SGLT2 in the Diabetic Kidney #ExpBio

Empagliflozin (original image https://commons.wikimedia.org/wiki/File:Empagliflozin.png )

Glucose in the glomerular filtrate gets reabsorbed in the proximal tubule by two transporters, known as sodium-glucose cotransporters (SGLT). The bulk of the glucose gets removed by SGLT2 with a smaller amount retrieved farther down the tubule by SGLT1. With normal blood sugar levels, these molecules can reclaim all the filtered load of glucose, leaving none of this sugar in the urine.

In diabetes, glycosuria occurs when blood sugars exceed the limits of SGLTs. Agents have been around for a while that inhibit these transporters, but only recently have inhibitors of SGLT2 been shown to reduce blood glucose in diabetes in clinical settings. Large trials over the past couple of years have shown additional benefits of this class of drug beyond their ability to reduce hyperglycemia. They seem to reduce cardiovascular events and to have beneficial effects on progression of diabetic kidney disease.

Liu Z, Hall E, and Singh P:  SGLT2 inhibition decreases oxygen consumption and increases oxygen tension in diabetic rats

Liu et al present a possible mechanism for these beneficial effects at this meeting. They made rats diabetic with streptozocin (a model of type 1 diabetes, not the condition these drugs are used for clinically) and examined oxygen consumption and tension in their kidneys.

Sodium reabsorption drives metabolic demand for oxygen consumption in the kidney. In addition to allowing glucose to escape, SGLT inhibitors prevent sodium reclamation and reduce this demand. They found that diabetes increased renal oxygen consumption as previously demonstrated and the SGLT inhibitor Empagliflozin (EMPA in figure) prevented this change. Oxygen tension in the renal cortex was reduced by diabetes, with SGLT inhibition once again preventing this change. Medullary oxygen tension was not affected by these states.

Click link to abstract to see other specific data

SGLT inhibitors may have important effects in organs aside from lowering blood glucose. Studies like these may help us understand these interesting new agents, and point toward other therapeutic targets.

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