O'Brien B A, Harmon B V, Cameron D P, Allan D J
School of Life Science, Queensland University of Technology, Brisbane, Australia.
J Pathol. 1996 Feb;178(2):176-81. doi: 10.1002/(SICI)1096-9896(199602)178:2<176::AID-PATH433>3.0.CO;2-8.
Although insulin-dependent diabetes mellitus (IDDM) results from irreversible loss of beta cells, the mode of cell death responsible for this loss has not previously been categorized. In this study, the multiple low-dose streptozotocin (stz) model (intraperitoneal injection of stz at a concentration of 40 mg/kg body weight per day for five consecutive days) was used to investigate beta-cell death during the development of IDDM in male C57B1/6 mice. Apoptotic cells were evident by light microscopy within the islets of Langerhans of treated animals from day 2 (the day of the second stz injection) until day 17. Immunohistochemical localization of insulin to the dying cells confirmed the beta-cell origin of the apoptosis. Two peaks in the incidence of beta-cell apoptosis occurred: the first at day 5, which corresponded to an increase in blood glucose concentration, and the second at day 11, when lymphocytic infiltration of the islets (insulitis) was maximal. Insulitis did not begin until day 9, by which time treated animals had developed overt diabetes as revealed by blood glucose and pancreatic immunoreactive insulin (IRI) measurements. Beta-cell apoptosis preceded the appearance of T-cells in the islets and continued throughout the period of insulitis. Thus, whether induced by stz or a subsequent immune response, apoptosis is the mode of cell death responsible for beta-cell loss in the multiple low-dose stz model of IDDM.
尽管胰岛素依赖型糖尿病（IDDM）是由β细胞的不可逆丧失所致，但此前尚未对造成这种丧失的细胞死亡方式进行分类。在本研究中，采用多次低剂量链脲佐菌素（STZ）模型（每天腹腔注射浓度为40mg/kg体重的STZ，连续5天）来研究雄性C57B1/6小鼠IDDM发生过程中的β细胞死亡情况。从第2天（第二次注射STZ之日）至第17天，在接受治疗动物的胰岛内，通过光学显微镜可明显观察到凋亡细胞。胰岛素在濒死细胞中的免疫组织化学定位证实了凋亡细胞来源于β细胞。β细胞凋亡发生率出现两个峰值：第一个峰值在第5天，此时血糖浓度升高；第二个峰值在第11天，此时胰岛的淋巴细胞浸润（胰岛炎）最为严重。胰岛炎直到第9天才开始，此时通过血糖和胰腺免疫反应性胰岛素（IRI）测量发现，接受治疗的动物已发展为明显的糖尿病。β细胞凋亡先于胰岛中T细胞的出现，并在整个胰岛炎期间持续存在。因此，无论是由STZ诱导还是由随后的免疫反应诱导，凋亡都是IDDM多次低剂量STZ模型中导致β细胞丧失的细胞死亡方式。
