Targeting orphan G protein‐coupled receptors for the treatment of diabetes and its complications: C‐peptide and GPR146

Abstract G protein‐coupled receptors ( GPCR s) are the most abundant receptor family encoded by the human genome and are the targets of a high percentage of drugs currently in use or in clinical trials for the treatment of diseases such as diabetes and its associated complications. Thus, orphan GPCR s, for which the ligand is unknown, represent an important untapped source of therapeutic potential for the treatment of many diseases. We have identified the previously orphan GPCR , GPR 146, as the putative receptor of proinsulin C‐peptide, which may prove to be an effective treatment for diabetes‐associated complications. For example, we have found a potential role of C‐peptide and GPR 146 in regulating the function of the retinal pigment epithelium, a monolayer of cells in the retina that serves as part of the blood–retinal barrier and is disrupted in diabetic macular oedema. However, C‐peptide signalling in this cell type appears to depend at least in part on extracellular glucose concentration and its interaction with insulin. In this review, we discuss the therapeutic potential of orphan GPCR s with a special focus on C‐peptide and GPR 146, including past and current strategies used to ‘deorphanize’ this diverse family of receptors, past successes and the inherent difficulties of this process.