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

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. Therapeutic approaches to the treatment of type 2 diabetes mellitus that are designed to increase insulin secretion either directly target beta-cells or indirectly target gastrointestinal enteroendocrine cells (EECs), which release hormones that modulate insulin secretion (for example, incretins). Given that beta-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.

Automated summary

This Review summarizes the physiological functions, pharmacology, and clinical studies of G protein-coupled receptors specific for lipid metabolite ligands and discusses the challenges associated with developing therapeutics for type 2 diabetes mellitus. Currently, therapeutic approaches targeting these receptors focus on increasing insulin secretion either by directly acting on beta-cells or indirectly on gastrointestinal enteroendocrine cells that release hormones regulating insulin secretion.