Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
Section of Cell Biology and Functional Genomics & Imperial Consortium for Islet Biology and Diabetes, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
Peptides. 2018 Feb;100:75-84. doi: 10.1016/j.peptides.2017.12.013.
Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut-derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage. Greater understanding of the interactions between the GLP-1 receptor (GLP-1R) and both the endogenous and artificial ligands therefore holds promise to provide more efficacious compounds. Here, we discuss recent findings concerning the signalling and trafficking of the GLP-1R in pancreatic beta cells. Leveraging "bias" at the receptor towards cAMP generation versus the recruitment of β-arrestins and extracellular signal-regulated kinases (ERK1/2) activation may allow the development of new analogues with significantly improved clinical efficacy. We describe how, unexpectedly, relatively low-affinity agonists, which prompt less receptor internalisation than the parent compound, provoke greater insulin secretion and consequent improvements in glycaemia.
胰高血糖素样肽-1（GLP-1）和其他肠道来源的肽刺激胰岛素分泌是摄入营养物质后肠促胰岛素反应的核心。GLP-1 的类似物及其分解抑制剂已广泛用于治疗 2 型糖尿病（T2D）和肥胖症。这些肽的释放是减肥手术后血糖控制改善和疾病缓解的基础。给予 GLP-1 类似物会导致包括恶心在内的副作用，从而限制了剂量。因此，更深入地了解 GLP-1 受体（GLP-1R）与内源性和人工配体之间的相互作用，有望提供更有效的化合物。在这里，我们讨论了最近关于胰腺 β 细胞中 GLP-1R 的信号转导和运输的发现。利用受体对 cAMP 生成的“偏向”而不是β-arrestin 和细胞外信号调节激酶（ERK1/2）激活的募集，可能允许开发具有显著改善临床疗效的新类似物。我们描述了出乎意料的是，相对亲和力较低的激动剂比母体化合物引起的受体内化少，会引发更大的胰岛素分泌，并相应改善血糖。
