Early Treatment with Empagliflozin and GABA Improves β-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice

• Published in: Journal of diabetes research 2019, Vol.2019 (2019), p.1-14
• Main Authors: Lysy, Philippe A., Robert, A., Vanderroost, Juliette, Boughaleb, Hasnae, Welsch, Sophie, Daems, Caroline, Sokal, Etienne
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Benzhydryl Compounds - administration & dosage; Benzhydryl Compounds - pharmacology; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell Count; Cell Proliferation - drug effects; Diabetes; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Disease control; Drug Administration Schedule; Drug Therapy, Combination; Early intervention; Early Medical Intervention; gamma-Aminobutyric Acid - administration & dosage; gamma-Aminobutyric Acid - pharmacology; Glucose; Glucose Tolerance Test; Glucosides - administration & dosage; Glucosides - pharmacology; Injections, Intraperitoneal; Insulin; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - physiology; Laboratory animals; Male; Metabolism; Mice; Neurotransmitters; Rodents; Streptozocin; Studies; Time Factors
• ISSN: 2314-6745; 2314-6753
• DOI: 10.1155/2019/2813489

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to β-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect β-cell mass against glucotoxicity and to increase β-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates α-to-β cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, 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 target for the protection of β-cell mass after new-onset T1D.