MR Research Centre, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Diabetologia. 2018 Feb;61(2):445-454. doi: 10.1007/s00125-017-4445-6. Epub 2017 Sep 21.
AIMS/HYPOTHESIS: Metformin inhibits hepatic mitochondrial glycerol phosphate dehydrogenase, thereby increasing cytosolic lactate and suppressing gluconeogenesis flux in the liver. This inhibition alters cytosolic and mitochondrial reduction-oxidation (redox) potential, which has been reported to protect organ function in several disease states including diabetes. In this study, we investigated the acute metabolic and functional changes induced by metformin in the kidneys of both healthy and insulinopenic Wistar rats used as a model of diabetes.
Diabetes was induced by intravenous injection of streptozotocin, and kidney metabolism in healthy and diabetic animals was investigated 4 weeks thereafter using hyperpolarised C-MRI, Clark-type electrodes and biochemical analysis.
Metformin increased renal blood flow, but did not change total kidney oxygen consumption. In healthy rat kidneys, metformin increased [1-C]lactate production and reduced mitochondrial [1-C]pyruvate oxidation (decreased the C-bicarbonate/[1-C]pyruvate ratio) within 30 min of administration. Corresponding alterations to indices of mitochondrial, cytosolic and whole-cell redox potential were observed. Pyruvate oxidation was maintained in the diabetic rats, suggesting that the diabetic state abrogates metabolic reprogramming caused by metformin.
CONCLUSIONS/INTERPRETATION: This study demonstrates that metformin-induced acute metabolic alterations in healthy kidneys favoured anaerobic metabolism at the expense of aerobic metabolism. The results suggest that metformin directly alters the renal redox state, with elevated renal cytosolic redox states as well as decreased mitochondrial redox state. These findings suggest redox biology as a novel target to eliminate the renal complications associated with metformin treatment in individuals with impaired renal function.
目的/假设：二甲双胍抑制肝线粒体甘油磷酸脱氢酶，从而增加细胞浆内的乳酸并抑制肝脏内的糖异生通量。这种抑制作用改变了细胞浆和线粒体的还原-氧化（氧化还原）电势，据报道，这种电势变化在包括糖尿病在内的几种疾病状态下可以保护器官功能。在这项研究中，我们研究了二甲双胍在作为糖尿病模型的健康和胰岛素缺乏 Wistar 大鼠的肾脏中引起的急性代谢和功能变化。
通过静脉注射链脲佐菌素诱导糖尿病，4 周后使用极化 C-MRI、Clark 型电极和生化分析研究健康和糖尿病动物的肾脏代谢。
二甲双胍增加了肾血流量，但没有改变总肾耗氧量。在健康大鼠的肾脏中，二甲双胍在给药后 30 分钟内增加了[1-C]乳酸的产生，并减少了线粒体[1-C]丙酮酸的氧化（降低了 C-重碳酸盐/[1-C]丙酮酸的比值）。同时观察到线粒体、细胞浆和整个细胞氧化还原电势的相应变化。在糖尿病大鼠中，丙酮酸氧化得以维持，这表明糖尿病状态消除了二甲双胍引起的代谢重编程。
结论/解释：本研究表明，二甲双胍在健康肾脏中引起的急性代谢变化有利于无氧代谢，而不利于有氧代谢。结果表明，二甲双胍直接改变了肾脏的氧化还原状态，使肾脏细胞浆的氧化还原状态升高，线粒体的氧化还原状态降低。这些发现表明，氧化还原生物学是一种新的靶点，可以消除肾功能受损个体中与二甲双胍治疗相关的肾脏并发症。
