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Title: The molecular mechanisms by which metformin inhibits gluconeogenesis
Author: Alshawi, Ahmed Fadhil Oudah
ISNI:       0000 0004 8505 8606
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2019
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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. This thesis used primary hepatocytes to investigate the mechanism(s) by which low metformin concentrations relevant to the therapeutic dose inhibit gluconeogenesis. It tested the hypotheses of involvement of inhibition of Complex 1 and / or inhibition of mGPDH. The results from this study show that metformin has a biphasic effect on the mitochondrial NADH/NAD redox state in hepatocytes. A low cell dose of metformin (therapeutic equivalent:  2nmol/mg) caused a more oxidised mitochondrial NADH/NAD state and an increase in the 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 oxidised (dihydroxyacetone) and reduced (xylitol) substrates by preferential partitioning of substrate towards glycolysis by a redoxindependent mechanism that is best explained by allosteric regulation at phosphorfructokinase-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. This study supports the conclusion that at a low pharmacological load, the metformin effects on the lactate/pyruvate ratio are explained by attenuation of transmitochondrial electrogenic transport mechanisms with consequent compromised malate-aspartate shuttle and the inhibition of gluconeogenesis is best explained by changes in allosteric effectors of PFK1 and FBP1 independently of inhibition of both Complex 1 and mGPDH.
Supervisor: Not available Sponsor: Higher Committee for Education Development in Iraq (HCED)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available