Incretin combination therapy for the treatment of non-alcoholic steatohepatitis.
GIP, GLP-1
experimental pharmacology
fatty liver disease
glucagon
incretin therapy
Journal
Diabetes, obesity & metabolism
ISSN: 1463-1326
Titre abrégé: Diabetes Obes Metab
Pays: England
ID NLM: 100883645
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
28
12
2019
revised:
04
03
2020
accepted:
16
03
2020
pubmed:
21
3
2020
medline:
25
6
2021
entrez:
21
3
2020
Statut:
ppublish
Résumé
To test specific mono-agonists to the glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic peptide receptor (GIPR), individually and in combination, in a mouse model of diet-induced non-alcoholic steatohepatitis (NASH) and fibrosis in order to decipher the contribution of their activities and potential additive effects to improving systemic and hepatic metabolism. We induced NASH by pre-feeding C57BL/6J mice a diet rich in fat, fructose and cholesterol for 36 weeks. This was followed by 8 weeks of treatment with the receptor-specific agonists 1-GCG (20 μg/kg twice daily), 2-GLP1 (3 μg/kg twice daily) or 3-GIP (30 μg/kg twice daily), or the dual (1 + 2) or triple (1 + 2 + 3) combinations thereof. A dual GLP-1R/GCGR agonistic peptide, 4-dual-GLP1/GCGR (30 μg/kg twice daily), and liraglutide (100 μg/kg twice daily) were included as references. Whereas low-dose 1-GCG or 3-GIP alone did not influence body weight, liver lipids and histology, their combination with 2-GLP1 provided additional weight loss, reduction in liver triglycerides and improvement in histological disease activity score. Notably, 4-dual-GLP-1R/GCGR and the triple combination of selective mono-agonists led to a significantly stronger reduction in the histological non-alcoholic fatty liver disease activity score compared to high-dose liraglutide, at the same extent of body weight loss. GCGR and GIPR agonism provide additional, body weight-independent improvements on top of GLP-1R agonism in a murine model of manifest NASH with fibrosis.
Substances chimiques
Glucagon-Like Peptide-1 Receptor
0
Incretins
0
Receptors, Glucagon
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1328-1338Subventions
Organisme : This work was supported by a grant from Agence Nationale pour la Recherche (ANR-16-RHUS-0006-PreciNASH).
Pays : International
Informations de copyright
© 2020 John Wiley & Sons Ltd.
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