Genetic subtypes of type 2 diabetes are distinguished through the lens of abdominal MRI

Elena P Sorokin^1*Madeleine Cule¹Marjola Thanaj²Nicolas Basty²Brandon Whitcher²Naveed Sattar³Elizabeth Louise Thomas²Jimmy David Bell²Hanieh Yaghootkar^4*

• ¹Calico Life Sciences LLC, South San Francisco, United States
• ²Research Center for Optimal Health, School of Life Sciences, University of Westminster, London, UK, London, United Kingdom
• ³School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom
• ⁴School of Natural Science, College of Health and Science, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, United Kingdom

This study seeks to understand type 2 diabetes (T2D) heterogeneity through detailed phenotypic characterization of various T2D genetic subtypes using advanced magnetic resonance imaging (MRI) techniques. Study design and method MRI data from over 44,000 UK Biobank participants was used to characterize distinct T2D genetic subtypes based on a compendium of imaging-derived phenotypes (IDPs) quantifying body fat distribution, organ volumes, and muscle quality. Partitioned polygenic risk scores (pPS) representing genetic T2D subtypes were associated with adipose tissue distribution across ten compartments, liver and pancreas volume, three muscle mass indices, and fatty acid composition in subcutaneous and visceral fat.Subtype pPS marked by insulin deficiency were associated with lower subcutaneous fat, while insulin resistance subtypes were associated with higher adiposity with evidence of fat excess in multiple organs, including the pancreas, paraspinal muscle, thigh muscle, iliopsoas muscle, and other organs not routinely quantified at scale in human cohorts. Distinct patterns of muscle mass and fatty acid composition further differentiated subtype pPS, underscoring variation in metabolic profiles linked to specific genetic pathways.The use of non-invasive MRI to phenotype T2D at a granular level has provided unique insights into the disease's heterogeneity, confirming and expanding upon known genetic associations. These findings highlight the potential of using MRI for pathophysiological insights into T2D.What is already known? Type 2 diabetes (T2D) is heterogeneous, with multiple genetic subtypes and variable phenotypic presentations. What this study has found? Using abdominal MRI acquisitions and 20 quantitative traits from nine organs/tissues in a large population-based cohort, we uncovered distinct differences in fat distribution, muscle quality, pancreas volume, and fatty acid composition across T2D subtype partitioned polygenic scores (pPS). What are the implications of the study? Quantitative imaging can non-invasively delineate subtype-specific profiles in T2D, advancing our understanding of disease heterogeneity and informing personalized management or therapeutic intervention strategies.