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.

Trial registration: ClinicalTrials.gov NCT00194896.

© 2012 British Society for Immunology.

Figures

Fig. 1

Mean ± standard error T cell responses to islet proteins for glyburide-treated (circles and dotted line) and rosiglitazone-treated (squares and solid line) phenotypic type 2 diabetes mellitus (T2DM) patients. The number of blot sections stimulatory to T cells [stimulation index (SI) > 2·0] is demonstrated on the y-axis. A horizontal line at three blot sections represents the cut-off for T cell positivity. Asterisk at 9 months identifies significant (P < 0·05) differences from baseline for both patient groups. Asterisks at other time-points identify significant (P < 0·03) differences between the groups.

Fig. 2

Mean ± standard error glucagon-stimulated C-peptide (ng/ml) responses for glyburide-treated (closed circles) and rosiglitazone-treated (open squares) autoimmune phenotypic phenotypic type 2 diabetes mellitus (T2DM) patients. Asterisks represent significant differences from baseline (P < 0·05) and between the groups. Significant differences between slopes (P < 0·01) are not shown on graphs.

Fig. 3

Mean ± standard error of number of spots for the enzyme-linked immunospot (ELISPOT) cytokine response (a) interferon (IFN)-γ and (b) interleukin (IL)-12 production in rosiglitazone-treated (open squares) and glyburide-treated (closed circles) during follow-up. Asterisks identify significant differences (P < 0·05) from baseline and between the groups.

Fig. 4

Mean ± standard error of adiponectin responses in the serum of glyburide-treated (closed circles and dotted line) and rosiglitazone-treated (open squares and solid line) patients at baseline and every 12 months of follow-up. Asterisks identify significant differences from baseline and between groups (P < 0·001).