Journal
DIABETES & METABOLISM
Volume 44, Issue 3, Pages 250-260Publisher
MASSON EDITEUR
DOI: 10.1016/j.diabet.2017.10.007
Keywords
Apoptosis; beta-cell; GLP-1 receptor; Cell proliferation; Dulaglutide; Durability
Categories
Funding
- Japan Society for the Promotion of Science [16K09770]
- Kawasaki Medical School [28-084, 28-021]
- Grants-in-Aid for Scientific Research [16K09770] Funding Source: KAKEN
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Aims. - It is well-known that chronic exposure to large amounts of ligand leads to downregulation of its receptor. It is not known, however, whether a GLP-1R agonist downregulates its receptor. For this reason, our study examined whether GLP-1R expression is reduced after long-term exposure to dulaglutide (Dula) in non-diabetic and diabetic mice. Methods. - Seven-week-old male db/db and db/m mice were given either Dula (0.6 mg/kg x 2/week) or a control vehicle (CTL) for 17 weeks. Various metabolic parameters, such as glucose-stimulated insulin secretion (GSIS), insulin and TG content in islets, were evaluated after the intervention. beta-cell-related gene expression was also analyzed by real-time RT-PCR. Results. - In db/m mice, GLP-1R expression in beta-cells did not decrease, not even after long-term administration of Dula, compared with control mice, while GLP-1R expression in 24-week-old db/db mice treated with Dula was augmented, rather than downregulated, compared with 24-week-old CTL db/db mice. This was probably due to improved glycaemic control. In db/db mice treated with Dula, food intake and blood glucose levels were significantly decreased up to 24 weeks of age compared with CTL db/db mice, and their expression levels of various beta-cell-related genes, insulin content and GSIS were also enhanced. In contrast, oxidative and endoplasmic reticulum stress, inflammation, fibrosis and apoptosis were suppressed with Dula treatment. Conclusion. - Dula exerts beneficial effects on glycaemic control and has long-lasting protective effects on pancreatic beta-cells. GLP-1R expression levels were not reduced at all in non-diabetic as well as diabetic mice despite long-term dulaglutide exposure. (C) 2017 Elsevier Masson SAS. All rights reserved.
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