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Metformin improves cardiovascular outcomes in type 2 diabetes, but its exact mechanisms of action remain controversial. We used hyperpolarized [1-(13)C]pyruvate magnetic resonance spectroscopy to determine the effects of metformin treatment upon heart and liver pyruvate metabolism in rats in vivo Both oral treatment for four weeks and a single intravenous metformin infusion significantly increased the cardiac [1-(13)C]lactate:[1-(13)C]pyruvate ratio, but had no effect on the [1-(13)C]bicarbonate + (13)CO2:[1-(13)C]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 whole cell [NAD(+)]/[NADH] ratio. Hyperpolarized magnetic resonance imaging localised 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 unrecognised effect upon cardiac redox state and help to refine the design of impending hyperpolarized magnetic resonance studies in humans.

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Department of Physiology, Anatomy and Genetics, University of Oxford, OX1 3PT Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, OX3 9DU.