Type 2 diabetes mellitus alters cardiac mitochondrial content and function in a non-obese mice model

Abstract Type 2 diabetes mellitus (T2DM) is associated with an increase of premature appearance of several disorders such as cardiac complications. Thus, we test the hypothesis that a combination of a high fat diet (HFD) and low doses of streptozotocin (STZ) recapitulate a suitable mice model of T2DM to study the cardiac mitochondrial disturbances induced by this disease. Animals were divided in 2 groups: the T2DM group was given a HFD and injected with 2 low doses of STZ, while the CNTRL group was given a standard chow and a buffer solution. The combination of HFD and STZ recapitulate the T2DM metabolic profile showing higher blood glucose levels in T2DM mice when compared to CNTRL, and also, insulin resistance. The kidney structure/function was preserved. Regarding cardiac mitochondrial function, in all phosphorylative states, the cardiac mitochondria from T2DM mice presented reduced oxygen fluxes when compared to CNTRL mice. Also, mitochondria from T2DM mice showed decreased citrate synthase activity and lower protein content of mitochondrial complexes. Our results show that in this non-obese T2DM model, which recapitulates the classical metabolic alterations, mitochondrial function is impaired and provides a useful model to deepen study the mechanisms underlying these alterations.

摘要：2型糖尿病（T2DM）可引发多种疾病提前发作，心脏并发症便是其中之一。本研究旨在验证如下假说：高脂饮食（HFD）联合低剂量链脲佐菌素（STZ）可构建适配的T2DM小鼠模型，用于探究该疾病诱导的心脏线粒体功能紊乱。实验将受试动物分为两组：T2DM组予以高脂饮食并注射2次低剂量STZ，对照组（CNTRL）予以标准啮齿类饲料及缓冲液。高脂饮食联合STZ可重现T2DM的代谢表型：与CNTRL组相比，T2DM小鼠血糖水平显著升高，且存在胰岛素抵抗。两组小鼠的肾脏结构与功能均保持完好。针对心脏线粒体功能而言，相较于CNTRL组小鼠，T2DM小鼠的心脏线粒体在所有磷酸化状态下的氧通量均显著降低。此外，T2DM小鼠的线粒体柠檬酸合酶活性下降，且线粒体复合物的蛋白含量降低。本研究结果表明，该非肥胖型T2DM模型可重现经典的代谢异常特征，其线粒体功能存在损伤，该模型可为深入探究此类异常的潜在机制提供可靠的研究工具。