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Low metformin causes a more oxidized mitochondrial NADH/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism

Lookup NU author(s): Ahmed Alshawi, Professor Loranne Agius

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society for Biochemistry and Molecular Biology, Inc., 2019.

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Abstract

The mechanisms by which metformin (dimethylbiguanide) inhibits hepatic gluconeogenesis at concentrations relevant for type 2 diabetes therapy remain debated. Two proposed mechanisms are: inhibition of mitochondrial Complex 1 with consequent compromised ATP and AMP homeostasis; or inhibition of mitochondrial glycerophosphate dehydrogenase (mGPDH) and thereby attenuated transfer of reducing equivalents from the cytoplasm to mitochondria resulting in a raised lactate/pyruvate ratio and redox-dependent inhibition of gluconeogenesis from reduced but not oxidised substrates. Here we show that metformin has a biphasic effect on the mitochondrial NADH/NAD redox state in mouse hepatocytes. A low cell dose of metformin (therapeutic equivalent: <2 nmol / mg) caused a more oxidized mitochondrial NADH/NAD state and an increase in lactate / pyruvate ratio, whereas a higher metformin dose (>5nmol/mg) caused a more reduced mitochondrial NADH/NAD state similar to Complex 1 inhibition by rotenone. The low metformin dose inhibited gluconeogenesis from both oxidized (dihydroxyacetone) and reduced (xylitol) substrates by preferential partitioning of substrate towards glycolysis by a redox-independent mechanism that is best explained by allosteric regulation at phosphor-fructokinase-1 (PFK1) and/or fructose bisphosphatase-1 (FBP-1) in association with a decrease in cell glycerol 3-P, an inhibitor of PFK1 rather than by inhibition of transfer of reducing equivalents. We conclude that at a low pharmacological load, the metformin effects on the lactate / pyruvate ratio and glucose production are explained by attenuation of transmitochondrial electrogenic transport mechanisms with consequent compromised malate-aspartate shuttle and changes in allosteric effectors of PFK1 and FBP1.


Publication metadata

Author(s): Alshawi A, Agius L

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2019

Volume: 294

Pages: Epub ahead of print

Online publication date: 27/12/2018

Acceptance date: 27/12/2018

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: https://doi.org/10.1074/jbc.RA118.006670

DOI: 10.1074/jbc.RA118.006670

PubMed id: 30591586


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