Dityrosine administration induces dysfunction of insulin secretion accompanied by diminished thyroid hormones T3 function in pancreas of mice
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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.
KeywordsDityrosine C57BL/6J mice MIN-6 cells Glucose metabolism Energy metabolism Thyroid hormone resistance
The author would like to thank Dr. Harimana Yves and Dr. Md Ramim Tanver Rahman from Jiangnan University for language polishing and Dr. Lingjie Sun from Jiangnan University for technical support in the measurement of whole body energy metabolism. This work is supported by the Chinese Nature Science Foundation (31571841), Natural Science Foundation of Jiangsu Providence, China (BK20140147).
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
And all animal treatments have been performed in accordance with the ethical standards laid down in the guidelines of National Institutes of Health Guide for the Care and Use of Laboratory Animals (China) and in the 1964 Declaration of Helsinki and its later amendments. All animal studies were approved by Laboratory Animals Ethics Committee of Jiangnan University.
- Aguayo-Mazzucato C, Koh A, El Khattabi I, Li WC, Toschi E, Jermendy A, Juhl K, Mao K, Weir GC, Sharma A, Bonner-Weir S (2011) Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells. Diabetologia 54(3):583–593. doi: 10.1007/s00125-010-2026-z CrossRefPubMedGoogle Scholar
- Bhattacharjee S, Pennathur S, Byun J, Crowley J, Mueller D, Gischler J, Hotchkiss RS, Heinecke JW (2001) NADPH oxidase of neutrophils elevates o,o′-dityrosine cross-links in proteins and urine during inflammation. Arch Biochem Biophys 395(1):69–77. doi: 10.1006/abbi.2001.2557 CrossRefPubMedGoogle Scholar
- Cao M, Long Y, Tong Y, Wan J, Tong N (2012) Activation of PPARdelta up-regulates the expression of insulin gene transcription factor MafA and ameliorates glucose-induced insulin secretion impaired by palmitate. Mol Cell Biochem 366(1–2):183–189. doi: 10.1007/s11010-012-1296-9 CrossRefPubMedGoogle Scholar
- Dalsgaard TK, Nielsen JH, Brown BE, Stadler N, Davies MJ (2011) Dityrosine, 3,4-dihydroxyphenylalanine (DOPA), and radical formation from tyrosine residues on milk proteins with globular and flexible structures as a result of riboflavin-mediated photo-oxidation. J Agric Food Chem 59(14):7939–7947. doi: 10.1021/jf200277r CrossRefPubMedGoogle Scholar
- El Refaey M, Watkins CP, Kennedy EJ, Chang A, Zhong Q, Ding KH, Shi XM, Xu J, Bollag WB, Hill WD, Johnson M, Hunter M, Hamrick MW, Isales CM (2015) Oxidation of the aromatic amino acids tryptophan and tyrosine disrupts their anabolic effects on bone marrow mesenchymal stem cells. Mol Cell Endocrinol 410:87–96. doi: 10.1016/j.mce.2015.01.034 CrossRefPubMedPubMedCentralGoogle Scholar
- Li YY, Yu LF, Zhang LN, Qiu BY, Su MB, Wu F, Chen DK, Pang T, Gu M, Zhang W, Ma WP, Jiang HW, Li JY, Nan FJ, Li J (2013) Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice. Toxicol Appl Pharmacol 273(2):325–334. doi: 10.1016/j.taap.2013.09.006 CrossRefPubMedGoogle Scholar
- Li ZL, Shi Y, Le G, Ding Y, Zhao Q (2016) 24-week exposure to oxidized tyrosine induces hepatic fibrosis involving activation of the MAPK/TGF-β1 signaling pathway in Sprague–Dawley rats model. Oxid Med Cell Longev 1:1–12Google Scholar
- Medina MC, Molina J, Gadea Y, Fachado A, Murillo M, Simovic G, Pileggi A, Hernandez A, Edlund H, Bianco AC (2011) The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion. Endocrinology 152(10):3717–3727. doi: 10.1210/en.2011-1210 CrossRefPubMedPubMedCentralGoogle Scholar
- Mitchell CS, Savage DB, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D, Halsall D, Northcott S, Raymond-Barker P, Curran S, Henning E, Keogh J, Owen P, Lazarus J, Rothman DL, Farooqi IS, Shulman GI, Chatterjee K, Petersen KF (2010) Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Investig 120(4):1345–1354. doi: 10.1172/JCI38793 CrossRefPubMedPubMedCentralGoogle Scholar
- Pijl H, de Meijer PH, Langius J, Coenegracht CI, van den Berk AH, Chandie Shaw PK, Boom H, Schoemaker RC, Cohen AF, Burggraaf J, Meinders AE (2001) Food choice in hyperthyroidism: potential influence of the autonomic nervous system and brain serotonin precursor availability. J Clin Endocrinol Metab 86(12):5848–5853. doi: 10.1210/jcem.86.12.8112 CrossRefPubMedGoogle Scholar