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

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 (similar to 1 mu g/mL) of metformin stimulated the tyrosine kinase activity of the intracellular portion of the beta-subunit of the human insulin receptor (IP beta IRK), 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 IP beta IRK. Two derivatives more effective than metformin in patients were also more effective than metformin in stimulating IP beta IRK. Higher levels (10-100 mu g/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. (C) 1998 Elsevier Science Inc.