Tilton R G, Chang K, Nyengaard J R, Van den Enden M, Ido Y, Williamson J R
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri.
Diabetes. 1995 Feb;44(2):234-42. doi: 10.2337/diab.44.2.234.
These experiments were undertaken to assess the role of sorbitol dehydrogenase in mediating sorbitol pathway-linked neural and vascular dysfunction in rats with streptozocin-induced diabetes. 2-methyl-4-[N,N-dimethylsulfamoyl-piperazino]-pyrimidine (S-0773), a putative inhibitor of sorbitol dehydrogenase, was given in the drinking water to control and diabetic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were increased twofold and were unaffected by S-0773. Sorbitol levels in diabetic rats were increased 11- to 14-fold in ocular tissues and sciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. Diabetes-associated increases in fructose levels and lactate:pyruvate ratios in retina and in sciatic nerve were markedly attenuated by S-0773. S-0773 also attenuated, but did not completely normalize, impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sciatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dysfunction (in ocular tissues, peripheral nerve, and aorta) and electrophysiological dysfunction (in peripheral nerve) induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose than to putative osmotic effects of elevated sorbitol levels or redox and metabolic imbalances associated with reduction of glucose to sorbitol by aldose reductase.
进行这些实验是为了评估山梨醇脱氢酶在介导链脲佐菌素诱导的糖尿病大鼠中与山梨醇途径相关的神经和血管功能障碍中的作用。将一种假定的山梨醇脱氢酶抑制剂2-甲基-4-[N，N-二甲基氨磺酰基-哌嗪基]-嘧啶（S-0773）添加到饮用水中，给予对照大鼠和糖尿病大鼠。糖尿病5周后，糖化血红蛋白水平增加了两倍，且不受S-0773的影响。糖尿病大鼠眼组织和坐骨神经中的山梨醇水平增加了11至14倍；S-0773使这些相同组织中的山梨醇水平又增加了4倍或更多，但对其他组织的影响要小得多。S-0773显著减弱了糖尿病相关的视网膜和坐骨神经中果糖水平的升高以及乳酸：丙酮酸比率的升高。S-0773还减弱了糖尿病大鼠眼组织、坐骨神经和主动脉中的尾神经传导受损和血管功能障碍，但未完全使其恢复正常。这些观察结果与其他证据一起表明，糖尿病诱导的与山梨醇途径相关的血管功能障碍（在眼组织、外周神经和主动脉中）和电生理功能障碍（在外周神经中）与山梨醇氧化为果糖的增加比与山梨醇水平升高的假定渗透作用或与醛糖还原酶将葡萄糖还原为山梨醇相关的氧化还原和代谢失衡更密切相关。
