1425-P: Modelling Vascular Dysfunction in Lean Type 2 Diabetes Using IPSC-Derived Endothelial Cells Under Metabolic Stress

by sugaradmin



Introduction and Objective: Although obesity is a major driver of type 2 diabetes (T2D), lean T2D represents 3-8% of global cases and remains understudied. Diabetes-associated cardiovascular disease is well characterized; vascular modeling of lean T2D is limited. We aim to determine whether induced pluripotent stem cell (iPSC)-derived endothelial cells from patients with lean T2D exhibit disease-relevant responses under metabolic stress.Methods: Endothelial cells (ECs) were differentiated from iPSCs derived from five individuals with T2D (body mass index ≤23 kg/m2; age >60 years). Cells were cultured on gelatin-coated plates in endothelial growth medium. Metabolic stress was induced using high glucose (20 mM) and TNF-α (10 ng/mL) for 48 hours, while baseline cells were maintained in 5.5 mM glucose. Total RNA was isolated from ten samples and analyzed by bulk RNA sequencing. Differential expression and pathway enrichment analyses were performed.Results: Metabolic stress was associated with marked transcriptional changes in T2D ECs compared with baseline conditions. Enriched pathways included extracellular matrix organization, inflammatory cytokine signaling, integrin-mediated cell surface interactions, tumor necrosis factor signaling, and AGE-RAGE pathways. Several inflammation- and adhesion-related genes, including SELE, VCAM1, ICAM1, CCL2, CCL20, CXCL10, CXCL5, IL6, CSF2, TNF, TNFRSF9, TLR2, and IDO1, were upregulated >5 folds (adjusted p <0.05). Gene set enrichment analysis demonstrated overlap between stressed iPSC-derived ECs and primary endothelial cells from individuals with T2D in a publicly available dataset.Conclusion: iPSC-derived ECs from patients with lean T2D recapitulate key inflammatory and extracellular matrix remodeling signatures under metabolic stress. This platform provides a disease-relevant model for studying vascular dysfunction in diabetes and supports its use in future mechanistic and translational studies.

Disclosure

D. Patra: None. X. Yang: None. S. Mukherjee: Consultant; Current; Greenstone Biosciences. Employee; Ended; Greenstone Biosciences. M.J. Chandy: None. J.C. Wu: None.

Funding

ADVANCE (Accelerate Innovation in Diabetes LeVeraging Unique PAthways iN Asians) Program, Stanford Center for Asian Health Research and Education (CARE)



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