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Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo

Nature Medicine volume 24, pages 1384–1394 (2018)Cite this article

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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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Fig. 1: Acute treatment with 50 mg kg–1 metformin administered i.v. inhibits contributions from lactate but not alanine to hepatic gluconeogenesis in normal SD rats.
Fig. 2: Acute treatment with 50 mg kg–1 metformin administered i.v. inhibits contributions from lactate but not alanine to hepatic gluconeogenesis in ZDF rats.
Fig. 3: Acute treatment with 50 mg kg–1 metformin administered i.v. decreases fasting plasma glucose and inhibits EGP in the ACC DKI mouse model by modulating redox.
Fig. 4: Infusion of pyruvate and DHA and infusion of MB both abrogate the effects of acute i.v. treatment with 50 mg kg–1 metformin on plasma glucose and EGP in normal SD rats.
Fig. 5: Portal vein infusion of 50 mg kg–1 metformin acutely inhibits hepatic gluconeogenesis and selectively alters lactate, β-OHB and glycerol turnover and clearance rates without altering alanine turnover and alanine clearance rates or impacting mitochondrial VCS in a HFD–STZ SD rat model of T2D.
Fig. 6: Chronic oral metformin treatment (3.5 mg mL–1 in the drinking water for 14 d) specifically inhibits contributions from lactate but not alanine to hepatic gluconeogenesis without impacting mitochondrial VCS in a flux HFD–STZ SD rat model of T2D.

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  • 07 February 2019

    In the version of this article originally published, the VPC and VCS flux data shown in Fig. 6e,f were inadvertently duplicated from Fig. 5j,k. The correct data are now shown in Fig. 6e,f. In these corrected data, VPC flux in response to chronic oral metformin treatment was still significantly decreased (Fig. 6e), and there was still no impact of metformin on VCS flux (Fig. 6f). Therefore, the text describing these data remains the same and this correction does not change the conclusion of this study.

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Acknowledgements

The authors would like to thank J. Dong, M. Kahn, S. Dufour, J. Stack, Y.Kosover, A. Nasiri, X. Ma, W. Zhu, and K. Harry for their technical support and V. Samuel, S. Caprio, and D. Kibbey for helpful discussions. This publication was supported by grants from the US Department of Health and Human Services: R01 DK113984, P30 DK45735, P30 DK034989, K99 CA215315 and R01 DK114793. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or the NIH. G.R.S. is supported by grants and fellowships from a Canada Research Chair in Metabolism and Obesity, the J. Bruce Duncan Endowed Chair in Metabolic Diseases at McMaster University and Diabetes Canada. B.E.K. is supported by grants and a Fellowship (BEK) from the National Health and Medical Research Council (1068813 and 1085460) and the Victorian Government Operational Infrastructure Support Scheme.

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  1. These authors contributed equally: Anila K. Madiraju, Yang Qiu.

Authors and Affiliations

  1. Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

    Anila K. Madiraju, Yang Qiu, Rachel J. Perry, Yasmeen Rahimi, Xian-Man Zhang, Dongyan Zhang, João-Paulo G. Camporez, Gary W. Cline, Gina M. Butrico, Gregori Casals, Daniel F. Vatner, Kitt F. Petersen & Gerald I. Shulman

  2. Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA

    Anila K. Madiraju & Gerald I. Shulman

  3. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA

    Anila K. Madiraju & Gerald I. Shulman

  4. Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China

    Yang Qiu

  5. 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

    Bruce E. Kemp

  6. Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Gregory R. Steinberg

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Contributions

A.K.M., Y.Q., R.J.P., J.-P.G.C., D.F.V., K.F.P., and G.I.S. designed the experimental protocols. A.K.M., Y.Q., Y.R., X.-M.Z., D.Z., G.W.C., G.M.B., G.C., J.-P.G.C., and K.F.P. performed the studies. A.K.M., Y.Q., R.J.P., X-M. Z., G.W.C., G.C., and J.-P.G.C. analyzed the data. B.E.K. and G.R.S. supplied reagents.A.K.M., Y.Q., R.J.P, G.W.C., D.F.V., K.F.P., and G.I.S. wrote the manuscript with contributions from all of the other authors.

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Madiraju, A.K., Qiu, Y., Perry, R.J. et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24, 1384–1394 (2018). https://doi.org/10.1038/s41591-018-0125-4

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