The Utah Diabetic Neuropathy Study

描述（由申请人提供）：糖尿病神经病变一旦确立，在人体试验中的可逆性较差。敏感的诊断措施是必要的，以确定患者非常早期的轴突损伤谁可能是更好的候选人进行干预，甚至预防性治疗。糖尿病神经病变皮肤测量（CMND）研究广泛描述了221名糖尿病受试者的外周神经功能，并进行了纵向随访。CMND显示早期糖尿病神经病变的特征在于进行性小纤维损失，并将表皮内神经纤维密度（IENFD）皮肤活检确定为神经病变严重程度的敏感定量替代指标。IENFD与神经病变的临床和电诊断指标密切相关，在糖尿病受试者中，包括那些没有神经病变症状的受试者，IENFD在两年内显著下降。我们已经证明，通过个体化饮食和运动咨询，对患有与糖耐量受损相关的早期神经病变的受试者实现代谢改善，显著改善了小纤维神经病变的测量，包括疼痛和IENFD。我们假设：1）早期IENFD下降可预测未来发生具有临床意义的糖尿病神经病变，2）基于糖耐量受损神经病变研究，通过积极的生活方式干预纠正IENFD下降，将成功导致体重减轻、代谢参数改善、糖尿病神经病变发生风险降低或进展减缓。目标1将对CMND糖尿病受试者进行额外4年的随访，以确定IENFD早期下降的幅度，从而预测症状性远端多发性神经病的未来发展。目标2将随机分配175名无神经病变症状的糖尿病受试者，以确定两年积极的饮食和运动咨询是否会减少IENFD进展或症状性神经病变的发生率。两个目的均将检查代谢综合征、肥胖或特定基线代谢参数、胰岛素抵抗（HOMA-IR）或脂肪因子水平是否可预测IENFD下降率或未来神经病变发展风险。由于糖尿病（糖尿病性神经病变）导致的最长周围神经损伤非常常见。糖尿病神经病变越早发现，治疗越有效。这项提案将测试一种计算皮肤神经的方法，看看它是否能预测未来的糖尿病神经病变，并测试饮食和运动对预防神经损伤的影响。

DESCRIPTION (provided by applicant): Diabetic neuropathy, once well established, is poorly reversible in human trials. Sensitive diagnostic measures are necessary to identify patients with very early axonal injury who may be better candidates for intervention or even preventative therapy. The Cutaneous Measures of Diabetic Neuropathy (CMND) study extensively characterizes peripheral nerve function in 221 diabetic subjects, with longitudinal follow-up. CMND shows that early diabetic neuropathy is characterized by progressive small fiber loss, and identifies skin biopsy with intraepidermal nerve fiber density (IENFD) as a sensitive, quantitative surrogate measure of neuropathy severity. IENFD closely correlates with clinical and electrodiagnostic measures of neuropathy, and declines significantly over two years in diabetic subjects, including those without neuropathy symptoms. We have shown that metabolic improvement achieved through individualized diet and exercise counseling for subjects with early neuropathy associated with impaired glucose tolerance significantly improves measures of small fiber neuropathy, including pain and IENFD. We hypothesize that 1) early IENFD decline predicts future development of clinically meaningful diabetic neuropathy, and 2) correction of IENFD decline with aggressive lifestyle intervention based on the impaired glucose tolerance neuropathy studies will successfully result in weight loss, improved metabolic parameters, and reduced risk of diabetic neuropathy development or slowing of its progression. Aim 1 will follow CMND diabetic subjects for an additional four years to determine the magnitude of early decline in IENFD that predicts future development of symptomatic distal polyneuropathy. Aim 2 will randomize 175 additional diabetic subjects without neuropathy symptoms to determine if two years of aggressive diet and exercise counseling reduces IENFD progression, or incidence of symptomatic neuropathy. Both Aims will examine if metabolic syndrome, obesity or specific baseline metabolic parameters, insulin resistance (HOMA-IR) or adipokine levels predict rate of IENFD decline or risk of future neuropathy development. PUBLIC HEALTH RELEVANCE Injury to the very longest peripheral nerves due to diabetes (diabetic neuropathy) is very common. The earlier diabetic neuropathy can be identified, the more effective treatment is likely to be. This proposal will test a method to count nerves in skin to see if it predicts future diabetic neuropathy, and tests the effect of diet and exercise on preventing nerve injury.