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 ß-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.

Glucagon like peptides-1 modulators as newer target for diabetes.

Diabetes mellitus (DM) has been recognized as a growing world-wide epidemic by many health advocacy groups including the World Health Organization (WHO). DM affects about 6% of the North American population. A recent report estimated that 8.2% of adult population worldwide has impaired glucose tolerance. Current treatment approaches include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. New therapies are still needed to control metabolic abnormalities, and also to preserve beta-cell mass and to prevent loss of beta-cell function. In many cases monotherapy gradually fails to improve blood glucose control and combination therapy is employed. The long-term success of these treatments varies substantially. Thus, there is an imperative need for novel therapeutic approaches for glycemic control that can complement existing therapies and possibly attempt to preserve normal physiological response to meal intake. Glucagon-like peptide 1 (GLP-1) is a drug candidate which potentially fulfils these conditions. Glucoregulatory actions of GLP-1 include glucose-dependent enhancement of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying and reduction of food intake. GLP-1 is rapidly inactivated by amino peptidase, Dipeptidyl Peptidase-IV (DPP-IV) and the utility of DPP-IV inhibitors are also under investigation. There is a recent upsurge in the development of GLP-1 mimetics and DPP-IV inhibitors as potential antidiabetic agents. The present review summarizes the concepts of GLP-1 based therapy for type 2 diabetes and the current preclinical and clinical development in GLP-1 modulators.