Tilton Ronald G
Department of Pharmacology, Texas Biotechnology Corporation, Houston, Texas 77030, USA.
Microsc Res Tech. 2002 Jun 1;57(5):390-407. doi: 10.1002/jemt.10092.
A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. These involve either increased reductive or oxidative stress to the cell, or the activation of numerous protein kinase pathways, particularly protein kinase C and mitogen-activated protein kinases. As detailed below, there is tremendous crosstalk between these competing hypotheses. We propose that increased tissue glucose levels alter cytosolic coenzyme balance by increased flux of glucose through the sorbitol pathway increasing free cytosolic NADH levels. Increased NADH levels can generate reactive oxygen species via numerous mechanisms, lead to the formation of intracellular advanced glycation end products, and induce growth factor expression via mechanisms involving protein kinase C activation. The elevation in growth factors, particularly vascular endothelial growth factor (VEGF), is responsible for the vascular dysfunction via numerous mechanisms reported here in detail.
高血糖导致与糖尿病环境相关的血管功能和结构变化的机制，我们仍未完全从生化角度理解。近年来，众多被认为在糖尿病血管疾病发病机制中起因果作用的生化和代谢途径，已被归纳为几个统一的假说。这些假说要么涉及细胞内还原应激或氧化应激增加，要么涉及众多蛋白激酶途径的激活，尤其是蛋白激酶C和丝裂原活化蛋白激酶。如下所述，这些相互竞争的假说之间存在大量相互作用。我们提出，组织葡萄糖水平升高会通过山梨醇途径中葡萄糖通量增加，导致胞质辅酶平衡改变，从而增加游离胞质NADH水平。NADH水平升高可通过多种机制产生活性氧，导致细胞内晚期糖基化终末产物的形成，并通过涉及蛋白激酶C激活的机制诱导生长因子表达。生长因子的升高，尤其是血管内皮生长因子（VEGF），通过本文详细报道的多种机制导致血管功能障碍。
