Empagliflozin And GABA Improve β-Cell Mass And Glucose Tolerance In New-Onset Type 1 Diabetes

Caroline Daems1*, Sophie Welsch1*, Hasnae Boughaleb1, Juliette Vanderroost1, Annie Robert2, Etienne Sokal1, Philippe A. Lysy1 1Pôle de Pédiatrie, 2Pôle d’Epidémiologie et Biostatistique, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av. Hippocrate 10, B-1200 Brussels, Belgium *These authors contributed equally to this work, and they are thus sharing first authorship. Presently, the autoimmune character of T1D is challenged, but it is indisputable that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to β-cell mass destruction through maintenance of inflammation. Here, we aimed to evaluate, after diabetes onset, the potential of empagliflozin (EMPA) to protect β-cell mass against glucotoxicity, in monotherapy or in association with GABA, tested for its potential to increase residual β-cell mass. In a streptozotocin-based mouse model of T1D, empagliflozin and/or GABA were delivered by oral gavage or intraperitoneal injection, respectively, during seven days or three weeks. As shown by glucose tolerance test, EMPA-treated T1D mice had a better glucose homeostasis as compared to untreated T1D mice (236.9 ± 28.4 vs 454.4 ± 30.5 mg/dL). Furthermore, FFA level was decreased in EMPA-treated T1D mice compared to untreated T1D mice (0.7 ± 0.1 vs 1.5 ± 0.2 mmol/L). EMPA-treated T1D mice had a better islet density, numbers and preservation of islet architecture, compared to T1D mice. T1D mice showed islet with immune infiltration whereas EMPA-treated T1D mice displayed no islet infiltrate (0 ± 0 vs 21 ± 13%). Islets from EMPA-treated mice were also less subjected to ER stress and inflammation, as shown by qPCR analysis. Furthermore, parameters of glucose homeostasis and β-cell mass were also improved, as compared to diabetic controls, when T1D mice were treated for 3 weeks with GABA and EMPA. Interestingly, T1D EMPA+GABA mice had higher glucagon levels than T1D mice (79.4 ± 26.5 vs 161.44 ± 5.2 pg/mL), without modifications of glucagon area/islet area ratios (28.8 ± 4.3 vs 33.0 ± 4.4%). Empagliflozin and GABA, used in monotherapy, have positive effects on β-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic treatment to protect β-cell mass after T1D diagnosis.