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Endocrine Abstracts (2019) 63 GP210 | DOI: 10.1530/endoabs.63.GP210


1Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 2Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK; 3Human Metabolism Research Unit, WISDEM Centre, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; 41st Department of Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece; 5Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 6Peromyscus Genetic Stock Center, University of South Carolina, Columbia, South Carolina, USA; 7Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA; 8Division of Life and Health Sciences, Aston University, Birmingham, UK.

Introduction: Type 2 diabetes mellitus (T2DM) is characterized by progressive impairment/ loss of pancreatic beta cell function Activation of endoplasmic reticulum (ER) stress by glucose variation has been suggested as an essential step towards beta cell dysfunction. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are widely used in the treatment of T2DM considering their beneficial cardiometabolic sequalae. In the present study, we aimed to investigate the effect of Empagliflozin on ER stress-induced apoptosis in murine pancreatic islet/beta cell lines.

Material and methods: Hamster HIT-T15 (islet) and mouse BTC-6 (Beta) pancreatic cell lines were maintained in RPMI media, supplemented with 15% FBS.Both cell lines were seeded in 12 well plates and serum starved 16 hrs prior to treatments. After starvation cells were incubated with various concentrations of tunicamycin (5 ug/ml, 10 ug/ml, 20 ug/ml) or Empagliflozin (10−8, 10−9 and 10−10 M) alone or co-incubated with both agents simultaneously. The expression levels of SGLT-1, SGLT-2, GRP-94, Bip, PERK, elf-2α and CHOP were measured by quantitative real time PCR while protein levels of GRP-94, Bip, p-PERK, elf-2α, P- elf-2α and CHOP were measured by western blotting. Cell proliferation and apoptosis were measured by XTT and Annexin V FITC assays respectively.

Results: SGLT-1 mRNA was detected only in BTC-6 cells while SGLT-2 mRNA was not detected in either cell line. Incubation of BTC-6 cells, but not HIT-T15, with Empagliflozin (10−8, 10−9 M. P<0.05) resulted in significant increase in cell proliferation compared to untreated cells. Both Hit-15 and BTC-6 cells were sensitive to tunicamycin and underwent significant cell death after 48h treatment (P<0.01). Co-incubation of cells with Empagliflozin significantly inhibited tunicamycin (5 ug/ml and 10 ug/ml) -induced cell apoptosis with more robust effect observed in BTC-6 cell line (P<0.01) as compared with HIT-T15 cell line. Particularly, co-incubation of BTC-6 cells with tunacamycin and Empagliflozin reduced (ER) stress-induced apoptosis through down regulation of p-elf-2α (P<0.01) and CHOP (P<0.01) while in HIT-T15 the ER stress was reduced through reduction of Bip (P<0.01), p-PERK (P<0.05) and CHOP (P<0.05) protein expression. These results were in line with mRNA expression results.

Conclusion: Our data indicate that Empagliflozin increases proliferation and reduces cell apoptosis in beta-pancreatic cells, at least in part, via reducing ER stress. The effect of Empagliflozin on beta-cell apoptosis/survival could be mediated through SGLT-1. More studies are needed to verify the efficacy of this class of drugs in maintenance of pancreatic cells survival and function.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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