Stimulation of the intracellular portion of the human insulin receptor by the antidiabetic drug metformin

Biochem Pharmacol. 1998 Feb 15;55(4):533-6. doi: 10.1016/s0006-2952(97)00540-6.


Our prior work suggested that the antidiabetic metformin must enter the cell to act and that the drug stimulates tyrosine kinase activity. We now report that therapeutic concentrations (approximately 1 microg/mL) of metformin stimulated the tyrosine kinase activity of the intracellular portion of the beta-subunit of the human insulin receptor (IPbetaIRK), the intracellular portion of the epidermal growth factor receptor and pp60-src, but not cAMP-dependent protein kinase. A derivative of metformin unable to lower glucose was ineffective in stimulating IPbetaIRK. Two derivatives more effective than metformin in patients were also more effective than metformin in stimulating IPbetaIRK. Higher levels (10-100 microg/mL) of metformin or methylglyoxyl bis(guanylhydrazone) inhibited the tyrosine kinases, and this inhibition may be responsible for the ability of these two drugs to block cell proliferation.

Publication types

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

MeSH terms

  • Buformin / pharmacology
  • Cell Division / drug effects
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • In Vitro Techniques
  • Intracellular Fluid / metabolism
  • Metformin / pharmacology*
  • Mitoguazone / pharmacology
  • Protein Conformation
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, Insulin / chemistry
  • Receptor, Insulin / drug effects*
  • Receptor, Insulin / metabolism


  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Metformin
  • Protein-Tyrosine Kinases
  • Receptor, Insulin
  • Mitoguazone
  • Buformin