Assessment of Metformin-Induced Changes in Cardiac and Hepatic Redox State Using Hyperpolarized [1-13C]Pyruvate
Assessment of Metformin-Induced Changes in Cardiac and Hepatic Redox State Using Hyperpolarized [1-13C]Pyruvate
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DOI：
10.2337/db16-0804
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发表时间：
2016-12-01
期刊：
影响因子：
7.7
通讯作者：
Tyler, Damian J.
中科院分区：
文献类型：
--
作者：
Lewis, Andrew J. M.;Miller, Jack J. J.;Tyler, Damian J.
二甲双胍改善2型糖尿病的心血管结局，但其确切的作用机制仍有争议。我们使用超极化[1-C-13]丙酮酸磁共振波谱来确定二甲双胍治疗对大鼠体内心脏和肝脏丙酮酸代谢的影响。口服治疗4周和单次静脉输注二甲双胍均显著增加了心脏[1-C-13]乳酸盐：[1-C-13]丙酮酸盐比率，但对[1-C-13]碳酸氢盐+（CO2）-C-13：[1-C-13]丙酮酸盐比率（丙酮酸脱氢酶通量的指标）无影响。这些变化被心脏和肝脏细胞溶质氧化还原状态的显著增加所证实，这是根据[乳酸]：[丙酮酸]比率而不是全细胞[NAD（+）][NADH]比率估计的。超极化MRI将心脏乳酸盐增加定位于左心室心肌，这意味着直接心肌效应，尽管二甲双胍对收缩期或舒张期心脏功能无影响。这些发现证明了超极化丙酮酸磁共振波谱检测二甲双胍诱导的细胞溶质氧化还原生物学变化的能力，表明二甲双胍对心脏氧化还原状态有以前未被认识的影响，并有助于完善即将到来的人体超极化磁共振研究的设计。
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.