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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • 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

摘要

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’tRFGlu(CTC) and 5’tRFGly(GCC) are elevated in β-cells and iMACs from db/db mice and in islets from individuals with type 2 diabetes; 5’tRFGlu(CTC) also rises in prediabetes and inversely correlates with insulin secretion. Lipotoxicity triggers 5’tRF biogenesis, and targeted inhibition of 5’tRFGlu(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’tRFGlu(CTC) in iMAC-like cells prevents their activation switch and protects β-cells from lipotoxicity. Mechanistically, 5’tRFGlu(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.