Boston Medical Center, EBRC 820, Diabetes & Metabolism Unit, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Antioxid Redox Signal. 2010 Jan;12(1):39-51. doi: 10.1089/ars.2009.2502.
These experiments were undertaken to assess the importance of cytoplasmic (c) sorbitol oxidation versus mitochondrial (m) pyruvate oxidation in mediating neural and vascular dysfunction attributable to hyperglycemia in diabetic rats. Increased oxidation of sorbitol is coupled to enzymatic reduction of free oxidized NAD(+)c to reduced NADHc, manifested by an increased ratio of NADH to NAD(+)c. Likewise, increased oxidation of pyruvate is coupled to reduction of NAD(+)m to NADHm, which increases the NADH/NAD(+)m ratio. Specific inhibitors of sorbitol production or sorbitol oxidation normalized: increased diabetic nerve NADH/NAD(+)c, impaired nerve-conduction velocity, and vascular dysfunction in sciatic nerve, retina, and aorta; however, they had little or no impact on increased NADH/NAD(+)m. These observations provide, for the first time, strong in vivo evidence for the primacy of sorbitol oxidation versus. pyruvate oxidation in mediating the metabolic imbalances, impaired nerve conduction, and vascular dysfunction evoked by diabetes. These findings are consistent with (a) the fact that oxidation of sorbitol produces "prooxidant" NADHc uncoupled from subsequent production of "antioxidant" pyruvate required for reoxidation of NADHc to NAD(+)c by lactate dehydrogenase, and (b) the hypothesis that neural and vascular dysfunction in early diabetes are caused primarily by increased NADHc, which fuels superoxide production by NADH-driven oxidases.
这些实验旨在评估细胞质（c）山梨醇氧化与线粒体（m）丙酮酸氧化在介导糖尿病大鼠高血糖引起的神经和血管功能障碍中的重要性。山梨醇的氧化增加与游离氧化 NAD（+）c 到还原 NADHc 的酶促还原偶联，表现为 NADH 与 NAD（+）c 的比值增加。同样，丙酮酸氧化增加与 NAD（+）m 到 NADHm 的还原偶联，这增加了 NADH/NAD（+）m 的比值。山梨醇产生或山梨醇氧化的特异性抑制剂使：糖尿病神经 NADH/NAD（+）c 增加、神经传导速度受损和坐骨神经、视网膜和主动脉血管功能障碍正常化；然而，它们对增加的 NADH/NAD（+）m 几乎没有或没有影响。这些观察结果首次提供了强有力的体内证据，证明山梨醇氧化相对于丙酮酸氧化在介导糖尿病引起的代谢失衡、神经传导受损和血管功能障碍方面具有首要作用。这些发现与以下事实一致：（a）山梨醇的氧化产生与随后产生的“抗氧化剂”丙酮酸解偶联的“促氧化剂”NADHc，而丙酮酸是通过乳酸脱氢酶将 NADHc 再氧化为 NAD（+）c 所必需的；（b）神经和血管功能障碍在早期糖尿病中主要是由 NADHc 增加引起的，NADH 驱动的氧化酶通过 NADH 产生超氧化物。
