Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 306, Issue 2, Pages F188-F193Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00518.2013
Keywords
proximal tubule; glucose reabsorption; glucose transport; sodium glucose cotransport inhibitor; diabetes mellitus
Categories
Funding
- National Institutes of Health [R01DK56248, R01HL94728]
- UAB/UCSD O'Brien Center of Acute Kidney Injury [NIH-P30DK079337]
- American Heart Association (Scientist Development Grant) [10SDG2610034]
- Carl W. Gottschalk Research Grant of the American Society of Nephrology
- Manpei Suzuki Diabetes Foundation
- Department of Veterans Affairs
- Boehringer Ingelheim
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL094728] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK079337, R01DK056248] Funding Source: NIH RePORTER
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In the kidney, the sodiumglucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and similar to 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 glucose excretion (UGE) in wild-type (WT) mice. The dose-response curve was shifted leftward and the maximum response doubled in Sglt1 knockout (Sglt1-/-) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5-to 2-fold higher urine glucose/creatinine ratios in Sglt1-/- vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1-/- vs. WT after 24 h (-33 vs. -11%). Subsequent inulin clearance studies under anesthesia revealed free plasma concentrations of the SGLT2-I (corresponding to early proximal concentration) close to the reported IC50 for SGLT2 in mice, which were associated with FGR of 64 2% in WT and 17 2% in Sglt1-/-. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations -10-fold and reduced FGR to 44 +/- 3% in WT and to -1 +/- 3% in Sglt1-/-. The absence of renal glucose reabsorption was confirmed in male and female Sglt1/Sglt2 double knockout mice. In conclusion, SGLT2 and SGLT1 account for renal glucose reabsorption in euglycemia, with 97 and 3% being reabsorbed by SGLT2 and SGLT1, respectively. When SGLT2 is fully inhibited by SGLT2-I, the increase in SGLT1-mediated glucose reabsorption explains why only 50-60% of filtered glucose is excreted.
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