Learning From Glycosuria

Abstract

Plasma glucose is filtered freely through the glomerular barrier. In a 70-kg adult with a glomerular filtration rate of 120 mL · min-1 per 1.73 m2 and an average, around-the-clock plasma glucose concentration of 120 mg/dL (6.7 mmol/L), ∼200 g of glucose are transferred daily from the bloodstream into the preurine. If nothing else happened, the whole-body mass of free glucose (some 20 g in a distribution volume of 250 mL/kg) would be emptied out in less than 3 h. What prevents this catastrophe is, on the one hand, virtually complete glucose reabsorption at the level of the kidney and on the other hand, a precisely matched modulation of endogenous glucose release (chiefly by the liver and possibly also by the kidney itself). The kidney is well engineered to perform coupled glucose and sodium reabsorption. In the S1/S2 segment of the proximal tubule, a member of the sodium glucose transporter (SGLT) family of transmembrane proteins, SGLT-2—encoded in the SLC5 gene—is expressed at high levels and cotransports filtered glucose and sodium into the tubular cell cytoplasm. Downstream to the S1/S2 segment along the S3 segment of the proximal tubule, another SGLT isoform—SGLT-1, abundantly expressed in the enterocyte—also performs coupled sodium-glucose cotransport. At the basolateral membrane of the tubular cell, a glucose transporter of a different family, GLUT-2, affects the transfer of intracellular glucose to the interstitium by a facilitated transport process (via Na+-K+-ATPase). Recent detailed physiological studies (1) in human embryonic kidney (HEK293T) cells coexpressing human SGLT-2 and SGLT-1 have established that, contrary to a long held belief (2, …