Figure 2.

Downstream effects of proximal tubule SGLT1/2 inhibition. Glucose is freely filtered at the glomerulus into the tubular lumen, and normally, all of it is reabsorbed along the apical brush border membrane by the SGLT2 (and SGLT1 to a lesser extent) in the proximal tubule. Inhibition of SGLT2 or dual inhibition of SGLT1/2 establishes a concentration gradient that may drive glucose entry from the peritubular capillaries via the bidirectional GLUT2 transporter. The fate of glucose entering proximal tubule cells via this pathway is not known. SGLT inhibition reduces NHE3 activity and may contribute to increased luminal Na⁺ concentrations. NaCl detected at the macula densa and via tubuloglomerular feedback results in decreased single nephron glomerular filtration rate (SNGFR). Experimental evidence indicates that SGLT2 inhibition may inhibit the diabetes-induced upregulation of renal gluconeogenesis. Increased luminal glucose may facilitate intracellular urate exchange via GLUT9. This promotes uric acid urinary excretion reducing serum levels in diabetes. Diuresis and calorie loss result in reductions in body weight and blood pressure, translating into improved insulin sensitivity and reduced arterial stiffness. Finally, increased urinary excretion of glucose lowers hyperglycaemia and alleviates glucotoxicity on multiple tissue including benefits for insulin secretion.

SGLT: sodium-dependent glucose transporter; GLUT: facilitative glucose transporter; NHE3: sodium hydrogen exchanger-3.