Athauda D, Foltynie T
Sobell Department of Motor Neuroscience, UCL Institute of Neurology & The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, United Kingdom.
Prog Neurobiol. 2016 Oct-Nov;145-146:98-120. doi: 10.1016/j.pneurobio.2016.10.001. Epub 2016 Oct 3.
There is growing evidence that patients with Type 2 diabetes have an increased risk of developing Parkinson's disease and share similar dysregulated pathways suggesting common underlying pathological mechanisms. Historically insulin was thought solely to be a peripherally acting hormone responsible for glucose homeostasis and energy metabolism. However accumulating evidence indicates insulin can cross the blood-brain-barrier and influence a multitude of processes in the brain including regulating neuronal survival and growth, dopaminergic transmission, maintenance of synapses and pathways involved in cognition. In conjunction, there is growing evidence that a process analogous to peripheral insulin resistance occurs in the brains of Parkinson's disease patients, even in those without diabetes. This raises the possibility that defective insulin signalling pathways may contribute to the development of the pathological features of Parkinson's disease, and thereby suggests that the insulin signalling pathway may potentially be a novel target for disease modification. Given these growing links between PD and Type 2 diabetes it is perhaps not unsurprising that drugs used the treatment of T2DM are amongst the most promising treatments currently being prioritised for repositioning as possible novel treatments for PD and several clinical trials are under way. In this review, we will examine the underlying cellular links between insulin resistance and the pathogenesis of PD and then we will assess current and future pharmacological strategies being developed to restore neuronal insulin signalling as a potential strategy for slowing neurodegeneration in Parkinson's disease.
越来越多的证据表明，2型糖尿病患者患帕金森病的风险增加，且存在相似的失调通路，提示有共同的潜在病理机制。历史上，胰岛素被认为仅是一种负责葡萄糖稳态和能量代谢的外周作用激素。然而，越来越多的证据表明，胰岛素能够穿过血脑屏障，影响大脑中的多种过程，包括调节神经元存活和生长、多巴胺能传递、突触维持以及与认知有关的通路。同时，越来越多的证据表明，即使在没有糖尿病的帕金森病患者大脑中，也会发生类似于外周胰岛素抵抗的过程。这增加了胰岛素信号通路缺陷可能导致帕金森病病理特征发展的可能性，从而表明胰岛素信号通路可能是疾病修饰的一个新靶点。鉴于帕金森病与2型糖尿病之间的联系日益增多，用于治疗2型糖尿病的药物成为目前最有希望被重新定位为帕金森病新治疗方法的药物之一，并且正在进行多项临床试验，这或许并不令人意外。在这篇综述中，我们将研究胰岛素抵抗与帕金森病发病机制之间的潜在细胞联系，然后评估目前正在开发的以及未来为恢复神经元胰岛素信号而制定的药理学策略，以此作为减缓帕金森病神经退行性变的潜在策略。
