What is the pathophysiology of renal glucosuria?

Updated: Dec 10, 2018
  • Author: Rajendra Bhimma, MBChB, MD, PhD, DCH (SA), FCP(Paeds)(SA), MMed(Natal); Chief Editor: Craig B Langman, MD  more...
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Answer

Two means of glucose transport are noted: facilitative and secondary active transport. Facilitative transport occurs in essentially all cell types and is driven by the concentration gradient across cellular membranes. This form of glucose transport is predominantly mediated by members of the GLUT transporter family. Secondary active transport occurs in the intestine and the kidney tubules (predominantly proximal tubule) and is mediated by members of the SGLT transporter family. GLUTs are encoded by the SLC2 genes, and the SGLTs are encoded by the SLC5 genes.

Reabsorption of glucose predominantly occurs on the brush border membrane of the convoluted segment of the proximal tubule. Glucose enters at the luminal side of the proximal tubular cells by an active carrier-mediated transport process that requires energy provided by the sodium gradient between the intra- and extracellular compartments generated by sodium-potassium ATPase. Glucose enters the cell along with sodium, and sodium exits the cell at the basolateral side of the cell, which is sodium-independent and a facilitative transport requiring no energy.

There are two different families of glucose transporters expressed in the proximal tubule:

(i) The apical transporters are SGLT-1 (type 1) and SGLT-2. These transporters require energy and are sodium dependent.

(ii) The glucose carriers expressed in the basolateral domain are GULT-1 and GLUT-2 that do not require energy, sodium, or any other ion.

In the initial proximal tubule (termed S1), only SGLT-2 and GLUT-2 are expressed, whilst SGLT-1 and GLUT-1 are expressed in the distal medullary part of the proximal tubule (termed S3). The affinity of SGLT-2 is less than that for SGLT-1.  SGLT2 is a low-affinity, high-capacity glucose transporter.  It carries only one molecule of glucose whilst SGLT1 is a high-affinity, low capacity glucose transporter and carries two molecules of glucose. These transporters initially bind sodium, before binding glucose, and the electrochemical sodium gradient generated by the Na+/K+-ATPase is the driving force for the symporter activity. Under normal conditions the expression of these transporters does not vary and thus the capacity of the kidneys to reabsorb glucose is constant. Also, there are no hormones that impact on these transporters.

SGLT1 and SGLT2 are members of the SLC5A gene family (also known as the sodium substrate symporter gene family [SSSF]). Twelve of these have been identified in the human genome, which has over 230 members; several of these (including SGLT1 and SGLT2) are associated with sodium glucose transport. SGLT members are multifunctional membrane-bound proteins. Apart from glucose, they also are involved in sodium-coupled transport of other sugars, monocarboxylates, amino acids, vitamins, ions, and osmolytes. They also exhibit sodium uniporter activity, channels for urea and water, glucose sensing, and tumor suppression. [9]

In addition to causing glycosuria, a defect of glucose reabsorption also affects the absorption of water and ions. A decrease in glucose reabsorption is associated with a loss of about 70% of water filtered at the glomerulus. As calcium reabsorption in the proximal tubule follows water reabsorption, glycosuria is generally associated with increased calcium excretion.


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