Abstract
OBJECTIVE: Despite growing evidence, the mechanisms connecting adipose tissue (AT) function to type 2 diabetes (T2DM) remain incompletely understood. A detailed analysis of AT transcriptomes could offer valuable insights into this relationship. Here, we examined gene expression patterns in bulk subcutaneous AT, focusing on biological pathways and cellular composition associated with glycated haemoglobin (HbA1c) levels. METHODS: A transcriptomic dataset was obtained from subcutaneous AT samples of 901 adults collected during elective surgical procedures. We characterized cellular composition within subcutaneous AT in association with blood HbA1c levels by performing bulk adipose transcriptomes cell deconvolution analysis. We also conducted differential gene expression and overrepresentation analyses. We validated our cross-sectional study using two independent validation cohorts, performing further downstream analyses. RESULTS: Subcutaneous AT from subjects with increased HbA1c had lower adipocytes, smooth muscle, pericytes and other endothelial cell numbers. Pathways associated with HbA1c levels included cellular senescence and telomere-related pathways and extracellular matrix organisation. We identified the expression of RHO GTPases associated with HbA1c not previously linked to glucose homeostasis, with a possible sexual dimorphism shaped by the obesity state. The findings were confirmed in both longitudinal cohorts. At the gene level, HLA-DR, CCL13, and S100A4 mRNA levels were strongly correlated with HbA1c levels. CONCLUSIONS: This study underscores the utility of AT transcriptome analysis in unravelling T2DM complexities. Our findings enhance knowledge of glucose homeostasis' molecular and cellular underpinnings, paving the way for potential therapeutic targets to mitigate the impact of AT dysfunction in metabolic diseases.