SGLTs

Sodium-glucose cotransporters (SGLTs) are a family of membrane proteins that mediate the sodium-dependent uptake of glucose across epithelial cells. The most studied members are SGLT1 and SGLT2. SGLT1 is primarily expressed on the brush border of the small-intestinal epithelium and in the late proximal tubule of the kidney, where it reabsorbs glucose from filtered urine. SGLT2 is located mainly in the early proximal tubule (S1/S2 segments) and accounts for the majority of glucose reabsorption in the kidney.

Mechanism: SGLTs co-transport glucose with sodium using the inward sodium gradient established by Na+/K+ ATPase. Glucose is then released into the bloodstream via basolateral transporters. In the kidney, SGLT2 reabsorbs about 90% of filtered glucose; SGLT1 reabsorbs most of the remaining glucose along the later proximal tubule, providing redundancy to limit glucosuria.

Clinical relevance: SGLT2 inhibitors (gliflozins) such as canagliflozin, dapagliflozin, and empagliflozin reduce plasma glucose by promoting urinary glucose excretion. Beyond glycemic control, they have demonstrated nephroprotective and cardioprotective effects and are used in heart failure and chronic kidney disease, sometimes in patients without diabetes. Potential adverse effects include genital and urinary tract infections, dehydration, ketoacidosis, and rare kidney injury, with reduced efficacy in advanced kidney disease.

Genetic and research notes: Genetic defects of SGLTs illustrate their physiological importance: SGLT1 deficiency causes glucose-galactose malabsorption, while SGLT2 dysfunction is associated with mild glucosuria. Research continues into broader SGLT-targeted therapies, including dual SGLT1/2 inhibitors and tissue-specific approaches.