Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, India.
Biomed Pharmacother. 2018 Oct;106:472-482. doi: 10.1016/j.biopha.2018.06.168. Epub 2018 Jul 11.
To determine the histopathological and molecular changes in β-cells at different time intervals following streptozotocin (STZ)-induced diabetes.
STZ (65 mg/kg body weight) was given to overnight fasted rats that were sacrificed after 1, 3, and 10 days of injection. Changes in islet morphology and in the expression of various factors involved in β-cell proliferation, inflammation and apoptosis were analyzed.
Superoxide dismutase (Sod) expression was completely reduced and that of NF-kB and iNOS were significantly increased, along with lymphocytic infiltration in the islets within 24 h of STZ injection. In addition, the β-cell protective markers Bcl-2, IL-6, Ki67, Hif-1α, VEGF and insulin were also enhanced, indicating a compensatory response of the β-cells to the initial damaging effects. Lymphocytic infiltration decreased after 3 days of injection, accompanied by enhanced expression of both GLP-1R and GIP R. The unresponsiveness of the incretin ligands after STZ administration further suggested a compensatory approach by the incretin receptors independent of glucose regulation. After 10 days, lymphocytic infiltration and inflammatory markers again increased, along with a concomitant reduction in the expression of incretin receptors, and upregulation of the protective markers. Furthermore, the saturation peak of blood glucose indicated progressive diabetes.
The β-cells follow a biphasic pattern of expression of certain factors in order to achieve a balance between apoptosis, autophagy, neo-genesis, hypoxia and proliferation, and achieve homeostatic protection before the onset of diabetes. The drug interventions at an early stage, which are specific to these pathways, could be beneficial in preventing the progression of diabetes pathogenesis.
确定链脲佐菌素（STZ）诱导糖尿病后不同时间间隔β细胞的组织病理学和分子变化。
将 STZ（65mg/kg 体重）给予隔夜禁食的大鼠，注射后 1、3 和 10 天处死，分析胰岛形态变化和参与β细胞增殖、炎症和细胞凋亡的各种因子的表达变化。
STZ 注射后 24 小时内，胰岛内超氧化物歧化酶（Sod）表达完全降低，NF-kB 和 iNOS 表达显著增加，同时伴有淋巴细胞浸润。此外，β细胞保护标记物 Bcl-2、IL-6、Ki67、Hif-1α、VEGF 和胰岛素也增强，表明β细胞对初始损伤作用的代偿反应。注射后 3 天，淋巴细胞浸润减少，同时 GLP-1R 和 GIP R 表达增强。STZ 给药后肠促胰岛素配体无反应进一步表明，肠促胰岛素受体在不依赖葡萄糖调节的情况下具有代偿作用。10 天后，淋巴细胞浸润和炎症标志物再次增加，同时肠促胰岛素受体表达减少，保护标记物上调。此外，血糖饱和度峰值表明糖尿病逐渐进展。
β细胞遵循某些因子表达的双相模式，以在凋亡、自噬、新生、缺氧和增殖之间达到平衡，并在糖尿病发病前实现稳态保护。早期针对这些途径的药物干预可能有助于预防糖尿病发病机制的进展。
