5'tRNA-derived fragments modulate β-cell homeostasis and islet macrophage activation in type 2 diabetes.
basic_science · Level V
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- Record sourced from PubMed, PMID 42082525.
- Also identified by DOI 10.1038/s41467-026-72641-z.
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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<sup>Glu(CTC)</sup> and 5'tRF<sup>Gly(GCC)</sup> are elevated in β-cells and iMACs from db/db mice and in islets from individuals with type 2 diabetes; 5'tRF<sup>Glu(CTC)</sup> also rises in prediabetes and inversely correlates with insulin secretion. Lipotoxicity triggers 5'tRF biogenesis, and targeted inhibition of 5'tRF<sup>Glu(CTC)</sup> 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<sup>Glu(CTC)</sup> in iMAC-like cells prevents their activation switch and protects β-cells from lipotoxicity. Mechanistically, 5'tRF<sup>Glu(CTC)</sup> 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.