The nigrostriatal dopaminergic system (NDS) controls motor activity, and its impairment during type 2 diabetes (T2D) progression could increase Parkinson's disease risk in diabetics. If so, whether glycemia regulation prevents this impairment needs to be addressed. We investigated whether T2D impairs the NDS and whether dipeptidyl peptidase-4 inhibition (DPP-4i; a clinical strategy against T2D but also neuroprotective in animal models) prevents this effect, in middle-aged mice. Neither T2D (induced by 12 months of high-fat diet) nor aging (14 months) changed striatal dopamine content assessed by high-performance liquid chromatography. However, T2D reduced basal and amphetamine-stimulated striatal extracellular dopamine, assessed by microdialysis. Both the DPP-4i linagliptin and the sulfonylurea glimepiride (an antidiabetic comparator unrelated to DPP-4i) counteracted these effects. The functional T2D-induced effects did not correlate with NDS neuronal/glial alterations. However, aging itself affected striatal neurons/glia, and the glia effects were counteracted mainly by DPP-4i. These findings show NDS functional pathophysiology in T2D and suggest the preventive use of two unrelated anti-T2D drugs. Moreover, DPP-4i counteracted striatal age-related glial alterations suggesting striatal rejuvenation properties.

中文翻译：

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二肽基肽酶 4 抑制剂和磺脲类药物可防止衰老过程中糖尿病引起的黑质纹状体多巴胺能系统的进行性损伤

黑质纹状体多巴胺能系统 (NDS) 控制运动活动，其在 2 型糖尿病 (T2D) 进展过程中受损可能会增加糖尿病患者的帕金森病风险。如果是这样，需要解决血糖调节是否可以防止这种损害。我们在中年小鼠中研究了 T2D 是否会损害 NDS 以及二肽基肽酶 4 抑制（DPP-4i；一种针对 T2D 的临床策略，但在动物模型中也具有神经保护作用）是否可以防止这种影响。T2D（由 12 个月的高脂肪饮食诱发）和衰老（14 个月）均未改变通过高效液相色谱评估的纹状体多巴胺含量。然而，通过微透析评估，T2D 减少了基础和苯丙胺刺激的纹状体细胞外多巴胺。DPP-4i 利格列汀和磺脲类格列美脲（一种与 DPP-4i 无关的抗糖尿病对照药）都抵消了这些影响。功能性 T2D 诱导的影响与 NDS 神经元/神经胶质改变无关。然而，衰老本身会影响纹状体神经元/神经胶质，而神经胶质的影响主要被 DPP-4i 抵消。这些发现显示了 T2D 中 NDS 的功能病理生理学，并建议预防性使用两种不相关的抗 T2D 药物。此外，DPP-4i 抵消了纹状体年龄相关的神经胶质改变，表明纹状体再生特性。这些发现显示了 T2D 中的 NDS 功能病理生理学，并建议预防性使用两种不相关的抗 T2D 药物。此外，DPP-4i 抵消了纹状体年龄相关的神经胶质改变，表明纹状体再生特性。这些发现显示了 T2D 中的 NDS 功能病理生理学，并建议预防性使用两种不相关的抗 T2D 药物。此外，DPP-4i 抵消了纹状体年龄相关的神经胶质改变，表明纹状体再生特性。