Relationship between nigrostriatal DA depletion and insulin resistance

临床研究表明帕金森病（PD）与2型糖尿病（T2D）之间存在相关性。我们建议对这些疾病之间的关系进行临床前调查。该项目的长期目标是双重的：确定这些疾病是如何机械地联系起来的，并调查可能的治疗干预措施。我们的第一个目标是调查PD作为T2D的危险因素。我们将在黑质纹状体通路注射6-羟多巴胺，并分析多巴胺耗竭对大脑和外周胰岛素信号的影响。在我们的第二个实验目标中，我们将使用胰岛素抵抗（高脂肪饮食）模型来分析糖尿病可能在PD发展中发挥作用的机制。高血糖和胰岛素水平已被证明会影响大脑中的多巴胺功能。我们将分析胰岛素抵抗和高胰岛素血症对脑胰岛素信号、基底神经节DA功能和神经氧化应激水平的影响。我们的最终目的是研究胰岛素抵抗是否会加剧部分病变模型中的多巴胺能变性，以及药物干预是否可以减轻这种影响。这一点很重要，因为导致氧化损伤的环境因素，如杀虫剂，已被证明会增加患帕金森病的可能性。确定环境暴露于氧化剂的影响是否会与胰岛素抵抗复合是很重要的。确定这些疾病之间的联系是打破这种关系的第一步，并降低患有PD或T2D的个体日后患上这两种疾病的可能性。此外，我们也将提供更大的机制洞察病理介导每一个特定的疾病。与公众健康相关：许多帕金森患者有异常的糖耐量，左旋多巴治疗可能会加重这种情况，并增加治疗的副作用，如运动障碍。此外，最近的一项临床研究发现，T2D患者患PD的可能性比非糖尿病患者高83%，这表明T2D可能是PD的危险因素。T2D和PD之间的机制关联值得关注。如果不能解决这个迫在眉睫的临床问题，可能会导致每种疾病的发病率增加，疾病严重程度增加，治疗效果下降。

DESCRIPTION (provided by applicant): Clinical studies have shown a correlation between Parkinson's disease (PD) and Type 2 Diabetes (T2D). We propose a preclinical investigation of relationship between these diseases. The long term objective of this project is twofold: to determine how these diseases are linked mechanistically and to investigate possible therapeutic interventions. Our first aim is to investigate PD as a risk factor for T2D. We will inject 6-hydroxydopamine into the nigrostriatal pathway and analyze the effect of dopamine depletion on insulin signaling in the brain and periphery. In our second experimental aim, we will use a model of insulin resistance (high fat diet) to analyze mechanisms by which diabetes mellitus may play a role in development of PD. High blood glucose and insulin levels have been shown to affect dopamine function in the brain. We will analyze the effects of insulin resistance and hyperinsulinemia on brain insulin signaling, DA function in the basal ganglia, and neural oxidative stress levels. Our final aim will investigate whether insulin resistance exacerbates dopaminergic degeneration in a partial lesion model, and whether a pharmacological intervention can alleviate this effect. This is important because environmental factors that cause oxidative damage, such as pesticides, have been shown to increase the likelihood of developing PD. It is important to determine whether the effects of environmental exposure to oxidants could be compounded by insulin resistance. Determining how these diseases are linked is the first step in disrupting this relationship and decreasing the likelihood that an individual who suffers from either PD or T2D will later develop both diseases. In addition, we will also provide greater mechanistic insight into the pathologies mediating each specific disease. Relevance to public health: Many Parkinson's patients have abnormal glucose tolerance, which may be exacerbated by L-DOPA therapy and increase side effects of therapy such as dyskenesias. In addition, a recent clinical study has found individuals with T2D to be 83% more likely to develop PD than their non-diabetic counterparts, indicating T2D as a possible risk factor for PD. A mechanistic association between T2D and PD demands attention. Failure to address this looming clinical issue could result in increased incidence of each disease, increased disease severity, and decreased therapeutic effectiveness.