The Utah Diabetic Neuropathy Study

描述（由申请人提供）：糖尿病神经病变，一旦确定，在人体试验中是很差的可逆性。敏感的诊断措施是必要的，以确定患者早期轴索损伤谁可能是更好的候选人干预，甚至是预防性治疗。糖尿病神经病变的皮肤测量（CMND）研究广泛地描述了221名糖尿病患者的周围神经功能，并进行了纵向随访。CMND显示早期糖尿病神经病变以进行性小纤维丢失为特征，并通过表皮内神经纤维密度（IENFD）确定皮肤活检作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，在糖尿病患者（包括无神经病变症状的患者）中，IENFD在两年内显著下降。我们已经表明，通过个体化饮食和运动咨询，对糖耐量受损的早期神经病变患者的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下降预示着未来有临床意义的糖尿病神经病变的发展，2)基于糖耐量受损的神经病变研究，通过积极的生活方式干预来纠正IENFD下降将成功地导致体重减轻，改善代谢参数，降低糖尿病神经病变发展的风险或减缓其进展。目的1将对CMND糖尿病患者进行额外四年的随访，以确定IENFD早期下降的程度，预测症状性远端多发性神经病变的未来发展。目的2将随机选取175名没有神经病变症状的糖尿病患者，以确定两年积极饮食和运动咨询是否能减少IENFD的进展或症状性神经病变的发生率。这两个目标将检查代谢综合征、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能预测IENFD下降率或未来神经病变发展的风险。糖尿病引起的最长周围神经损伤（糖尿病神经病变）是非常常见的。越早发现糖尿病性神经病变，治疗越有可能有效。该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效果。

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.