Glucose transport by human renal Na+/d-glucose cotransporters SGLT1 and SGLT2
Open Access
- 1 January 2011
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 300 (1), C14-C21
- https://doi.org/10.1152/ajpcell.00388.2010
Abstract
The human Na+/d-glucose cotransporter 2 (hSGLT2) is believed to be responsible for the bulk of glucose reabsorption in the kidney proximal convoluted tubule. Since blocking reabsorption increases urinary glucose excretion, hSGLT2 has become a novel drug target for Type 2 diabetes treatment. Glucose transport by hSGLT2 was studied at 37°C in human embryonic kidney 293T cells using whole cell patch-clamp electrophysiology. We compared hSGLT2 with hSGLT1, the transporter in the straight proximal tubule (S3 segment). hSGLT2 transports with surprisingly similar glucose affinity and lower concentrative power than hSGLT1: Na+/d-glucose cotransport by hSGLT2 was electrogenic with apparent glucose and Na+ affinities of 5 and 25 mM, and a Na+:glucose coupling ratio of 1; hSGLT1 affinities were 2 and 70 mM and coupling ratio of 2. Both proteins showed voltage-dependent steady-state transport; however, unlike hSGLT1, hSGLT2 did not exhibit detectable pre-steady-state currents in response to rapid jumps in membrane voltage. d-Galactose was transported by both proteins, but with very low affinity by hSGLT2 (≥100 vs. 6 mM). β-d-Glucopyranosides were either substrates or blockers. Phlorizin exhibited higher affinity with hSGLT2 ( Ki 11 vs. 140 nM) and a lower Off-rate (0.03 vs. 0.2 s−1) compared with hSGLT1. These studies indicate that, in the early proximal tubule, hSGLT2 works at 50% capacity and becomes saturated only when glucose is ≥35 mM. Furthermore, results on hSGLT1 suggest it may play a significant role in the reabsorption of filtered glucose in the late proximal tubule. Our electrophysiological study provides groundwork for a molecular understanding of how hSGLT inhibitors affect renal glucose reabsorption.Keywords
This publication has 32 references indexed in Scilit:
- Biology of Human Sodium Glucose TransportersPhysiological Reviews, 2011
- SGLT2 Mediates Glucose Reabsorption in the Early Proximal TubuleJournal of the American Society of Nephrology, 2011
- Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and ExerciseDiabetes Care, 2010
- The Crystal Structure of a Sodium Galactose Transporter Reveals Mechanistic Insights into Na + /Sugar SymportScience, 2008
- Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 DiabetesJournal of Medicinal Chemistry, 2008
- Inhibitor Binding in the Human Renal Low- and High-Affinity Na+/Glucose CotransportersThe Journal of pharmacology and experimental therapeutics, 2007
- Common mechanisms of inhibition for the Na+/glucose (hSGLT1) and Na+/Cl−/GABA (hGAT1) cotransportersBritish Journal of Pharmacology, 2001
- Molecular Characteristics of Na+-coupled Glucose Transporters in Adult and Embryonic Rat KidneyOnline Journal of Public Health Informatics, 1995
- Further studies of proximal tubular brush border membraned-glucose transport heterogeneityThe Journal of Membrane Biology, 1982
- THE ACTION OF PHLORIZIN ON THE EXCRETION OF GLUCOSE, XYLOSE, SUCROSE, CREATININE AND UREA BY MANJCI Insight, 1933