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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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.
The authors declare no competing interests.
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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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