Central Journal of Endocrinology, Diabetes & Obesity Mini Review Special Issue on Role of Thyroid Hormone Pancreatic and Islet Develop- in Metabolic Homeostasis ment and Function: The Role of *Corresponding authors Teresa L Mastracci, Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Thyroid Hormone Pediatric Research, 635 Barnhill Dr, MS2031, Indianapolis, IN, USA 46202, Tel: 317-278-8940; Fax: 317-274-4107; Teresa L Mastracci1,5* and Carmella Evans-Molina2,3,4,5* Email: 1Department of Pediatrics, Indiana University School of Medicine, USA Carmella Evans-Molina, Department of Medicine, 2Department of Medicine, Indiana University School of Medicine, USA Cellular and Integrative Physiology, Biochemistry and 3Department of Cellular and Integrative Physiology, Indiana University School of Molecular Biology, Herman B Wells Center for Pediatric Medicine, USA Research, Indiana University School of Medicine, 4Department of Biochemistry and Molecular Biology, Indiana University School of Indiana University School of Medicine, 635 Barnhill Dr., Medicine, USA MS2031, Indianapolis, IN, USA 46202, Tel: 317-278-3177; 5Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Fax: 317-274-4107; Email: USA Submitted: 12 June 2014 Accepted: 17 July 2014 Published: 19 July 2014 Abstract ISSN: 2333-6692 A gradually expanding body of literature suggests that Thyroid Hormone (TH) Copyright and Thyroid Hormone Receptors (TRs) play a contributing role in pancreatic and islet © 2014 Mastracci et al. cell development, maturation, and function. Studies using a variety of model systems capable of exploiting species-specific developmental paradigms have revealed the OPEN ACCESS contribution of TH to cellular differentiation, lineage decisions, and endocrine cell specification. Moreover,in vitro and in vivo evidence suggests that TH is involved in islet Keywords b cell proliferation and maturation; however, the signaling pathway(s) connected with • Thyroid hormone this function of TH/TRs are not well understood. The purpose of this review is to discuss • Thyroid hormone receptor the current literature that has defined the effects of TH and TRs on pancreatic and islet • Pancreatic islet; b cell; Insulin secretion cell development and function, describe the impact of hyper- and hypothyroidism on whole body metabolism, and highlight future and potential applications of TH in novel therapeutic strategies for diabetes. ABBREVIATIONS of this organ from the fetal and perinatal stages through to the adult. As these studies demonstrate, understanding structure E: Embryonic day; Pdx1: Pancreatic and Duodenal often lends great insight into function. Homeobox 1; Ptf1a: Pancreatic Transcription Factor 1a; Cpa1: Carboxypeptidase A1; Cmyc: Myelocytomatosis oncogene; In the mouse, pancreas development begins around TH: Thyroid Hormone; T4: Thyroxine (T4); T3: 3,5,3’-Triiodo- embryonic day (E) 8.5 when cells of the foregut endoderm begin L-Thyronine; TR: Thyroid Hormone Receptors; P: Postnatal to express markers that instruct pancreas formation. The dorsal day; Cdx1: Caudal Type Homeobox Transcription Factor 1; and ventral pancreatic buds evaginate from the primitive gut tube Cdx2: Caudal Type Homeobox Transcription Factor 2; PI3K: due to signals from the adjacent mesoderm [2]; the progenitor Phosphoinositide 3-Kinase; AKT: Protein Kinase B cells that comprise the buds co-express Pdx1 (pancreatic and duodenal homeobox 1) and Ptf1a (pancreatic transcription factor INTRODUCTION 1a) [3]. The stage of embryonic pancreas development from E9.5 The pancreas is a compound digestive gland, comprised of an to E12.5 is known as the primary transition (reviewed in [4]) during which progenitor cells in the dorsal and ventral epithelial exocrine and an endocrine compartment that secrete digestive buds organize into an epithelial arbor structure with both “tip” enzymes and hormones, respectively. The exocrine pancreas is comprised of duct and acinar cells, whereas the endocrine wave” endocrine cells (composed mostly of glucagon-expressing pancreas is organized into structures known as the islets of and “trunk” domains,secondary as well transition as a few[6] isearly characterized differentiated mainly “first by Langerhans [1]. While endocrine mass comprises only ~2% of the differentiation and expansion of the endocrine and exocrine the total pancreas mass, the contribution of hormone-producing cellα cells populations. [5]). The In particular, multipotent progenitor cells in the “tip” domain (Cpa1+ (carboxypeptidase A1), Ptf1a+, Cmyc+ of studies focused on development of the pancreas in the mouse (myelocytomatosis oncogene)) give rise to acinar cells, whereas (endocrineMus musculus cells )to havewhole uncovered body metabolism the structural