What is the role of SGLT2 protein in 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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SGLT2 is the major contributor to renal glucose reabsorption. SGLT2 is a low-affinity sodium/glucose cotransporter responsible for the bulk of tubular reabsorption of filtered glucose. It is responsible for 80-90% of renal glucose reabsorption. [10] The SGLT2 gene encodes a sodium/glucose cotransporter protein that contains 672 amino acid residues. It is almost exclusively expressed in the luminal brush border of the early proximal tubule (termed S1) of the renal cortex and to a much lower degree in other organs such as the liver, brain, thyroid, muscle, and heart. It shares a 59% homology with SGLT-1 and has 14 putative transmembrane domains. It is localized to chromosome 6.

SGLT1 is a protein comprising 664 amino acid residues and is a high amino acid cotransporter protein that is strongly expressed in the small intestine and, to some extent, in the kidney, near the medullary proximal tubule (termed S3). It has a molecular weight of approximately 73 kDa and 13 transmembrane domains. It is responsible for reabsorption for the bulk of the remaining glucose. Despite the homology between the two, only one mutation is common: Arg137His. The human intestinal SGLT1 has been localized to chromosome 22.

Several other co-transporters in this family include SGLT4, SGLT5, SGLT6, and SMIT1 that are expressed in several tissues, including the kidneys. SGLT3 is a glucose-gated ion channel expressed in cholinergic neurons and the neuromuscular junction and may play a role in diet-trigged intestinal motility.

The facilitative glucose transporters have isoforms GLUT 1-5. GLUT2 is mainly associated with glucose transport in the convoluted portion of the proximal tubule. In segments with high reabsorptive rates (S1 and S2 segments), the carrier is high capacity, low affinity. At birth, a high-affinity, low-capacity pathway is also present to compensate for the reduced activity of the high-capacity, low-affinity pathway.

Glucose reabsorption is age dependent. In premature infants born at less than 30 weeks' gestation, glucosuria is quite common because the filtered load of glucose delivered to the kidney is often too high for the immature nephron to handle. Glucosuria normally occurs when the plasma glucose content is above 300 mg/dL, but some glucose may be seen in the urine at plasma glucose levels as low as 150 mg/dL because the glucose-handling capacity of individual nephrons widely varies. This variability arises from variation in the length of the proximal tubule and differences in glomerular size and location. The bulk of glucose is reabsorbed at the S1 segment by the high-capacity SGLT2 transporter, whereas the remaining glucose that enters the S3 segment is reabsorbed by the high-affinity SGLT1 transporter; together they minimize glucose loss in the urine. [11]

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