title: 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 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.
authors.affiliation: Gubra, Hørsholm, Denmark (H.H.H., J.J., C.F.H., G.H., N.V.); and Boehringer Ingelheim Pharma, Biberach, Germany (M.M., T.K., E.M.) hbh@gubra.dk.
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
authors.affiliation: Gubra, Hørsholm, Denmark (H.H.H., J.J., C.F.H., G.H., N.V.); and Boehringer Ingelheim Pharma, Biberach, Germany (M.M., T.K., E.M.).
authors.forename: Jacob
authors.initials: J
authors.lastname: Jelsing
authors.affiliation: Gubra, Hørsholm, Denmark (H.H.H., J.J., C.F.H., G.H., N.V.); and Boehringer Ingelheim Pharma, Biberach, Germany (M.M., T.K., E.M.).
authors.forename: Carl Frederik
authors.initials: CF
authors.lastname: Hansen
authors.affiliation: Gubra, Hørsholm, Denmark (H.H.H., J.J., C.F.H., G.H., N.V.); and Boehringer Ingelheim Pharma, Biberach, Germany (M.M., T.K., E.M.).
authors.forename: Gitte
authors.initials: G
authors.lastname: Hansen
authors.affiliation: Gubra, Hørsholm, Denmark (H.H.H., J.J., C.F.H., G.H., N.V.); and Boehringer Ingelheim Pharma, Biberach, Germany (M.M., T.K., E.M.).
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
authors.affiliation: Gubra, Hørsholm, Denmark (H.H.H., J.J., C.F.H., G.H., N.V.); and Boehringer Ingelheim Pharma, Biberach, Germany (M.M., T.K., E.M.).
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.affiliation: Gubra, Hørsholm, Denmark (H.H.H., J.J., C.F.H., G.H., N.V.); and Boehringer Ingelheim Pharma, Biberach, Germany (M.M., T.K., E.M.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: Gubra, Hørsholm, Denmark (H.H.H., J.J., C.F.H., G.H., N.V.); and Boehringer Ingelheim Pharma, Biberach, Germany (M.M., T.K., E.M.).
authors.forename: Eric
authors.initials: E
authors.lastname: Mayoux
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood* / Q000188:drug therapy; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin