Exenatide regulates Th17/Treg balance via PI3K/Akt/FoxO1 pathway in db/db mice

Abstract

Background The T helper 17 (Th17)/T regulatory (Treg) cell imbalance is involved in the course of obesity and type 2 diabetes mellitus (T2DM). In the current study, the exact role of glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on regulating the Th17/Treg balance and the underlying molecular mechanisms are investigated in obese diabetic mice model. Methods Metabolic parameters were monitored in db/db mice treated with/without exenatide during 8-week study period. The frequencies of Th17 and Treg cells in vivo and in vitro were assessed. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box O1 (FoxO1) pathway was detected by western blotting. Results Exenatide treatment obviously improved β-cell function and insulitis. Increased Th17 and decreased Treg cells in peripheral blood were present as diabetes progressed while exenatide corrected this imbalance. Progressive IL-17 + T cell infiltration of pancreatic islets was alleviated by exenatide intervention. In vitro study showed that palmitate could promote Th17 but suppress Treg differentiation along with down-regulating the phosphorylation of PI3K/Akt/FoxO1, which could be reversed by exenatide intervention. FoxO1 inhibitor AS1842856 could abrogate all these effects of exenatide against lipid stress. Conclusions Exenatide could protect β-cell function in db/db mice partially by restoring Th17/Treg balance via PI3K/Akt/FoxO1 pathway.

FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

“…Moreover, studies indicates that as insulin resistance and OS progresses, FoxO1 acts to combat these conditions but over time its protein levels decline causing b-cell dedifferentiation and marking a molecular switch to T2D pathology (165,166). Furthermore, the GLP-1RA exenatide decreases inflammation and boosts b-cell function by improving the balance between CD4+ Thelper 17 (Th17) cells and regulatory T-cells (Tregs) (167). The FoxO1 inhibitor AS1842856 reversed these effects indicating that FoxO1 activity may be important for T17/Treg balance and reduced inflammation.…”