title: 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.
authors.affiliation: Department of Medicine, VA Puget Sound Health Care System, Seattle, WA 98108, USA. bbrooks@u.washington.edu
authors.forename: B M
authors.initials: BM
authors.lastname: Brooks-Worrell
authors.forename: J P
authors.initials: JP
authors.lastname: Palmer
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000187:drug effects; D002096:C-Peptide / Q000097:blood; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000276:immunology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005905:Glyburide / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; D002096:C-Peptide; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D018664:Interleukin-12; D007371:Interferon-gamma; D005905:Glyburide