Metformin potentiates the antigluconeogenic action of insulin

The interaction of metformin and insulin in the control of hepatic gluconeogenesis was examined in isolated hepatocytes from 48h starved rats using lactate (10(-2) mol/l) with pyruvate (10(-3) mol/l) as substrate. During 1 h incubations in the absence of added insulin, 10(-2) and 10(-3) mol/l metformin reduced gluconeogenesis by 65% and 59% respectively, but lower concentrations of metformin were not effective. Insulin alone (10(-6)-10(-8) mol/l) reduced (37%-16%) gluconeogenesis. The effect of insulin was enhanced (further reductions of 11%-24%) by 5 x 10(-4) mol/l metformin, although this concentration of metformin was not effective in the absence of insulin. At lower insulin concentrations (10(-9) and 10(-10) mol/l) which did not significantly affect gluconeogenesis alone, 5 x 10(-4) mol/l metformin decreased gluconeogenesis (32% and 28% respectively). At 10(-10) mol/l insulin, metformin concentrations of 10(-3)-10(-7) mol/l decreased gluconeogenesis by 60-20%. The results suggest that therapeutic concentrations of metformin may act synergistically with physiological concentrations of insulin to suppress hepatic gluconeogenesis.