5’tRNA-derived fragments modulate -cell homeostasis and islet macrophage activation in type 2 diabetes [iMAC]

Using a β-cell/macrophage co-culture system, we show that β-cell contact shapes a unique macrophage phenotype (iMAC-like) that shifts upon palmitate exposure—recapitulating in vivo observations. Inhibiting 5’tRFGlu(CTC) in iMAC-like cells prevents this activation switch, reduces β-cell stress, and improves insulin secretion. Mechanistically, 5’tRFGlu(CTC) interacts with RNA-binding proteins to regulate transcriptional and post-transcriptional pathways linked to immune activation, ECM remodeling, neurogenesis, and oxidative stress.

Our study identifies 5’tRFs as key mediators of islet microenvironment remodeling in diabetes, offering new insights into intercellular stress signaling in metabolic disease.