Exendin‐4 Therapy in NOD Mice with New‐Onset Diabetes Increases Regulatory T Cell Frequency

Abstract

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.

Glucagon-like peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells

“…Treatment with 200 ng Ex-4 for 30 days increased the number of splenic Tregs. Furthermore, a trend towards enhanced Treg function was observed in CD4+CD25+ splenocytes isolated from Ex-4-treated mice [15]. Our data demonstrated that GLP-1R activation leads to a modest but significant increase in cAMP accumulation in mixed leucocyte populations.…”

“…A subset of patients with type 2 diabetes may also exhibit a dysregulated immune system [25][26][27]. Previous work from our laboratory [12], as well as others [15] suggested that GLP-1R signalling may regulate T cell subsets, including Tregs. We have now assessed the effects of activating or eliminating the GLP-1R in subsets of murine immune cells.…”

“…In fact, Tregs express high levels of cAMP, and are able to induce cAMP accumulation in activated target cells by multiple mechanisms [34,35]. Taking into consideration that GLP-1R activation modulates Treg function [15], it is possible to speculate that this mechanism is cAMP dependent. Further experiments are required to elucidate potential mechanism(s) by which GLP-1R activation augments Treg function.…”

“…Nevertheless, little is known about the effects of GLP-1 on the immune system. Glp1r mRNA transcripts have been detected in murine lymphoid tissue [12], and GLP-1R activation stimulates regulatory T cells (Tregs), by both increasing the frequency and improving the function of these cells in recently diagnosed diabetic NOD mice [15].…”

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

“…GLP-1 receptor activation modestly delayed diabetes onset in NOD mice (171). Mechanistically, exenatide not only stimulates insulin secretion, but might also enhance beta-cell replication and neogenesis in rats (478), protect against IFN-␥-mediated beta-cell death (102), and increase Treg frequency in NOD mice (479). However, the effects on beta-cell mass and the immune system are controversial.…”