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
2026-05-04
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.