Although it has long been recognized that the kidneys play a significant role in glucose balance, they have only recently been considered a potential target for type 2 diabetes (T2DM) therapy. The kidneys contribute approximately 20% of the glucose released into the circulation of a normal individual after fasting overnight.[1,2] Normally, the kidneys reabsorb essentially all the approximately 180 g of glucose that it filters daily. Reabsorption occurs in the proximal convoluted tubule (PCT) by two isoforms of the sodium-glucose-transporter (SGLT; Figure 1).[4,5] SGLT2 reclaims approximately 90% of filtered glucose. This carrier has a high capacity, but low affinity, for glucose transport, and is located in the S1 and S2 segments of the PCT (Figure 2). SGLT1 reabsorbs the remainder.
Renal glucose handling. In healthy individuals, the vast majority of the glucose filtered by the kidney is reabsorbed by SGLT2 in the S1/S2 segments of the proximal convoluted tubule and the remaining glucose is reabsorbed by SGLT1 in the S3 segment.
SGLT2 mediates glucose reabsorption in the kidney. SGLT2 catalyzes the active transport of glucose (against a concentration gradient) across the luminal membrane by coupling it with the downhill transport of Na+. The inward Na+ gradient across the luminal epithelium is maintained by active extrusion of Na+ across the basolateral surface into the blood. Glucose diffuses out of the cell down a concentration gradient via the basolateral facilitative transporter GLUT2.
Adapted from Wright et al. 2011.4
Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of agents that lower plasma glucose by blocking renal glucose reabsorption, as well as increase the renal threshold for glucose excretion. Inducing glucosuria (glucose in the urine) is a seemingly counterintuitive approach for treatment, since it employs what has long been regarded solely as a marker of uncontrolled diabetes. This unique mechanism of action is independent of insulin secretion or action. Consequently, hypoglycemia would not be expected to be a significant side effect. As glucosuria results in loss of calories, weight loss should also result. This Update will focus mainly on canagliflozin (INVOKANA), the first SGLT2 inhibitor approved by the FDA.
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