Inhibition of hepatic gluconeogenesis by metformin. Synergism with insulin.
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.
Wollen
N
N
Department of Pharmaceutical Sciences, Aston University, Birmingham, U.K.
Bailey
C J
CJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000409:Alanine / Q000493:pharmacokinetics; D000818:Animals; D004357:Drug Synergism; D005943:Gluconeogenesis / Q000187:drug effects*; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009243:NAD / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D007328:Insulin; D009243:NAD; D000255:Adenosine Triphosphate; D008687:Metformin; D000409:Alanine