Dityrosine administration induces dysfunction of insulin secretion accompanied by diminished thyroid hormones T3 function in pancreas of mice

Abstract

Oxidized tyrosine products are commonly found in food with high protein content and have been demonstrated to cause damage of liver and kidney in our previous studies. Dityrosine (Dityr) is a typical oxidized tyrosine product. Due to its structural homology with thyroid hormones T3, we assumed that one of the endocrine systems most likely considered in connection with its disruption by Dityr may be the T3 action. T3 plays important roles in insulin synthesis, and thyroid hormone resistance (RTH) is associated with the impairment of glucose metabolism. Therefore, this study determined whether Dityr exposure impaired T3 function in pancreas leading to glucose metabolism disruption. After 10-week gavage with Dityr, mice exhibited impaired glucose tolerance and disturbed energy metabolism. The elevated free THs content in plasma, the up-regulation of THs synthesis-specific genes expressions in thyroid glands, and the increased thyroid follicles histology shapes and areas indicated that Dityr enhanced the THs synthesis in thyroid glands. In addition, Dityr-induced RTH, which reflected as elevated plasma free THs in the presence of unsuppressed thyroid stimulating hormone. The mRNA downregulation of membrane transporter of T3 (MCT8) and co-activator factors (RXRα, Src-1), together with the decreased protein level of thyroid hormone receptor β1 (TRβ1) in pancreas illustrated that the activation ability of T3 to downstream gene involved in insulin synthesis was suppressed by Dityr. In MIN-6 cell experiment, T3 improved glucose-stimulated insulin secretion by upregulating mRNA levels of insulin synthesis-related genes (Ins2, MafA, Pdx1) and T3 action-related genes, as well as increasing protein level of TRβ1. These data suggest that Dityr suppress T3-regulated insulin synthesis stimulated by glucose via an indirect way of decreasing sensibility to T3 in pancreas. All these findings indicate that Dityr can disrupt THs function in pancreas leading to glucose metabolism disorder.

Long‐Chain n‐3 PUFA Content and n‐6/n‐3 PUFA Ratio in Mammal, Poultry, and Fish Muscles Largely Explain Differential Protein and Lipid Oxidation Profiles Following In Vitro Gastrointestinal Digestion

“…As Estévez and Luna reviewed, protein oxidation during digestion may be related to the onset and/or development of various chronic diseases. For example, oxidation products of lysine and tyrosine have been shown to alter glucose homeostasis and insulin secretion . Additional studies are however necessary to truly understand the (patho)physiological effects of PCC formed during the gastrointestinal digestion of foods.…”

Intake of Oxidized Proteins and Amino Acids and Causative Oxidative Stress and Disease: Recent Scientific Evidences and Hypotheses

“…Li, Mo, Le, and Shi () found around 0.5 mg dityrosine per kg of protein in caseins oxidized in vitro. However, in subsequent studies, the same authors also found pathological effects lowering the dose of dityrosine to 320 μg/kg bw/day (Ding, Li et al., ). Using this dose, the authors hypothesized whether dityrosine could affect endocrine functions via the disruption of the T3 thyroid hormone owing to their structural homology.…”

“…The intestinal uptake of specific protein oxidation products after oral administration, and the subsequent organic accumulation proves the bioavailability and bioactivity of these species which seem to have certain tropism for target tissues. This is the case of protein carbonyls for the intestinal epithelium (Keshavarzian et al., ), the α‐amino adipic acid for pancreas (Wang et al., ), and oxidized tyrosines for pancreas, kidney and liver (Ding, Cheng et al., ; Ding, Li et al., ; Ding, Tang et al., ; Yang, Zhang et al., , Yang, Yan et al., ). Finally, it is worth noting that the elevation of protein oxidation markers in blood and tissues may not only be caused by the intake of such species.…”

“…Other pathological mechanisms may involve exacerbated antioxidant and immune responses, which facilitate chronic inflammation and tissue degeneration (Keshavarzian et al., ). Proteomic, genomic, and metabolomics studies have recently observed the ability of oxidized amino acids to modulate gene expression, leading to impaired physiological functions (Li, Shi, Le, Ding, & Zhao, ; Yang, Zhang et al., ; Yang, Yan et al., ,). Finally, animal proteins, heme iron and derived protein oxidation products may alter the microbiome, making the intestinal mucosa more sensitive to both biological and chemical threats (Constante, Fragoso, Calvé, Samba‐Mondonga, & Santos, ; Portune et al., ; Van der Leek, Yanishevsky, & Kozyrskyj, ).…”

Benefits of wine‐based marination of strip steaks prior to roasting: inhibition of protein oxidation and impact on sensory properties

“…According to Yang et al ., the intake of dityrosines impairs assorted systemic metabolic processes, facilitates fat accumulation in liver, induces hepatic and renal injury, affects the gut microbiota function, and increases the risk factor for cardiovascular diseases. Ding et al . observed that dietary dityrosines disrupt pancreas functionality, leading to glucose metabolism disorder.…”