Nature Reviews:靶向脂质GPCR治疗2型糖尿病(综述)
  • 多种刺激作用通过GPCR调节肠内分泌和胰岛激素分泌;
  • 脂质GPCR包括游离脂肪酸受体1 (FFA1,也称GPR40)、FFA2 (GPR43)、FFA3 (GPR41)和FFA4 (GPR120)及脂代谢特异性葡萄糖依赖性促胰岛素受体(GPR119),是胰岛和肠道激素分泌的重要调节因子;
  • 许多脂质GPCR激动剂已在临床前研究中显示出对糖稳态的调控作用;
  • 但脂质GPCR激动剂在临床治疗2型糖尿病是否能得到成功应用仍然面临挑战。
β-细胞及胃肠道内分泌细胞均表达多种G蛋白偶联受体(GPCR)以调节胰岛素分泌,靶向这些GPCR是开发2型糖尿病治疗药物的策略之一。Nature Reviews Endocrinology上发表的一篇综述文章,详细介绍了游离脂肪酸特异性GPCR(即脂质GPCR)的表达分布、生理功能、信号通路及天然配体,并概述了靶向这些GPCR的脂质GPCR激动剂的临床前及临床研发的情况。

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



01-25, Review

Abstract & Authors:展开

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.

First Authors:
Julien Ghislain

Correspondence Authors:
Vincent Poitout

All Authors:
Julien Ghislain,Vincent Poitout