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.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology