Biology

Glycerol kinase

Citrate synthase

Cytosol

Endocrinology

Metabolism

Biochemistry

Pyruvate carboxylase

Enzyme

Internal medicine

Mitochondrion

Pharmacology

Medicine

Chemistry

Biguanide

Gluconeogenesis

Metformin

Diabetes mellitus

Nature Medicine

Metformin, the universal first-line treatment for type 2 diabetes, exerts its therapeutic glucose-lowering effects by inhibiting hepatic gluconeogenesis. However, the primary molecular mechanism of this biguanide remains unclear, though it has been suggested to act, at least partially, by mitochondrial complex I inhibition. Here we show that clinically relevant concentrations of plasma metformin achieved by acute intravenous, acute intraportal or chronic oral administration in awake normal and diabetic rats inhibit gluconeogenesis from lactate and glycerol but not from pyruvate and alanine, implicating an increased cytosolic redox state in mediating metformin’s antihyperglycemic effect. All of these effects occurred independently of complex I inhibition, evidenced by unaltered hepatic energy charge and citrate synthase flux. Normalizing the cytosolic redox state by infusion of methylene blue or substrates that contribute to gluconeogenesis independently of the cytosolic redox state abrogated metformin-mediated inhibition of gluconeogenesis in vivo. Additionally, in mice expressing constitutively active acetyl-CoA carboxylase, metformin acutely decreased hepatic glucose production and increased the hepatic cytosolic redox state without altering hepatic triglyceride content or gluconeogenic enzyme expression. These studies demonstrate that metformin, at clinically relevant plasma concentrations, inhibits hepatic gluconeogenesis in a redox-dependent manner independently of reductions in citrate synthase flux, hepatic nucleotide concentrations, acetyl-CoA carboxylase activity, or gluconeogenic enzyme protein expression. Using 13C-labeled substrates in vivo, this group shows that metformin inhibits mG3PDH to reduce hepatic gluconeogenesis and lower glycemia by altering the redox potential of the cytosol of hepatocytes rather than affecting substrate availability.

Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo