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

Sam Tsz Wai Cheng,Po Sing Leung,Eric Mayoux,Lihua Chen,Stephen Yu Ting Li,Angel Nadal

doi:10.1371/journal.pone.0147391

Sam Tsz Wai Cheng, Po Sing Leung + Show 4 more

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https://doi.org/10.1371/journal.pone.0147391

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Abstract

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 β-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 β-cell areas, β-cell proliferation, apoptosis of pancreatic β-cells, and reactive oxygen species production in the pancreatic β-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 β-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 β-cells. Taken together, the results of this study indicate that empagliflozin may have a beneficial effect on preserving β-cell regeneration, thus improving blood glucose homeostasis in type 1 diabetes mellitus, probably via the protection of pancreatic β-cell from glucotoxicity-induced oxidative stress.

Highlights

Type 1 diabetes mellitus (T1DM), known as insulin-dependent diabetes mellitus or juvenile onset diabetes, represents 5–10% of all diagnosed cases of diabetes in the United States [1]
T1DM mice treated with hydroxy ethyl cellulose (HEC) demonstrated glucose intolerance after challenge by intraperitoneal injection of glucose compared with normal mice (Fig 1A and 1B; Area under the curve (AUC) normal mice 1237±55 vs vehicle 3694±86)
Since there were no significant differences in blood glucose homeostasis with the two different doses of empagliflozin, and random blood glucose levels of T1DM mice were significantly improved by 3mg/kg of empagliflozin (Fig 1C and 1D), we investigated the effect of the lower dose of empagliflozin (3mg/kg) on preserving β-cell mass and function

Summary

Introduction

Type 1 diabetes mellitus (T1DM), known as insulin-dependent diabetes mellitus or juvenile onset diabetes, represents 5–10% of all diagnosed cases of diabetes in the United States [1]. T1DM is caused by autoimmune pancreatic β-cell destruction with consequent severe insulin deficiency [2]. T1DM is currently incurable and patients rely on daily insulin injections.

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