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2.
Am J Physiol Renal Physiol ; 306(12): F1520-33, 2014 Jun 15.
Article in English | MEDLINE | ID: mdl-24761001

ABSTRACT

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.


Subject(s)
Benzhydryl Compounds/pharmacology , Glucose/metabolism , Glucosides/pharmacology , Macaca fascicularis/urine , Phlorhizin/pharmacology , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2/drug effects , Animals , COS Cells/metabolism , COS Cells/pathology , Chlorocebus aethiops , DNA, Complementary/genetics , Dose-Response Relationship, Drug , In Vitro Techniques , Kidney/metabolism , Kidney/pathology , Male , Methylglucosides/metabolism , Models, Animal , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 1/drug effects , Sodium-Glucose Transporter 1/genetics , Sodium-Glucose Transporter 2/genetics
3.
Development ; 140(3): 639-48, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23293295

ABSTRACT

Congenital biliary atresia is an incurable disease of newborn infants, of unknown genetic causes, that results in congenital deformation of the gallbladder and biliary duct system. Here, we show that during mouse organogenesis, insufficient SOX17 expression in the gallbladder and bile duct epithelia results in congenital biliary atresia and subsequent acute 'embryonic hepatitis', leading to perinatal death in ~95% of the Sox17 heterozygote neonates in C57BL/6 (B6) background mice. During gallbladder and bile duct development, Sox17 was expressed at the distal edge of the gallbladder primordium. In the Sox17(+/-) B6 embryos, gallbladder epithelia were hypoplastic, and some were detached from the luminal wall, leading to bile duct stenosis or atresia. The shredding of the gallbladder epithelia is probably caused by cell-autonomous defects in proliferation and maintenance of the Sox17(+/-) gallbladder/bile duct epithelia. Our results suggest that Sox17 plays a dosage-dependent function in the morphogenesis and maturation of gallbladder and bile duct epithelia during the late-organogenic stages, highlighting a novel entry point to the understanding of the etiology and pathogenesis of human congenital biliary atresia.


Subject(s)
Biliary Atresia/genetics , Gene Expression Regulation, Developmental , HMGB Proteins/metabolism , Haploinsufficiency , SOXF Transcription Factors/metabolism , Animals , Animals, Newborn , Bile Ducts/metabolism , Bile Ducts/pathology , Biliary Atresia/pathology , Cell Proliferation , Cholestasis/genetics , Cholestasis/pathology , Embryo, Mammalian/metabolism , Embryo, Mammalian/pathology , Endoplasmic Reticulum Stress , Epithelium/metabolism , Epithelium/pathology , Female , Gallbladder/metabolism , Gallbladder/ultrastructure , HMGB Proteins/genetics , Hepatitis, Animal/genetics , Hepatitis, Animal/metabolism , Hepatitis, Animal/pathology , Hepatocytes/metabolism , Heterozygote , Immunohistochemistry , Liver/metabolism , Liver/ultrastructure , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Pregnancy , SOXF Transcription Factors/genetics , Time Factors
4.
Am J Physiol Endocrinol Metab ; 304(4): E414-23, 2013 Feb 15.
Article in English | MEDLINE | ID: mdl-23249697

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.


Subject(s)
Benzhydryl Compounds/adverse effects , Glucosides/adverse effects , Glycosuria/chemically induced , Hypoglycemic Agents/adverse effects , Kidney/drug effects , Sodium Channel Blockers/adverse effects , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 2 Inhibitors , Absorption/drug effects , Animals , Benzhydryl Compounds/administration & dosage , Benzhydryl Compounds/pharmacokinetics , Benzhydryl Compounds/therapeutic use , Blood Glucose/analysis , Creatinine/metabolism , Creatinine/urine , Dose-Response Relationship, Drug , Gluconeogenesis/drug effects , Glucosides/administration & dosage , Glucosides/pharmacokinetics , Glucosides/therapeutic use , Glycosuria/etiology , Hyperglycemia/blood , Hyperglycemia/drug therapy , Hyperglycemia/metabolism , Hyperglycemia/urine , Hypoglycemia/blood , Hypoglycemia/chemically induced , Hypoglycemia/metabolism , Hypoglycemia/urine , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Kidney/metabolism , Male , Phlorhizin/administration & dosage , Phlorhizin/adverse effects , Phlorhizin/pharmacokinetics , Phlorhizin/therapeutic use , Rats , Rats, Wistar , Sodium Channel Blockers/administration & dosage , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/therapeutic use , Sodium-Glucose Transporter 1/metabolism , Sodium-Glucose Transporter 2/metabolism
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