SGLT1 does compensate for SGLT2 inhibition

Dear Editor, as explained in the review article on SGLT2 inhibition by de Leeuw et al.,¹ SGLT2 is a low-affinity high-capacity cotransporter, expressed proximally in the tubular system (see figure 2 of de Leeuw et al., Segment S1), contrasting with SGLT1 which has higher affinity but lower capacity and is expressed more distally (see figure 2 of de Leeuw et al., Segment S3). It follows that most of the glucose reabsorption (>90%) is achieved proximally by SGLT2, and SGLT1 acts more distally on the remaining glucose (<10%) in the proximal tubule.²

It is therefore surprising to read that no compensatory role of SGLT1 has been described during SGLT2 inhibition.¹ Standard doses of SGLT2 inhibitors achieve near 100% inhibition of the SGLT2 activity in humans.³ If there was no compensation, over 90% of the filtered glucose (along with a substantial amount of sodium and water) would be excreted. Clearly, this is not the case as only 30–50% of the renal glucose reabsorption is inhibited, even with extremely high doses of SGLT2 inhibitors,³ or in familial renal glucosuria.²

Conceivably, compensation by other mechanisms unrelated to SGLT1 activity might occur.³ However, an elegant experiment by Rieg et al., with SGLT1 knockout, showed conclusively that an increase in SGLT1-mediated transport fully accounts for the unexplained renal glucose reabsorption, both in pharmacological SGLT2 inhibition and in SGLT2 knockout mice.⁴

In conclusion, we cannot accept that no compensatory role of SGLT1 is at work during SGLT2 inhibition. Additionally, we would like to point out that SGLT2 expression in the α cells of the pancreatic islet has been reported and is involved in the regulation of glucagon secretion⁵; thus, Table 2 in the review¹ is incomplete.

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