Empagliflozin inhibits the apoptosis of pancreatic β-cells through amelioration of endoplasmic reticulum (ER) stress
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…
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