Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.
Max Planck Institute for Multidisciplinary Science, Göttingen, Germany.
J Parkinsons Dis. 2024;14(5):917-924. doi: 10.3233/JPD-230104.
Aging is a major risk factor for Parkinson's disease (PD). Genetic mutations account for a small percentage of cases and the majority appears to be sporadic, with yet unclear causes. However, various environmental factors have been linked to an increased risk of developing PD and, therefore, understanding the complex interplay between genetic and environmental factors is crucial for developing effective disease-modifying therapies. Several studies identified a connection between type 2 diabetes (T2DM) and PD. T2DM is characterized by insulin resistance and failure of β-cells to compensate, leading to hyperglycemia and serious comorbidities. Both PD and T2DM share misregulated processes, including mitochondrial dysfunction, oxidative stress, chronic inflammation, altered proteostasis, protein aggregation, and misregulation of glucose metabolism. Chronic or recurring hyperglycemia is a T2DM hallmark and can lead to increased methylglyoxal (MGO) production, which is responsible for protein glycation. Glycation of alpha-synuclein (aSyn), a central player in PD pathogenesis, accelerates the deleterious aSyn effects. Interestingly, MGO blood plasma levels and aSyn glycation are significantly elevated in T2DM patients, suggesting a molecular mechanism underlying the T2DM - PD link. Compared to high constant glucose levels, glycemic variability (fluctuations in blood glucose levels), can be more detrimental for diabetic patients, causing oxidative stress, inflammation, and endothelial damage. Accordingly, it is imperative for future research to prioritize the exploration of glucose variability's influence on PD development and progression. This involves moving beyond the binary classification of patients as diabetic or non-diabetic, aiming to pave the way for the development of enhanced therapeutic interventions.
衰老 是帕金森病（PD）的一个主要危险因素。遗传突变占少数病例，而大多数病例似乎是散发性的，其病因尚不清楚。然而，各种环境因素与 PD 发病风险增加有关，因此，了解遗传和环境因素之间的复杂相互作用对于开发有效的疾病修饰疗法至关重要。有几项研究表明 2 型糖尿病（T2DM）与 PD 之间存在关联。T2DM 的特征是胰岛素抵抗和β细胞无法代偿，导致高血糖和严重的合并症。PD 和 T2DM 都存在调节异常的过程，包括线粒体功能障碍、氧化应激、慢性炎症、蛋白质稳态改变、蛋白质聚集和葡萄糖代谢失调。慢性或反复的高血糖是 T2DM 的一个特征，可导致甲基乙二醛（MGO）产生增加，从而导致蛋白质糖基化。α-突触核蛋白（aSyn）的糖基化，aSyn 是 PD 发病机制的核心参与者，加速了有害的 aSyn 效应。有趣的是，T2DM 患者的 MGO 血浆水平和 aSyn 糖基化显著升高，这表明 T2DM 与 PD 之间存在潜在的分子机制。与高恒定葡萄糖水平相比，血糖变异性（血糖水平波动）对糖尿病患者的危害更大，可导致氧化应激、炎症和内皮损伤。因此，未来的研究必须优先探索葡萄糖变异性对 PD 发展和进展的影响。这涉及超越将患者分为糖尿病或非糖尿病的二元分类，旨在为开发增强的治疗干预措施铺平道路。
