Exendin-4 therapy in NOD mice with new-onset diabetes increases regulatory T cell frequency

Ann N Y Acad Sci. 2008 Dec;1150:152-6. doi: 10.1196/annals.1447.049.


Recent studies, albeit controversial, have suggested that the incretin exendin-4 (Ex-4) is capable of inducing beta cell proliferation in vivo. Furthermore, this compound has been shown to enhance the ability of other agents (e.g., anti-CD3, antilymphocyte serum) to reverse type 1 diabetes (T1D) in NOD mice. However, the mechanisms underlying this beneficial action for disease reversal remain largely unclear. Herein, we tested the hypothesis that Ex-4 therapy may act as a stimulator of regulatory T cells (Tregs). We evaluated the effect of Ex-4 (Byetta; 0.2 microg/mouse/day for 30 days) treatment on the frequency and function of Tregs and changes in the cytokine profile of NOD mice with recently diagnosed T1D. In comparison to that of saline-treated control NOD mice, the frequency of Tregs was increased in Ex-4-treated mice. Suppression assays demonstrated a trend towards increased Treg suppression after administration of Ex-4, but were limited by small sample size. Lastly, Ex-4 treatment induced production of IL-10, indicating a possible shift towards a more Th2-like phenotype. Taken collectively, these data suggest that in addition to its potential effects on beta cell proliferation, Ex-4 may also act as a regulator of the immune response.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / veterinary
  • Drug Evaluation, Preclinical
  • Exenatide
  • Female
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-2 / metabolism
  • Interleukin-4 / metabolism
  • Lymphocyte Count
  • Mice
  • Mice, Inbred NOD
  • Peptides / pharmacology
  • Peptides / therapeutic use*
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / pathology
  • Tumor Necrosis Factor-alpha / metabolism
  • Venoms / pharmacology
  • Venoms / therapeutic use*


  • Hypoglycemic Agents
  • Interleukin-2
  • Peptides
  • Tumor Necrosis Factor-alpha
  • Venoms
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma
  • Exenatide