Therapeutic approaches to Type 2 diabetes mellitus

Diabetes is a significant healthcare problem worldwide and its incidence is rising. Type 2 diabetes patients are at significant risk of developing add itional major diseases, especially obesity, hypertension, and dyslipidaemia . All of these conditions are associated with adverse cardiovascular events including myocardial infarction, stroke, and death. Current research is fo cused on several distinct classes of pharmacological targets in an effort t o identify effective therapies for diabetes. Recently, several antidiabetic agents have been identified that promote anabolism, such as agonists for p eroxisome proliferator activated receptor gamma (PPAR gamma) and retinoid X receptor (RXR). PPAR gamma and RXR are ligand activated transcription fact ors that form a heterodimeric complex that mediates fat cell differentiatio n and expression of genes involved in lipid and carbohydrate metabolism. PP AR gamma and RXR agonists, such as the thiazolidinediones (TZDs) and rexino ids, respectively, improve insulin sensitivity and increase repartitioning of sugars and lipids from serum into peripheral tissues. In addition, molec ular targets affecting catabolism, such as pg-adrenoceptors (beta(3)-ARs) a nd uncoupling proteins (UCPs), are being evaluated for treating Type 2 diab etes and obesity. Agents that increase UCP and beta(3)-AR activity increase thermogenesis and metabolic rate, which may result in decreased fat and ca rbohydrate storage. Since diabetes results from a wide variety of clinical and metabolic problems arising from multiple cellular defects, it is likely that a combination of these pharmacological approaches will be required to treat the disease. Specifically, a combination of anabolic and catabolic a gents that promote fat and carbohydrate utilisation in peripheral tissues ( i.e., fat and muscle) may provide the greatest benefit for treating patient s with diabetes.