Painful versus insensate diabetic neuropathy

 描述(申请人提供)：糖尿病神经病变(DN)是糖尿病最常见和最令人衰弱的并发症之一。然而，糖尿病肾病在很大程度上仍然是一种无法治疗的疾病，目前的策略仅针对疼痛控制。已经确定了许多导致糖尿病肾病的细胞机制，但没有解释为什么某些患者会出现疼痛，或者发生无感觉的感觉丧失。这种信息的缺乏阻碍了临床医生为患者制定预防性治疗策略，以充分预防疼痛或无知觉的神经病。我们的长期目标是了解外周轴突的变化如何导致糖尿病患者的各种感觉症状。在过去的几年里，我们已经确定了更好地反映人类糖尿病肾病不同症状的啮齿动物模型，并使用这些模型来了解表皮内轴突亚型的变化如何与糖尿病肾病的特定症状有关。表皮神经支配来源于两个不同的轴突群体，它们由不同的神经化学标志物和神经营养反应来区分。这两种感觉轴突亚型被称为肽能轴突或非肽能轴突。我们认为，这些表皮轴突亚型中的关键修饰发生在糖尿病肾病进展的早期，可能导致疼痛或感觉丧失。 中心假设是，支配皮肤的两种轴突亚型的比例和损害对于确定糖尿病患者的感觉障碍至关重要。拨款的目的包括：1)测试 这些研究包括：1)研究糖尿病患者表皮轴突的变化是否会导致疼痛或感觉丧失，2)测试炎症和神经生长因子是否导致表皮轴突表型的变化，2)运动干预是否阻止或逆转表皮轴突表型的变化，3)皮肤活检分析是否可用于预测和跟踪与人类小纤维糖尿病肾病相关的表皮变化。这些拟议的实验是独一无二的，因为他们提出了一个简单但可验证的假设，可以解释糖尿病患者中不同的感觉并发症是如何发生的。重要的是，我们的方法很容易翻译到人类研究中，并可能与其他形式的神经病非常相关。在此进行的皮肤活检分析可能会提供新的预测能力，以确定有发生神经病变的风险的患者，也可能在未来的糖尿病神经病变临床试验中用作神经病变改善的更好指标。

 DESCRIPTION (provided by applicant): Diabetic neuropathy (DN) is one of the most prevalent and debilitating complications of diabetes. However, DN remains largely an untreatable condition and current strategies only address pain control. A number of cellular mechanisms have been identified that lead to DN, but no explanation exists as to why certain patients develop pain, or alternatively develop insensate sensory loss. This paucity of information has hampered clinicians in developing prophylactic treatment strategies for patients that adequately prevent painful or insensate neuropathy. Our long-range goal is to understand how changes in peripheral axons can lead to varied sensory symptoms in diabetes. In previous funding years, we have identified rodent models that better reflect the varied symptoms of human DN and used these models to understand how changes in axonal subtypes within the epidermis may be related to specific symptoms of DN. Epidermal innervation is derived from two distinct axonal populations that are differentiated by different neurochemical markers and neurotrophic responsiveness. These two sensory axon subtypes are referred to as peptidergic or nonpeptidergic axons. We believe that key modifications occur in these epidermal axon subtypes early in the progression of DN that can lead to pain, or alternatively, loss of sensation. The central hypothesis is that the ratio and damage to two axonal subtypes innervating the skin is critical in specifying sensory dysfunction in diabetes. The aims of the grant include 1) testing whether changes in epidermal axons can drive pain or loss of sensation in diabetes, and testing whether inflammation and NGF responsible for changing epidermal axon phenotypes, 2) whether exercise intervention prevent or reverse changes in epidermal axon phenotypes, and 3) whether skin biopsy analyses be used to predict and follow epidermal changes associated with small fiber DN in humans. These proposed experiments are unique as they present a simple, but testable hypothesis that may explain how the divergent sensory complications can develop in diabetes. Importantly, our approaches are easily translatable to human studies and may be very relevant to other forms of neuropathy. The analyses of skin biopsies as performed here may provide new predictive power to identify patients at risk for developing neuropathy, and may also be used as a better indicator of neuropathy improvement in future clinical trials of diabetic neuropathy.