Dietary Dityrosine Impairs Glucose Homeostasis by Disrupting Thyroid Hormone Signaling in Pancreatic β-Cells

Growing evidence links processed red meat consumption to increased diabetes risk, with oxidized proteins and/or amino acids proposed as potential mediators. We investigated whether dityrosine (Dityr), a key oxidation biomarker in high-oxidative pork (HOP) and structural analog of thyroid hormone T3, mediates HOP-induced glucose dysregulation via thyroid hormone (TH) signaling disruption. C57BL/6J mice were fed control, low-oxidative pork (LOP), HOP, LOP + Dityr, or Dityr diets for 12 weeks. HOP and Dityr impaired glucose tolerance and induced hyperglycemia and hypoinsulinemia. Both induced oxidative stress and inflammation that partly contributed to pancreatic β-cell dysfunction and reduction in insulin secretion. Crucially, they downregulated pancreatic thyroid hormone receptor β1 (TRβ1) and monocarboxylate transporter 8 (MCT-8), impairing TH signaling. This reduced TH transport in pancreatic tissue and triggered β-cell apoptosis by modulating TRβ1-mediated expression of TH-responsive genes and proteins involved in pancreatic function, ultimately leading to diminished insulin secretion and elevated blood glucose levels. Dityr alone recapitulated the metabolic and molecular disruptions of HOP. We conclude that Dityr drives HOP-induced glucose metabolism disorders primarily by disrupting TH signaling, along with promoting oxidative stress and inflammation that collectively impair β-cell function. Minimizing dietary Dityr exposure via modified cooking methods or antioxidant-rich diets may mitigate diabetes risk.