A Biological-Systems-Based Analyses Using Proteomic and Metabolic Network Inference Reveals Mechanistic Insights into Hepatic Lipid Accumulation: An IMI-DIRECT Study
Abstract
Objective: To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). Research Design and Methods: We used Bayesian network analyses to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with fatty liver using data from the IMI-DIRECT prospective cohort study. Measurements were made of glucose and insulin dynamics (using frequently-sampled metabolic challenge tests), MRI-derived abdominal and liver fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults free from diabetes at enrolment. The common protocols used in these two cohorts provided the opportunity for replication analyses to be performed. When the direction of the effect could not be determined with high probability through Bayesian networks, complementary two-sample Mendelian randomization (MR) was employed. Results: High basal insulin secretion rate (BasalISR) was identified as the primary causal driver of liver fat accumulation in both diabetes and non-diabetes. Excess visceral adipose tissue (VAT) was bidirectionally associated with liver fat, indicating a self-reinforcing metabolic loop. Basal insulin clearance (Clinsb) worsened as a consequence of liver fat accumulation to a greater degree before the onset of T2D. Out of 446 analysed proteins, 34 mapped to these metabolic networks and 27 were identified in the non-diabetes network, 18 in the diabetes network, and 11 were common between the two networks. Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses revealed distinct proteomic drivers: GUSB and LEP were most predictive of liver fat in females and males, respectively. Conclusions: Basal insulin hypersecretion is a modifiable, causal driver of MASLD, particularly prior to glycaemic decompensation. Our findings highlight a multifactorial, sex- and disease-stage-specific proteo-metabolic architecture of hepatic steatosis. Proteins such as GUSB, ALDH1A1, LPL, and IGFBPs warrant further investigation as potential biomarkers or therapeutic targets for MASLD prevention and treatment.
Authors 59
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University of Copenhagen · Lund University · University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Helsingborg, Sweden
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Affiliation as printed
Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Helsingborg, Sweden
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Dartmouth–Hitchcock Medical Center · Lund University
Affiliation as printed
Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Helsingborg, Sweden
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, USA
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University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism
Affiliation as printed
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Affiliation as printed
Institute of Neuroscience, National Research Council, Padova, Italy
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University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism
Affiliation as printed
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Broad Institute · MIT Computer Science and Artificial Intelligence Laboratory · Massachusetts Institute of Technology
Affiliation as printed
Broad Institute of MIT and Harvard, Cambridge, USA
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, USA
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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University of Dundee · Ninewells Hospital
Affiliation as printed
Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland
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Herlev Hospital · Copenhagen University Hospital · Gentofte Hospital
Affiliation as printed
Department of Diagnostic Radiology, Copenhagen University Hospital Herlev Gentofte, Herlev, Denmark
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Technical University of Denmark
Affiliation as printed
Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
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Technical University of Denmark
Affiliation as printed
Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
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University of Dundee · Ninewells Hospital
Affiliation as printed
Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland
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Amsterdam Public Health · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of General Practice, Amsterdam UMC-location Vumc, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
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Affiliation as printed
Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Helsingborg, Sweden
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University of Dundee · Ninewells Hospital
Affiliation as printed
Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland
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Affiliation as printed
Metabolomics and Proteomics Core, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany
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University of Copenhagen · Zealand University Hospital Køge · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Department of Medicine, Zealand University Hospital, Køge, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Herlev Hospital · Copenhagen University Hospital · Gentofte Hospital
Affiliation as printed
Department of Diagnostic Radiology, Copenhagen University Hospital Herlev Gentofte, Herlev, Denmark
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Affiliation as printed
Department of Clinical and Biomedical Sciences, University of Exeter College of Medicine & Health, Exeter, UK
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Affiliation as printed
Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
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Affiliation as printed
Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Helsingborg, Sweden
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Centre for Human Genetics · University of Oxford
Affiliation as printed
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
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Royal Devon & Exeter NHS Foundation Trust
Affiliation as printed
Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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Affiliation as printed
Diabetes Research Network, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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Amsterdam Public Health · Amsterdam University Medical Centers
Affiliation as printed
Amsterdam Public Health, Health Behaviors & Chronic Diseases, Amsterdam, The Netherlands
Amsterdam UMC, Epidemiology and Data Science, Amsterdam, The Netherlands
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Novo Nordisk Foundation · Technical University of Denmark
Affiliation as printed
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark
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Affiliation as printed
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
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Amsterdam Public Health · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of General Practice, Amsterdam UMC-location Vumc, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research · Steno Diabetes Center Copenhagen
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Steno Diabetes Center, Copenhagen, Denmark
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University of Ljubljana · National University of Singapore · Helmholtz Munich
Affiliation as printed
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Healt, Neuherberg, Germany
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Amsterdam University Medical Centers
Affiliation as printed
Amsterdam UMC, Epidemiology and Data Science, Amsterdam, The Netherlands
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Technical University of Denmark
Affiliation as printed
Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
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Affiliation as printed
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
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Affiliation as printed
Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Helsingborg, Sweden
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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University of Copenhagen · Zealand University Hospital Køge · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Department of Medicine, Zealand University Hospital, Køge, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Leen M. ‘t Hart Aachen Department of Biomedical Data Sciences Section Molecular Epidemiology Department of Cell and Chemical Biology
Leiden University Medical Center · Amsterdam Public Health · Amsterdam University Medical Centers
Affiliation as printed
Amsterdam Public Health, Health Behaviors & Chronic Diseases, Amsterdam, The Netherlands
Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, The Netherlands
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Affiliation as printed
Department of Clinical and Biomedical Sciences, University of Exeter College of Medicine & Health, Exeter, UK
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University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism
Affiliation as printed
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Affiliation as printed
Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
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Broad Institute · University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Affiliation as printed
Center for Environmental and Climate Science, Lund University, Lund, Sweden
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Affiliation as printed
Center for Clinical Metabolic Research, Herlev and Gentofte University Hospital, Copenhagen, Denmark
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Affiliation as printed
Department of Clinical Science, Lund University, Malmö, Sweden
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Boehringer Ingelheim (Germany)
Affiliation as printed
Boehringer Ingelheim International GmbH, Ingelheim, Germany
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Amsterdam Public Health · Amsterdam University Medical Centers
Affiliation as printed
Amsterdam Public Health, Health Behaviors & Chronic Diseases, Amsterdam, The Netherlands
Amsterdam UMC, Epidemiology and Data Science, Amsterdam, The Netherlands
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Affiliation as printed
Science for Life Laboratory, School of Biotechnology, Solna, Sweden
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University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism
Affiliation as printed
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Affiliation as printed
School of Chemistry, College of Health and Science, University of Lincoln, Lincoln, UK
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University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism
Affiliation as printed
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Centre for Human Genetics · University of Oxford
Affiliation as printed
Wellcome Trust Centre for Human Genetics, University of Oxford, UK
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Affiliation as printed
Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK
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Affiliation as printed
Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK
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Affiliation as printed
Eli Lilly Regional Operations Ges.m.b.H., Vienna, Austria
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University of Dundee · Ninewells Hospital
Affiliation as printed
Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland
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University of Dundee · Ninewells Hospital
Affiliation as printed
Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland
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Paul W. Franks corresponding
Queen Mary University of London · Lund University
Affiliation as printed
Department of Clinical Science, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Helsingborg, Sweden
Precision Healthcare University Research Institute, Queen Mary University of London, London, UK
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