TY - JOUR T1 - The Sodium Glucose Cotransporter Type 2 Inhibitor Empagliflozin Preserves <em>β</em>-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 SP - 657 LP - 664 DO - 10.1124/jpet.114.213454 VL - 350 IS - 3 AU - Henrik H. Hansen AU - Jacob Jelsing AU - Carl Frederik Hansen AU - Gitte Hansen AU - Niels Vrang AU - Michael Mark AU - Thomas Klein AU - Eric Mayoux Y1 - 2014/09/01 UR - http://jpet.aspetjournals.org/content/350/3/657.abstract N2 - 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. ER -