The Utah Diabetic Neuropathy Study

描述(申请人提供)：糖尿病神经病变，一旦得到很好的证实，在人体试验中很难逆转。敏感的诊断措施是必要的，以确定早期轴索损伤的患者，他们可能是更好的干预甚至预防性治疗的对象。糖尿病神经病变皮肤测量(CMND)研究广泛地表征了221名糖尿病患者的周围神经功能，并进行了纵向随访。CMND表明，早期糖尿病神经病变的特征是进行性小纤维丢失，并将皮肤活检与表皮内神经纤维密度(IENFD)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措施密切相关，在糖尿病患者中，包括那些没有神经病变症状的患者，IENFD在两年内显著下降。我们已经证明，对于与糖耐量受损相关的早期神经病患者，通过个性化饮食和运动咨询实现的代谢改善显著改善了小纤维神经病的指标，包括疼痛和IENFD。我们假设，1)早期IENFD下降预示着有临床意义的糖尿病神经病变的未来发展，以及2)基于糖耐量受损神经病变研究的积极生活方式干预纠正IENFD下降将成功地导致体重减轻、代谢参数改善，并降低糖尿病神经病变发展或减缓其进展的风险。目的1将对CMND糖尿病患者再追踪四年，以确定IENFD早期下降的幅度，以预测未来症状性远端多神经病的发展。目的2将对另外175名没有神经病变症状的糖尿病患者进行随机研究，以确定两年的积极饮食和运动咨询是否会减少IENFD的进展或症状性神经病变的发生率。这两个目标都将检验代谢综合征、肥胖或特定的基线代谢参数、胰岛素抵抗(HOMA-IR)或脂肪因子水平是否预测IENFD下降的速度或未来神经病变发展的风险。与公共卫生相关的糖尿病(糖尿病神经病变)对最长的周围神经的损伤是非常常见的。越早发现糖尿病神经病变，治疗就可能越有效。这项提案将测试一种计算皮肤神经数量的方法，看看它是否可以预测未来的糖尿病神经病变，并测试饮食和运动在预防神经损伤方面的效果。

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.