Sodium Glucose Cotransporter 2 Inhibition in the Diabetic Kidney

An Update

Aleksandra Novikov; Volker Vallon


Curr Opin Nephrol Hypertens. 2016;25(1):50-58. 

In This Article

Diabetes Increases Renal Sodium Glucose Cotransporter 2 Expression and Glucose Reabsorption

In T1DM and T2DM, the kidneys increase their glucose transport maximum by ~20% to 600 gram/day. This could be secondary to proximal tubular growth and an increase in SGLT2 expression; however, no data using primary tissue samples and validated antibodies are available in humans, and previous studies in rodents provided conflicting results.[5,12] Using knockout mice as critical negative antibody controls, renal protein expression of SGLT2 was shown to be increased by 40–80% in genetic models of T2DM db/db mice and T1DM Akita mice[13,14] (Fig. 2).

Renal SGLT1 protein expression was increased in T2DM ob/ob mice, whereas SGLT1 mRNA was reduced.[15] Other studies indicated that renal SGLT1 protein expression is suppressed whenever the late proximal tubule is exposed to high glucose levels, as observed in normoglycemic SGLT2−/− mice,[7] as well as in nondiabetic mice given a SGLT2 inhibitor or in T1DM Akita mice.[14] Despite this downregulation, overall glucose transport through SGLT1 was greatly increased in those settings because of the increased glucose load to the late proximal tubule[7,11] (Fig. 2). We speculated that downregulation of SGLT1 is a protective mechanism to attenuate glucotoxicity in the vulnerable S3 segments within the outer medulla.[4] Upregulation of SGLT2 and downregulation of SGLT1 in diabetes are both expected to enhance the glucosuric and thereby the blood glucose lowering effect of SGLT2 inhibition.