Insulin Receptor Isoforms and Insulin-Like Growth Factor Receptor in Human Follicular Cell Precursors From Papillary Thyroid Cancer and Normal Thyroid. (E) Diplopia response (percent of patients with improvement of at least 1 grade from baseline). Left panel: under normal [Ca. Further, IGF-I appears to skew the accumulating HA molecules toward higher molecular weight species and to promote the proliferation of perimysial GD-OF (120). Igs From Patients With Graves Disease Induce the Expression of T Cell Chemoattractants in Their Fibroblasts. Teprotumumab for Thyroid-Associated Ophthalmopathy. J Clin Oncol: Off J Am Soc Clin Oncol (2011) 29:457480. {Beta}-Arrestin Is Crucial for Ubiquitination and Down-Regulation of the Insulin-Like Growth Factor-1 Receptor by Acting as Adaptor for the MDM2 E3 Ligase. Endocr Rev (1995) 16:14363. doi: 10.1007/s12020-013-9981-3, 50. CMH weighting was used to estimate the common risk difference and the 95% Confidence Interval (95% CI) of the common risk difference for the primary and secondary endpoints of overall responder, percent with CAS 0 or 1, and diplopia responder; least squares mean difference was calculated for secondary endpoints of change in proptosis from baseline and change in Graves Orbitopathy quality of life (GO-QOL) questionnaire from baseline using the Mixed-Model Repeated-Measures (MMRM) analysis of covariance (ANCOVA). Pappo AS, Patel SR, Crowley J, Reinke DK, Kuenkele KP, Chawla SP, et al. Insulin-like growth factor (IGF) signaling is regulated by a conserved family of IGF binding proteins (IGFBPs) in vertebrates. doi: 10.1677/joe.0.1350115, 86. Brain Res (1987) 406:3242. doi: 10.1007/s00280-013-2372-x, 112. Insulin-like growth factor signaling in fish. 50th Anniversary of the Discovery of That Hormone. J Endocrinol (2006) 189:60515. Teprotumumab for Dysthyroid Optic Neuropathy: Early Response to Therapy. subsequently reported that signaling initiated by both rhTSH and GD-IgG could be attenuated in vitro by 1H7, a monoclonal anti-IGF-IR-inhibitory antibody (98). The efficacy of insulin-like growth factor 1 (IGF-1) in the treatment of peripheral facial nerve palsy was investigated using an animal model. Thyroid (2012) 22:4306. Blethen SL, White NH, Santiago JV, Daughaday WH. Thus, there exists substantial molecular rationale for considering the importance of a functional interplay between IGF-IR and TSHR and for targeting this protein complex therapeutically. Proc Natl Acad Sci USA (2012) 109:206205. Endocrinology (2001) 142:51319. Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes. Ortiz L, Zannini M, Di Lauro R, Santisteban P. Transcriptional Control of the Forkhead Thyroid Transcription Factor TTF-2 by Thyrotropin, Insulin, and Insulin-Like Growth Factor I. J Biol Chem (1997) 272:233349. Ozzello DJ, Kikkawa DO, Korn BS. The efficacy of the drug in stable disease is being addressed, not only in the formal study currently under development but also by monitoring real-world experience. JAAD Case Rep (2020) 12812 doi: 10.1016/j.jdcr.2020.09.003, 133. Based on the results of the two clinical trials conducted for teprotumumab in TAO, the FDA approved its use in that disease in January, 2020 (128). Brenner-Gati L, Berg KA, Gershengorn MC. J Ultrasound (2010) 13:907. Phosphatidylinositol 3-Kinase/Nuclear Factor-Kappa B Signaling Pathway is Involved in the Regulation of IGF-I on Fas-Associated Death Domain-Like interleukin-1-Converting Enzyme-Inhibitory Protein Expression in Cultured FRTL Thyroid Cells. Sulfation factor underwent a name change to somatomedin C in 1972 (4) and finally to its current designation, IGF-I, in the early 1980s (5). This phenomenon may result from enhanced thyroid sensitivity to the actions of TSH caused by either