title: Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats.
abstract: To understand the risk of hypoglycemia associated with urinary glucose excretion (UGE) induced by sodium-glucose cotransporter (SGLT) inhibitors, it is necessary to know the relationship between the ratio of contribution of SGLT2 vs. SGLT1 to renal glucose reabsorption (RGR) and the glycemic levels in vivo. To examine the contributions of SGLT2 and SGLT1 in normal rats, we compared the RGR inhibition by tofogliflozin, a highly specific SGLT2 inhibitor, and phlorizin, an SGLT1 and SGLT2 (SGLT1/2) inhibitor, at plasma concentrations sufficient to completely inhibit rat SGLT2 (rSGLT2) while inhibiting rSGLT1 to different degrees. Under hyperglycemic conditions by glucose titration, tofogliflozin and phlorizin achieved ≥50% inhibition of RGR. Under hypoglycemic conditions by hyperinsulinemic clamp, RGR was reduced by 20-50% with phlorizin and by 1-5% with tofogliflozin, suggesting the smaller contribution of rSGLT2 to RGR under hypoglycemic conditions than under hyperglycemic conditions. Next, to evaluate the hypoglycemic potentials of SGLT1/2 inhibition, we measured the plasma glucose (PG) and endogenous glucose production (EGP) simultaneously after UGE induction by SGLT inhibitors. Tofogliflozin (400 ng/ml) induced UGE of about 2 mg·kg⁻¹·min⁻¹ and increased EGP by 1-2 mg·kg⁻¹·min⁻¹, resulting in PG in the normal range. Phlorizin (1,333 ng/ml) induced UGE of about 6 mg·kg⁻¹·min⁻¹ and increased EGP by about 4 mg·kg⁻¹·min⁻¹; this was more than with tofogliflozin, but the minimum PG was lower. These results suggest that the contribution of SGLT1 to RGR is greater under lower glycemic conditions than under hyperglycemic conditions and that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Nagata
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukazawa
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Honda
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yata
authors.forename: Mio
authors.initials: M
authors.lastname: Kawai
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yamane
authors.forename: Naoaki
authors.initials: N
authors.lastname: Murao
authors.forename: Koji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsui
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Sachiya
authors.initials: S
authors.lastname: Ikeda
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kawabe
mesh_terms: D000042:Absorption / Q000187:drug effects; D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D003404:Creatinine / Q000378:metabolism / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005943:Gluconeogenesis / Q000187:drug effects; D005960:Glucosides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006029:Glycosuria / Q000139:chemically induced* / Q000209:etiology; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000652:urine; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000652:urine; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010695:Phlorhizin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C495676:Slc5a1 protein, rat; C490300:Slc5a2 protein, rat; D026941:Sodium Channel Blockers; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D003404:Creatinine; D010695:Phlorhizin; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol