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Discovery of dipeptidyl peptidase-4 inhibitor specific biomarker in non-alcoholic fatty liver disease mouse models using modified basket trial.
- Source :
-
Clinical and molecular hepatology [Clin Mol Hepatol] 2022 Jul; Vol. 28 (3), pp. 497-509. Date of Electronic Publication: 2022 Apr 28. - Publication Year :
- 2022
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Abstract
- Background/aims: We aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD).<br />Methods: An exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy.<br />Results: DPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels.<br />Conclusion: The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.
- Subjects :
- Animals
Biomarkers
Diet, High-Fat
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases metabolism
Humans
Hypoglycemic Agents
Insulin-Like Growth Factor Binding Protein 1 genetics
Insulin-Like Growth Factor Binding Protein 1 metabolism
Liver pathology
Mice
Dipeptidyl-Peptidase IV Inhibitors metabolism
Dipeptidyl-Peptidase IV Inhibitors pharmacology
Dipeptidyl-Peptidase IV Inhibitors therapeutic use
Non-alcoholic Fatty Liver Disease diagnosis
Non-alcoholic Fatty Liver Disease metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2287-285X
- Volume :
- 28
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical and molecular hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 35484644
- Full Text :
- https://doi.org/10.3350/cmh.2022.0019