is significant. organization Decades Cite this article: Mastracci TL, Evans-Molina C (2014) Pancreatic and Islet Development and Function: The Role of Thyroid Hormone. J Endocrinol Diabetes Obes 2(3): 1044. Mastracci et al. (2014) Email: Central progenitor cells in the “trunk” domain (Neurog3+) delaminate from the epithelial cords and differentiate into the hormone- (transcribedand bones, and from death an byinternal five weeks promoter of life located [21]. Thein intron mutation 7), of TRα that also affects the naturally truncated TRΔα isoform [7].expressing The existence endocrine of distinct cells, including domains β of (insulin), progenitor α (glucagon), cells, which δ give(somatostatin), rise to the differentiatedPP (pancreatic cell polypeptide), populations and in εthe (ghrelin) developing cells genesdemonstrates Cdx1 (caudal that TRαtype ishomeobox important transcription for intestinal factor maturation 1) and pancreas, suggests that fate decisions may be decided in these Cdx2as well (Caudal as transcriptional type homeobox activation transcription of the factor intestine-specific 2) [15]. With early progenitor cells [8,9]; however, recent studies have also begun to shed light on the plasticity of differentiated pancreatic the hypothalamic-pituitary-thyroid axis, the retina, and impairs cells [10-13]. While the current body of work is quite limited, respect to loss of the TRβ isoform, deletion of TRβ alone alters Thyroid Hormone (TH) and the Thyroid Hormone Receptors dysfunctionhearing [22]. of The the generationpituitary-thyroid of mice axis, with impaired a homozygous weight gainTRβ development, maturation, and function. andmutation abnormal that isbone also development, found in humans which (TRβPV) is a distinct results phenotype in severe (TRs) may be factors of significance to pancreatic and islet cell PANCREAS AND ISLET DEVELOPMENT The deiodination of the precursor thyroxine (T4) permits the displaycompared severe with thegrowth TRβ reduction,null mutant hypothermia [23]. Interestingly, and hearing when synthesis of thyroid hormone (3,5,3’-triiodo-L-thyronine; T3; impairmentthe TRα and [24].TRβ mutationsOverall, these are combined,studies point mice to are loss viable of TRsbut TH). The subsequent action of T3 is mediated by two Thyroid having a profound effect on the normal development and Thra; function of many organs; however, the necessity and function of Nr1a1 Thrb; Nr1a2) contain alternative promoters TRs for pancreas development and/or pancreatic and islet cell Hormoneand splice Receptorsvariants ultimately (TRs). The resulting genes inthat the encode production TRα of( four function remains a fairly understudied area of research. As will ) and TRβ ( be discussed in the following section, there is mounting evidence that TH plays a functional role in pancreatic cell fate decisions, quitemRNAs complex, and the andsynthesis numerous of four mouse nuclear models receptors have – TRα1,been gener TRβ1,- as well as structural organization of the pancreatic organ proper. atedTRβ2, to TRβ3 dissect [14]. the The function action of and TH antagonism and the various of the TR receptors isoforms. is CELLULAR DIFFERENTIATION expressed, resulting in distinct protein expression patterns. Cer- The process of cellular differentiation is critical to the With regard to gene expression, TRα and TRβ are differentially development of all organs, and various model organisms have been used to understand the stages or processes involved in how isoformstain TRα isoformsare found are in ubiquitous, liver, pituitary, whereas hypothalamus, others are specifically inner ear, the pancreas develops. The mouse (Mus musculus) is the most retina,expressed kidney, in the lung, intestine skeletal [15]. muscle, While heart, also widely spleen expressed,and brain [14]. TRβ widely used model system for studies investigating mammalian With respect to the pancreas, the expression of TR isoforms is physiology and metabolism; however, this model has also noted in rat pancreas [16,17] and mouse islets [18]; however, the expression pattern of TH and the TRs has not been carefully ex- Danio rerio), amined at the cellular level in the embryonic pancreas. Aiello and thebeen African used clawedto decipher frog (Xenopuskey factors laevis that), and instruct the chicken or influence (Gallus galluspancreatic organogenesis. Additionally, zebrafish ( transcript in whole embryonic pancreas from E12.5 through pancreatic studies. For example, given the complicated models/ colleagues [19] assessed the abundance of TRα and TRβ mRNA genetics) exhibitrequired species-specific to study pancreas experimental regeneration advantages in the mouse for and steadily increases as pancreas development proceeds until postnatal