Montreal Diabetes Research Center, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
Department of Medicine, Université de Montréal, Montréal, QC, Canada.
Nat Rev Endocrinol. 2021 Mar;17(3):162-175. doi: 10.1038/s41574-020-00459-w. Epub 2021 Jan 25.
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.
治疗 2 型糖尿病的方法旨在直接针对β细胞或间接针对胃肠道肠内分泌细胞（EEC）增加胰岛素分泌，EEC 释放调节胰岛素分泌的激素（例如肠促胰岛素）。鉴于β细胞和 EEC 都表达大量调节胰岛素分泌的 G 蛋白偶联受体（GPCR），因此已经进行了大量的研究和开发工作，以设计针对这些 GPCR 的治疗药物。其中包括专门针对游离脂肪酸配体的 GPCR（脂质 GPCR），包括游离脂肪酸受体 1（FFA1，也称为 GPR40）、FFA2（GPR43）、FFA3（GPR41）和 FFA4（GPR120），以及结合葡萄糖依赖性胰岛素分泌受体的脂质代谢物（GPR119）。这些脂质 GPCR 在胰岛和肠道激素分泌的控制中发挥了重要作用。脂质 GPCR 药理学的进展导致了一些合成激动剂的鉴定，这些激动剂在临床前研究中对葡萄糖稳态具有有益的作用。然而，迄今为止，将这些有前途的结果转化为临床应用一直令人失望。在这篇综述中，我们介绍了这些脂质受体的生理学作用、药理学和临床研究，并讨论了它们在治疗 2 型糖尿病的临床开发中所面临的挑战。
