Insulin-Like Growth Factor Pathway and the Thyroid.

Terry J Smith

doi:10.3389/fendo.2021.653627

Abstract

The insulin-like growth factor (IGF) pathway comprises two activating ligands (IGF-I and IGF-II), two cell-surface receptors (IGF-IR and IGF-IIR), six IGF binding proteins (IGFBP) and nine IGFBP related proteins. IGF-I and the IGF-IR share substantial structural and functional similarities to those of insulin and its receptor. IGF-I plays important regulatory roles in the development, growth, and function of many human tissues. Its pathway intersects with those mediating the actions of many cytokines, growth factors and hormones. Among these, IGFs impact the thyroid and the hormones that it generates. Further, thyroid hormones and thyrotropin (TSH) can influence the biological effects of growth hormone and IGF-I on target tissues. The consequences of this two-way interplay can be far-reaching on many metabolic and immunologic processes. Specifically, IGF-I supports normal function, volume and hormone synthesis of the thyroid gland. Some of these effects are mediated through enhancement of sensitivity to the actions of TSH while others may be independent of pituitary function. IGF-I also participates in pathological conditions of the thyroid, including benign enlargement and tumorigenesis, such as those occurring in acromegaly. With regard to Graves’ disease (GD) and the periocular process frequently associated with it, namely thyroid-associated ophthalmopathy (TAO), IGF-IR has been found overexpressed in orbital connective tissues, T and B cells in GD and TAO. Autoantibodies of the IgG class are generated in patients with GD that bind to IGF-IR and initiate the signaling from the TSHR/IGF-IR physical and functional protein complex. Further, inhibition of IGF-IR with monoclonal antibody inhibitors can attenuate signaling from either TSHR or IGF-IR. Based on those findings, the development of teprotumumab, a β-arrestin biased agonist as a therapeutic has resulted in the first medication approved by the US FDA for the treatment of TAO. Teprotumumab is now in wide clinical use in North America.

Highlights

Among the most ubiquitous regulatory factors governing functions in the mammalian body are those belonging to the insulin and insulin-like growth factor-I (IGF-I) family, including their respective receptors, binding and related proteins, and extensive signaling pathways that mediate/ modulate their actions
The incidence of thyroid nodules was found to be increased substantially in children with extreme insulin resistance [34] bringing clinical relevance to the basic observations made in the laboratory. Signaling through both insulin-like growth factor-I receptor (IGF-IR) and IR is considered essentially indispensable in the normal function of the thyroid gland, both through their independent support of thyroid epithelial survival and vitality and by virtue of the interactions of their downstream pathways with those of the thyrotropin receptor (TSHR) [35]
Subsequent studies have disclosed the physical and functional interactions between IGF-IR and TSHR occurring in thyroid epithelial cells, Graves’ disease (GD)-OF and in situ in thyroid-associated ophthalmopathy (TAO) orbital fat [98]

Summary

INTRODUCTION

Among the most ubiquitous regulatory factors governing functions in the mammalian body are those belonging to the insulin and insulin-like growth factor-I (IGF-I) family, including their respective receptors, binding and related proteins, and extensive signaling pathways that mediate/ modulate their actions. The incidence of thyroid nodules was found to be increased substantially in children with extreme insulin resistance [34] bringing clinical relevance to the basic observations made in the laboratory Signaling through both IGF-IR and IR is considered essentially indispensable in the normal function of the thyroid gland, both through their independent support of thyroid epithelial survival and vitality and by virtue of the interactions of their downstream pathways with those of the thyrotropin receptor (TSHR) [35]. IGF-IR engagement in cultured thyroid epithelial cells has been shown to activate the expression of chemokines and cytokines such as IL-16 and RANTES [39] Both insulin and IGF-I can regulate the rate of major histocompatibility complex class 1 (MHC class 1) gene transcription [40]. Elevated levels of the IGF-IEc isoform have been reported in differentiated papillary thyroid carcinoma and are associated with advanced disease [46]

THE THYROID IN ACROMEGALY

Findings

ARE DISEASE INDICATIONS BEYOND TAO IN STORE FOR TEPROTUMUMAB?