Yoon J W
Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Alberta, Canada.
Curr Top Microbiol Immunol. 1990;164:95-123. doi: 10.1007/978-3-642-75741-9_6.
The development of IDDM results from the destruction of pancreatic beta cells. Genetic factors, various immune system alterations, and environmental factors have been studied as the possible causes of IDDM. The concordance rate for developing IDDM between monozygotic twins approaches 50%, suggesting that genetic factors are necessary, but nongenetic factors such as various immune system alterations and environmental factors also influence the clinical expression of genetic susceptibility. Environmental factors (e.g., viruses, chemicals, and diet) affecting the induction of diabetes may act as primary injurious agents which damage pancreatic beta cells or as triggering agents of autoimmunity. Certain viruses including EMC-D and Mengo virus 2T can directly infect pancreatic beta cells and replicate in the cells. The replication of viruses in the beta cells results in the destruction of the cells within 3 days, and the infected mice develop a diabeteslike syndrome in 3-4 days without the involvement of autoimmunity. In contrast, rubella virus appears to be somewhat weakly associated with autoimmune IDDM in hamsters. In addition, endogenous retrovirus expressed in pancreatic beta cells is clearly associated with the development of insulitis and diabetes in NOD mice. In man, there appears to be no correlation between the detection of islet cell autoantibodies and anti-Coxsackie B viral antibodies in newly diagnosed IDDM. In contrast, persistent infection of CMV and rubella virus appears to be associated with the presence of autoantibodies in newly diagnosed IDDM patients. It is particularly noteworthy that human CMV can induce islet cell autoantibodies that react specifically with a 38 kDa islet cell protein which may represent islet cell-specific antigens in a proportion of CMV-associated IDDM cases. These observations suggest that the association of diabetes with Coxsackie B viruses might be due to cytolytic infection of the beta cells with no link to autoimmunity, while both rubella virus and CMV are probably associated with autoimmune IDDM. A number of structurally diverse chemicals including alloxan, streptozotocin, chlorozotocin, Vacor, and cyproheptadine are diabetogenic mainly in rodents and sometimes in man. Possible mechanisms for beta cell destruction by these chemicals include (a) generation of oxygen free radicals and alteration of endogenous scavengers of these reactive species; (b) breakage of DNA and a consequent increase in the activity of poly-ADP-ribose synthetase, an enzyme depleting nicotinamide adenine dinucleotide in beta cells; and (c) inhibition of active calcium transport and calmodulin-activated protein kinase activity. (ABSTRACT TRUNCATED AT 400 WORDS)
胰岛素依赖型糖尿病（IDDM）的发生是由于胰腺β细胞被破坏。遗传因素、各种免疫系统改变和环境因素已被作为IDDM的可能病因进行研究。同卵双胞胎患IDDM的一致率接近50%，这表明遗传因素是必要的，但诸如各种免疫系统改变和环境因素等非遗传因素也会影响遗传易感性的临床表达。影响糖尿病诱发的环境因素（如病毒、化学物质和饮食）可能作为直接损伤胰腺β细胞的原发性损伤因子，或作为自身免疫的触发因子。某些病毒，包括脑心肌炎病毒（EMC-D）和门戈病毒2T，可直接感染胰腺β细胞并在细胞内复制。病毒在β细胞内的复制会在3天内导致细胞破坏，受感染的小鼠在3 - 4天内会出现类似糖尿病的综合征，且无自身免疫参与。相比之下，风疹病毒似乎与仓鼠的自身免疫性IDDM有较弱的关联。此外，在胰腺β细胞中表达的内源性逆转录病毒与非肥胖糖尿病（NOD）小鼠胰岛炎和糖尿病的发生明显相关。在人类中，新诊断的IDDM患者中胰岛细胞自身抗体的检测与抗柯萨奇B病毒抗体之间似乎没有相关性。相反，巨细胞病毒（CMV）和风疹病毒的持续感染似乎与新诊断的IDDM患者中自身抗体的存在有关。特别值得注意的是，人类CMV可诱导胰岛细胞自身抗体，这些抗体能与一种38 kDa的胰岛细胞蛋白特异性反应，在部分与CMV相关的IDDM病例中，该蛋白可能代表胰岛细胞特异性抗原。这些观察结果表明，糖尿病与柯萨奇B病毒的关联可能是由于β细胞的溶细胞性感染，与自身免疫无关，而风疹病毒和CMV可能与自身免疫性IDDM有关。许多结构多样的化学物质，包括四氧嘧啶、链脲佐菌素、氯脲佐菌素、灭鼠优和赛庚啶，主要在啮齿动物中有时也在人类中具有致糖尿病作用。这些化学物质破坏β细胞的可能机制包括：（a）产生氧自由基并改变这些反应性物质的内源性清除剂；（b）DNA断裂，随后多聚ADP - 核糖合成酶活性增加，该酶会消耗β细胞中的烟酰胺腺嘌呤二核苷酸；（c）抑制主动钙转运和钙调蛋白激活的蛋白激酶活性。（摘要截断于400字）
