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Historically, type 2 diabetes (T2D) was considered a metabolic disease of ageing. However, recent discoveries have demonstrated the role of chronic systemic inflammation in the development of insulin resistance and subsequent progression to T2D. Over the years, investigations into the pathophysiology of T2D have identified the presence of islet-specific T cells and islet autoimmune disease in T2D patients. Moreover, the cell-mediated islet autoimmunity has also been correlated with the progressive loss of β-cell function associated with T2D disease pathogenesis. In this manuscript, the involvement of cell-mediated islet autoimmune disease in the progression of T2D disease and the similarities in islet-specific T-cell reactivity between type 1 diabetes (T1D) and T2D are discussed., (© 2013 John Wiley & Sons Ltd.)

Context: The previously reported absence of 65-kDa glutamate decarboxylase antibody (GAD65Ab)-specific antiidiotypic antibodies (anti-Id) in type 1 diabetes (T1D) patients at clinical onset could be due to an inability to mount an antibody response to GAD65Ab or a longitudinal decline in anti-Id levels., Objective and Design: We investigated anti-Id levels in longitudinal samples obtained from T1D patients (n = 41) (clinical diagnosis - 12 months), and latent autoimmune diabetes in adults (LADA) patients (n = 32) who received alum-formulated human recombinant GAD65 (baseline - 12 months). We also determined anti-Id levels in a small cohort of Type 2 diabetes patients during their development of autoimmune T cell responses., Results: At clinical onset T1D patients presented no or low anti-Id levels. However, 22/41 T1D patients showed ≥50% increase in GAD65Ab-specific anti-Id levels during follow-up; peaking at 3 (n = 1), 6 (n = 10), 9 (n = 10), or 12 (n = 1) months. Increasing anti-Id levels marked patients who experienced a temporary increase in C-peptide levels. Anti-Id levels correlated significantly with glycated hemoglobin and C-peptide levels at 6 and 9 months (P values ranged from <0.001 to <0.05). In LADA patients receiving placebo, anti-Id levels declined in seven of nine patients, whereas four of five patients receiving 20 μg alum-formulated human recombinant GAD65 showed increasing anti-Id levels. Changes in anti-Id and C-peptide levels closely correlated (P < 0.0001). The significant decline in anti-Id levels (P = 0.03) in T2D patients developing T cell autoimmune responses supports our hypothesis that declining anti-Id levels are associated with developing islet autoimmunity., Conclusions: The close association between GAD65Ab-specific anti-Id levels and β-cell function may provide a novel marker for the progression of autoimmune diabetes.

Type 1 diabetes is a chronic autoimmune disease mediated by autoreactive T-cells. Several experimental therapies targeting T-cells are in clinical trials. To understand how these therapies affect T-cell responses in vivo, assays that directly measure human T-cell function are needed. In a blinded, multicenter, case-controlled study conducted by the Immune Tolerance Network, we tested responses in an immunoblot and T-cell proliferative assay to distinguish type 1 diabetic patients from healthy control subjects. Peripheral blood cells from 39 healthy control subjects selected for DR4 and 23 subjects with recently diagnosed type 1 diabetes were studied. Autoantibody responses were measured in serum samples. Positive responses in both assays were more common in peripheral blood mononuclear cells from new-onset type 1 diabetic patients compared with control subjects. The proliferative, immunoblot, and autoantibody assays had sensitivities of 58, 91, and 78% with specificities of 94, 83, and 85%, respectively. When cellular assays were combined with autoantibody measurements, the sensitivity of the measurements was 75% with 100% specificity. We conclude that cellular assays performed on peripheral blood have a high degree of accuracy in discriminating responses in subjects with type 1 diabetes from healthy control subjects. They may be useful for assessment of cellular autoimmune responses involved in type 1 diabetes.

The clinical efficacy of peroxisome proliferator-activated receptor gamma ( PPAR-γ) agonists in cell-mediated autoimmune diseases results from down-regulation of inflammatory cytokines and autoimmune effector cells. T cell islet autoimmunity has been demonstrated to be common in patients with phenotypic type 2 diabetes mellitus ( T2DM) and islet-specific T cells ( T+) to be correlated positively with more severe beta cell dysfunction. We hypothesized that the beneficial effects of the PPAR-γ agonist, rosiglitazone, therapy in autoimmune T2DM patients is due, in part, to the immunosuppressive properties on the islet-specific T cell responses. Twenty-six phenotypic T2DM patients positive for T cell islet autoimmunity ( T+) were identified and randomized to rosiglitazone ( n = 12) or glyburide ( n = 14). Beta cell function, islet-specific T cell responses, interleukin ( IL)-12 and interferon ( IFN)-γ responses and islet autoantibodies were followed for 36 months. Patients treated with rosiglitazone demonstrated significant ( P < 0·03) down-regulation of islet-specific T cell responses, although no change in response to tetanus, a significant decrease ( P < 0·05) in IFN-γ production and significantly ( P < 0·001) increased levels of adiponectin compared to glyburide-treated patients. Glucagon-stimulated beta cell function was observed to improve significantly ( P < 0·05) in the rosiglitazone-treated T2DM patients coinciding with the down-regulation of the islet-specific T cell responses. In contrast, beta cell function in the glyburide-treated T2DM patients was observed to drop progressively throughout the study. Our results suggest that down-regulation of islet-specific T cell autoimmunity through anti-inflammatory therapy may help to improve beta cell function in autoimmune phenotypic T2DM patients. [ABSTRACT FROM AUTHOR]