Journal Article Epublish 1 citation
PubMed: 42597725 DOI: 10.1016/j.metop.2026.100488
Empagliflozin inhibits the apoptosis of pancreatic β-cells through amelioration of endoplasmic reticulum (ER) stress.
Metabol Open 31:100488
Authors: Narjes Nasiri-Ansari, Manpal S Randeva, Christina-Maria Flessa, Ioannis Kyrou, Panagiotis Lembessis, Hippokratis Kiaris, Maria-Eleni Chondrogianni, Maria Dalamaga, Athanasios G Papavassiliou, Harpal S Randeva, Eva Kassi
Affiliations
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, Athens, 11527, Greece.
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK. Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Discoveries in Life Sciences Research Centre, Coventry University, Coventry, CV1 5FB, UK.
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
- College of Health, Psychology and Social Care, University of Derby, Derby, DE22 IGB, UK.
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, 11527, Greece.
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, United States.
- Endocrine Unit, First Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, 11527, Greece.
- Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
Abstract
BACKGROUND
Progressive loss of pancreatic β-cell function in type 2 diabetes mellitus (T2DM) is linked to endoplasmic reticulum (ER) stress-induced apoptosis. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have glucose-lowering and potential cytoprotective effects. We investigated whether empagliflozin protects β-cells from ER stress-mediated apoptosis and the underlying pathway.
METHODS
Mouse Beta-TC-6 (BTC-6) and hamster HIT-T15 pancreatic β-cell lines were exposed to tunicamycin (5 or 10 μg/mL) to induce ER stress, with or without empagliflozin (10 -8, 10 -9, 10 -10 M). SGLT-1 and SGLT-2 mRNA were assessed by RT-qPCR. Expression of ER stress markers (GRP-94, BiP, PERK, eIF-2α, IRE-1, ATF-4, CHOP) was measured by RT-qPCR; eIF-2α, phospho-eIF-2α and CHOP protein levels were analyzed by Western blot. Cell proliferation and apoptosis were quantified by XTT and Annexin V-FITC assays.
RESULTS
BTC-6 cells expressed SGLT-1 but not SGLT-2. Empagliflozin (10 -8 and 10 -9 M) increased BTC-6 proliferation (p < 0.01 and p < 0.05 respectively). Tunicamycin caused significant apoptosis after 48h (p < 0.001). Co-treatment with empagliflozin (10 -8, 10 -9 M) significantly reduced tunicamycin-induced apoptosis, especially at 5 μg/ml tunicamycin (p < 0.01). Empagliflozin co-incubation lowered PERK, eIF-2α, IRE-1α and CHOP mRNA levels versus tunicamycin alone (all p < 0.05), and decreased phospho-eIF-2α (p < 0.01) and CHOP (p < 0.05) protein levels. Similar anti-apoptotic effects were observed in HIT-T15 cells.
CONCLUSIONS
Empagliflozin enhances β-cell proliferation and attenuates ER stress-induced apoptosis in vitro, primarily via downregulation of the PERK-eIF-2α-CHOP pathway. These findings support further investigation of SGLT-2 inhibitors for preservation of β-cell survival and function.
MeSH
Diabetes Mellitus, Cells, Tunicamycin, Stress, Physiological, Endoplasmic Reticulum, Apoptosis, Diabetes Mellitus, Type 2