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

作者：Lewis Andrew J M; Miller Jack J J; McCallum Chloe; Rider Oliver J; Neubauer Stefan; Heather Lisa C; Tyler Damian J

来源：Diabetes, 2016, 65(12): 3544-3551.

DOI：10.2337/db16-0804

Metformin improves cardiovascular outcomes in type 2 diabetes, but its exact mechanisms of action remain controversial. We used hyperpolarized [1-C-13]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-C-13]lactate:[1-C-13]pyruvate ratio but had no effect on the [1-C-13]bicarbonate + (CO2)-C-13:[1-C-13]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.

• 出版日期2016-12