Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2.
نویسندگان
چکیده
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 (K(i) 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.
منابع مشابه
The Na(+)/glucose cotransporters: from genes to therapy.
Glucose enters eukaryotic cells via two types of membrane-associated carrier proteins, the Na(+)/glucose cotransporters (SGLT) and the facilitative glucose transporters (GLUT). The SGLT family consists of six members. Among them, the SGLT1 and SGLT2 proteins, encoded by the solute carrier genes SLC5A1 and SLC5A2, respectively, are believed to be the most important ones and have been extensively...
متن کاملMolecular determinants of renal glucose reabsorption. Focus on "Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2".
ABOUT 180 g of glucose are filtered daily in the glomeruli of the kidneys in a healthy normoglycemic subject, which is equivalent to approximately one third of the total energy consumed by the human body in a day. Most of the glucose entering the tubular system is reabsorbed along the nephron segments, primarily in the proximal tubule, such that urine is almost free of glucose. This is differen...
متن کاملIncrease in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia.
In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ∼3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40-50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage with a selective SGLT2 inhibitor (SGLT2-I) dose dependently increased urinary g...
متن کاملThe human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose.
The major reabsorptive mechanism for D-glucose in the kidney is known to involve a low affinity high capacity Na+/glucose cotransporter, which is located in the early proximal convoluted tubule segment S1, and which has a Na+ to glucose coupling ratio of 1:1. Here we provide the first molecular evidence for this renal D-glucose reabsorptive mechanism. We report the characterization of a previou...
متن کاملRenal Na(+)-glucose cotransporters.
In humans, the kidneys filter approximately 180 g of D-glucose from plasma each day, and this is normally reabsorbed in the proximal tubules. Although the mechanism of reabsorption is well understood, Na(+)-glucose cotransport across the brush-border membrane and facilitated diffusion across the basolateral membrane, questions remain about the identity of the genes responsible for cotransport a...
متن کاملImmunohistochemical Studies of Na/D-glucose Cotransporters in the Intestine and Kidney of Squalus acanthias and Leucoraja erinacea
In preceding studies different characteristics for the Na/D-glucose cotransport in the kidneys of the little skate (Leucoraja erinacea) and the spiny dogfish (Squalus acanthias) were detected. The transporter in the skate showed a high affinity for D-glucose (Km=0.12 mM) and an apparent coupling ratio of 2 Na to 1 D-glucose, whereas the affinity of the shark transporter was much lower (Km=1.90 ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- American journal of physiology. Cell physiology
دوره 300 1 شماره
صفحات -
تاریخ انتشار 2011