Chapter 9 New Nonpeptide-Binding GPCRs as Targets for Diabetes and the Metabolic Syndrome

Publisher Summary This chapter describes research aimed at discovering modulators of new nonpeptide-binding G-protein-coupled receptors (GPCRs), considered more druggable than their counterparts possessing peptidic ligands as potential therapies for type 2 diabetes (T2D), obesity, and related metabolic disorders. In particular, it focuses on GPCRs that have been deorphanized for which physiological ligands have been discovered, in the past few years. In human and rodent tissues, GPR119 (previously called GPCR) mRNA is principally localized in the pancreas and gastrointestinal tract. Many areas of the rodent brain also show GPR119 expression—a phenomenon that has not been demonstrated in humans. Within the rodent pancreas, immunofluorescent staining has implicated the islet b-cells as the main site of expression, a premise supported by evidence of GPR119 expression in b-cell derived insulinoma cell lines. The proteins of the GPR40 family, comprising GPR40, GPR41, and GPR43, have attracted attention recently as potential targets for diabetes and the metabolic syndrome due to their function as receptors for plasma-free fatty acids (FFAs) in cell types central to these conditions. The chapter also discusses GPR40 family; GPR120; GPR55 and GPR35; and GPR109A and GPR109B.