Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana.
Department of Pharmacology, University of Mostar, School of Medicine, Mostar, Bosnia and Herzegovina.
Am J Physiol Heart Circ Physiol. 2019 Nov 1;317(5):H1086-H1092. doi: 10.1152/ajpheart.00341.2019. Epub 2019 Sep 6.
One of the major characteristics of hyperglycemic states such as type 2 diabetes is increased reactive oxygen species (ROS) generation. Since mitochondria are a major source of ROS, it is vital to understand the involvement of these organelles in the pathogenesis of ROS-mediated conditions. Therefore, we investigated mitochondrial function and ROS production in cerebral blood vessels of 21-wk-old Zucker diabetic fatty obese rats and their lean controls. We have previously shown that in the early stages of insulin resistance, and short periods of type 2 diabetes mellitus, only mild differences exist in mitochondrial function. In the present study, we examined mitochondrial respiration, mitochondrial protein expression, and ROS production in large-surface cerebral arteries. We used 21-wk-old animals exposed to peak glucose levels for 7 wk and compared them with our previous studies on younger diabetic animals. We found that the same segments of mitochondrial respiration (basal respiration and proton leak) were diminished in diabetic groups as they were in younger diabetic animals. Levels of rattin, a rat humanin analog, tended to decrease in the diabetic group but did not reach statistical significance ( = 0.08). Other mitochondrial proteins were unaffected, which might indicate the existence of compensatory mechanisms with extension of this relatively mild form of diabetes. Superoxide levels were significantly higher in large cerebral vessels of diabetic animals compared with the control group. In conclusion, prolonged dietary diabetes leads to stabilization, rather than deterioration, of metabolic status in the cerebral circulation, despite continued overproduction of ROS. We have characterized for the first time the dynamics of mitochondrial function during the progression of type 2 diabetes mellitus with regard to mitochondrial respiration, protein expression, and reactive oxygen species production. In addition, this is the first measurement of rattin levels in the cerebral vasculature, which could potentially lead to novel treatment options.
高血糖状态（如 2 型糖尿病）的一个主要特征是活性氧（ROS）生成增加。由于线粒体是 ROS 的主要来源，因此了解这些细胞器在 ROS 介导的疾病发病机制中的作用至关重要。因此，我们研究了 21 周龄 Zucker 糖尿病肥胖大鼠及其 lean 对照的脑血管中线粒体功能和 ROS 产生。我们之前已经表明，在胰岛素抵抗的早期阶段和 2 型糖尿病的短时间内，线粒体功能只有轻微差异。在本研究中，我们检查了大表面脑动脉中的线粒体呼吸、线粒体蛋白表达和 ROS 产生。我们使用了暴露于峰值葡萄糖水平 7 周的 21 周龄动物，并将其与我们以前对年轻糖尿病动物的研究进行了比较。我们发现，与年轻糖尿病动物一样，糖尿病组的相同线粒体呼吸段（基础呼吸和质子渗漏）减少。大鼠人源素类似物 rattin 的水平趋于降低，但未达到统计学意义（= 0.08）。其他线粒体蛋白不受影响，这可能表明存在代偿机制，使这种相对温和的糖尿病形式得以延长。与对照组相比，糖尿病动物的大动脉中超氧化物水平明显升高。总之，尽管 ROS 持续过度产生，但延长的饮食性糖尿病导致大脑循环中代谢状态的稳定，而不是恶化。我们首次描述了线粒体呼吸、蛋白表达和活性氧产生方面 2 型糖尿病进展过程中线粒体功能的动态变化。此外，这是首次在脑血管中测量 rattin 水平，这可能为新的治疗方法提供潜在的途径。
