Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-09

AUTHORS

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, Bruce E. Kemp, Gregori Casals, Gregory R. Steinberg, Daniel F. Vatner, Kitt F. Petersen, Gerald I. Shulman

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. More... »

PAGES

1384-1394

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41591-018-0125-4

    DOI

    http://dx.doi.org/10.1038/s41591-018-0125-4

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1105714183

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30038219


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    416 https://www.grid.ac/institutes/grid.47100.32 schema:alternateName Yale University
    417 schema:name Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
    418 Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
    419 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
    420 rdf:type schema:Organization
     




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