Work

TERT/FOXO1 signaling promotes islet β-cell dysfunction in type 2 diabetes mellitus by regulating ATG9A-mediated autophagy

Year: 2025

Type: article

Abstract: BACKGROUND Type 2 diabetes mellitus (T2DM) is a severe global health problem that causes prolonged disease exposure and an elevated risk for chronic complications, posing a substantial health burden. Although therapies, such as GLP-1 receptor agonists and SGLT2 inhibitors, have been successfully developed, new therapeutic options are still expected to offer better blood glucose control and decrease complications. AIM To elucidate the mechanism by which TERT/FOXO1 affects high glucose (HG)-induced dysfunction in islet β-cells via the regulation of ATG9A-mediated autophagy. METHODS High-fat diet (HFD)-fed/streptozotocin (STZ)-treated mice or HG-treated MIN6 cells were used to establish T2DM models. Fasting blood glucose (FBG) and insulin levels in mice, as well as morphological changes in islet tissues, were assessed. Cell proliferation and the apoptosis rate were measured via EdU assays and flow cytometry, respectively. The expression levels of TERT, FOXO1, ATG9A and autophagy-related proteins (LC3B, p62) were analyzed via western blotting. The relationship between FOXO1 and ATG9A was assessed using dual-luciferase reporter gene assays and ChIP assays. RESULTS T2DM modeling in HFD-fed/STZ-treated mice and HG-treated MIN6 cells led to elevated TERT and FOXO1 expression and reduced ATG9A expression. Mice with T2DM were found to have decreased body weight, worsened morphology, elevated FBG and suppressed insulin levels. HG-treated MIN6 cells presented decreased viability and LC3B expression, in addition to increased p62 expression and apoptosis rates. FOXO1 knockdown both in vitro and in vivo protected mice and cells against islet β-cell dysfunction via the activation of autophagy. The molecular mechanism involved the suppression of ATG9A expression by TERT through FOXO1 transcription activation. CONCLUSION Our results suggested that TERT/FOXO1 inhibits ATG9A expression to decrease islet β-cell function in T2DM.

Source: World Journal of Diabetes

DOI: 10.4239/wjd.v16.i5.102994