@article {Hansenjpet.114.213454, author = {Henrik H Hansen and Jacob Jelsing and Frederik Hansen and Gitte Hansen and Niels Vrang and Michael Mark and Thomas Klein and Eric Mayoux}, title = {The SGLT-2 inhibitor empagliflozin preserves beta cell mass and restores glucose homeostasis in the male diabetic ZDF rat}, elocation-id = {jpet.114.213454}, year = {2014}, doi = {10.1124/jpet.114.213454}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Type 2 diabetes is characterized by impaired β-cell function associated with progressive reduction of insulin secretion and β-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-cell protection and anti-diabetic efficacy. Through an insulin and β-cell independent mechanism, empagliflozin, a specific sodium glucose co-transporter type-2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the anti-diabetic 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 β-cell function in Zucker diabetic Fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and HbA1c 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 to 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 a less reduction in β-cell mass with empagliflozin or liraglutide at week 4, while only empagliflozin showed β-cell sparing effects at week 8. While this study cannot be used to dissociate the absolute anti-diabetic efficacy among those different mechanisms of action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-cell protection ZDF rats. In comparison to other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-cell protection and anti-diabetic efficacy.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2014/07/03/jpet.114.213454}, eprint = {https://jpet.aspetjournals.org/content/early/2014/07/03/jpet.114.213454.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }