Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
Authors: Xian-Man Zhang
Derek M Erion
Sanjay Bhanot
Varman T Samuel
Brett J Prigaro
Anila K Madiraju
Richard G Kibbey
Hui-Young Lee
Michael J Jurczak
John L Wood
Gary W Cline
Ronald A Albright
Demetrios T Braddock
Joao-Paulo Camporez
Yasmeen Rahimi
Gerald I Shulman
Michael J MacDonald
Journal: Nature (2014)
Discipline: Multidisciplinary
Keywords: Metformin; type 2 diabetes; hepatic gluconeogenesis; redox state; mitochondrial glycerophosphate dehydrogenase
Affiliations: 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA., Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA., Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA., Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA., Cancer Prevention Research Institute of Texas Scholar, Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, USA., Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, California 92010, USA., University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA, 53706., 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA., 1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark, DK-2200.

Abstract:  Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin's blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes. 

Retracted: No

PubPeer comments:
 **Retracted 14 December, 2021:** https: link.springer.com article 10.1007 s12517-021-09278-3 Retraction note: * The Editor-in-Chief and the Publisher have retracted this article because the content of this article is nonsensical. The peer review process was not carried out in accordance with the Publisher s peer review policy. Author Jia Zhu has not responded to correspondence regarding this retraction. The Publisher has not been able to obtain a current email address for author Chen Qin. * This is one of the articles published as a part of Topical Collection u201cSmart agriculture and geo-informaticsu201d in Arabian Journal of Geosciences. Editorial expression of concern published on 28 September 2021 states as follows: * Following the publication of this topical collection of the Arabian Journal of Geosciences, the Publisher became aware of serious research integrity concerns within the collection. The peer review process was not carried out in accordance with the Publisheru2019s peer review policy (see https: www.springer.com gp editorial-policies peer-review-policy-process), and may have been deliberately manipulated. All articles in this topical collection are currently being assessed. The Publisher will take further editorial action where appropriate, once this investigation is complete. The authors were informed of the publication of this Editorial Expression of Concern using email addresses provided at submission. * Editorial expression of concern including other retracted papers from this collection: https: link.springer.com article 10.1007 s12517-021-08470-9 , 
 Responsible editor: [Hoshang Kolivand] . ,