Effects of dietary oxidized tyrosine products on insulin secretion via the thyroid hormone T3-regulated TRβ1-Akt-mTOR pathway in the pancreas

Oxidized tyrosine products (OTPs) have been detected in commercial foods with high protein content. Dityrosine (Dityr) is a typical oxidized tyrosine product. The previous studies in our lab demonstrated that dityrosine administration impaired glucose tolerance and suppressed the bio-function of thyroid hormone T3 of mice. The T3-activated Akt-mTOR signaling pathway plays important roles in insulin synthesis in pancreatic beta cells. Due to the structural homology between dityrosine and T3, the molecular binding domain for these two compounds in TR beta 1 might be the same site. Therefore, the present study investigates the potential impact of dietary OTPs on the pancreatic function. Sprague Dawley (SD) rats were fed a diet containing OTPs for 12 weeks. In addition, a 10 week gavage experiment using C57BL/J mice was performed to explore whether dityrosine was responsible for the injury induced by OTPs. The blood glucose, plasma insulin levels, and plasma free thyroid hormones (THs) were then measured. After 12 week dietary OTPs or 10 week OTPs/dityrosine gavage, elevated fasting blood glucose and decreased plasma insulin levels were detected both in rats and mice in the presence of enhanced plasma free THs content, which indicated dysfunction of the pancreatic islets and that the regulation of T3 to insulin synthesis was suppressed by OTPs and dityrosine. A cell experiment using mouse MIN-6 cells was performed to explore the mechanism of the diminished T3 bio-function in pancreatic islets induced by dityrosine. Dityrosine incubation attenuated the T3-mediated insulin synthesis via an indirect way of regulating the mRNA expression of genes related to insulin synthesis and decreasing the protein level of TR beta 1. In addition, dityrosine inhibited the Akt phosphorylation activated by T3 in MIN-6 cells. Dityrosine treatment altered the T3-activated translation factors involved in the Akt-mTOR signaling pathway. These findings indicate that decreased insulin secretion triggered by dietary OTPs may be mediated by suggested T3-stimulated protein synthesis in pancreatic beta cells.