Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis - UTU Research Portal

A1 Refereed original research article in a scientific journal

Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis

Authors: Sabatini, Silvia; Sen, Partho; Carli, Fabrizia; Pezzica, Samantha; Rosso, Chiara; Lembo, Erminia; Verrastro, Ornella; Daly, Ann; Govaere, Olivier; Cockell, Simon; Hyötyläinen, Tuulia; Mingrone, Geltrude; Bugianesi, Elisabetta; Anstee, Quentin M.; Orešič, Matej; Gastaldelli, Amalia

Publisher: Cell Press

Publication year: 2024

Journal: Cell Reports Medicine

Journal name in source: Cell Reports Medicine

Article number: 101820

Volume: 5

Issue: 11

eISSN: 2666-3791

DOI: https://doi.org/10.1016/j.xcrm.2024.101820

Web address : http://doi.org/10.1016/j.xcrm.2024.101820

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/470958291

Abstract

Metabolic 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.

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Funding information in the publication:
This work was supported by the European Union’s Horizon 2020 Research Programme for the project EPOS (grant agreement no. 634413), the Innovative Medicines Initiative 2 Joint Undertaking for the project LITMUS (grant agreement no. 777377), and the Innovative Health Initiative Joint Undertaking for the project GRIPonMASH (grant agreement no. 101132946). Additional support for this study was provided by Novo Nordisk Foundation (grant agreement no. NNF20OC0063971) and the Research Council of Finland (grant agreement no. 333981).