Exploring Newer Target Sodium Glucose Transporter 2 for the Treatment of Diabetes Mellitus

Diabetes mellitus is an independent risk factor for the development of coronary artery disease, myocardial infarction, hypertension, and dyslipidemia. The treatment of diabetes has been mainly focused on maintaining normal blood glucose concentrations. Insulin and hypoglycemic agents have been used as standard therapeutic strategies. However, these are characterized by limited efficacy and adverse side effects, making the development of new therapeutic alternatives mandatory. Inhibition of glucose reabsorption in the kidney, mediated by Sodium Glucose Transporters (SGLT's), represents a promising therapeutic approach. The high-affinity sodium glucose cotransporter (SGLT1) is expressed to some extent in the kidney and contributes to glucose reabsorption, However Genetic mutations in the SGLT1 gene leading to a functional defect are responsible for glucose/galactose malabsorption. The low-affinity sodium glucose cotransporter (SGLT2), which is expressed specifically in the kidney, plays a major role in renal glucose reabsorption in the proximal tubule. We focused on SGLT2 as a molecular target for this review because it plays a major role in renal glucose reabsorption, and its tissue distribution is limited in the kidney to reduce the likelihood for mechanism-based side effects. Phlorizin, a natural phenolic O-glucoside has been known to induce glucosuria for more than 100 years. As it is not a specific SGLT inhibitor, later on o-glucoside is replaced by c-glycoside as it is resistant to hydrolysis by beta-glucosidases. The present review summarizes the concept of SGLT2 selective target based therapy for diabetes mellitus and the current clinical and preclinical development of SGLT2 inhibitors.