Zhou Qing, Zhang Li Yong, Gao Xue Lin, Zou Chao Chun, Liu Hui
Department of Endocrinology, Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center, Fujian Maternity and Child Health Hospital, Fuzhou, China.
Department of Thyroid Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Endocr Connect. 2025 Aug 11;14(8). doi: 10.1530/EC-25-0158. Print 2025 Aug 1.
Hashimoto's thyroiditis (HT) is one of the most common autoimmune disorders. Patients with HT are more likely to be affected by insulin resistance, even euthyroid individuals. Endoplasmic reticulum (ER) stress is related to the pathogenesis of several immunological diseases, such as HT. Thus, the aim of the present study was to explore the potential mechanism and effect of HT on insulin resistance in HT model mice in vivo and to assess the role of ER stress in this process. In this study, euthyroid HT model mice were established by simultaneously giving high amounts of iodine in drinking water and twice subcutaneously injecting thyroglobulin emulsified with Freund's adjuvant. HT mice were treated with or without 4-phenylbutyric acid (4-PBA), an inhibitor of ER stress. We detected increased protein expression of binding immunoglobulin protein (Bip), activating transcription factor 6 (ATF6), and upregulated phospho-inositol-requiring enzyme 1 (IRE1) and phospho-c-Jun N-terminal kinase (JNK) in the thyroid tissue and adipose tissue of HT mice. In addition, HT mice exhibited impaired insulin sensitivity, decreased insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and protein kinase B (AKT) phosphorylation in adipose tissue, but these effects were alleviated by 4-PBA. Moreover, HT mice had higher serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels than control mice. Similarly, the ER stress inhibitor 4-PBA significantly decreased TNF-α and IL-6 levels compared with those in HT mice. These findings suggest that HT is related to the development of insulin resistance, and that the mechanism may involve ER stress.
桥本甲状腺炎（HT）是最常见的自身免疫性疾病之一。即使是甲状腺功能正常的个体，HT患者也更易受到胰岛素抵抗的影响。内质网（ER）应激与包括HT在内的多种免疫性疾病的发病机制相关。因此，本研究的目的是在体内探索HT对HT模型小鼠胰岛素抵抗的潜在机制和影响，并评估ER应激在此过程中的作用。在本研究中，通过同时在饮用水中给予大量碘并两次皮下注射用弗氏佐剂乳化的甲状腺球蛋白，建立甲状腺功能正常的HT模型小鼠。HT小鼠接受或不接受ER应激抑制剂4-苯基丁酸（4-PBA）治疗。我们检测到HT小鼠甲状腺组织和脂肪组织中结合免疫球蛋白蛋白（Bip）、活化转录因子6（ATF6）的蛋白表达增加，以及磷酸化肌醇需要酶1（IRE1）和磷酸化c-Jun氨基末端激酶（JNK）上调。此外，HT小鼠表现出胰岛素敏感性受损，脂肪组织中胰岛素受体底物1（IRS-1）酪氨酸磷酸化和蛋白激酶B（AKT）磷酸化降低，但这些作用被4-PBA减轻。此外，HT小鼠血清肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平高于对照小鼠。同样，与HT小鼠相比，ER应激抑制剂4-PBA显著降低了TNF-α和IL-6水平。这些发现表明，HT与胰岛素抵抗的发生有关，其机制可能涉及ER应激。
