Attenuation of islet‐specific T cell responses is associated with C ‐peptide improvement in autoimmune type 2 diabetes patients

Summary 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.