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mechanism of glycosuria

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Glucose transporters in the kidney:

Glucose is the main source of energy in eukaryotes and the main fuel providing energy for regular metabolic activity in humans

  • as a polar molecule, glucose is not soluble in the plasma membrane and must be transported across it by carrier proteins, named glucose transporters
  • glucose transporters are divided into two families:
        • the facilitative diffusion glucose transporters (GLUTs)
        • (SGLTs)
      • both GLUTs and SGLTs belong to one of the 43 families of solute carrier genes (SLC1-SLC43)

    • glucose transporters play an essential role in the maintenance of euglycemia, not only by determining glucose uptake in all cellular types, but also by releasing glucose from the liver when circulating glucose levels decrease

      • also these transporters are responsible for absorbing glucose from the diet in the intestine, and for reabsorbing the glucose from the glomerular filtrate in kidneys

    • transepithelial glucose transport in cells from the small intestine, the renal proximal tubules and salivary gland ducts occurs by the coordinate action of
      • SGLTs allowing glucose influx through the luminal membrane,
      • and GLUTs allowing glucose efflux through the basolateral membrane

Filtration and the reabsorption of glucose in the kidney

    • for a healthy adult, approximately 180g of glucose is filtered by the glomerulus every day
      • under normal circumstances, almost all of this glucose is reabsorbed with less than 1% being excreted in the urine

      • glucose reabsorption in the tubules is a multi-step process involving several transport mechanisms
        • glucose is filtered through the tubule and then transported via the tubular epithelial cells through the basolateral membrane into the peritubular capillary. Under optimal conditions, when tubular glucose load is approximately 120mg/min or less, there is no glucose loss in urine
          • however, when the glucose load exceeds approximately 220mg/min (glucose threshold), glucose starts to appear in the urine

        • blood glucose level required to provide such a tubular load covers a range of values in humans. A study of this process reported that the blood glucose concentration required to exceed the tubular glucose threshold ranged between 130 and 300mg/dl (1)
          • in addition, the study found a relationship between age and increased threshold levels
          • approximately 90% of filtered glucose is reabsorbed by the high absorption capacity of 2 sodium-glucose cotransporter (SGLT2) transporter in the convoluted segment of the proximal tubule, and the approximately 10% of filtered glucose is reabsorbed by the SGLT1 transporter in the straight segment of the descending proximal tubule
            • as a result, no glucose appears in the urine

          • the maximum renal capacity for tubular reabsorption (Tm) of glucose is greater in animal models with type 1 and type 2 diabetes
            • in people with type 1 diabetes, Mogensen et al. showed that the glucose Tm is increased. Conflicting results have been reported in patients with type 2 diabetes
            • clinically, the most common cause of glycosuria is diabetes
              • patients do not excrete glucose in the urine until the concentration of blood glucose is over 180mg/dl, which does not normally occur in people without diabetes (3)
  • transepithelial glucose transport involves the two classes of glucose transporters, 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

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.

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