Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada.
The Department of Medicine, Division of Endocrinology, Department of Pharmacology and Cancer Biology, Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Endocr Rev. 2021 Mar 15;42(2):101-132. doi: 10.1210/endrev/bnaa032.
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.
胰高血糖素样肽-1（GLP-1）由肠道内分泌细胞和大脑产生，通过激素和神经途径发挥作用，调节胰岛功能、饱腹感和肠道运动，支持开发 GLP-1 受体（GLP-1R）激动剂用于治疗糖尿病和肥胖症。经典观念认为 GLP-1 是一种来自远端肠道的餐刺激激素，但支持 GLP-1 在胰岛内分泌细胞中产生的数据以及脑源性 GLP-1 在控制神经活动中的重要性对这一观念提出了挑战。此外，很难将 GLP-1 的直接作用与间接作用区分开来，因为 GLP-1 作用的许多组织和细胞靶标没有表现出强烈或可检测到的 GLP-1R 表达。此外，GLP-1R 的可靠检测在技术上具有挑战性，高度依赖方法，并且容易产生误解。在这里，我们重新审视 GLP-1 的作用，仔细审查支持肠道与肠外 GLP-1 合成和分泌的关键概念。我们讨论了新的见解，这些见解细化了 GLP-1R 表达的细胞定位，并整合了最近的数据，以完善我们对 GLP-1 如何以及在何处发挥作用以控制炎症、心血管功能、胰岛激素分泌、胃排空、食欲和体重的理解。这些发现更新了我们对将内源性与药理学 GLP-1 作用与经典 GLP-1R 激活以及多个器官代谢活动控制联系起来的细胞类型和机制的认识。
