Ghislain Julien, Poitout Vincent
Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.
CRCHUM, University of Montreal, 900 rue St Denis, Montreal, QC, Canada, H2X 0A9.
Handb Exp Pharmacol. 2017;236:159-180. doi: 10.1007/164_2016_51.
Of the 415 million people suffering from diabetes worldwide, 90% have type 2 diabetes. Type 2 diabetes is characterized by hyperglycemia and occurs in obese individuals as a result of insulin resistance and inadequate insulin levels. Accordingly, diabetes drugs are tailored to enhance glucose disposal or target the pancreatic islet β cell to increase insulin secretion. The majority of the present-day insulin secretagogues, however, increase the risk of iatrogenic hypoglycemia, and hence alternatives are actively sought. The long-chain fatty acid, G protein-coupled receptor FFA1/Gpr40, is expressed in β cells, and its activation potentiates insulin secretion in a glucose-dependent manner. Preclinical data indicate that FFA1 agonism is an effective treatment to restore glucose homeostasis in rodent models of diabetes. This initial success prompted clinical trials in type 2 diabetes patients, the results of which were promising; however, the field suffered a significant setback when the lead compound TAK-875/fasiglifam was withdrawn from clinical development due to liver safety concerns. Nevertheless, recent developments have brought to light a surprising complexity of FFA1 agonist action, signaling diversity, and biological outcomes, raising hopes that with a greater understanding of the mechanisms at play the second round will be more successful.
全球4.15亿糖尿病患者中，90%患有2型糖尿病。2型糖尿病的特征是高血糖，发生在肥胖个体中，是胰岛素抵抗和胰岛素水平不足的结果。因此，糖尿病药物旨在增强葡萄糖代谢或靶向胰岛β细胞以增加胰岛素分泌。然而，目前大多数胰岛素促分泌剂会增加医源性低血糖的风险，因此人们正在积极寻找替代药物。长链脂肪酸G蛋白偶联受体FFA1/Gpr40在β细胞中表达，其激活以葡萄糖依赖的方式增强胰岛素分泌。临床前数据表明，FFA1激动作用是恢复糖尿病啮齿动物模型葡萄糖稳态的有效治疗方法。这一初步成功促使了针对2型糖尿病患者的临床试验，其结果很有希望；然而，由于肝脏安全性问题，先导化合物TAK-875/法格列净退出临床开发，该领域遭受了重大挫折。尽管如此，最近的进展揭示了FFA1激动剂作用、信号多样性和生物学结果惊人的复杂性，这让人们燃起希望，即随着对其中机制的更多了解，第二轮试验将更成功。
