|Topic:||Role of the Kidney in Blood Glucose Control .|
|Details:|| Although the liver is the major site of glucose homeostasis, the kidney plays a vital role in the overall process of regulating the level of blood glucose. The kidney carries out gluconeogenesis primarily using the carbon skeleton of glutamine and while so doing allows for the elimination of waste nitrogen and maintaining plasma pH balance. For the role of the kidneys in gluconeogenesis please visit that section of the Gluconeogenesis page. In addition to carrying out gluconeogenesis, the kidney regulates blood glucose levels via its ability to excrete glucose via glomerular filtration as well as to reabsorb the filtered glucose in the proximal convoluted tubules. In the average adult the kidneys will filter around 180gm of glucose per day. Of this amount less than 1% is excreted in the urine due to efficient reabsorption. This reabsorption process is critical for maintaining blood glucose homeostasis and for retaining important calories for energy production.
Transport of glucose from the tubule into the tubular glomerular epithelial cells is carried out by specialized transport proteins termed sodium-glucose co-transporters (SGLTs). The SGLTs represent a family of transporters that are involved in the transport of glucose, amino acids, vitamins, and ions and other osmolytes across the brush-border (apical) membranes of kidney tubule cells and intestinal epithelial cells. There are two SGLT transporters in the kidney involved in glucose reabsorption. SGLT1 is found primarily in the distal S3 segment of the proximal tubule and SGLT2 is expressed in the S1 and S2 segments (see the Figure below). The location of SGLT2 in the proximal tubule means that it is primarily responsible for glucose reabsorption. SGLT2 is a high-capacity low-affinity transporter that, due to its expression location, is responsible for approximately 90% of the glucose reabsorption activity of the kidney.
As would be expected from the name of the renal glucose transporters, SGLT1 and SGLT2 catalyze the active transport of glucose against a concentration gradient across the lumenal (apical) membrane of the tubule cell and couple this transport to sodium uptake. The inward sodium uptake is maintained by ATP-driven active transport of the sodium across the basolateral membrane into the blood (coupled to inward uptake of potassium) via the activity of the renal Na+,K+-ATPase. The reabsorbed glucose passively diffuses out of the tubule cell into the blood via the basolateral membrane associated GLUT2. Under normal conditions saturation of the ability of SGLT2 to reabsorb glucose is never reached. The kidney can filter and reabsorb approximately 375mg of glucose per minute. The plasma concentration of glucose required to exceed this capacity is well above that considered normal and is only observed in situations of renal dysfunction/disease or most importantly in type 2 diabetes. Because of the importance of SGLT2 in renal reabsorption of glucose this transporter has become the target for therapeutic intervention of the hyperglycemia associated with type 2 diabetes. By specifically inhibiting SGLT2 there will be increased glucose excretion in the urine and thus, a lowering of plasma glucose levels. Several SGLT2-specific inhibitors have recently been approved for use in the treatment of the hyperglycemia of type 2 diabetes. All of the names of the drugs in the SGLT2 inhibitor class have the suffix, -gliflozin. For information on the SGLT2 inhibitors visit the Diabetes page.
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