Increase 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 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.
Div. of Nephrology and Hypertension, Depts. of Medicine and Pharmacology, University of California San Diego, and VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA 92161. vvallon@ucsd.edu.
Timo
T
Rieg
Takahiro
T
Masuda
Maria
M
Gerasimova
Eric
E
Mayoux
Kenneth
K
Platt
David R
DR
Powell
Scott C
SC
Thomson
Hermann
H
Koepsell
Volker
V
Vallon
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001693:Biological Transport, Active / Q000502:physiology; D001786:Blood Glucose / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000502:physiology; D004435:Eating / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005960:Glucosides / Q000494:pharmacology; D006029:Glycosuria / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000502:physiology*; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014563:Urodynamics / Q000187:drug effects / Q000235:genetics
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; C495675:Slc5a1 protein, mouse; C490299:Slc5a2 protein, mouse; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin; D005947:Glucose
diabetes mellitus; glucose reabsorption; glucose transport; proximal tubule; sodium glucose cotransport inhibitor