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Higher Hepatic Glucose Production and Gluconeogenesis are Features of Severe Metabolic Dysfunction-Associated Steatohepatitis Even in Absence of T2D

31 Pages Posted: 13 Sep 2023 Publication Status: Review Complete

See all articles by Silvia Sabatini

Silvia Sabatini

National Research Council (CNR)

Partho Sen

Technische Universität München (TUM)

Fabrizia Carli

National Research Council (CNR)

Samantha Pezzica

National Research Council (CNR)

Chiara Rosso

University of Turin - Department of Medical Sciences

Erminia Lembo

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Ornella Verrastro

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Ann Daly

Newcastle University - Translational and Clinical Research Institute

Olivier Govaere

Newcastle University - Translational and Clinical Research Institute

Simon Cockel

Newcastle University - Translational and Clinical Research Institute

Tuulia Hyötyläinen

Örebro University

Geltrude Mingrone

Catholic University of Milan - Fondazione Policlinico Universitario Agostino Gemelli; King’s College London - Diabetes and Nutritional Sciences

Elisabetta Bugianesi

University of Turin - Division of Gastroenterology

Quentin M. Anstee

University of Newcastle (Australia)

Matej Orešič

Örebro University

Amalia Gastaldelli

National Research Council (CNR)

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, steatohepatitis (MASH), are associated with a higher prevalence of type 2 diabetes (T2D) and obesity. Individuals with MASLD commonly exhibit insulin resistance (IR) and hyperglycemia, but the mechanisms are still unknown. Here, we investigated hepatic glucose metabolism within the full spectrum of MASLD using stable-isotope tracer infusion (fluxomics) and genome-scale metabolic modeling (GSMM) in large cohorts of individuals with biopsy-proven MASLD. Tracer-measured hepatic glucose production (HGP) and Hepatic-IR were increased with MASH severity. Intra-hepatic flux analysis by GSMM of the liver indicates that high HGP was due to increased gluconeogenesis, anaplerosis and increased uptake of glucogenic metabolites rather than upregulation of glucogenic gene expression. Critical genes involved in insulin signaling (IRS1, IRS2, and AKT2) showed reduced expression as the severity of MASH increased. Such alterations were associated mainly with the severity of liver fibrosis and were more pronounced in individuals with obesity and T2D. Thus, our findings contribute to explain the mechanisms for increased risk of hyperglycemia and T2D in subjects with MASH.

Note:
Funding Information: Horizon 2020 Framework Programme (777377 and 634413).

Declaration of Interests: G.M. reports consulting fees from Novo Nordisk, Fractyl Inc, and Recor Inc. She is also scientific advisor of Metadeq Inc, Keyron Ltd, GHP Scientific Ltd, and Jemyll Ltd. G.M. reports receiving research grants from Metadeq Inc and Fractyl Inc. A.G. has served as a consultant for: Boehringer Ingelheim, Eli Lilly and Company, Metadeq Diagnostics and Fractyl Health; has participated in advisory boards for: Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Metadeq Diagnostics and Pfizer; and has received speaker's honorarium and other fees from: Eli Lilly and Company, Merck Sharp & Dohme, and Novo Nordisk. Q.M.A. reports grants, personal fees and other from Allergan/Tobira, other from E3Bio, other from Eli Lilly & Company Ltd, other from Galmed, grants, personal fees and other from Genfit SA, personal fees and other from Gilead, other from Grunthal, other from Imperial Innovations, grants and other from Intercept Pharma Europe Ltd, other from Inventiva, other from Janssen, personal fees from Kenes, other from MedImmune, other from NewGene, grants, personal fees and other from Pfizer Ltd, other from Raptor Pharma, grants and other from Novartis Pharma AG, grants from Abbvie, personal fees and other from BMS, grants from GSK, other from NGMBio, other from Madrigal, other from Servier, other from EcoR1, other from 89Bio, other from Altimmune, grants and other from AstraZeneca, other from Axcella, other from Blade, other from BNN Cardio, other from Celgene, other from Cirius, other from CymaBay, other from Genentech, other from HistoIndex, other from Indalo, other from IQVIA, other from Metacrine, other from North Sea Therapeutics, personal fees and other from Novo Nordisk, other from Poxel, other from Terns, other from Viking Therapeutics, grants from Glympse Bio, other from PathAI, outside the submitted work. All other authors declare no competing interests.

Keywords: steatotic liver disease, type 2 diabetes, genome-scale metabolic modeling, fluxomics, hepatic glucose production, gluconeogenesis, insulin resistance

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Suggested Citation

Sabatini, Silvia and Sen, Partho and Carli, Fabrizia and Pezzica, Samantha and Rosso, Chiara and Lembo, Erminia and Verrastro, Ornella and Daly, Ann and Govaere, Olivier and Cockel, Simon and Hyötyläinen, Tuulia and Mingrone, Geltrude and Bugianesi, Elisabetta and Anstee, Quentin M. and Orešič, Matej and Gastaldelli, Amalia, Higher Hepatic Glucose Production and Gluconeogenesis are Features of Severe Metabolic Dysfunction-Associated Steatohepatitis Even in Absence of T2D. Available at SSRN: https://ssrn.com/abstract=4563031 or http://dx.doi.org/10.2139/ssrn.4563031
This version of the paper has not been formally peer reviewed.

Silvia Sabatini

National Research Council (CNR) ( email )

Partho Sen

Technische Universität München (TUM) ( email )

Fabrizia Carli

National Research Council (CNR) ( email )

Samantha Pezzica

National Research Council (CNR) ( email )

Chiara Rosso

University of Turin - Department of Medical Sciences ( email )

Erminia Lembo

Fondazione Policlinico Universitario Agostino Gemelli IRCCS ( email )

Ornella Verrastro

Fondazione Policlinico Universitario Agostino Gemelli IRCCS ( email )

Ann Daly

Newcastle University - Translational and Clinical Research Institute ( email )

Olivier Govaere

Newcastle University - Translational and Clinical Research Institute ( email )

Simon Cockel

Newcastle University - Translational and Clinical Research Institute ( email )

Tuulia Hyötyläinen

Örebro University ( email )

Geltrude Mingrone

Catholic University of Milan - Fondazione Policlinico Universitario Agostino Gemelli ( email )

Largo Agostino Gemelli, 8
Rome, 00168
Italy

King’s College London - Diabetes and Nutritional Sciences ( email )

United Kingdom

Elisabetta Bugianesi

University of Turin - Division of Gastroenterology ( email )

Italy

Quentin M. Anstee

University of Newcastle (Australia) ( email )

University Drive
Callaghan, NSW 2308
Australia

Matej Orešič

Örebro University ( email )

Fakultetsgatan 1
SE-701 82
Örebro, 70210
Sweden

Amalia Gastaldelli (Contact Author)

National Research Council (CNR)

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