The Role of Kidney in Glucose Homeostasis — SGLT2 Inhibitors, a New Approach in Diabetes Treatment

Vasileios Andrianesis; John Doupis

Disclosures

Expert Rev Clin Pharmacol. 2013;6(5):519-539. 

In This Article

Renal Glucose Transporters

Transporters involved in the mechanism of tubular glucose reabsorption are separated into two main families: the SGLTs secondary active Na+/D-glucose co-transporters, located at the brush border of tubular cells and the GLUTs facilitated diffusion glucose transporters located at the basolateral membrane of tubular cells.[1]

SGLTs Na/Glucose Co-transporters

The SGLTs belong to the SLC5 gene family that includes more than 220 members both in animal and human genome.[22] The human members of SLC5 gene family code protein transporters are listed in Table 1 .[22,23] As for the renal tubules, early in vitro perfusion studies demonstrated that tubular glucose reabsorption was facilitated by two different transporters.[24] A low-affinity/high capacity Na+-coupled glucose transporter in S1 segments of proximal tubules (Km for D-glucose of 1.64 mM and a maximal transport rate Jmax of 83 pmol/min per mm) and a high-affinity/low capacity NA+-coupled glucose transporter located in S3 segments (Km for D-glucose of 0.35 mM and a maximal transport rate Jmax of 7.9 pmol/min/mm).[24] Further glucose uptake studies of Turner et al.[25,26] into brush border membrane vesicles from rabbit and human kidney cortex were in accordance with the model of two different Na+/glucose co-transporters and demonstrated that the one at the early S1/2 tubular segments exhibits low affinity (Km of 6 mM) and 1: 1 Na: glucose coupling and the other at the S3 segment presents high affinity (Km of 0.3 mM) and 2: 1 coupling.[25,26] It was also identified that SGLT2 and SGLT1 meet these transporter features, respectively (Figure 1).[27–29] Recent in vitro studies in cultured human embryonic kidney cells[30] have shown that affinity for D-glucose – one of the two stereoisomers of glucose – is almost similar for SGLT1 and 2 (5 mM for SGLT2 and 2 mM for SGLT1) under normal conditions. According to the same in vitro study that mentioned before,[30] the role of SGLT1 has been upgraded and it is believed that SGLT1 not only re-absorbs glucose that 'escape' SGLT2 reabsorption in S1/2 segment, but is also responsible for a significant part of glucose reabsorption exceeding the50% of the SGLT2 reabsorption.[30]

Figure 1.

A model for Na/glucose transport in the kidney. In the tubular cells of S1 and S3 segment of proximal convoluted tubule, Na/K ATPase pump is a primary active co-transporter and for every three sodium that exports to the interstitium, imports 2 K. The required energy for this transportation is provided by the ATP–ADP transformation. The function of this pump creates the sodium gradient needed for the operation of the secondary active SGLTs co-transporter, which imports both Na and glucose from the tubular lumen into tubular cells. Glucose moves against its electrochemical gradient following Na transportation along its gradient. Intracellular glucose moves to the interstitium through GLUTs passive diffusion transporters, which are located at the basolateral membrane of the tubular cells. Contrary to SGLT1, which is found at the S3 segment and has a stoichiometry of 2Na to 1 glucose, SGLT2 is situated at the S1 segment and has one to one stoichiometry. Both transporters are located on the brush border of tubular cells.[25–29,39] The pharmacological effect of SGLT2 inhibitors on SGLT2 secondary active co-transporters at S1 segment tubular cells is depicted in the figure (grey arrows). Inhibition of SGLT2 blocks filtered glucose from being reabsorbed into the proximal tubule. Excess glucose is excreted into the urine (glucosuria).

Direct experimental in vivo evidence for the role of SGLT2 co-transporter in tubular glucose reabsorption that accrued from the study of Vallon et al. on gene-targeted mice lacking Sglt2, demonstrated that the SGLT2 protein is located at the brush border of the early proximal tubule, it is responsible for all glucose reabsorption at this tubular segment and for the bulk of glucose reabsorption in the kidney overall.[31] According to this study, in wild-type mice (express SGLT2), 99.7 ± 0.1% of fractional glucose is reabsorbed and in Sglt2−/− mice (not express SGLT2), only 36 ± 8% is reabsorbed. From free-flow collections of tubular fluid, it was also estimated that in wild-type mice 78 ± 6% of the filtered glucose was reabsorbed at early proximal tubules and this proportion reached 93 ± 1% at late proximal tubules, whereas in Sglt2−/− mice, no glucose (0.2 ± 6.8%) is reabsorbed at early proximal tubules and only 21 ± 6% at late proximal tubules.[31] Therefore, SGLT2 mediates all glucose reabsorption in early proximal tubule.[31] It was also found that in Sglt2−/− mice, even if SGLT1 glucose reabsorption is increased (SGLT1 transporters reach their transport maximum), up regulation of SGLT1 expression does not occur (both SGLT1 mRNA and protein expression are reduced by ~40%) when the amount of glucose in proximal tubule is increased.[31]

The physiological role of Na+/D-glucose co-transporter SGLT1 in small intestine and kidney was evaluated in vivo by Gorboulev et al.[32] According to this study, in which Sglt1−/− mice were generated and compared with wild-type mice (Sglt1+/+), were presented that only 3% of the filtered glucose is not reabsorbed in Sglt1−/−mice. The results of this study are in correspondence with those of Vallon et al., and it is suggested that wild-type mice do not use the maximal transport capacity of SGLT1 at normoglycemic conditions contrary to conditions that glucose load to the SGLT1 is increased (for instance, diabetes and SGLT2 inhibition) when SGLT1 may operate at full transport capacity.[32,33]

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