The Effects of Empagliflozin, an SGLT2 Inhibitor, on Pancreatic β-Cell Mass and Glucose Homeostasis in Type 1 Diabetes

The novel sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has recently been reported to improve glycemic control in streptozotocin-induced type 1 diabetic rats in an insulin-independent manner, via an increase in urinary glucose output. We investigated the potential of empagliflozin to recover insulin pathways in type 1 diabetes by improving pancreatic beta-cell mass. Blood glucose homeostasis was assessed by an intraperitoneal glucose tolerance test. Serum insulin levels and insulin mRNA expression were determined using commercial insulin ELISA kits and real-time quantitative polymerase chain reaction, respectively. Immunohistochemistry was used to investigate beta-cell areas, beta-cell proliferation, apoptosis of pancreatic beta-cells, and reactive oxygen species production in the pancreatic beta-cells. Results showed that glucose tolerance was significantly improved in streptozotocin-induced type 1 diabetic mice treated with empagliflozin. Empagliflozin-treated mice also showed an increase in insulin mRNA expression. Higher serum insulin levels were detected in mice treated with empagliflozin compared with the vehicle group. Immunohistochemistry indicated that beta-cell area/total pancreatic area and the expression of cell proliferation marker Ki-67 (co-stained with insulin) were significantly enhanced by empagliflozin treatment. These effects were due, probably, to a reduction in apoptosis and reactive oxygen species in the pancreatic beta-cells. Taken together, the results of this study indicate that empagliflozin may have a beneficial effect on preserving beta-cell regeneration, thus improving blood glucose homeostasis in type 1 diabetes mellitus, probably via the protection of pancreatic beta-cell from glucotoxicity-induced oxidative stress.