Assessment of Metformin-Induced Changes in Cardiac and Hepatic Redox State Using Hyperpolarized[1-13C]Pyruvate.

Lewis AJM., Miller JJJ., McCallum C., Rider OJ., Neubauer S., Heather LC., Tyler DJ.

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.

DOI

10.2337/db16-0804

Type

Journal article

Journal

Diabetes

Publication Date

12/2016

Volume

65

Pages

3544 - 3551

Keywords

Animals, Bicarbonates, Carbon Isotopes, Heart, Lactic Acid, Liver, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Metformin, Myocardium, Oxidation-Reduction, Pyruvic Acid, Rats, Rats, Wistar

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