Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2

Abstract

The concentration of glucose in plasma is held within narrow limits (4–10 mmol/l), primarily to ensure fuel supply to the brain. Kidneys play a role in glucose homeostasis in the body by ensuring that glucose is not lost in the urine. Three membrane proteins are responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule: sodium−glucose cotransporters SGLT1 and SGLT2, in the apical membrane, and GLUT2, a uniporter in the basolateral membrane. ‘Knockout’ of these transporters in mice and men results in the excretion of filtered glucose in the urine. In humans, intravenous injection of the plant glucoside phlorizin also results in excretion of the full filtered glucose load. This outcome and the finding that, in an animal model, phlorizin reversed the symptoms of diabetes, has stimulated the development and successful introduction of SGLT2 inhibitors, gliflozins, in the treatment of type 2 diabetes mellitus. Here we summarise the current state of our knowledge about the physiology of renal glucose handling and provide background to the development of SGLT2 inhibitors for type 2 diabetes treatment.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4656-5) contains a slideset of the figures for download, which is available to authorised users.

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

“…NKA maintains a sodium gradient across the basolateral membrane of PT cells that provides the driving force for the SGLT activity [146]. In this way, changes in NKA activity presumably have an impact on SGLT function and glucose recovery.…”

Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney

“…4). SGLT2 reabsorbs glucose in the S1 and S2 segments of the proximal tubule and SGLT1 (SLC5A1) is located in S3 32 . The delineation between S1/S2 and S3 was less clear in the snRNA-seq dataset ( Supplementary Fig.…”

“…4), which suggests that snATAC-seq provides complementary information that may refine cell type assignment; particularly for genes transcribed at low levels or genes that are not detected by snRNA-seq. The chromatin accessibility profile of S1/S2 may be of clinical interest in determining the factors that drive glucose reabsorption, which is the therapeutic target of SGLT2 inhibitors 32 . Together, our multimodal snATAC-seq and snRNA-seq analysis improved our ability to dissect cellular heterogeneity.…”

SGLT2 inhibition to address the unmet needs in diabetic nephropathy

“…Entry of sodium and glucose within tubular cells via SGLT1/2 follows a sodium gradient generated by a Na‐K‐ATPase pump. After reabsorption, glucose moves passively into the interstitium using the facilitative glucose transporters GLUT1 and GLUT2, which are expressed on the basolateral membrane of PT cells …”

“…After reabsorption, glucose moves passively into the interstitium using the facilitative glucose transporters GLUT1 and GLUT2, which are expressed on the basolateral membrane of PT cells. 16,17…”