Characterisation of diabetes-associated adipose tissue dysfunction across the spectrum of body mass index

Abstract Diabetes mellitus (DM) and obesity frequently coexist. Both are associated with adipose dysfunction, yet the contribution of DM remains uncertain. Using bulk transcriptomics of subcutaneous and visceral adipose tissue (SAT and VAT, respectively), we show that DM is associated with shared and distinct patterns of differential gene expression in these depots. Gene ontology analysis of hits across depots highlighted extracellular matrix, inflammatory pathways, metabolism, axon guidance and endoplasmic reticulum stress. Histology revealed larger SAT adipocytes in people with DM, but only in the overweight category. Body mass index (BMI)-stratified transcriptomic analyses of SAT identified DM-associated hits present only in the overweight group. These were validated in plasma protein form using UK Biobank, informing our development of an adipose risk score that predicted incident DM in overweight people beyond a clinical risk score. Hence, molecular signatures of diabetic SAT can define high-risk adiposity, which may aid the targeting of clinical interventions.