Journal article

Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo

Anila K Madiraju, Yang Qiu, Rachel J Perry, Yasmeen Rahimi, Xian-Man Zhang, Dongyan Zhang, Joao-Paulo G Camporez, Gary W Cline, Gina M Butrico, Bruce E Kemp, Gregori Casals, Gregory R Steinberg, Daniel F Vatner, Kitt F Petersen, Gerald Shulman

Nature Medicine | NATURE PUBLISHING GROUP | Published : 2018

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 ..

View full abstract

Grants

Awarded by US Department of Health and Human Services


Awarded by National Health and Medical Research Council


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Funding 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.