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Published on: May 6, 2013
TERT/FOXO1 signaling promotes islet β-cell dysfunction in type 2 diabetes mellitus by regulating ATG9A-mediated
Xiao-Tian Lei1, Xiang-Fen Chen2, Sheng Qiu1
1Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 402360, China.
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.
Insights
Telomerase reverse transcriptase (TERT) and forkhead box O1 (FOXO1) inhibit autophagy by suppressing ATG9A expression, leading to islet beta-cell dysfunction in type 2 diabetes mellitus (T2DM). This pathway offers a potential therapeutic target for T2DM.
Area of Science:
- Molecular Biology
- Endocrinology
- Cell Biology
Background:
- Type 2 diabetes mellitus (T2DM) presents a significant global health challenge, necessitating novel therapeutic strategies beyond current treatments like GLP-1 receptor agonists and SGLT2 inhibitors.
- Effective management of T2DM requires improved blood glucose control and reduced chronic complications.
Purpose of the Study:
- To investigate the role of TERT/FOXO1 in high glucose-induced islet beta-cell dysfunction.
- To elucidate the mechanism involving ATG9A-mediated autophagy in this process.
Main Methods:
- Establishment of T2DM models in mice (HFD/STZ) and MIN6 cells (HG treatment).
- Assessment of blood glucose, insulin levels, islet morphology, cell proliferation, and apoptosis.
- Analysis of TERT, FOXO1, ATG9A, and autophagy protein expression (LC3B, p62) via Western blotting.
- Investigation of the FOXO1-ATG9A interaction using dual-luciferase reporter and ChIP assays.
Main Results:
- T2DM models exhibited elevated TERT and FOXO1, with reduced ATG9A expression.
- Mice showed decreased body weight, impaired islet morphology, higher FBG, and lower insulin.
- HG-treated cells displayed reduced viability, decreased LC3B, increased p62, and higher apoptosis rates.
- FOXO1 knockdown protected against islet beta-cell dysfunction by activating autophagy.
- TERT suppresses ATG9A via FOXO1-mediated transcriptional activation, impairing autophagy.
Conclusions:
- TERT/FOXO1 signaling pathway inhibits ATG9A expression, thereby reducing islet beta-cell function in T2DM.
- This mechanism highlights a novel pathway contributing to T2DM pathogenesis.
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