title: Analysis of the effect of canagliflozin on renal glucose reabsorption and progression of hyperglycemia in zucker diabetic Fatty rats.
abstract: Sodium-glucose cotransporter 2 (SGLT2) plays a major role in renal glucose reabsorption. To analyze the potential of insulin-independent blood glucose control, the effects of the novel SGLT2 inhibitor canagliflozin on renal glucose reabsorption and the progression of hyperglycemia were analyzed in Zucker diabetic fatty (ZDF) rats. The transporter activity of recombinant human and rat SGLT2 was inhibited by canagliflozin, with 150- to 12,000-fold selectivity over other glucose transporters. Moreover, in vivo treatment with canagliflozin induced glucosuria in mice, rats, and dogs in a dose-dependent manner. It inhibited apparent glucose reabsorption by 55% in normoglycemic rats and by 94% in hyperglycemic rats. The inhibition of glucose reabsorption markedly reduced hyperglycemia in ZDF rats but did not induce hypoglycemia in normoglycemic animals. The change in urinary glucose excretion should not be used as a marker to predict the glycemic effects of this SGLT2 inhibitor. In ZDF rats, plasma glucose and HbA1c levels progressively increased with age, and pancreatic β-cell failure developed at 13 weeks of age. Treatment with canagliflozin for 8 weeks from the prediabetic stage suppressed the progression of hyperglycemia, prevented the decrease in plasma insulin levels, increased pancreatic insulin contents, and minimized the deterioration of islet structure. These results indicate that selective inhibition of SGLT2 with canagliflozin controls the progression of hyperglycemia by inhibiting renal glucose reabsorption in ZDF rats. In addition, the preservation of β-cell function suggests that canagliflozin treatment reduces glucose toxicity via an insulin-independent mechanism.
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kuriyama
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Jun Zhi
authors.initials: JZ
authors.lastname: Xu
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Seunghun Paul
authors.initials: SP
authors.lastname: Lee
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Jenson
authors.initials: J
authors.lastname: Qi
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kimata
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Kakimoto
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Taniuchi
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hikida
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.).
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan (C.K., H.K., T.K., K.N., Y.W., N.T., K.H., Y.M., K.A., A.S., K.U., M.S.); and Janssen Research & Development LLC, Spring House, Pennsylvania (J.Z.X., S.P.L., J.Q.) shiotani.masaharu@mr.mt-pharma.co.jp.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shiotani
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D000068896:Canagliflozin; D003921:Diabetes Mellitus, Experimental; D004285:Dogs; D005947:Glucose / Q000378:metabolism*; D005960:Glucosides / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051381:Rats; D011924:Rats, Zucker; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D000068896:Canagliflozin; D005947:Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D051297:Sodium-Glucose Transporter 2; D013876:Thiophenes