The global spread and ever increasing incidence of metabolic

The global spread and ever-increasing incidence of metabolic syndrome over the past few decades has not only categorized it as an ‘epidemic’ but has also dramatically increased the risk of cardiovascular diseases and diabetes. The increase in prevalence of diabetes in the United States alone has been estimated at 24 million and more than 180 million people world wide . As a result, there is concern over the increasing incidence of microvascular and macrovascular complications. Given the relationship of lipid and carbohydrate metabolism abnormalities in type 2 diabetes, obesity and associated cardiovascular diseases, it is imperative to have a range of pharmacological interventions in addition to lifestyle modifications to achieve successful long-term management. The global pharmaceutical sales for diabetes has witnessed an average growth rate of nearly 20% from around US$4 billion in 1995 to over US$17 billion in 2005. Overall, anti-diabetic drug sales are expected to grow dramatically over the next five years to over US$ 22 billion in 2012 to address the unmet needs of ever increasing patient population given the severity of disease and associated co-morbidities . The pharmacological management of type 2 diabetes, obesity, hyperlipidemia and related co-morbidities requires an aggressive and comprehensive approach with early intervention required to delay or even prevent the progression of the disease or the use of combination therapies to reach acceptable glycemic and lipid control during the late stages of the disease. There are various drugs available with different modes of actions, relating to insulin secretion (sulfonylureas, meglitinides, DPP-IV inhibitors; glucagon-like peptide-1 (GLP-1) analogues or mimetic); hepatic glucose production (metformin, thiazolidinediones); peripheral tissue insulin resistance (metformin, thiazolidinediones); inhibition of dietary carbohydrate breakdown (α-glucosidase inhibitors) and reduction of circulating lipid (statins, fibrates), yet there is a need for new pharmacological tools, not dealing solely with reducing blood glucose or lipid but tackling the problem of metabolic syndrome as a whole. In the search for such emerging tools, bile chemokine receptor antagonist receptors have been identified as potential targets and are being explored to address the various aspects of metabolic disorders. Bile acids have long been considered as the products of cholesterol catabolism and viewed as components involved in solubilization of cholesterol, fatty acids and lipophilic vitamins, owing to their detergent-based amphiphatic properties . The historical perspective related to the roles of bile acids in digestion, absorption and transport of dietary lipids underestimated the therapeutic applications of the bile acids. Recent discoveries have ushered a new chapter in the profile of bile acids, recognizing those paracrine and endocrine functions related to the homeostasis of cholesterol, lipid and carbohydrate metabolism and regulation of the immune system . In 1999, an orphan farnesoid X receptor (FXR; also known as NR1H4) was identified as an endogenously expressing bile acid nuclear receptor , . FXR is now recognized as a master regulator of the pleiotropic actions of endogenous bile acids in the regulation of enterohepatic recycling of bile acids and in the feedback regulation of bile acid biosynthesis in the liver and intestine (). Activation of FXR-α protects against the toxic accumulation of bile acids through increased conjugation in the liver, followed by their excretion into bile canaliculi, thereby promoting bile flow , , . Apart from these roles, FXR is also implicated in regulation of lipid metabolism, renal expression of inflammatory cytokines and oxidative stress enzymes ; immune response under certain chronic states ; production of corticosteroids through regulation of 3beta-hydroxysteroid dehydrogenase type 2 in the adrenal cortex and glucose metabolism through regulation of gluconeogenesis and glycogenolysis in the liver , and regulation of peripheral insulin sensitivity in the adipose tissue (). The discovery of FXR was followed by the pregnane X receptor (PXR; also known as NR1I2) and the vitamin D receptor (VDR; also known as NR1I1), which are other bile acid-activated receptors , . The genomic functions of bile acids contributed to activation of these nuclear receptors, however, the non-genomic functions of bile acids in terms of intracellular signaling and functional responses were not established until 2002, when TGR5 (also known as M-BAR or BG37 or GPBAR1)—a metabotropic receptor of the bile acid was discovered () , . The present review highlights the role of TGR5, therapeutic relevance, reasons for increasing therapeutic interest, current developments and the future landscape of the target.