Incretin combination therapy for the treatment of non-alcoholic steatohepatitis.
Diabetes Obes Metab
; 22(8): 1328-1338, 2020 08.
Article
in En
| MEDLINE
| ID: mdl-32196896
ABSTRACT
AIMS:
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. MATERIALS ANDMETHODS:
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.RESULTS:
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.CONCLUSIONS:
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Incretins
/
Non-alcoholic Fatty Liver Disease
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Diabetes Obes Metab
Journal subject:
ENDOCRINOLOGIA
/
METABOLISMO
Year:
2020
Document type:
Article
Affiliation country:
Germany