Fig. 1.

Key sites of action of sodium-glucose co-transporter (SGLT) inhibitors. SGLT2 (encoded by the solute carrier gene slc5a2) is expressed almost entirely in the luminal membrane of epithelial cells lining the first and second segments of the proximal tubules. It is a high capacity co-transporter acting with a sodium-glucose stoichiometry of 1:1 to mediate the reabsorption of most of the filtered glucose. SGLT1 (encoded by slc5a1) is expressed in the luminal membrane of cells lining the third (straight) segment of the proximal tubules. It acts with a sodium-glucose stoichiometry of 2:1 and has a lower capacity but higher affinity than SGLT2 to retrieve low concentrations of glucose remaining in the tubule. SGLT1 is expressed widely and occurs most abundantly in the apical membranes of enterocytes in the small intestine where it mediates glucose uptake from the intestinal lumen. Both transporters are secondary active symporters that depend on the sodium gradient created by Na + -K + -ATPase pumps in the basolateral membranes which lower the intracellular sodium concentration. Glucose that is taken up by sodium-glucose co-transporters into proximal tubule cells and enterocytes is eliminated across the basolateral membranes and into the interstitium via facilitative glucose transporters (e.g. GLUT1 and GLUT2)