A THERMAL PROBE METHOD FOR STAGING DIABETIC NEUROPATHY

糖尿病性神经病变是糖尿病的常见并发症。如果要在疾病最容易逆转的时候开始治疗，早期诊断是必不可少的。神经再生的敏感检测是决定临床治疗试验成功的关键。目前的方法缺乏这些任务所需的灵敏度。皮肤神经的形态学检查，特别是表皮的神经纤维，与糖尿病患者的神经病变程度密切相关。表皮神经纤维的减少可能是糖尿病神经病变的第一个形态学征象。表皮神经的实验性去神经支配可通过局部或皮内暴露于辣椒素（辣椒中的活性成分）而产生。停止辣椒素后，神经再生导致恢复。与辣椒素引起的表皮神经丧失相一致的是，受试者失去了对直径3毫米的热探针引起的热痛的感知能力。当停止治疗时，他们恢复了热痛敏感性。表皮神经纤维的密度与检测前臂部位热痛的能力之间存在直接相关性。然而，当使用更大的30x30 mm商用探针时，没有检测到灵敏度的变化。这种小热探针有望作为早期诊断神经病变的临床工具。辣椒素模型将用于开发一般临床使用的小探针方法。用局部辣椒素治疗不同身体部位皮肤的最佳探针大小、温度设置和热暴露时间将在正常受试者和糖尿病受试者中确定。糖尿病神经病变中通常受表皮神经丧失影响的皮肤部位，如小腿，将受到特别关注。结果将与辣椒素应用期间和辣椒素停药后恢复期间表皮神经纤维计数相关。一旦确定了最佳探针尺寸、温度和暴露量，将在一组正常和糖尿病志愿者身上进行测试，以确定热探针在临床环境中的敏感性。辣椒素对表皮神经的影响将通过电子显微镜研究，以证明免疫组化染色方法所见的神经纤维的损失确实是神经纤维破坏的结果。本研究将开发一种用于临床神经病变分期的小型热探针，证明神经纤维染色缺失等同于神经破坏，并证明糖尿病神经病变患者的神经再生能力。

Diabetic neuropathy is a common complication of diabetes. Early diagnosis is essential if treatment is to be initiated when the disease is most amenable to reversal. Sensitive detection of nerve regeneration is critical for determining the success of a clinical therapeutic trial. Current methods lack the required sensitivity for these tasks. Morphological examination of skin nerves, particularly the nerve fibers in epidermis, relates closely to the degree of neuropathy in diabetic subjects. Reduction of epidermal nerve fibers may be the first morphological sign of diabetic neuropathy. Experimental denervation of epidermal nerves can be produced by topical or intradermal exposure to capsaicin, the active ingredient in hot chili peppers. After discontinuation of capsaicin, nerve regeneration results in recovery. Coincident with capsaicin induced epidermal nerve loss, subjects lost their ability to detect heat pain induced by a 3 mm diameter thermal probe. They recovered hot pain sensitivity when treatment was discontinued. A direct correlation exists between the density of epidermal nerve fibers and ability to detect hot pain in the forearm location studied. However, no change in sensitivity was detected when a larger 30x30 mm commercial probe was used. The small thermal probe holds promise for use as a clinical tool for early diagnosis of neuropathy. The capsaicin model will be used to develop the small probe method for general clinical use. Optimal probe size, temperature setting, and time of heat exposure for skin of different body locations treated with topical capsaicin will be determined in both normal and diabetic subjects. Skin locations that are usually affected by epidermal nerve loss during diabetic neuropathy, e.g. the calf, will receive particular attention. The results will be correlated with counts of epidermal nerve fibers during capsaicin application and during recovery after capsaicin withdrawal. Once the optimal probe size, temperature and exposure are determined the probe will be tested on a cohort of normal and diabetic volunteers to determine the sensitivity of the thermal probe in a clinical setting. The effects of capsaicin on epidermal nerves will be studied by electron microscopy to prove that the loss of nerve fibers seen with immunohistochemical staining methods is indeed the result of destruction of the nerve fibers. This study will develop a small thermal probe for staging neuropathy in a clinical setting, prove that the absence of nerve fibers staining is tantamount to nerve destruction, and demonstrate the capacity for nerve regeneration in subjects with diabetic neuropathy.