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 from peripheral blood and pancreas in db/db mice were assessed. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box O1 (FoxO1) pathway in Th17 and Treg cells from the spleens of male C57BL/6J mice was detected by western blotting. In addition, the expression of glucagon-like peptide-1 receptor (GLP-1R) in peripheral blood mononuclear cells (PBMCs) of male C57BL/6J mice was analyzed. Results Exenatide treatment improved β-cell function and insulitis in addition to glucose, insulin sensitivity and weight. 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 no significant difference in the level of GLP-1R expression in PBMCs between control and palmitate (PA) groups. In addition, PA could promote Th17 but suppress Treg differentiation along with down-regulating the phosphorylation of PI3K/Akt/FoxO1, which was reversed by exenatide intervention. FoxO1 inhibitor AS1842856 could abrogate all these effects of exenatide against lipid stress. Conclusions Exenatide could restore systemic Th17/Treg balance via regulating FoxO1 pathway with the progression of diabetes in db/db mice. The protection of pancreatic β-cell function may be partially mediated by inhibiting Th17 cell infiltration into pancreatic islets, and the resultant alleviation of islet inflammation.

Evaluating the causal effects between Grave’s disease and diabetes mellitus: a bidirectional Mendelian randomization study

“…Th17 cells play a role in promoting in ammation and immune responses, whereas Tregs act as immunosuppressors. There may be a link between the onset and progression of DM (types 1 and 2) and an imbalance between Tregs and Th17 cells [43][44][45] . A population-based study conducted in Finland revealed a signi cant correlation between T1D and other autoimmune diseases, including GD 46 .…”

Different patterns of lipid droplet and mitochondria contacts mediate lipid metabolism during T2DM-induced NAFLD

“…Studies have shown that after binding insulin in the liver, the insulin receptor autophosphorylates and goes on to phosphorylate several insulin receptor substrates, thereby activating classical IRS signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)-phosphatidylinositol-dependent kinase (PDK)-protein kinase B (AKT) signaling pathway 21 . However, we found that protein levels of p-PI3K/PI3K and p-AKT/AKT were signi cantly lower in the livers of diabetic mice than in the livers of db/m mice, as detected by western blotting (Fig.…”

T cells in obesity‐associated inflammation: The devil is in the details

“…19 Th17 cells are also elevated in murine PBMCs and adipose tissue following high-fat diet feeding. 20,21 The Th17 population in adipose tissue of obese mice is activated by CD11c + DC cells, demonstrating the importance of innate/adaptive immune cell cross talk in obesity-associated inflammation. 20 At the same time, obesity reduces the T regulatory cell (Treg) population in visceral fat, while Treg frequency in the spleen of the same animals was similar to animals on control diet.…”

“…Surprisingly, single‐cell RNA analysis showed that there is no change in Th1 and Th2 populations in adipose tissue of obese mice when compared to lean mice 19 . Th17 cells are also elevated in murine PBMCs and adipose tissue following high‐fat diet feeding 20,21 . The Th17 population in adipose tissue of obese mice is activated by CD11c + DC cells, demonstrating the importance of innate/adaptive immune cell cross talk in obesity‐associated inflammation 20 …”