Peking University Fifth School of Clinical Medicine, Beijing, China.
Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Beijing, China.
Oxid Med Cell Longev. 2021 Nov 11;2021:2482453. doi: 10.1155/2021/2482453. eCollection 2021.
Subclinical hypothyroidism (SCH) is associated with diabetic peripheral neuropathy (DPN); however, the mechanism underlying this association remains unknown. This study is aimed at examining neurofunctional and histopathological alterations in a type 2 diabetes (T2DM) mouse model of SCH and investigating the impact of thyroid-stimulating hormone (TSH) in an in vitro DPN cell model established using RSC96 cells under high glucose (HG) and palmitic acid (PA) stimulation. Our results indicated that T2DM, in combination with SCH, aggravated abnormal glucose and lipid metabolism in T2DM and dramatically destroyed the peripheral nervous system by increasing paw withdrawal latency, decreasing motor nerve conduction velocity, and exacerbating ultrastructural deterioration of the damaged sciatic nerve caused by diabetes. Furthermore, the results of our in vitro experiments showed that TSH intensified HG/PA-induced RSC96 cell damage by inducing oxidative stress, mitochondrial dysfunction, and apoptosis. More importantly, TSHR knockout or inhibition of PA-induced TSHR palmitoylation could alleviate the apoptosis induced by TSH. Overall, in this study, the novel mechanisms by which TSH, as an independent risk factor for DPN progression, aggravating Schwann cell apoptosis and demyelination, are elucidated. These findings indicate that TSHR could be a potential target for both the prevention and treatment of DPN and, possibly, other microvascular diseases, and have implication in the clinical management of patients with DPN.
亚临床甲状腺功能减退症（SCH）与糖尿病周围神经病变（DPN）有关；然而，这种关联的机制尚不清楚。本研究旨在检查SCH 型 2 型糖尿病（T2DM）小鼠模型中的神经功能和组织病理学改变，并研究在高葡萄糖（HG）和棕榈酸（PA）刺激下使用 RSC96 细胞建立的体外 DPN 细胞模型中，促甲状腺激素（TSH）的影响。我们的结果表明，T2DM 合并 SCH 加重了 T2DM 异常的糖脂代谢，并通过增加足底撤回潜伏期、降低运动神经传导速度以及加剧糖尿病引起的受损坐骨神经超微结构恶化，显著破坏外周神经系统。此外，我们的体外实验结果表明，TSH 通过诱导氧化应激、线粒体功能障碍和细胞凋亡，加剧了 HG/PA 诱导的 RSC96 细胞损伤。更重要的是，TSHR 敲除或抑制 PA 诱导的 TSHR 棕榈酰化可减轻 TSH 诱导的细胞凋亡。总的来说，在这项研究中，阐明了 TSH 作为 DPN 进展的独立危险因素，加重施万细胞凋亡和脱髓鞘的新机制。这些发现表明 TSHR 可能成为预防和治疗 DPN 以及其他微血管疾病的潜在靶点，并对 DPN 患者的临床管理具有启示意义。