growth hormone, IGF-I, or both. Several important exclusions in the profiles of eligible patients who were enrolled in those studies have resulted in additional questions needing answers during the post-approval period. Ren M, Guan Q, Zhong X, Gong B, Sun Y, Xin W, et al. Arch Endocrinol Metab (2020) 64:26975. Slentz D, Smith TJ, Kim DS, Joseph SS. The mitogenic activities of both normal and acromegalic sera can be attenuated by pretreating them with neutralizing monoclonal anti-IGF-I antibodies. The muscle volume was reduced by 49% (yellow arrowhead). Douglas RS, Gianoukakis AG, Kamat S, Smith TJ. Clin Endocrinol (1983) 19:33744. 12:653627. doi: 10.3389/fendo.2021.653627. Solomon J, Greep RO. doi: 10.1210/endo.131.3.1380443, 83. Among the six distinct types of IGFBPs, IGFBP-5 is the most highly conserved across species and has the broadest range of biological activities. In contrast, Iodine downregulated the levels of this mRNA. In studies of FRTL-5 rat thyroid cells, IGF-II but not IGF-I was found to be synthesized and released (27). Together with insulin and GH, IGFs regulate glucose and lipid metabolism, and thereby regulate body composition. Among these, IGFs impact the thyroid and the hormones that it generates. Figure 3 IGF-IR can form functional RTK/GPCR hybrids, thus aggregating tyrosine kinase and GPCR signaling. doi: 10.1042/bj3030467, 72. The Insulin-Like Growth Factor-Binding Protein (IGFBP) Superfamily. Based on those findings, the development of teprotumumab, a -arrestin biased agonist as a therapeutic has resulted in the first medication approved by the US FDA for the treatment of TAO. Among the main physiological functions of IGF is increased _____ uptake amino acid The hormone released by the pancreas that regulates blood glucose levels is insulin The _________ is the origin of cortisol adrenal cortex The hormonal ratio used to monitor overall anabolic and catabolic status of the body is the ______ ratio 382; 341-352. The structure of IGFBP-5. Mediating the actions of insulin and IGF-I are their respective, closely related receptors (IGF-IR and IR, respectively), both belonging to the tyrosine kinase family (Figure 2). Cells (2020) 9. doi: 10.3390/cells9040862, 122. doi: 10.1007/BF03346614, 7. -, Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-Meek S, Dalton D, et al. Eur J Endocrinol (1995) 132:6012. Wster C, Steger G, Schmelzle A, Gottswinter J, Minne HW, Ziegler R. Increased Incidence of Euthyroid and Hyperthyroid Goiters Independently of Thyrotropin in Patients With Acromegaly. 12 Articles, This article is part of the Research Topic, Impact of GH and its Primary Effector, IGF-I, on the Thyroid Gland, Interplay Between IGF-I and Thyroid Hormone Metabolism and Pathways, Impact of Thyroidal Status on the GH/IGF-I Axis, IGF-I and Insulin Enhance the Actions of TSH and Thyroid-Stimulating Immunoglobulins: Evidence for Interplaying Pathways, Emerging Relevance of IGF-IR in the Pathogenesis of GD and TAO, Culmination of Evidence That IGF-IR Represents A Clinically Important Therapeutic Target in TAO, Teprotumumab Becomes First Ever FDA-Approved Medical Therapy for TAO. Individuals who had previously undergone orbital surgery, had received tocilizumab or rituximab or who had been treated with high-dose glucocorticoids for TAO (excepting those receiving < 1 gm prednisone equivalent following a 6-week washout period) were excluded. Figure 5 (A) Trial profile describing enrollment, randomization, and follow-up. Those open questions are also under study. doi: 10.1200/jco.2010.28.15_suppl.10000, 109. However, several studies have shown an association between increased levels of circulating IGF-1 and the risk of developing solid malignancies, including PCa. doi: 10.1210/endo-119-3-1204, 