Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia

Abstract

.-In the kidney, the sodiumglucose cotransporters SGLT2 and SGLT1 are thought to account for Ͼ90 and ϳ3% 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 (Sglt1Ϫ/Ϫ) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5-to 2-fold higher urine glucose/creatinine ratios in Sglt1Ϫ/Ϫ vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1Ϫ/Ϫ vs. WT after 24 h (Ϫ33 vs. Ϫ11%). 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 Ϯ 2% in WT and 17 Ϯ 2% in Sglt1Ϫ/Ϫ. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations ϳ10-fold and reduced FGR to 44 Ϯ 3% in WT and to Ϫ1 Ϯ 3% in Sglt1Ϫ/Ϫ. 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. proximal tubule; glucose reabsorption; glucose transport; sodium glucose cotransport inhibitor; diabetes mellitus ABOUT 180 G OF GLUCOSE ARE filtered daily by the kidney and enter the renal tubular system in a healthy normoglycemic subject. Glucose in urine is absent or at very low concentrations in healthy adults due to near complete reabsorption along the nephron segments, primarily in the proximal tubule. The renal Na ϩ -glucose cotransporter SGLT2 (SLC5A2) is localized to the early proximal tubule and thought to mediate the bulk of tubular glucose uptake across the apical membrane of the kidney (14,17,20). Studies in mice lacking Sglt2 demonstrated that SGLT2 mediates all glucose reabsorption in the early proximal tubule and most of overall glucose reabsorption by the kidney (17). In comparison, low-capacity SGLT1 (SLC5A1) "cleans up" most of the remaining luminal glucose in further distal parts of the proximal tubule (1,3,14,20). Studies in mice lacking Sglt1 (Sglt1Ϫ/Ϫ) revealed a fractional glucose excretion of 3% compared with 0.2% in wild-type (WT) (3). Whether glucose transporters other than SGLT2 and SGLT1 contribute in a measurable extent to renal glucose reabsorption across the luminal membrane of the renal epithelia has never been tested. Potential candidates include a lowaffinity Na ϩ -D-glucose cotransporter cloned from the rat named NaGL...

The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension

“…While this result was surprising and cannot be explained, a previous study (4) has also demonstrated differential expression of SGLT1 mRNA and protein. From these results, we interpret that diabetic BTBR ob/ob mice do not show a mechanism of compensatory increased SGLT1-mediated glucose reabsorption under complete SGLT2 blockade, as has been demonstrated by Vallon and coworkers in C57Bl/6 mice (25).…”

A mathematical model of rat proximal tubule and loop of Henle

“…10 cannot claim to be secure in estimating the glycosuric effect of SGLT2 inhibitors. Nevertheless, Rieg et al (61) reported that with chronic empagliflozin administration to mice, fractional glucose reabsorption was about 45-50%. With reference to the calculations of this model (Fig.…”

Sodium–glucose cotransporter-2 inhibition and acidosis in patients with type 2 diabetes: a review of US FDA data and possible conclusions

“…1 These inhibitors may also decrease insulin secretion with blood glucose levels that remain close to the normal range due to the blockade of glucose reabsorption at the renal proximal tubule. 2 Problems have emerged with the use of SGLT2 inhibitors, some of which might have arisen directly from their high level of efficiency.…”