The kidney is one of important players regulating the homeostasis of glucose and carbohydrates. One of the involved mechanisms is glucose excretion and reabsorption, mediated by sodium-glucose cotransporters, mainly type 2 (SGLT2), located in the S1 segment of the proximal tubule. This transporter is encoded by SLC5 (specifically SCL5A2) gene (1). It is characterized by high capacity, but low affinity for glucose, and is responsible for about 90% of the reabsorption of glucose from the tubuli (2, 3) (the remaining 10% of glucose is in the physiological conditions reabsorbed by type 1 transporter, SGLT1, located in the S2/S3 segment of proximal tubule (4). The molar ratio of transferred glucose to transferred to sodium is 1:1 for the SGLT2 transporter (1:2 for SGLT1) (2, 5). Sodium-glucose transporter type 2 is sodium-dependent, one-way co-transporter, expressed on the luminal side of the nephron proximal tubule cells (5, 6). It is responsible for active glucose transport from the lumen of renal proximal tubule to renal epithelial cells, against the concentration gradient. Transported to epithelial cells glucose produces gradient between the cell and interstitial fluid, which is then used by GLUT transporters (7, 8).

SGLT2 inhibitors are structurally similar to fenyloglukozide called phlorizin, a non-selective blocker that blocks both type 1 and 2 receptor (9). There is evidence that it acts on SGLT in a double manner: by carbohydrate group and by sugar-free part of the aromatic ring. It seems that glucose-free parts of of SGLT proteins, having a polar structures located on a large transmembranous loop, with the help of which they can interact with glucose-free parts of the inhibitors, play a key role in the mechanism of blocking. On this basis phlorizine binds to nonspecific hydrophobic pocket formed in the last part of the loop (9-11). It should be noted that the SGLT 2 is a protein composed of 672 amino acids which form fourteen transmembranous segments arranged in loops (12, 13).

All SGLT2 inhibitors are administered orally. Pharmacokinetical parameters such as rate of absorption, time to maximal serum concentration after exposure, time of dissociation from the receptor are different in different drugs of the class. For example, dapagliflozine and ipragliflozine are rapidly absorbed. Peak serum dapagliflozine concentration is achieved after about 1 hour of exposure (12). Ipragliflozin is similarly absorbed and its half-time is about 12 hours (13, 14). The relationship between the dose, plasma concentration and time is linear. Ipragliflozine has several inactive metabolites, called M1, M2, M3, M4 and M6, the main metabolite is M2 (13). Seragliflozine is rapidly absorbed and also rapidly metabolized, maximum concentration is achieved after 30-45 minutes after exposure. The half-life is approximately 0.5 hours to 1 hour (15). Pharmacokinetic of canagliflozine is dose dependent, but much longer than in case of previously mentiod SGLT2 inhibitors. The half-life is approximately 12-15 hours, and time peak concentration after exposure is achieved after similar time (16).

It has been proven that patients with type 2 diabetes have a higher expression of SGLT2 receptors compared to healthy subjects (11, 17, 18). Blocking of these transporters leads to increased urinary excretion of glucose and reduction of both fasting and postprandial plasma glucose concentration. It is estimated that SGLT2 inhibitors may block the reabsorption of glucose at about 60%. Therefore, these compounds may be used in the treatment of diabetes-especially type 2 diabetes mellitus. Indeed, dapagliflozine is the first drug of the calss which is accepted by European Medicine Agency and may be marketed in the European Union.

SGLT2 inhibitors reduce blood glucose not influencing insulin levels, however they may also improve insulin sensitivity and reduce gluconeogenesis in the liver (18). They seem not only to improve glucose control (percentage of glycated hemoglobin, fasting and postprandial plasma glucose) but also body weight as well systolic blood pressure (18). The two latter effects seem to be dependent on the diuretic effect of these medications. This effect, in turn, is probably dependent on the osmotic effect exerted by glucosuria, however it may also result from natriuresis. Sodium excretion occurs in the last parts of nephrons as a rebound after the sodium reabsorption in the proximal parts. There is no evidence up to date that SGLT2 inhibitors may increase natriuresis directly (17, 18).