Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan.
Department of Diabetes and Endocrinology, Faculty and Graduate School of Medicine, Mie University, Tsu 514-8507, Mie, Japan.
Cells. 2021 Aug 29;10(9):2237. doi: 10.3390/cells10092237.
Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.
糖尿病是全球人类健康的一大威胁。糖尿病的根本原因是与胰腺β细胞数量减少相关的胰岛素产生和分泌不足。细胞凋亡是功能性β细胞进行性丧失的一个重要且公认的机制。然而，目前尚无可用的抗糖尿病细胞凋亡药物。本研究评估了重组人血栓调节蛋白是否可以抑制β细胞凋亡并改善糖尿病小鼠模型的葡萄糖耐量。通过链脲佐菌素诱导建立糖尿病小鼠模型，并每周三次用血栓调节蛋白或生理盐水处理 8 周。评估葡萄糖耐量和β细胞凋亡。与用生理盐水处理的对照疾病小鼠相比，用重组人血栓调节蛋白治疗的糖尿病小鼠显示出明显改善的葡萄糖耐量、增加的胰岛素分泌、减少的胰岛凋亡β细胞面积以及增强的调节性 T 细胞和耐受性树突状细胞在脾脏中的比例。非糖尿病小鼠没有变化。本研究表明，在日本目前用于治疗凝血功能障碍患者的药物重组人血栓调节蛋白通过保护胰岛β细胞免受凋亡和调节糖尿病小鼠的免疫反应来改善葡萄糖耐量。这一观察结果表明重组人血栓调节蛋白可能成为治疗糖尿病的一种有前途的抗细胞凋亡药物。
