Renal Effects of SGLT2 Inhibitors: An Update

Josselin Nespoux; Volker Vallon


Curr Opin Nephrol Hypertens. 2020;29(2):190-198. 

In This Article

SGLT2 and SGLT1 can Explain all Renal Glucose Reabsorption in Nondiabetic and Diabetic Mice

In normoglycemia and with normal GFR, the two kidneys of a healthy individual filter up to 180 g of glucose daily. Glucose is a valuable energy substrate and, as a consequence, filtered glucose is basically completely reabsorbed (~99.9%) by the tubular system, primarily through SGLT2 and SGLT1 in the proximal tubule. Studies in nondiabetic mice showed that SGLT2 reabsorbs all filtered glucose in the early proximal tubule (S1/S2 segments) and the majority of glucose (~97%) on the whole kidney level. SGLT1 reabsorbs the remaining glucose delivered to the late proximal tubule (S2/S3 segments) (for review see[4,5]). Recent studies confirmed that SGLT2 and SGLT1 can explain all renal glucose reabsorption in nondiabetic mice and extended the finding to genetic models of T2DM (db/db) and T1DM (Akita).[25]

Hyperglycemia enhances glomerular filtration of glucose. To prevent the renal loss of glucose, human kidneys increase their glucose reabsorption maximum capacity by ~20% to up to 600 g/day. This is associated with tubular growth.[4,5] Yakovleva et al.[26] used quantitative drug–disease systems modelling to propose that higher renal glucose reabsorption in T2DM patients vs. healthy individuals is associated with 54 and 28% greater transport maximum (Vmax) for SGLT1 and SGLT2, respectively. Studies in humans with T2DM[27,28] and genetic rodent models of T2DM and T1DM support an upregulation of renal SGLT2 protein expression,[27,29,30] whereas the response in SGLT1 is less clear.[4,5]

The early proximal tubule not only reabsorbs glucose (via SGLT2) but also generates glucose by gluconeogenesis. The latter not only occurs particularly in the postprandial phase but also in response to metabolic acidosis, as tubular gluconeogenesis is linked to bicarbonate formation. In this regard, Onishi et al.[31] linked enhanced renal gluconeogenesis to an inhibition of SGLT2 expression inasmuch as upregulation of renal gluconeogenesis to compensate for impaired bicarbonate reabsorption in mice lacking tubular NHE3 was associated with marked suppression of SGLT2 protein expression, probably to prevent glucose overload in these cells. In other words, if diabetes is associated with metabolic acidosis, then the resulting increase in renal gluconeogenesis can lower renal SGLT2 expression. The studies by Onishi et al.[31] further indicated that in this setting of suppressed SGLT2 expression, the downstream shift of glucose was associated with upregulation of SGLT1-mediated glucose reabsorption suggesting a coordinated response.

The uricosuric and blood urate-lowering effect of SGLT2 inhibitors is a class effect.[4] Using knockout mouse models for SGLT2, SGLT1, URAT1 and GLUT9, studies by Novikov et al.[32] indicated a role of luminal glucose delivery and inhibition of the proximal tubule urate transporter URAT1 in the uricosuric effect of the SGLT2 inhibitor canagliflozin. Insulin enhances URAT1 activity.[33] Therefore, SGLT2 inhibition may reduce URAT1 activity by enhancing luminal glucose delivery or lowering insulin levels (Figure 2), or SGLT2 and URAT1 may functionally interact in the proximal tubule, such that inhibition of SGLT2 partially inhibits URAT1.