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  1. Diabetes is the name given to a collection of diseases that have elevations in blood glucose levels in common. Population studies have defined cutoff levels of glycemia that are eventually associated with increased microvascular disease such as retinopathy. Two replicate fasting levels that exceed 126 mg/dl (>7 mM) are diagnostic in the absence of symptoms. Persons with fasting levels between 110 and 126 mg/dl are at risk of diabetes (impaired fasting glycemia). Replicate, 2-h glycemic responses >200 mg/dl (>11.1 mM) after a standard oral glucose tolerance test indicates diabetes also. This stage is often reached, however, before the fasting glucose levels are seen to rise. Type 1 diabetes comprises those forms of diabetes that are primarily due to insulin deficiency, however a relative insulin deficiency also is part of type 2 diabetes, which is however less severe, though it is compounded by degrees of insulin resistance, often associated with obesity. Long-term type 2 diabetes is complicated by glucose (glucosamine) toxicity, which decreases the patients' abilities to secrete insulin further, leading to diagnostic confusion with type 1 diabetes. Whereas type 2 diabetes is usually strongly familial, type 1 is much less so, having only one member of the family so affected in 90 percent of cases.

  2. The immune-mediated form of type 1 diabetes (IMD) is most common amongst Caucasian races and is presumed present when autoantibodies to islet cells and/or to insulin and/or to defined islet proteins are detected in the presence of diabetes. However, an insulin-deficient type of diabetes in the presence of the risk HLA phenotypes is presumptive evidence. Adult onset IMD is characterized by a gradual decline in insulin secretion compared to children, a situation readily confused with type 2 diabetes unless autoantibodies to islet cell cytoplasm (ICA) and/or to glutamic acid decarboxylase (GAD65) can be detected.

  3. The pathogenesis of IMD involves multiple genetic lesions affecting immunoregulation against self, coupled to strong influences from the environment affecting penetrance. Studies from rodent models of the disease suggest that there is a gene dose effect of quantitative trait loci, with accumulating numbers of susceptibility genes compounding the risk. There are protective genes also. The obligate genes, however, are those encoding DR and DQ A plus B chain heterodimers. Both loci are involved in human patients. The nonobese diabetic (NOD) mouse expresses no IE (DR homologous) molecules but only a unique recombinant b/d haplotype IA molecule (DQ homologous). This IAg7 is a poor antigen binder, and thus may allow leakage of autoreactive T cells from the thymus into the peripheral blood. This could account for the increased propensity to develop multiple organ-specific autoimmune diseases comprising the type 2 autoimmune polyglandular syndrome of which IMD is a part. The others include Addison disease, thyroid autoimmune disease especially Hashimoto, atrophic gastritis/pernicious anemia, vitiligo, and celiac disease. Further, poor expression of islet cell antigens by the thymus may similarly lead to defective eradication of potentially autoimmune-provoking CD4+ T cells. Similarly, some studies suggest that class-I major histocompatibility complex (MHC) antigens may carry some relevant genetic information in addition to the class-II MHC, perhaps by analogy resulting in defective thymic ablation of CD8+ cytotoxic T cells with high-affinity receptors for islet antigens.

  4. However, even in normal persons, autoreactive T cells with low-affinity receptors capable of reactivity to self escape the thymus and need multiple fail-safe mechanisms to regulate them. Such mechanisms are inherently faulty in IMD. An active down-regulation by cytokine-rich natural killer T cells (NK-T cells) is one emerging mechanism mediated by regulatory T cells that in the mouse appear to have a CD4+/CD25+ (IL-2 receptor+) phenotype and be responsive to TNF-α cytokine, or be mediated by suppressor macrophages. NOD mice have near absence of NK-T cells in their early life, and humans appear to be defective in them also. Further, in NOD mice, if not in patients with IMD, there is evidence that, once activated, T cells persist abnormally. In patients there is an association with a T cell apoptosis gene (CTLA-4) that suggests that a defect in expression of this inducible molecule would lead to persistence of T cells that become activated against self. Autoimmune destruction of pancreatic insulin-secreting β-cells is promoted by T helper responses of the Th1 phenotype, which promote T cell-mediated cytolysis, promoted in part by INF-λ. Experimental procedures that create Th2 responses to islet antigens are generally protective. The Th2 pathway promotes antibody-biased responses, sometimes leading to allergies, mediated in part by IL-4. Thus autoimmune responses that are deviated to the protective Th2 type may inhibit pathogenic autoimmune responses of the Th1 type.

