Attenuation of islet-specific T cell responses is associated with C-peptide improvement in autoimmune type 2 diabetes patients.
ABSTRACT 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.
- SourceAvailable from: onlinelibrary.wiley.com[Show abstract] [Hide abstract]
ABSTRACT: 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.Diabetes Obesity and Metabolism 09/2013; 15. DOI:10.1111/dom.12167 · 5.46 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Type 1 diabetes (T1D) results from a complex interplay between genetic susceptibility and environmental factors which have been implicated in the pathogenesis of disease both as triggers and potentiators of beta cell destruction. CD8 T cells are the main cell type found in human islets and they have been shown in vitro to be capable of killing beta-cells over-expressing MHC class I. Here we report that CD8 T cells infiltrate the exocrine pancreas of diabetic subjects in high numbers, and not only endocrine areas. T1D subjects present significantly higher CD8 T cell density in the exocrine tissue without the presence of prominent insulitis. Even T1D donors without remaining insulin containing islets (ICIs) and long disease duration show elevated levels of CD8 T cells in the exocrine compartment. In addition, higher numbers of CD4+ and CD11c+ cells were found in the exocrine tissue. Preliminary data in T2D subjects indicates that overall, there might be a spontaneous inflammatory infiltration of the exocrine tissue, common to both T1D and T2D subjects. Our study provides the first information on the precise tissue distribution of CD8 T cells in pancreata from T1D, T2D, Ab+ and healthy controls.Diabetes 06/2014; 63(11). DOI:10.2337/db14-0549 · 8.47 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cross-sectional studies have suggested that Islet autoimmunity may be more prevalent in type 2 diabetes (T2D) than previously appreciated and may contribute to the progressive decline in β-cell function. In this study, we longitudinally evaluated the effect of islet autoimmune development on the progressive β-cell dysfunction in T2D patients.Diabetes Care 09/2014; 37(12). DOI:10.2337/dc14-0961 · 8.57 Impact Factor