Competitive inhibition of SGLT2 by tofogliflozin or phlorizin induces urinary glucose excretion through extending splay in cynomolgus monkeys.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed a glucose lowering effect in type 2 diabetes patients through inducing renal glucose excretion. Detailed analysis of the mechanism of the glucosuric effect of SGLT2 inhibition, however, has been hampered by limitations of clinical study. Here, we investigated the mechanism of urinary glucose excretion using nonhuman primates with SGLT inhibitors tofogliflozin and phlorizin, both in vitro and in vivo. In cells overexpressing cynomolgus monkey SGLT2 (cSGLT2), both tofogliflozin and phlorizin competitively inhibited uptake of the substrate (α-methyl-d-glucopyranoside; AMG). Tofogliflozin was found to be a selective cSGLT2 inhibitor, inhibiting cSGLT2 more strongly than did phlorizin, with selectivity toward cSGLT2 1,000 times that toward cSGLT1; phlorizin was found to be a nonselective cSGLT1/2 inhibitor. In a glucose titration study in cynomolgus monkeys under conditions of controlled plasma drug concentration, both tofogliflozin and phlorizin increased fractional excretion of glucose (FEG) by up to 50% under hyperglycemic conditions. By fitting the titration curve using a newly introduced method that avoids variability in estimating the threshold of renal glucose excretion, we found that tofogliflozin and phlorizin lowered the threshold and extended the splay in a dose-dependent manner without significantly affecting the tubular transport maximum for glucose (TmG). Our results demonstrate the contribution of SGLT2 to renal glucose reabsorption (RGR) in cynomolgus monkeys and demonstrate that competitive inhibition of cSGLT2 exerts a glucosuric effect by mainly extending splay and lowering threshold without affecting TmG.
Research Division, Chugai Pharmaceutical Company, Limited., Gotemba, Shizuoka, Japan; and.
Takumi
T
Nagata
Research Division, Chugai Pharmaceutical Company, Limited., Gotemba, Shizuoka, Japan; and.
Masayuki
M
Suzuki
Research Division, Chugai Pharmaceutical Company, Limited., Gotemba, Shizuoka, Japan; and fukazawamsn@chugai-pharm.co.jp.
Masanori
M
Fukazawa
Research Division, Chugai Pharmaceutical Company, Limited., Gotemba, Shizuoka, Japan; and.
Kiyofumi
K
Honda
Research Division, Chugai Pharmaceutical Company, Limited., Gotemba, Shizuoka, Japan; and.
Mizuki
M
Yamane
Chugai Research Institute for Medical Science, Incorporated, Gotemba, Shizuoka, Japan.
Ayae
A
Yoshida
Chugai Research Institute for Medical Science, Incorporated, Gotemba, Shizuoka, Japan.
Hiroko
H
Azabu
Chugai Research Institute for Medical Science, Incorporated, Gotemba, Shizuoka, Japan.
Hidekazu
H
Kitamura
Chugai Research Institute for Medical Science, Incorporated, Gotemba, Shizuoka, Japan.
Naoto
N
Toyota
Research Division, Chugai Pharmaceutical Company, Limited., Gotemba, Shizuoka, Japan; and.
Yoshiyuki
Y
Suzuki
Research Division, Chugai Pharmaceutical Company, Limited., Gotemba, Shizuoka, Japan; and.
Yoshiki
Y
Kawabe
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D019556:COS Cells / Q000378:metabolism / Q000473:pathology; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D005960:Glucosides / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis / Q000652:urine*; D008297:Male; D008757:Methylglucosides / Q000378:metabolism; D023421:Models, Animal; D010695:Phlorhizin / Q000494:pharmacology*; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D051297:Sodium-Glucose Transporter 2 / Q000187:drug effects* / Q000235:genetics; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D001559:Benzhydryl Compounds; D018076:DNA, Complementary; D005960:Glucosides; D008757:Methylglucosides; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C027020:methylglucoside; D010695:Phlorhizin; D005947:Glucose; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol
sodium-glucose transporter inhibitor; splay; transport maximum for glucose