Lookup NU author(s): Ahmed Alshawi,
Professor Loranne Agius
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.
For re-use rights please refer to the publisher's terms and conditions.
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.
Author(s): Alshawi A, Agius L
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
Pages: Epub ahead of print
Online publication date: 27/12/2018
Acceptance date: 27/12/2018
Date deposited: 09/01/2019
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology, Inc.
PubMed id: 30591586
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