV-deficient F344/DuCrj rats (approximately 1.6-fold at 3 and 5h after administration of 300mg/kg). This treatment had no effect on blood glucose levels. Similarly, phenformin and buformin (30 and 100mg/kg) elevated plasma intact GLP-1 levels in F344/DuCrj rats. In DPPIV-positive F344/Jcl rats, coadministration of metformin (300mg/kg) and valine-pyrrolidide (30mg/kg) resulted in elevation of plasma active GLP-1, but neither metformin nor valine-pyrrolidide treatment alone had any effect. These findings suggest that metformin has no direct inhibitory effect on DPPIV activity and that metformin and the other biguanides enhance GLP-1 secretion, without altering glucose metabolism. Combination therapy with metformin and a DPPIV inhibitor should be useful for the treatment of diabetes.

MeSH terms

  • Animals
  • Biguanides / pharmacology*
  • Buformin / pharmacology
  • Dipeptidyl Peptidase 4 / metabolism
  • Glucagon / blood
  • Glucagon / metabolism*
  • Glucagon-Like Peptide 1
  • Glucose / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology
  • In Vitro Techniques
  • Male
  • Metformin / pharmacology
  • Peptide Fragments / blood
  • Peptide Fragments / metabolism*
  • Phenformin / pharmacology
  • Protease Inhibitors / pharmacology
  • Protein Precursors / blood
  • Protein Precursors / metabolism*
  • Pyrroles / pharmacology
  • Rats
  • Rats, Inbred F344
  • Valine / pharmacology


  • Biguanides
  • Hypoglycemic Agents
  • Peptide Fragments
  • Protease Inhibitors
  • Protein Precursors
  • Pyrroles
  • valine-pyrrolidide
  • Glucagon-Like Peptide 1
  • Glucagon
  • Metformin
  • Phenformin
  • Dipeptidyl Peptidase 4
  • Valine
  • Glucose
  • Buformin