Sodium-glucose cotransporters: Functional properties and pharmaceutical potential

Abstract

Glucose is the most abundant monosaccharide, and an essential source of energy for most living cells. Glucose transport across the cell membrane is mediated by two types of transporters: facilitative glucose transporters (gene name: solute carrier 2A) and sodium-glucose cotransporters (SGLTs; gene name: solute carrier 5A). Each transporter has its own substrate specificity, distribution, and regulatory mechanisms. Recently, SGLT1 and SGLT2 have attracted much attention as therapeutic targets for various diseases. This review addresses the basal and functional properties of glucose transporters and SGLTs, and describes the pharmaceutical potential of SGLT1 and SGLT2.

Keywords: Antidiabetic drugs; Sodium-glucose cotransporter 1; Sodium-glucose cotransporter 2.

Figure 1

Glucose handling through sodium–glucose cotransporter (SGLT)1 and SGLT2. In the small intestine, dietary glucose is mainly absorbed by SGLT1 on the brush border membrane. SGLT1 has a high‐affinity (Michaelis–Menten constant [K _m] = 0.4 mmol/L) for glucose, and transports sodium and glucose with a 2:1 stoichiometry. In the kidney, filtered glucose by the renal glomerulus is reabsorbed by SGLT2 and SGLT1 expressed in the luminal membrane of the segment (S)1 and S2 segments, and S3 segment of proximal tubules, respectively. The affinity of SGLT2 for glucose is lower (K _m = 2 mmol/L), and transport of sodium and glucose by SGLT2 occurs with a 1:1 stoichiometry. GLUT, glucose transporter.

Figure 2

Capacity of sodium–glucose cotransporter (SGLT)1 and SGLT2 for filtered glucose reabsorption under euglycemic conditions. Under euglycemic conditions, most filtered glucose is reabsorbed by SGLT2 expressed in the segment (S)1 and S2 segments of proximal tubules, and the remaining is reabsorbed by SGLT1 expressed in the S3 segment of proximal tubules, resulting in no glucose being detected in the urine. Complete suppression of transport activity of SGLT1 (e.g., SGLT1 knockout [KO] or inhibition) only slightly increases the urinary glucose excretion, because most filtered glucose is reabsorbed by SGLT2. If SGLT2 is absent (e.g., SGLT2 KO or inhibition), SGLT1 reabsorbs 40–50% of filtered glucose. If both SGLT1 and SGLT2 are absent (e.g., SGLT1/2 double KO [DKO] or dual inhibition), almost all of the filtered glucose is excreted in the u‐rine.