PROTEIN GLYCATION AND DIABETIC NEUROPATHY

虽然高血糖症和糖尿病的发展之间存在因果关系， 糖尿病的许多并发症已经确定， 由高血糖症引起的分子事件的详细序列， 导致功能缺陷的原因尚待阐明。 许多 所提议的机制尚未证明是完全令人满意的。 的 多种蛋白质的广泛非酶糖基化，这已经被 被证明可以改变它们的物理、化学和生物特性， 在糖尿病患者中观察到， 病理 我们已经观察到白蛋白，IgG， 和免疫球蛋白浓度的神经内膜，束，腓肠神经活检， 有或无多发性神经病的糖尿病患者。 这些增长， 没有神经病变异常的糖尿病患者表明， 高水平的神经内膜血浆蛋白可能先于病理性 改变。 我们现在计划测试这样一个假设，即这些增加在 糖尿病患者活组织检查中血清成分的浓度 可能与蛋白质本身有关，而不是与独特的改变有关。 在内皮或神经束膜屏障中。 我们假设糖化 白蛋白和推测的其它糖化血清蛋白可以优先 运输通过血神经屏障，以说明定量的 在腓肠神经束活检中增加。 我们已经开发 渗透系数表面积的量化方法 使用i.v. 在插管的肱静脉和动脉中的团注技术 正常大鼠和实验性糖尿病神经病变大鼠。 这项建议 将检查白蛋白糖化的动力学，以确定 糖基化持续时间与其通透性之间存在相关性， 评估糖化白蛋白在腓肠神经活检中的渗透性， 糖尿病伴或不伴神经病变。 此外，实验 将对糖尿病神经病变动物模型链脲佐菌素进行评估， 测定白蛋白和糖化白蛋白穿过血液的渗透性 神经屏障，以及确定神经内膜浓度 白蛋白和糖化白蛋白。 这些变化 将与生理和形态指标相关， 神经病变，以确定它们是否先于神经病变的发展。 这些意见将对进一步加强我们的 了解人类糖尿病神经病变。

Although a causal connection between hyperglycemia and the development of the numerous complications of diabetes mellitus has been established, the detailed sequence of molecular events resulting from hyperglycemia and leading to functional deficits remains to be elucidated. Many of the proposed mechanisms have not proven to be entirely satisfactory. The extensive nonenzymatic glycation of a variety of proteins, which has been demonstrated to alter their physical, chemical, and biological properties, has been observed in diabetic patients and has been related to the vascular pathology. We have observed highly significant increases in albumin, IgG, and IgH concentrations in endoneurial, fascicular, sural nerve biopsies of diabetic patients with and without polyneuropathy. These increases for diabetics in the absence of neuropathic abnormalities suggest that the higher levels of endoneurial plasma proteins may precede the pathological alterations. We now plan to test the hypothesis that these increases in concentrations of serum constituents in the biopsies of diabetic patients may be related to the protein itself rather than to distinctive alterations in the endothelial or perineurial barrier. We hypothesize that glycated albumin and presumably other glycated serum proteins may be preferentially transported across the blood nerve barrier to account for the quantitative increases within the fascicular sural nerve biopsies. We have developed the methodologies to quantify the permeability coefficient surface area product for these proteins across the blood nerve barrier using an i.v. bolus injection technique in the catheterized brachial vein and artery of normal rats and rats with experimental diabetic neuropathy. This proposal will examine the kinetics of glycation of albumin to determine if a correlation exists betweeen the duration of glycation and its permeability, evaluate the permeability of glycated albumin in sural nerve biopsies of diabetics with and without neuropathy. In addition, the experimental animal model of diabetic neuropathy, streptozotocin, will be evaluated to determine the permeability of albumin and glycated albumin across the blood nerve barrier, as well as to determine the endoneurial concentrations of albumin and glycated albumin in the nerves of these animals. These changes will be correlated with physiological and morphometric indices of neuropathy to determine if they precede the development of the neuropathy. These observations would have important implications for furthering our understanding of human diabetic neuropathy.