Sodium-Glucose Cotransport Mechanisms in Renal Physiology

The kidney plays a central role in systemic glucose homeostasis through the coordinated action of sodium-glucose cotransporters located in the proximal tubule. Two main isoforms, SGLT2 and SGLT1, reabsorb the majority of filtered glucose by coupling its uphill transport to the downhill movement of sodium ions. SGLT2, expressed predominantly in the early (S1) segment, exhibits low affinity but high capacity, reclaiming roughly 90 % of the filtered load. SGLT1, localised to the later (S2/S3) segments, operates with high affinity and lower capacity, salvaging residual glucose to prevent glucosuria. The transport cycle follows an alternating-access mechanism, whereby binding of Na+ and glucose stabilises an outward-facing conformation, transitions through an occluded intermediate, and releases substrates intracellularly upon switch to an inward-facing state. Coordinated extrusion of glucose across the basolateral membrane via facilitative uniporters (GLUT2) completes reabsorption. Advances in structural biology and in vivo imaging have elucidated conformational transitions, gating residues and the influence of accessory proteins, thereby informing the design of specific inhibitors. Pharmacological blockade of SGLT2 reduces renal glucose reabsorption, lowers blood glucose in type 2 diabetes and confers nephro- and cardioprotection through mechanisms that extend beyond glycaemic control. Ongoing research addresses long-term safety, off-target effects and the full spectrum of functions served by renal SGLTs, including links to bone metabolism, longevity and neurodegeneration.

Research from Nature Portfolio

Recent studies have resolved high-resolution cryo-EM structures of human SGLT isoforms in multiple transport states. Structures of SGLT1 and SGLT2 in a substrate-bound, occluded conformation reveal how transmembrane helices form a sealed cavity to cage glucose and sodium, clarifying the path of conformational change between outward- and inward-facing states. Complementary analyses of the SGLT2–MAP17 complex bound to phlorizin and synthetic inhibitors demonstrate how Na+ binding at a conserved site stabilises the outward-facing state and how inhibitor moieties occupy the sugar pocket and vestibule, elucidating the molecular basis of subtype selectivity. These insights provide direct evidence for the Na+-coupled alternating-access mechanism and pinpoint residues critical for gating and drug affinity, thereby guiding rational design of next-generation gliflozins with improved efficacy and safety profiles.

Sodium-Glucose Cotransport Mechanisms in Renal Physiology publication trend

The graph below shows the total number of articles in sodium-glucose cotransport mechanisms in renal physiology across all publications each year (not limited to Nature Index journals).

Technical terms

SGLT1: High-affinity, low-capacity sodium-glucose cotransporter in late proximal tubule segments.

SGLT2: Low-affinity, high-capacity sodium-glucose cotransporter in early proximal tubule segments.

Proximal tubule: Initial portion of the nephron responsible for bulk reabsorption of solutes and water.

Cryo-EM: Cryo-electron microscopy, a method for determining high-resolution structures of proteins in near-native states.

Occluded conformation: Intermediate transport state in which both extracellular and intracellular gates are closed around the substrate.

Alternating-access mechanism: Model describing how transporters switch between outward- and inward-facing states to move substrates across membranes.

References

1. Structures of human SGLT in the occluded state reveal conformational changes during sugar transport. Nature Communications (2023).
2. Transport and inhibition mechanism of the human SGLT2–MAP17 glucose transporter. Nature Structural & Molecular Biology (2023).
3. Excretion of glucose analogue with SGLT2 affinity predicts response effectiveness to sodium glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus. European Journal of Nuclear Medicine and Molecular Imaging (2023).
4. Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2. Diabetologia (2018).