The Roles of Thyroid and Thyroid Hormone in Pancreas: Physiology and Pathology

Hindawi International Journal of Endocrinology Volume 2018, Article ID 2861034, 14 pages https://doi.org/10.1155/2018/2861034 Review Article The Roles of Thyroid and Thyroid Hormone in Pancreas: Physiology and Pathology Chaoran Chen,1 Zhenxing Xie ,2 Yingbin Shen ,3 and Shu Fang Xia 4 1 Institute of Nursing and Health, College of Nursing and Health, Henan University, Kaifeng, China School of Basic Medicine, Henan University, Jinming Avenue 475004, Henan, Kaifeng, China 3 Department of Food Science and Engineering, Jinan University, Guangzhou, China 4 Wuxi School of Medicine, Jiangnan University, Wuxi, China 2 Correspondence should be addressed to Zhenxing Xie; Received 19 February 2018; Revised 18 April 2018; Accepted 10 May 2018; Published 14 June 2018 Academic Editor: Alexander Schreiber Copyright © 2018 Chaoran Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It is widely accepted that thyroid hormones (THs), secreted from the thyroid, play important roles in energy metabolism. It is also known that THs also alter the functioning of other endocrine glands; however, their effects on pancreatic function have not yet been reviewed. One of the main functions of the pancreas is insulin secretion, which is altered in diabetes. Diabetes, therefore, could be related to thyroid dysfunction. Earlier research on this subject focused on TH regulation of pancreas function (such as insulin secretion) or on insulin function through TH-mediated increase of energy metabolism. Afterwards, epidemiological investigations and animal test research found a link between autoimmune diseases, thyroid dysfunction, and pancreas pathology; however, the underlying mechanisms remain unknown. Furthermore, recent studies have shown that THs also play important roles in pancreas development and on islet pathology, both in diabetes and in pancreatic cancer. Therefore, an overview of the effects of thyroid and THs on pancreas physiology and pathology is presented. The topics contained in this review include a summary of the relationship between autoimmune thyroid dysfunction and autoimmune pancreas lesions and the effects of THs on pancreas development and pancreas pathology (diabetes and pancreatic cancer). 1. Introduction 1.1. Thyroid Physiology. Thyroid hormones (THs) are involved in several processes, such as growth, development, reproduction, and metabolism. While THs act on almost every organ in the body, research has been focused on the central nervous system [1], the cardiovascular system [2], and the skeleton [3]. Recently, increasing prevalence of metabolic diseases (including obesity, diabetes, and hyperlipemia, among others) have reestablished the focus on thyroid hormone, since THs have the ability to improve energy metabolism in the body. TH-related studies are centered on TH effects on fat degradation, glucose oxidization, and oxidative phosphorylation acceleration, and other metabolic effects [4]. Meanwhile, thyroid hormone mimetics have been developed in order to treat obesity and diabetes. Nevertheless, a deeper knowledge of the mechanisms needs to be developed in order to understand the complex physiological effects of THs. THs include 3,5,3′,5′-tetraiodo-L-thyronine (T4) and 3,5,3′-triiodo-L-thyronine (T3); both hormones are synthesized and secreted from the thyroid gland. THs secreted from the thyroid are stimulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary gland. TSH is again regulated by the thyrotropin-releasing hormone (TRH), which is produced from the hypothalamus [5]. Most of blood T3 and T4 is found in their protein-combined forms, while small amounts are found in their free form. Only free T3 and free T4 have biological action; T3 has the most potent physiological function. Free T3 largely derives from T4 via 5′-deiodinases (D1 and D2), and T3 conversion from T4 takes place inside TH target cells. D3 inactivates 2 both T4 and T3 molecules in order to terminate thyroid hormone action in a timely manner [6]. Before being recognized by their receptors, THs must be transported into target cells by special transporters. One highly specific transporter is monocarboxylate transporter 8 (MCT8); its inactivating mutations could be the cause of diseases characterized by local TH shortage, such as Allan-Herndon-Dudley syndrome, a disorder characterized by normal TSH level and elevated T3 and decreased T4 serum levels [7]. Other TH secondary transporters include the aromatic amino acid transporter MCT10, the organic anion transporting polypeptide transporters (e.g., OATP1C1, OATP1A2, and OPTP1A4), the large neutral amino acid transporters (LAT1 and LAT2), and another amino acid transporter, the L-cystine and L-glutamate exchanger. In different organs, different expression patterns for both primary and secondary TH transporters have been described [8], suggesting that THs have different local actions in different organs. The physiological function of thyroid hormones requires the interaction of THs and their nuclear receptors (TRs). There are two major TR isoforms, encoded on separate genes [9, 10]: TRα and TRβ. The TRβ gene encodes three TRβ isoforms: TRβ1, TRβ2, and TRβ3. All TRβ isoforms bind to their cognate ligand T3 with high affinity to mediate target gene expression. In contrast, among the three TRα isoforms, only TRα1 is able to bind to T3 in order to activate or repress target genes, whereas TRα2 and TRα3 do not bind T3, antagonizing T3 action. TRs can bind to specific cis elements called thyroid hormone response elements (TREs), which are located in the promoter of target genes and form homodimers or heterodimers with retinoid X receptor (RXR) [11] and other receptors (such as estrogen receptor) [12]. Besides, THs produce nongenomic effects, which are not dependent on nuclear TRs. These effects have no structure-function relationships with THs analogs, and they have a fast onset of action by inducing membrane-related signaling pathways. The nongenomic effects are diverse; usually, they involve kinases or calmodulin, Ca2+-ATPase, adenylate cyclase, and glucose transporters (GLUT) [13]. Nevertheless, most T3 effects are assumed to be mediated by the regulation of TR target gene transcriptions in the nucleus. It is well known that THs can affect the action of other hormones (such as retinoid by RXR) and also have effects on other endocrine glands. One of these glands is the pancreas, which is involved in chronic and prevalent diseases, such as diabetes. Therefore, thyroid dysfunction, including autoimmune thyroid diseases, hypothyroidism and hyperthyroidism, and abnormal TH signaling pathway, could cause pancreas dysfunctions. Sequentially, thyroid dysfunction could cause system metabolism dysfunctions, which complicate diagnoses and even affect subsequent treatments. A b (...truncated)