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] [

Kilham rat virus (KRV) infection of BB/Wor diabetes-resistant (DR) RT1(u) rats induces autoimmune diabetes without direct cytolytic infection of pancreatic beta-cells and is a new model of virus-induced IDDM. To investigate genetic susceptibility to KRV-induced diabetes, major histocompatibility complex congenic and other inbred rats were infected with the virus and studied for the appearance of diabetes and insulitis. KRV infection alone induced insulitis, selective beta-cell necrosis, and diabetes in BB/Wor DR and LEW1.WR1 (RT1 A(u) B/D(u) C(a)) but not other rats. Thus, KRV, an environmentally ubiquitous rat parvovirus, can precipitate autoimmune diabetes in rats that are not susceptible to spontaneous diabetes. If rats are injected with poly(I.C) immediately before KRV infection, diabetes frequency increases to >90% in BB/Wor DR and LEW1.WR1 rats, and PVG.RT1(u) rats are converted from KRV-resistant to KRV-susceptible status. Susceptibility to KRV-induced diabetes thus requires the presence of class I A(u) and class II B/D(u) gene products, which are shared by DR, LEW1.WR1, and PVG.RT1(u) rats. The RT1(u) haplotype is not sufficient for susceptibility, however, because while WF rats are RT1(u), they resist KRV-induced diabetes. If rats are depleted of RT6.1+ regulatory T-cells before KRV infection, the frequency of diabetes is dramatically increased in DR and LEW1.WR1, but not PVG.RT1(u) or other rats. These data confirm a regulatory role of RT6.1+ T-cells in diabetes induction, but indicate that they may not operate as such in all rat strains. KRV-induced diabetes is T-cell-mediated: DR and LEW1.WR1 rats are protected from diabetes by treatment with monoclonal antibodies directed against alpha beta T-cell receptor (TCR)+, CD5+, and CD8+ T-cells. Concanavalin A-activated spleen cells from KRV-infected DR rats adoptively transfer diabetes and insulitis into class II(u) compatible rats, suggesting that KRV infection of susceptible rats leads to the activation of diabetogenic class II(u) restricted T-cells. The ability of a common rat virus to initiate IDDM in multiple strains of rats strengthens the possibility that viruses may also initiate IDDM in human populations.

Experimental allergic encephalomyelitis (EAE) is a model for the in vitro and in vivo study of T-cell activation. It is an autoimmune disease mediated by T lymphocytes of the helper T-cell (Th) subset. After sensitization to guinea-pig myelin basic protein in complete Freund's adjuvant, Lewis rats develop an autoimmune response to central nervous system (CNS) myelin basic protein, manifested clinically as paralysis and histologically by a perivascular mononuclear cell infiltrate of the CNS parenchyma. Suppressor cell regulation of EAE has long been suspected because Lewis rats, which spontaneously recover from active disease, are resistant to reinduction of active EAE, even though effector T-cell lines can be rescued from these recovered rats. Using cyclosporin A, an immunosuppressive agent believed to inhibit Th cell function, suppressor T-cell (Ts) lines have now been generated from recovered Lewis rats. These Ts cells, when admixed with guinea pig myelin basic protein-specific Th cells, will prevent the adoptive transfer of EAE. The Ts cells appear to be CD4+, which explains previous observations that CD8+ lymphocytes are not important in the recovery of EAE in the rat. This is the first direct demonstration of Ts-cell regulation of EAE.

The BB/Wor diabetes-prone rat is an animal model of human insulin-dependent diabetes mellitus. In this model of spontaneous autoimmunity, natural killer cells are candidate cytotoxic effector cells, believed to be the mediators of beta-cell cytolysis in vivo. We therefore studied the effects of an anti-natural killer cell monoclonal antibody on the spontaneous development of diabetes in the BB/Wor rat. The 3.2.3 monoclonal antibody recognizes a molecular present on rat natural killer cells and selectively depletes these cells in vivo. Chronic treatment of diabetic-prone rats with 3.2.3 monoclonal antibody cleared circulating phenotypic natural killer cells, depleted in vitro spleen natural killer cell function, and profoundly reduced intra-islet accumulation of 3.2.3+ cells, but did not prevent or delay the onset of diabetes. These results indicate that natural killer cells are not necessary for the development of spontaneous diabetes in BB/Wor rats.

The low proportion of patients achieving glycemic targets is well documented for both type 1 and type 2 diabetes. Postprandial glucose levels are often not monitored but contribute significantly to total glycemic burden. Prandial rapid-acting insulin analogues were introduced to address some of these problems but still do not provide a physiologic insulin replacement. Inhaled prandial insulins have been developed to free patients from multiple mealtime injections and make intensive insulin regimens more acceptable. Several inhaled formulations of prandial insulin are in development but differ significantly with respect to inhaler characteristics and pharmacokinetic profiles. This brief review summarizes the properties of the new prandial inhaled insulins and discusses how postprandial glycemic control is dependent not only on the insulin dose, but also on the pharmacokinetic characteristics of insulin delivery. There is no antihyperglycemic agent with a glucose-lowering effect superior to that of insulin; new prandial products that improve coordination between insulin availability and meal absorption and are more acceptable to patients may increase the proportion of diabetic patients achieving and maintaining glycemic targets. Drug Dev Res 69: 138-142, 2008. r2008 Wiley-Liss, Inc.