Inhibition of Renal Glucose Reabsorption as a Novel Strategy for Treatment of DiabetesBack to list
The etiology of type 2 diabetes mellitus (T2DM) is multifactorial and is characterized by the presence of both insulin deficiency and/or insulin resistance.1 The pathophysiological background causes the chronic elevation of glycemia, promoting glucotoxicity,2 which per se increases insulin resistance and impairs β cell function, thus triggering a vicious cycle leading to hyperglycemia; chronic hyperglycemia may cause damage to large and small blood vessels and peripheral nerves, potentially leading to heart attack, stroke, blindness, and kidney failure.3
Even though the kidney has been considered a victim of hyperglycemia rather than a target for therapeutic intervention, this organ is principally involved in the regulation of glucose homeostasis through gluconeogenesis and, above all, reabsorption of glucose from the glomerular filtrate. In presence of euglycemia, all the daily filtered glucose (180 g) is reabsorbed by Sodium-GLucose co-Transporters type 2 (SGLT-2), expressed in the brush-border membrane of the proximal renal tubules. These transporters mediate the majority of renal glucose reabsorption from the tubular fluid; when plasma glucose concentration exceeds the potential maximal activity of these transporters, glucose appears in the urine. The SGLT-2 inhibitors reduce SGLT-2 activity and block glucose reabsorption, thus glucose is massively lost with urines and plasma glucose lowers. Since antidiabetic therapeutic weapons presently available do not guarantee a longstanding normoglycemic profile and a combination of different drugs is routinely required to maintain glycemia under acceptable levels, competitive inhibition of SGLT-2 may become a unique mechanism to potentially lower the blood glucose levels in patients with diabetes, avoiding the risk of hypoglycemia and preventing the deleterious effect of hyperglycemia (glucose toxicity and glycemic variability). This review summarizes the functions and the physiology of renal glucose transporters and lastly describes the clinical pharmacology and safety of the SGLT-2 inhibitors, outlining that SGLT-2 inhibitors may represent a novel and safe treatment option for diabetes.
Type 2 diabetes mellitus treatment, renal glucose reabsorption, glucosuria, glucose toxicity, glucotoxicity, glucose variability, SGLT-2, SGLT-2 inhibitor, sergliflozin, remogliflozin, dapagliflozin, canagliflozin
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