5’tRNA-derived fragments modulate β-cell homeostasis and islet macrophage activation in type 2 diabetes
Cristina Cosentino, Rémy Klein, Véronique Menoud, Claudiane Guay, Elena Aiello, Stefano Auddino, Gianfranco Di Giuseppe, Gea Ciccarelli, Alessandra Galli, Francesco Alabiso, Eleonora Mangano, Flora Brozzi, Karim Bouzakri, Stefania D’Adamo, Silvia Cetrullo, Giuseppe Quero, Andrea Mari, Sergio Alfieri, Andrea Giaccari, Teresa Mezza, Francesco Dotta, Guido Sebastiani, Romano Regazzi
Abstract
Abstract Obesity and diabetes impose chronic stress on pancreatic β-cells, while reprogramming of islet-resident macrophages (iMACs) accelerates dysfunction. Here, we identify transfer RNA-derived fragments (tRFs) as previously unrecognized mediators of islet remodeling under metabolic stress. 5’tRF Glu(CTC) and 5’tRF Gly(GCC) are elevated in β-cells and iMACs from db/db mice and in islets from individuals with type 2 diabetes; 5’tRF Glu(CTC) also rises in prediabetes and inversely correlates with insulin secretion. Lipotoxicity triggers 5’tRF biogenesis, and targeted inhibition of 5’tRF Glu(CTC) preserves β-cell viability and function under palmitate exposure. In a β-cell/macrophage co-culture model, β-cell contact shapes a distinct iMAC-like phenotype that shifts after palmitate treatment. Inhibiting 5’tRF Glu(CTC) in iMAC-like cells prevents their activation switch and protects β-cells from lipotoxicity. Mechanistically, 5’tRF Glu(CTC) interacts with RNA-binding proteins to control immune activation, extracellular matrix remodeling, and oxidative stress pathways. These findings position tRFs as central effectors of cellular stress responses in both endocrine and immune cells.