85. Natchev E, Vandeva S, Kovatcheva R, Kirilov G, Kalinov K, Zacharieva S. Thyroid Gland Changes in Patients With Acromegaly. *Correspondence: Terry J. Smith, terrysmi@med.umich.edu, Special 2021 Frontiers in Endocrinology Collection for the 100th Anniversary of Insulin Discovery, View all The author declares US Patents covering the use of IGF-1 receptor inhibitors in autoimmune disease and consultancy for Horizon Therapeutics Consultant Immunovant. The trial enrolled patients with moderate to severe, active TAO between 18 and 75 years of age between July 2, 2013 and September 23, 2015. Metabolic IGF-1 functions mostly involve the maintenance of normal insulin sensitivity, glucose uptake increase, plasma triglyceride decrease, and cholesterol level regulation [ ]. In those studies, IGF-I transcript was undetectable in the absence of TSH, effects that were mimicked by forskolin. Insulin-Like Growth Factor Binding Protein Expression in the Hypothyroid Rat Is Age Dependent. doi: 10.1210/endo.132.2.7678799, 79. Pituitary (2010) 13:2428. For instance, all trial subjects must have manifested TAO for 9 months prior to their study enrolment, leaving uncertain whether more chronic, less active disease might respond to teprotumumab. doi: 10.1210/jc.2018-02289, 35. Various tissues, and particularly some tumour tissues, produce a protease which acts on IGFBP and so causes a local increase in the concentration of free IGF-1. The Endocrine Organs in Health and Disease: With an Historical Review. doi: 10.3109/08977199009071497, 36. doi: 10.1002/ijc.31779, 39. As suggested above, entanglement between the actions of GH, IGF-I and thyroid hormones is complex and can become unmasked with excesses or deficiencies in one or both pathways. Ghosh P, Dahms NM, Kornfeld S. Mannose 6-Phosphate Receptors: New Twists in the Tale. Susperreguy S, Miras MB, Montesinos MM, Mascanfroni ID, Muoz L, Sobrero G, et al. Further, none had received > 1 gram of prednisolone or equivalent for the treatment of TAO. In another report, serum IGF-I levels were lower in hyperthyroid patients while levels trended toward elevation in hypothyroid individuals (80). Thyroid Hormone-Mediated Growth and Differentiation of Growth Plate Chondrocytes Involves IGF-1 Modulation of Beta-Catenin Signaling. Diminished and Irregular Thyrotropin Secretion With Preserved Diurnal Rhythm in Patients With Active Acromegaly. Evaluation of IGFBP5 expression and plasma osteopontin level in COVID-19 patients. Microarray Analysis of Thyroid Stimulating Hormone, Insulin-Like Growth factor-1, and Insulin-Induced Gene Expression in FRTL-5 Thyroid Cells. IGF-I was recently found to enhance the expression of TSHR in orbital fibroblasts (112). Epub 2007 Feb 21. Insulin-Like Growth Factor-I Stimulates the Growth of Rat Thyroid Cells in Culture and Synergizes the Stimulation of DNA Synthesis Induced by TSH and Graves-Igg. Propylthiouracil treatment in rats results in substantially increased IGF-II binding site density on thyroid epithelial cells (84). (B) The pathogenesis of TAO also involves the infiltration of professional immune cells. Animals harboring the mutant transcription factor, Pit-1, (Snell dwarf mice), exhibit multiple deficiencies in anterior pituitary hormones resulting in defective B cell development (77). In that study, T3 was shown to enhance IGF-1R signaling and its upregulation of PI3K/Akt/GSK-3 signaling. