Inhibition of hepatic gluconeogenesis by metformin. Synergism with insulin

Biochem Pharmacol. 1988 Nov 15;37(22):4353-8. doi: 10.1016/0006-2952(88)90617-x.


The antihyperglycemic agent, metformin (dimethylbiguanide), inhibits hepatic gluconeogenesis. To investigate the mechanism involved, glucose production from collagenase-isolated hepatocytes of starved rats was determined after 1 hr incubations with different substrates. In the absence of insulin, glucose production from 10(-2) M lactate-10(-3) M pyruvate, 10(-2)M M alanine, 10(-2) M glutamine and 5 x 10(-3) M glycerol was decreased (35-78%) by high concentrations (10(-2) and 10(-3) M) of metformin. Lower concentrations of metformin were not effective in the absence of insulin, but a therapeutic concentration (10(-5) M) of metformin acted synergistically with insulin (10(-8) M) to suppress gluconeogenesis from each of the substrates by an additional 10-14% compared with insulin (10(-8) M) alone. The synergistic antigluconeogenic effect of metformin (10(-5) M) with insulin (10(-8) M) was achieved without alteration of the contents of NADH and NAD+ in digitonin-separated cytosolic and mitochondrial-rich hepatocyte fractions. Mitochondrial ATP was also unaltered by the metformin (10(-5) M)-insulin (10(-8) M) combination. However, the antigluconeogenic effect of 10(-2) M metformin alone was associated with an increased (by 109%) mitochondrial NADH:NAD+ ratio. Thus reduced gluconeogenesis by high concentrations of metformin (e.g. 10(-2) M) may involve changes of redox state. However, therapeutic concentrations of metformin (e.g. 10(-5) M) potentiate the antigluconeogenic effect of insulin to a similar extent from a range of substrates, without altering energy status or redox state.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Alanine / pharmacokinetics
  • Animals
  • Drug Synergism
  • Gluconeogenesis / drug effects*
  • Insulin / pharmacology*
  • Liver / drug effects*
  • Male
  • Metformin / pharmacology*
  • NAD / metabolism
  • Rats
  • Rats, Inbred Strains


  • Insulin
  • NAD
  • Adenosine Triphosphate
  • Metformin
  • Alanine