5′tRNA-derived fragments modulate β-cell homeostasis and islet macrophage activation in type 2 diabetes

During obesity and type 2 diabetes, pancreatic β-cells face chronic environmental stress, while islet-resident macrophages (iMACs) undergo metabolic reprogramming that exacerbates β-cell dysfunction. Stress-induced cleavage of transfer RNAs (tRNAs) generates tRNA-derived fragments (tRFs), whose role in this context is not fully understood. We identify elevated levels of 5′tRF Glu(CTC) and 5′tRF Gly(GCC) in β-cells and iMACs from db/db mice and in islets from type 2 diabetic patients. Notably, 5′tRF Glu(CTC) is also induced under prediabetic conditions and inversely correlates with insulin secretion. Lipotoxic stress triggers their production via Angiogenin-mediated cleavage. Blocking 5′tRF Glu(CTC) in islets protects against β-cell apoptosis and restores insulin secretion under palmitate stress. 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′tRF Glu(CTC) in iMAC-like cells prevents this activation switch, reduces β-cell stress, and improves insulin secretion. Mechanistically, 5′tRF Glu(CTC) interacts with RNA-binding proteins to regulate transcriptional and post-transcriptional pathways linked to immune activation, extracellular matrex 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.