Insulindependent Diabetes Mellitus Experimental Models

Ji-Won Yoon and Hee-Sook Jun, Department of Microbiology and Infectious Diseases, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; Institute for Medical Science, Ajou University School of Medicine, Suwon, Korea

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM), results from the destruction of insulin-producing pancreatic (3 cells, culminating in hypoinsulinemia and hyperglycemia. IDDM appears to be a disease of autoimmunity. Genetic susceptibility is believed to be a prerequisite for the development of IDDM and environmental factors, such as viruses, diet and toxins are also considered to be involved in the clinical expression of this disease (Figure 1).

Animal models of human autoimmune IDDM, such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, have enhanced our understanding of the pathogenic mechanisms of this disease. The spontaneously diabetic BB rat was discovered in 1974 in a colony of outbred Wistar rats

Figure 1 Etiology of IDDM. Genetic susceptibility appears to be prerequisite for most, if not all, cases of IDDM. Environmental factors influence the clinical expression of genetic susceptibility. Certain environmental factors, such as viruses and toxins, may act as primary injurious agents to pancreatic (3 cells, or as triggering agents for autoimmunity in humans and animals. Once p cell-specific autoimmunity has developed, autoimmune-mediated destruction of p cells results in the onset of IDDM. (3 cell-specific autoantigens, macrophages, helper T cells and autoantigen-specific cytotoxic T lymphocytes (CTLs) are involved in the autoimmune process. In addition, free radicals and cytokines released from macrophages and T cells, and autoantigen-specific T effector cells synergistlcally destroy p cells.

Figure 1 Etiology of IDDM. Genetic susceptibility appears to be prerequisite for most, if not all, cases of IDDM. Environmental factors influence the clinical expression of genetic susceptibility. Certain environmental factors, such as viruses and toxins, may act as primary injurious agents to pancreatic (3 cells, or as triggering agents for autoimmunity in humans and animals. Once p cell-specific autoimmunity has developed, autoimmune-mediated destruction of p cells results in the onset of IDDM. (3 cell-specific autoantigens, macrophages, helper T cells and autoantigen-specific cytotoxic T lymphocytes (CTLs) are involved in the autoimmune process. In addition, free radicals and cytokines released from macrophages and T cells, and autoantigen-specific T effector cells synergistlcally destroy p cells.

at the BioBreeding Laboratories in Ottawa, Canada. The cumulative incidence of diabetes in DP-BB/Wor rats is greater than 80%. The pattern of disease in the DP-BB rat is, in many ways, similar to human IDDM, with the exception of the association of T cell lymphopenia with the DP-BB rat (Table 1). The NOD mouse was developed in the course of a breeding program to establish a cataract-prone subline (CTS) from a subline outbred ICR mouse at Shionogi Research Laboratories in Osaka, Japan in 1974. The diabetic syndrome observed in NOD mice is similar to that of humans and BB rats with the exception of the incidence of disease between the sexes (Table 1). In the NOD mouse there is a greater incidence of diabetes in females (70-80%) when compared to males (10-20%).

Cumulative evidence indicates that (3 cell autoanti-gens, macrophages, CD4+ T cells, and CD8+ T cells are involved in the pathogenesis of (3 cell-specific autoimmune IDDM in the BB rat and in the NOD mouse. Cytokines produced from immunocytes and oxygen free radicals also contribute to the destruction of (3 cells. In addition, chemical toxins and viruses induce a diabetes-like syndrome in animals. Various strategies have been employed to prevent insulitis and diabetes in animal models. Most strategies are based on immune modulation or immune intervention in order to block the process of autoimmune P cell destruction at different stages.

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