Role of SGLTs and GLUTs in glucose metabolism

Transepithelial glucose transport

• transepithelial glucose transport involves the two classes of glucose transporters
  • sodium-glucose cotransporters (SGLTs) and facilitative diffusion glucose transporters (GLUTs)
    • renal glucose reabsorption occurs mainly in the S1 segment of the proximal tubule by the coordinated action of the SGLT2 and GLUT2 located in the luminal and basolateral membranes, respectively
    • only a small and residual amount of glucose is reabsorbed in the S3 segment, where SGLT1 is present in the luminal membrane, co-expressed with GLUT1 in the basolateral membrane
    • intestinal glucose absorption occurs mostly in the duodenum and in the initial portion of the jejunum, and involves the co-expression of SGLT1 and GLUT2
      • in all these processes, SGLTs present in the luminal membrane transport glucose from the lumen into the intracellular medium, where glucose accumulates generating a gradient that favors its transport through the GLUTs in the basolateral membrane, from the cytoplasm to the interstitium
        
        
• first step in the reabsorption of urine glucose involves the transport of glucose from the tubules to peritubular capillaries via tubular epithelial cells
  • accomplished with the family of sodium-glucose cotransporters (SGLT)
    • SGLTs include a variety of membrane proteins that act on the transport of glucose, amino acids, vitamins, ions and osmolytes across the brush border membrane of the renal proximal tubules and the intestinal epithelium
    • SGLTs constitute a large family of membrane proteins involved in the transport of glucose, amino acids, vitamins, osmolytes, and some ions across the brush border membrane of the small intestine epithelium and the renal proximal tubules
      • although 6 isoforms of Na+/glucose cotransporters have been described, the SGLT1 and SGLT2 proteins, encoded by the solute carrier genes SLC5A1 and SLC5A2, respectively, are believed to be the most important ones and have been extensively explored in studies focusing on glucose fluxes under both physiological and pathological conditions
        
        
    • SGLT1 is a low capacity and high affinity carrier
      • SGLT1 is a 75-kDa membrane protein with an Na+/glucose stoichiometry of 2:1 - two sodium ions are transported for each molecule of glucose.
      • SGLT1 protein, encoded by the SLC5A1 gene
        • found mainly in the gastrointestinal tract, but can also be found in the S3 segment of the renal proximal tubule
          • is located mainly in the intestine, but has also been detected in the kidney, parotid and submandibular salivary glands as well as in the heart
            • has high affinity for glucose, but low capacity of transporting it, and is specifically inhibited by phlorizin
            • cotransporter affinity is the same for glucose and galactose
      • although SGLT1 is the key transporter for glucose absorption in the gastrointestinal tract, its impact on the kidney is less important; representing about 10% of glucose reabsorption
        • been of some pharmacological interest because blocking this transporter theoretically reduces the gastrointestinal absorption of glucose and may provide a method for inducing weight loss or reducing postprandial hyperglycaemia
          
          
    • SGLT2 transporter has a high capacity and low affinity, and is found mainly in the kidney
      • differently from SGLT1, SGLT2 is a low-affinity and high-capacity glucose transporter, which transports 1 Na+ ion for each glucose molecule
      • SGLT2 encoding gene (SLC5A2) is predominantly expressed in kidneys, but low mRNA expression has also been demonstrated in mammary glands, liver, lungs, intestine, skeletal muscle, and spleen
      • most prevalent and functionally most important transporter in the kidney is SGLT2
        • responsible for 90% of glucose reabsorption in the kidney, and has become the subject of much interest in the diabetes field
        • transporter is found in a relatively high proportion in the initial segment of the proximal tubule
          • SGLT2 transports glucose by using the energy gradient of sodium reabsorption in the tubular filtration
            • process is called secondary active transport and is driven by the electrochemical gradient of sodium in the tubular filtration.
              
              
    • SGLT3, is widely found in skeletal muscle and the nervous system
      • not believed to be a glucose transporter, but acts as a sensor
      • encoded by the SLC5A4 gene, is considered to be a glucose-gated ion channel, expressed in the intestine, spleen, liver, kidneys, skeletal muscle, and cholinergic neurons

Reference:

• Butterfield WJH, Keen H, Whichelow MJ. Renal glucose threshold variations with age. BMJ 1967;4:505-7.
• Mogensen CE. Maximum tubular reabsorpiton capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scan J Clin Lab Invest 1971;28:101-9.
• Kamran M, Peterson RG, Dominguez JH. Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats. J Am Soc Nephol 1997;8:943-8.
• Wright EM. Renal Na-glucose transporters. Am J Physiol Renal Physiol 2001;280:F10-F18.