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

Clin Exp Immunol. 2013 Feb;171(2):164-70. doi: 10.1111/cei.12012.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Autoantibodies / blood
  • Autoimmunity / drug effects
  • C-Peptide / blood
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / immunology
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Glyburide / administration & dosage
  • Glyburide / adverse effects
  • Glyburide / pharmacology
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology
  • Immunosuppression
  • Interferon-gamma / immunology
  • Interleukin-12 / immunology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / physiology*
  • Male
  • Middle Aged
  • PPAR gamma / agonists*
  • Rosiglitazone
  • T-Cell Antigen Receptor Specificity / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Thiazolidinediones / administration & dosage*
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / pharmacology

Substances

  • Autoantibodies
  • C-Peptide
  • Hypoglycemic Agents
  • PPAR gamma
  • Thiazolidinediones
  • Rosiglitazone
  • Interleukin-12
  • Interferon-gamma
  • Glyburide

Associated data

  • ClinicalTrials.gov/NCT00194896