Publication in detail

Nat Med 2018 Jul 23. doi: 10.1038/s41591-018-0125-4. [Epub ahead of print]

Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo.

Madiraju, AK; Qiu, Y; Perry, RJ; Rahimi, Y; Zhang, XM; Zhang, D; Camporez, JG; Cline, GW; Butrico, GM; Kemp, BE; Casals, G; Steinberg, GR; Vatner, DF; Petersen, KF; Shulman, GI

Department of Medicine, Yale University School of Medicine, New Haven, CT, USA. Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA. Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China. St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne & Mary MacKillop Institute for Health Research, Australian Catholic University Fitzroy, Fitzroy, Victoria, Australia. Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA. gerald.shulman@yale.edu.

Abstract:
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.

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