The Sodium Glucose Cotransporter Type 2 Inhibitor Empagliflozin Preserves β-Cell Mass and Restores Glucose Homeostasis in the Male Zucker Diabetic Fatty Rat

Abstract

Type 2 diabetes is characterized by impaired b-cell function associated with progressive reduction of insulin secretion and b-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in b-cell protection and antidiabetic efficacy. Through an insulin and b cell-independent mechanism, empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient glucose homeostasis and b-cell function in Zucker diabetic fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and hemoglobin A1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared with week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by less reduction in b-cell mass with empagliflozin or liraglutide at week 4, whereas only empagliflozin showed b-cell sparing effects also at week 8. Although this study cannot be used to dissociate the absolute antidiabetic efficacy among the different mechanisms of drug action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and b-cell protection in the ZDF rat. In comparison with other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of b-cell protection and antidiabetic efficacy.

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

“…However, insulin-sensitivity is not fully restored as shown by the only partially normalized blood glucose values (fasting and non-fasting) and HbA1c values as well as the obvious hyperinsulinemia in the plasma of all ZDF groups. The increase in insulin plasma levels in ZDF rats with different SGLT2i drugs is well documented [25,[46][47][48][49]. Of importance is that empagliflozin was shown to lower blood glucose levels (thereby sparing insulin) in a preclinical model of streptozotocin-induced type 1 diabetes [50] and also in human studies [51,52].…”

“…The two doses were calculated upon correction for the significant differences in pharmacokinetic parameters and metabolism between rodents and humans (e.g. half-life around 1-2 h in rodent and 10-12 h in man) and were previously reported to be efficient and to correspond to the equivalent active dose in humans [25][26][27][28]. After 6 weeks of treatment duration, animals were killed under isoflurane anesthesia by transection of the diaphragm and removal of the heart and thoracic aorta.…”

Protective Effect of Ipragliflozin on Pancreatic Islet Cells in Obese Type 2 Diabetic db/db Mice

“…[20][21][22][23][24] Tofogliflozin, dapagliflozin, empagliflozin and luseogliflozin lower blood or plasma glucose levels and increase plasma insulin levels, and preserve pancreatic β-cell function in obese T2DM db/db mice. [20][21][22][23] Empagliflozin and luseogliflozin increase the expression levels of insulin-related genes and a proliferation marker protein, and reduce glucose toxicity and an apoptosis marker protein in islets of obese T2DM db/db mice.…”

“…22,23) Empagliflozin has antihyperglycemic effects in Zucker diabetic fatty rats, and slows the degradation of pancreatic β-cell function and β-cell mass. 24) However, the mechanism underlying the positive effects of SGLT2 inhibitors on pancreatic β-cell preservation has not been fully investigated. Although the attenuation of oxidative stress in pancreatic islet cells by SGLT2 inhibitors is a possible mechanism of action, [25][26][27][28] studies on this subject are limited.…”

The Making of Pancreatic β Cells: Advances and Apprehensions

“…Henrik H.Hansen et al [59] Vanadyl Sulfate(VOSO 4 ). Normalizes blood glucose level, Increases insulin sensitivity, increases the proliferation of β cells and β cell number.…”