Reference
Zheng, Z., Zong, Y., Ma, Y., Tian, Y., Pang, Y., Zhang, C., & Gao, J. (2024). Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy. Signal Transduction and Targeted Therapy, 9(1), 1–29. https://doi.org/10.1038/s41392-024-01931-z
Info
FirstAuthor:: Zheng, Zhikai
Author:: Zong, Yao
Author:: Ma, Yiyang
Author:: Tian, Yucheng
Author:: Pang, Yidan
Author:: Zhang, Changqing
Author:: Gao, Junjie
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Title:: Glucagon-like peptide-1 receptor: mechanisms and advances in therapy
Year:: 2024
Citekey:: ZhengEtAl_2024_GlucagonlikePeptide1Receptor
itemType:: journalArticle
Journal:: Signal Transduction and Targeted Therapy
Volume:: 9
Issue:: 1
Pages:: 1-29
DOI:: 10.1038/s41392-024-01931-z
Link
Abstract
The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.
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GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family
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CLASSICAL PATHOPHYSIOLOGICAL MECHANISMS OF GLP-1
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The rise in cAMP activates protein kinase A (PKA), which then promotes the synthesis and secretion of insulin and inhibits the release of glucagon.178,179
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cAMP can activate Rap1 through EPAC (Exchange Protein directly Activated by cAMP),180–182 which is involved in regulating insulin secretion.180,181,183 GLP-1 also activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, which is crucial for maintaining the survival and function of pancreatic β-cells.184–187
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increasing the sensitivity of peripheral tissues to insulin
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GLP-1 reduces hepatic glucose production
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The phosphorylation of Akt is necessary for its full activation, allowing it to regulate a variety of downstream effector proteins involved in cell survival, proliferation, metabolism, and glucose transport
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Simultaneously, Akt promotes cell survival by phosphorylating and inhibiting a series of pro-apoptotic proteins, such as Bad and the FOXO family.202–204 Moreover, Akt can activate mTORC1, further promoting
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GLP-1 not only plays a crucial role in the treatment of diabetes by enhancing the function and protecting pancreatic β-cells from apoptosis, but it may also offer potential therapeutic benefits in fields such as cardiovascular and neural protection
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In α-cells, increased cAMP affects glucagon synthesis and release.228 PKA, activated by cAMP, can regulate the activity of K-ATP channels in α-cells.228,229 The opening of these channels is controlled by the intracellular ATP/ ADP ratio.229 Specifically, PKA modifies the open state of K-ATP channels through phosphorylation, affecting the cell membrane’s potential and intracellular calcium ion concentration.230,231 By modulating the activity of K-ATP channels, GLP-1 indirectly controls the calcium signaling in α-cells, thereby influencing glucagon secretion.232,233 GLP-1 inhibits the release of glucagon from α-cells through multiple mechanisms. GLP-1 can directly bind to the receptors on the surface of α-cells in the pancreas, inhibiting the secretion of glucagon from these cells.
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GLP-1 can stimulate pancreatic β-cells to release insulin.236,237
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GLP-1 can reduce blood glucose production by delaying gastric emptying and decreasing appetite
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GLP-1 can slow down gastric emptying by activating the vagus nerve, a part of the autonomic nervous system crucial for regulating the activities of the gastrointestinal tract.268 When activated, the vagus nerve can reduce the contraction of the stomach, thereby slowing down food emptyin
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