  5. Though the inductive event in the disease remains enigmatic, immunization by an environmental antigen with molecular homology to an islet cell protein could be one such trigger. This could happen if the environmental antigen were the P2-C protein of Coxsackie B virus, because GAD has an 18-amino-acid homologous segment. Alternatively, a viral infection of pancreatic β-cells could result in a Th1 response within the islets, which could, in turn, induce a secondary bystander autoimmune reaction involving release of sequestered antigens.

  6. Much progress has been made in identifying the islet cell antigens targeted by islet cell autoimmunity. Autoimmunity to insulin itself appears early in the natural history of the disease. Islet cell reactivity as islet cell autoantibodies (ICA) detectable by indirect immunofluorescence microscopy comprise multiple antigenic determinants, such as those against the two tyrosine phosphatases IA-2 and IA-2β and against GAD65, and more are anticipated. These autoantibodies react to native antigens by their conformational epitopes. In the case of the transmembrane tyrosine phosphatases, only the internal domains react, which suggests that their involvement might be secondary. One or more of these antibodies begin to appear by the first year of life and most are evident if they are going to be, before age 3. Relatives and even persons from the general population who have two or more of these autoantibodies are at high risk of impending IMD, however those with only one antibody and none of the others are at only modest risk. Thus antigenic and epitopic spreading of the autoimmune response is usually a sign that the disease is progressive.

  7. Studies on T cell reactivity in IMD are hampered by the fact that autoreactive T cells once formed will leave the blood to migrate into the pancreatic islets resulting in “insulitis” lesions. Nevertheless, peripheral blood, proliferative T cell responses to in vitro exposure to the above islet cell antigens, and their peptides have been repeatedly reported, some with a Th1 to Th2 cytokine bias. In general, T cell reactivities to nonantigen-specific stimulations in IMD appear diminished in patients with IMD.

  8. The long natural history, and the relatively low concordance of IMD in twin pairs affected by the disease, provides a window of opportunity for disease prevention and the anticipation that protective effects from the environment appear sufficient to prevent overt diabetes and even evidence of β-cell destruction. A number of ongoing studies in academia and industry are actively exploring many approaches. Past studies with immunosuppressant agents such as azathioprine and cyclosporin A in newly diagnosed patients have documented a delay in the completion of β-cell destruction. However, the beneficial effects eventually wear off in most patients, and these drugs have the inherent risks of lymphoma induction and of infections. Several general immunosuppressants attacking accessory molecular engagements in the T cell activation sequence are under study, while antigen-based immunization procedures to block the pathogenic immune responses or deviate them to the protective Th2 type have begun.

  9. Pancreatic transplantations in late disease, often in context of companion kidney transplants, continue to improve, and have become clinically viable in selected cases, albeit successful transplants may be associated with a worsening microvascular disease such as retinopathy. The patients must of course be chronically maintained on immunosuppressant drugs to prevent rejection. In identical twins where one is the normal donor and the other the recipient, immunosuppressants are not required to prevent rejection, although diabetes may quickly reappear due to a recurrence of islet cell autoimmunity. Recent studies have held promise for islet cell transplantation: where a companion bone marrow transplantation has resulted in a stable chimera, sometimes long-term acceptance has been reported. Furthermore, the use of therapeutic antibodies that interfere with accessory molecule interactions such as B7 and CD28/CTLA or CD40 and CD40 ligand (CD154) has been reported to extend the life of engrafted tissues in primates. However the latter have led to unwelcome thrombotic phenomena, because platelets bear the marker also. At the time of writing, the first successes in human islet cell transplants have been reported by the group in Edmonton, Canada.259

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