A Novel Sodium-glucose Cotransporter Type 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

Niren K. Shah, Pharm.D.; Wasim E. Deeb, M.D.; Rushab Choksi, Pharm.D.; Benjamin J. Epstein, Pharm.D.


Pharmacotherapy. 2012;32(1):80-94. 

In This Article

Kidney Sodium-glucose Cotransporters and Glucose Homeostasis

Glucose homeostasis is generally characterized by three processes: glucose absorption through the small intestine, glucose production in the liver, and glucose consumption by tissue.[21] However, it has recently been shown that the kidney also plays a pivotal role in regulating plasma glucose through filtration and reabsorption of glucose.[22–24] Under normal physiologic conditions, the glomeruli filter approximately 180 g/day of glucose. Virtually all of this glucose is reabsorbed in the renal proximal tubule, and only a minimal amount of glucose is lost in urine (<0.5 g/day).[25,26] The reabsorption of glucose is mediated by SGLT type 1 (SGLT1) and SGLT2, which are two highly specialized proteins that traffic glucose in the kidney.[26] These transporters couple the transfer of glucose (against a concentration gradient) and sodium (down a concentration gradient) from the proximal tubule into epithelial cells found on the luminal membrane.[27] Once glucose enters and concentrates within the epithelial cell, facilitative diffusion transporters (GLUTs) found on the basolateral membrane reabsorb glucose into the interstitial fluid (Figure 1).[27]

Figure 1.

Sodium-glucose cotransporter types 1 (SGLT1) and 2 (SGLT2) receptors and epithelial transport of sodium and glucose. The SGLT receptors couple the transport of sodium and glucose across epithelial cells found on the luminal membrane of the renal proximal tubule, allowing for reabsorption of glucose. Inhibiting SGLT2 receptors results in an increase in glucosuria and subsequent reductions in plasma glucose concentrations. K+ = potassium; Na+ = sodium.

The SGLT1 is a high-affinity, low-capacity transporter of glucose (Km=0.4 mM) that plays only a minor role in the kidney. It is predominantly expressed in the late segment (S3) of the renal proximal tubule and is responsible for approximately 10% of glucose that is reabsorbed in the kidney.[28–30] The SGLT1 is largely found in the small intestinal cells, where it actively transports glucose and galactose across the intestinal brush border.[25,31] Patients with SGLT1 genetic mutations often experience glucose and galactose malabsorption, which results in watery diarrhea and dehydration; owing to why selective SGLT1 inhibitors will not likely serve as a therapeutic modality for patients with type 2 diabetes.[32,33]

The SGLT2 is the most salient kidney glucose transporter and is the therapeutic target for agents emerging in this class. Contrary to SGLT1, SGLT2 is a low-affinity, high-capacity transporter of glucose (Km=2 mM) found mainly at the apical domain of epithelial cells in the early segment (S1) of the renal proximal tubule (and to a lesser extent in mammary glands, liver, lung, intestine, skeletal muscle, and spleen).[34–36] Approximately 90% of glucose that is filtered by the glomeruli is reabsorbed at S1 by SGLT2,[37] suggesting that selectively inhibiting the SGLT2 receptor may be a hopeful option to treat hyperglycemia.


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