title: Assessment of Metformin-Induced Changes in Cardiac and Hepatic Redox State Using Hyperpolarized[1-13C]Pyruvate.
abstract: Metformin improves cardiovascular outcomes in type 2 diabetes, but its exact mechanisms of action remain controversial. We used hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy to determine the effects of metformin treatment on heart and liver pyruvate metabolism in rats in vivo. Both oral treatment for 4 weeks and a single intravenous metformin infusion significantly increased the cardiac [1-13C]lactate:[1-13C]pyruvate ratio but had no effect on the [1-13C]bicarbonate +13CO2:[1-13C]pyruvate ratio, an index of pyruvate dehydrogenase flux. These changes were paralleled by a significant increase in the heart and liver cytosolic redox state, estimated from the [lactate]:[pyruvate] ratio but not the whole-cell [NAD+]/[NADH] ratio. Hyperpolarized MRI localized the increase in cardiac lactate to the left ventricular myocardium, implying a direct myocardial effect, though metformin had no effect on systolic or diastolic cardiac function. These findings demonstrate the ability of hyperpolarized pyruvate magnetic resonance spectroscopy to detect metformin-induced changes in cytosolic redox biology, suggest that metformin has a previously unrecognized effect on cardiac redox state, and help to refine the design of impending hyperpolarized magnetic resonance studies in humans.
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.|Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
authors: Andrew J M
authors: AJ
authors: Lewis
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.|Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, U.K.
authors: Jack J J
authors: JJ
authors: Miller
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
authors: Chloe
authors: C
authors: McCallum
authors: Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
authors: Oliver J
authors: OJ
authors: Rider
authors: Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
authors: Stefan
authors: S
authors: Neubauer
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
authors: Lisa C
authors: LC
authors: Heather
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K. damian.tyler@dpag.ox.ac.uk.
authors: Damian J
authors: http://orcid.org/0000-0002-0780-8905
authors: DJ
authors: Tyler
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002247:Carbon Isotopes / Q000737:chemistry* / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001639:Bicarbonates; D002247:Carbon Isotopes; D019344:Lactic Acid; D019289:Pyruvic Acid; D008687:Metformin