Cotransporter2

Cotransporter2, most commonly known as sodium-glucose cotransporter 2 (SGLT2), is a membrane transporter in the renal proximal tubule that mediates the sodium-dependent reabsorption of glucose from the filtrate. It belongs to the solute carrier family SLC5 and is encoded by the SLC5A2 gene. SGLT2 plays a key role in reclaiming glucose from urine and helping regulate blood glucose levels.

Mechanism and location: SGLT2 is situated on the apical (luminal) membrane of proximal tubule cells, mainly in the S1 and S2 segments. It uses the inward sodium gradient established by the Na+/K+-ATPase on the basolateral side to cotransport one sodium ion with one glucose molecule from the tubular lumen into the cell. Glucose then exits basolaterally through facilitated transporters such as GLUT2. SGLT2 has high capacity but relatively low affinity for glucose and accounts for about 90% of filtered glucose reabsorption, with SGLT1 in the later segment reclaiming the remainder.

Physiological role and regulation: By reabsorbing most filtered glucose, SGLT2 helps prevent glucose loss in urine and contributes to overall energy balance. Its activity can be influenced by metabolic states and disease processes that alter proximal tubule function.

Clinical significance: Inhibitors of SGLT2 (SGLT2 inhibitors or gliflozins) reduce renal glucose reabsorption, promoting glucosuria and lowering blood glucose in type 2 diabetes. They have demonstrated cardiovascular and renal benefits beyond glycemic control. Common adverse effects include genital infections, urinary tract infections, volume depletion, and, less frequently, ketoacidosis. Examples include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.

History: The concept originated from phlorizin studies, with the development of selective SGLT2 inhibitors emerging in the 2010s to treat diabetes and related conditions.