RT Journal Article SR Electronic T1 The Sodium Glucose Cotransporter Type 2 Inhibitor Empagliflozin Preserves β-Cell Mass and Restores Glucose Homeostasis in the Male Zucker Diabetic Fatty Rat JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 657 OP 664 DO 10.1124/jpet.114.213454 VO 350 IS 3 A1 Hansen, Henrik H. A1 Jelsing, Jacob A1 Hansen, Carl Frederik A1 Hansen, Gitte A1 Vrang, Niels A1 Mark, Michael A1 Klein, Thomas A1 Mayoux, Eric YR 2014 UL http://jpet.aspetjournals.org/content/350/3/657.abstract AB 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 antidiabetic efficacy. Through an insulin and β 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 β-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 β-cell mass with empagliflozin or liraglutide at week 4, whereas only empagliflozin showed β-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 β-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 β-cell protection and antidiabetic efficacy.