A new, spontaneously diabetic syndrome has been recognized in nonobese outbred Wistar rats of both sexes. The age at detection of first glycosuria has varied from 48 to 120 days, with a mean of 67 days. Eighteen rats have been studied, 14 untreated and four during and after cessation of insulin treatment. The affected animals have demonstrated a spectrum of severity, with hyperglycemia (252-732 mg./dl.), hypoinsulinemia (0-1 ng./ml.), and hyperketonemia. The severely ketotic rats, with total blood ketone body levels between 6 and 13 mM, showed rapid loss in weight and dehydration over one to six days. The moderately ketotic (1-5 mM) declined gradually in weight over 15 days, with marked polyuria and glycosuria. The stable rats, with ketonemia less than 1 mM, sustained their weights, polyuria, and glycosuria for longer than 40 days. A relative or absolute increase in plasma immunoreactive glucagon and elevated levels of free fatty acids and branched-chain amino acids were observed in relation to the severity of the syndrome. Intraperitoneal arginine or tolbutamide elicited no insulin response, but the glucagon response to arginine was exaggerated. Pancreatic insulin content was normal or moderately decreased. Light-microscopic examination of pancreases of ketotic animals at the end stage of the disease showed islets to be very small and rare, consisting virtually of non-beta cells. In stable and earlier ketotic rats, the islets were small, with reduction in beta-cell number and a striking inflammatory cell infiltration. Surviving beta cells showed variable degranulation. This model of spontaneous diabetes in nonobese rats displays insulin deficiency, glucagon excess, and ketosis, with a dramatic inflammatory lesion during active beta-cell destruction.

Type I diabetes mellitus is an autoimmune disease resulting from the interaction of genetic and environmental factors. A virus that was identified serologically as Kilham's rat virus (KRV) was isolated from a spontaneously diabetic rat and reproducibly induced diabetes in naive diabetes-resistant (DR) BB/Wor rats. Viral antigen was not identified in pancreatic islet cells, and beta cell cytolysis was not observed until after the appearance of lymphocytic insulitis. KRV did not induce diabetes in major histocompatibility complex-concordant and discordant non-BB rats and did not accelerate diabetes in diabetes-prone BB/Wor rats unless the rats had been reconstituted with DR spleen cells. This model of diabetes may provide insight regarding the interaction of viruses and autoimmune disease [corrected]

Complete neonatal thymectomy reduced the frequency of spontaneous diabetes mellitus in BioBreeding/Worcester rats from 27 to 3 percent. Incomplete thymectomy also significantly reduced the frequency of diabetes (to 9 percent). These findings strengthen the hypothesis that thymus-dependent, cell-mediated autoimmune destruction of pancreatic B cells is responsible for the pathogenesis of diabetes in this experimental animal.

Injections of rabbit antiserum to rat lymphocytes reversed hyperglycemia in 36 percent of spontaneously diabetic rats (Bio Breeding/Worcester) and prevented diabetes in susceptible nondiabetic controls. These findings strengthen the hypothesis that cell-mediated autoimmunity plays a role in the pathogenesis of diabetes in this animal model that mimics many morpholigic and physiologic characteristics of human insulin-dependent diabetes mellitus.

Type I (insulin-dependent) diabetes mellitus is a T cell-mediated disease of polygenic origin in man, mouse and rat, which is strongly associated with MHC Class II susceptibility alleles [1±3]. In the rat, spontaneous autoimmune diabetes has been reported only in the BB/Wor diabetes-prone (DP) u rats develop an autoimmune diabetes after thymectomy and a series of g-irradiations [10] and after treatment with KRV and Poly IC [9]. Finally, the PVG.RT1 c rat has been reported to develop Type I diabetes, also after thymectomy and irradiation [11]. All these studies suggest that diabetes susceptibility genes are widely distribut- Diabetologia (2000) Abstract Aims/hypothesis. We did experiments to explore the pathways putatively leading to Type I (insulin-dependent) diabetes mellitus, and their association with the MHC locus, the major genetic determinant of disease susceptibility. Methods. Normal MHC congenic rat strains that do not spontaneously develop diabetes or any other autoimmune syndrome were injected with the interferon-alpha inducer polyinosinic-polycytidylic acid (Poly IC). Results. Insulitis and diabetes developed only in strains expressing Class II u genes and was independent of the Class I haplotype. Poly IC induced islet cell Class I hyperexpression, up regulation of pancreatic endothelial intercellular adhesion molecule-1 and vascular adhesion molecule-1 and a T-cell and macrophage infiltration of the pancreatic interstitium in all rat strains studied, including diabetes-resistant strains. Poly IC also induced the generation of diabetes-transferring spleen cells in most Class II u haplotype rats, including the diabetes-resistant WF rat. Conclusion/Interpretation. The minimum requirements for autoimmune diabetes development in the rat include: RT1 Class II u genes, a T-cell repertoire containing beta-cell autoreactive T cells and a triggering event which breaks tolerance by the local up regulation of pancreatic endothelial adhesion receptors. Even when all of the minimum requirements have, however, been met, most Class II u rats do not develop diabetes in response to autoimmune stimuli. It is clear, nonetheless, that susceptibility to diabetes is widely distributed in the RT1 u rat. [Diabetologia (2000) 43: 890±898] [