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Lookup NU author(s): Professor Ann DalyORCiD, Dr Olivier GovaereORCiD, Dr Simon CockellORCiD, Professor Quentin AnsteeORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The AuthorsMetabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-2H2-glucose, U-2H5-glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2–F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH.
Author(s): Sabatini S, Sen P, Carli F, Pezzica S, Rosso C, Lembo E, Verrastro O, Daly A, Govaere O, Cockell S, Hyotylainen T, Mingrone G, Bugianesi E, Anstee QM, Oresic M, Gastaldelli A
Publication type: Article
Publication status: Published
Journal: Cell Reports Medicine
Year: 2024
Volume: 5
Issue: 11
Print publication date: 19/11/2024
Online publication date: 19/11/2024
Acceptance date: 16/10/2024
Date deposited: 26/11/2024
ISSN (electronic): 2666-3791
Publisher: Cell Press
URL: https://doi.org/10.1016/j.xcrm.2024.101820
DOI: 10.1016/j.xcrm.2024.101820
Data Access Statement: RNA-seq data have been deposited in the NCBI GEO database under accession number GEO: GSE135251 and are publicly available as of the date of publication. Scripts for GSMM, contextualization, and data analysis can be downloaded from https://doi.org/10.5281/zenodo. 13837420 or alternatively from https://github.com/Silvia410/GSMM_ liver. The personalized GEMs (.mat files) of human-hepatocytes are available upon request. d Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
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