دورية أكاديمية
Targeting GLP-1 receptor trafficking to improve agonist efficacy
| العنوان: | Targeting GLP-1 receptor trafficking to improve agonist efficacy |
|---|---|
| المؤلفون: | Jones, Ben, Buenaventura, Teresa, Kanda, Nisha, Chabosseau, Pauline, Owen, Bryn M, Scott, Rebecca, Goldin, Robert, Angkathunyakul, Napat, Corrêa, Ivan R (Jr), Bosco, Domenico, Johnson, Paul R, Piemonti, Lorenzo, Marchetti, Piero, Shapiro, A M James, Cochran, Blake J, Hanyaloglu, Aylin C, Inoue, Asuka, Tan, Tricia, Rutter, Guy A, Tomas, Alejandra, Bloom, Stephen R |
| المصدر: | ISSN: 2041-1723 ; Nature Communications, vol. 9, no. 1 (2018) 1602. |
| سنة النشر: | 2018 |
| المجموعة: | Université de Genève: Archive ouverte UNIGE |
| مصطلحات موضوعية: | info:eu-repo/classification/ddc/617, Animals, Blood Glucose/drug effects, CHO Cells, Cell Membrane/drug effects/metabolism, Cricetulus, Diabetes Mellitus, Experimental, Type 2/blood/drug therapy/pathology, Endocytosis/drug effects, Glucagon-Like Peptide 1/metabolism, Glucagon-Like Peptide-1 Receptor/agonists/metabolism, HEK293 Cells, Humans, Hypoglycemic Agents/pharmacology/therapeutic use, Insulin/genetics/metabolism, Insulin-Secreting Cells/drug effects/metabolism, Male, Mice, Inbred C57BL, Nausea/chemically induced/epidemiology, Primary Cell Culture, Protein Transport/drug effects, RNA, Small Interfering/metabolism, Treatment Outcome |
| الوصف: | Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other Gprotein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/29686402; info:eu-repo/semantics/dataset/url/https://www.nature.com/articles/s41467-018-03941-2#Sec49Test; info:eu-repo/grantAgreement/EC/FP7/241592/EU/European Obesity Consortium studying the Hypothalamus and its Interaction with Peripheral organs./EUROCHIP; https://archive-ouverte.unige.ch/unige:128571Test; unige:128571 |
| الإتاحة: | https://doi.org/10.1038/s41467-018-03941-2Test https://archive-ouverte.unige.ch/unige:128571Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.4BD93AAC |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |