期刊
PEPTIDES
卷 100, 期 -, 页码 75-84出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2017.12.013
关键词
GLP-1; Beta cells; Insulin secretion; GLP-1 receptor; Endocytic trafficking; Receptor signalling
资金
- MRC Clinical Research Training Fellowship [MR/K023667/1]
- MRC Project [MR/M012646/1]
- Diabetes UK Early-Career Small Grant [16/0005441]
- Wellcome Trust Senior Investigator Award [WT098424AIA]
- MRC Programme grants [MR/J0003042/1, MR/L020149/1]
- Experimental Challenge Grant (DIVA) [MR/L02036X/1]
- BBSRC [BB/J015873/1]
- MRC [MR/N00275X/1]
- Diabetes UK [BDA/11/0004210, BDA/15/0005275, BDA 16/0005485]
- Imperial Confidence in Concept (ICiC) grants
- Royal Society Wolfson Research Merit Award
- MRC
- BBSRC
- NIHR
- Integrative Mammalian Biology (IMB) Capacity Building Award
- EuroCHIP grant [FP7- HEALTH- 2009- 241592]
- NIHR Biomedical Research Centre Funding Scheme
- Medical Research Council [MR/M012646/1, MR/K023667/1, MR/N00275X/1, MR/K001981/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10337, CL-2017-21-002, NF-SI-0513-10080] Funding Source: researchfish
- MRC [MR/L020149/1, MR/K023667/1, MR/K001981/1, MR/L02036X/1, MR/M012646/1] Funding Source: UKRI
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 beta-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.
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