Targeting lipid GPCRs to treat type 2 diabetes mellitus — progress and challenges

Therapeutic approaches to the treatment of type 2 diabetes mellitus that are designed to increase insulin secretion either directly target β-cells or indirectly target gastrointestinal enteroendocrine cells (EECs), which release hormones that modulate insulin secretion (for example, incretins). Given that β-cells and EECs both express a large array of G protein-coupled receptors (GPCRs) that modulate insulin secretion, considerable research and development efforts have been undertaken to design therapeutic drugs targeting these GPCRs. Among them are GPCRs specific for free fatty acid ligands (lipid GPCRs), including free fatty acid receptor 1 (FFA1, otherwise known as GPR40), FFA2 (GPR43), FFA3 (GPR41) and FFA4 (GPR120), as well as the lipid metabolite binding glucose-dependent insulinotropic receptor (GPR119). These lipid GPCRs have demonstrated important roles in the control of islet and gut hormone secretion. Advances in lipid GPCR pharmacology have led to the identification of a number of synthetic agonists that exert beneficial effects on glucose homeostasis in preclinical studies. Yet, translation of these promising results to the clinic has so far been disappointing. In this Review, we present the physiological roles, pharmacology and clinical studies of these lipid receptors and discuss the challenges associated with their clinical development for the treatment of type 2 diabetes mellitus. This Review summarizes the physiological functions, pharmacology and clinical studies of G protein-coupled receptors that are specific for lipid metabolite ligands. The challenges associated with the clinical development of therapeutics for type 2 diabetes mellitus that target these G protein-coupled receptors are also discussed. Key points Enteroendocrine and islet hormone secretion is regulated by diverse stimuli acting via G protein-coupled receptors (GPCRs). The free fatty acid-specific GPCRs, free fatty acid receptor 1 (FFA1, also known as GPR40), FFA2 (GPR43), FFA3 (GPR41) and FFA4 (GPR120) and the lipid metabolite-specific GPCR glucose-dependent insulinotropic receptor (GPR119) are critical regulators of islet and gut hormone secretion. Advances in lipid GPCR pharmacology have led to the identification of synthetic agonists that show promising effects in the control of glucose homeostasis in preclinical studies. Challenges remain for successful clinical application of lipid GPCR agonists for the treatment of type 2 diabetes mellitus.