期刊
ENDOCRINE REVIEWS
卷 42, 期 2, 页码 101-132出版社
ENDOCRINE SOC
DOI: 10.1210/endrev/bnaa032
关键词
diabetes; obesity; receptor; islets; brain; gastrointestinal tract; cardiovascular
资金
- CIHR [154321]
- Novo Nordisk
- CIHR
- Banting and Best Diabetes Centre fellowship
- Medical Research Council (MRC) [MR/N00275X/1, MR/S025618/1]
- Diabetes UK [17/0005681]
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [715884]
- American Diabetes Association [1-18-JDF-017]
- National Institutes of Health [DK123075, DK125353]
- Medical Research Council [MR/N02589X/1]
- British Heart Foundation [FS/14/43/30960]
- NIH [R01 DK095757]
- Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin Biology
- Novo Nordisk Foundation-Mt. Sinai Hospital fund
- MRC [MR/N02589X/1, MR/N00275X/1, 1854365, MR/S025618/1] Funding Source: UKRI
GLP-1 is produced in gut endocrine cells and in the brain to regulate islet function, satiety, and gut motility. However, there are challenges in determining direct vs indirect actions of GLP-1, as well as the technical difficulty in reliable detection of GLP-1R.
Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.
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