Department of Endocrinology, Shenzhen Hospital, Southern Medical University, China.
Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, China.
Oxid Med Cell Longev. 2019 Jan 10;2019:1896041. doi: 10.1155/2019/1896041. eCollection 2019.
Diabetic neuropathy (DN) is a common and severe complication of diabetes mellitus. There is still a lack of an effective treatment to DN because of its complex pathogenesis. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of thioredoxin, has been shown to be associated with diabetic retinopathy and nephropathy. Herein, we aim to investigate the role of TXNIP in prediabetic neuropathy and therapeutic potential of verapamil which has been shown to inhibit TXNIP expression. The effects of mediating TXNIP on prediabetic neuropathy and its exact mechanism were performed using high-fat diet- (HFD-) induced diabetic mice and palmitate-treated neurons. Our results showed that TXNIP upregulation is associated with prediabetic neuropathy in HFD-fed mice. TXNIP knockdown improved DN in HFD-induced prediabetic mice. Mechanistically, increased TXNIP in dorsal root ganglion is transferred into the cytoplasm and shuttled to the mitochondria. In cytoplasm, TXNIP binding to TRX1 results in the increased oxidative stress and inflammation. In mitochondria, TXNIP binding to TRX2 induced mitochondria dysfunction and apoptosis. TXNIP isolated from TRX2 then shuttles to the cytoplasm and binds to NLRP3, resulting in further increased TXNIP-NLRP3 complex, which induced the release of IL-1 and the development of inflammation. Thus, apoptosis and inflammation of dorsal root ganglion neuron eventually cause neural dysfunction. In addition, we also showed that verapamil, a known inhibitor of calcium channels, improved prediabetic neuropathy in the HFD-fed mice by inhibiting the upregulation of TXNIP. Our finding suggests that TXNIP might be a potential target for the treatment of neuropathy in prediabetic patients with dyslipidemia.
糖尿病神经病变（DN）是糖尿病的一种常见且严重的并发症。由于其发病机制复杂，目前仍缺乏有效的治疗方法。硫氧还蛋白相互作用蛋白（TXNIP）是一种内源性的硫氧还蛋白抑制剂，已被证明与糖尿病视网膜病变和肾病有关。在此，我们旨在研究 TXNIP 在糖尿病前期神经病变中的作用，以及已被证明能抑制 TXNIP 表达的维拉帕米的治疗潜力。使用高脂肪饮食（HFD）诱导的糖尿病小鼠和棕榈酸处理的神经元来研究介导 TXNIP 对糖尿病前期神经病变的作用及其确切机制。我们的结果表明，TXNIP 的上调与 HFD 喂养小鼠的糖尿病前期神经病变有关。TXNIP 敲低改善了 HFD 诱导的糖尿病前期小鼠的 DN。从机制上讲，背根神经节中增加的 TXNIP 转移到细胞质中，并转移到线粒体中。在细胞质中，TXNIP 与 TRX1 结合导致氧化应激和炎症增加。在线粒体中，TXNIP 与 TRX2 结合导致线粒体功能障碍和细胞凋亡。然后，从 TRX2 分离出来的 TXNIP 穿梭到细胞质中并与 NLRP3 结合，导致进一步增加的 TXNIP-NLRP3 复合物，从而诱导 IL-1 的释放和炎症的发展。因此，背根神经节神经元的凋亡和炎症最终导致神经功能障碍。此外，我们还表明，已知的钙通道抑制剂维拉帕米通过抑制 TXNIP 的上调改善了 HFD 喂养小鼠的糖尿病前期神经病变。我们的发现表明，TXNIP 可能是治疗伴有血脂异常的糖尿病前期患者神经病变的潜在靶点。