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Ock S, Ahn J, Lee SH, Kim HM, Kang H, Kim YK, et al. Growth Hormone (GH) Treatment Reduces Peripheral Thyroid Hormone Action in Girls With Turner Syndrome. doi: 10.1097/IOP.0000000000001831, 131. Congruent with that possibility, Chen etal. J Clin Endocrinol Metab (2011) 96:76674. doi: 10.1210/en.2019-00055, 123. The Thyroid-Stimulating Hormone Receptor: Impact of Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Antibodies on Multimerization, Cleavage, and Signaling. Clipboard, Search History, and several other advanced features are temporarily unavailable. Int Rev Cytol. Abstract. Effects of biomechanical and biochemical stimuli on angio- and vasculogenesis in a complex microvasculature-on-chip. Effects of Tri-Iodothyronine and Insulin-Like Growth Factor-I (IGF-I) on Alkaline Phosphatase Activity, [3H]Thymidine Incorporation and IGF-I Receptor mRNA in Cultured Rat Epiphyseal Chondrocytes. Thyroid gland volume is frequently impacted (49) and frank thyroid enlargement in acromegaly is not unusual. Endocrinology (1987) 121:74956. IGF-I and the IGF-IR share substantial structural and functional similarities to those of insulin and its receptor. It remains uncertain whether the relationship between IGF-I action, IGF-IR signaling, or any of the other components of the IGF-I pathway differ in their relationship to thyroid cancers when compared to other forms of neoplastic disease. 78. Pirazzoli P, Cacciari E, Mandini M, Sganga T, Capelli M, Cicognani A, et al. Figure 2 Classical model of signaling through the IGF-IR. Subjects aged 18-80 years, were randomized to receive either teprotumumab (n=41) or placebo (n=42). (C) Coronal, contrast-enhanced, fat-saturated, T1-weighted MRIs in a single patient receiving teprotumumab at baseline and at week 24. (1999) 140:517884. doi: 10.1507/endocrj.EJ11-0324, 63. IGF-I stimulates DNA synthesis and thyroid cell proliferation, actions synergistic with those of epidermal growth factor. Pediatr Endocrinol Rev. Among the IGF-IR/IR-activated pathways in thyroid cells are Erk 1/2, and Akt, while TSHR is G protein coupled and results in the generation of cAMP. 1. Some contradictory findings have been reported in human dysthyroidemia. J Immunol (Baltimore Md: 1950) (2008) 181:4397405. From N. Engl. Paik JS, Kim SE, Kim JH, Lee JY, Yang SW, Lee SB. Endocrinology (1990) 126:5504. Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, et al. Proc Natl Acad Sci USA (2014) 111:145127. Studies in Ewings sarcomacells treated with figitumumab, an IGF-IR antagonist, revealed that this antibody functioned as an IGF-1R-biased agonist through -arrestin1 recruitment to the receptor, enhancing IGF-IR ubiquination and provoking Erk phosphorylation in the absence of Akt activation (92). IGF-IR is over-expressed by GD-OF (9) as well as T cells (116) and B cells (117). Neuro Endocrinol Lett (2009) 30:3826. B and T cells and antigen-presenting cells which infiltrate the gland produce interleukins 1, 6, 12, 13, interferon , tumor necrosis factor , and CD40 ligand. The phase 3 trial included an extension where all non-responders were offered teprotumumab as an open label, regardless of whether or not they had received the active drug or placebo during the 24-week treatment phase. Su Y, Cao Y, Liu C, Xu Q, Li N, Lan M, Li L, Wang K, Zhang Z, Meng Q. Theranostics. Matsuo K, Yamashita S, Niwa M, Kurihara M, Harakawa S, Izumi M, et al. Transcriptional Regulation of Major Histocompatibility Complex Class I Gene by Insulin and IGF-I in FRTL-5 Thyroid Cells. 2013 10:473-484. Panel (A) Clinical photographs of a patient receiving placebo. Int J Cancer (2018) 143:245869. Thyroid and Glucocorticoid Hormones Synergistically Control Growth Hormone mRNA in Cultured GH1 Cells. A second, phase 3 trial, was initiated by Horizon Pharmaceuticals (now Horizon Therapeutics) after a licensing agreement was established with River Vision in 2017. Specifically, IGF-I supports normal function, volume and hormone synthesis of the thyroid gland. doi: 10.1210/jc.2009-0174, 48. J Immunol (Baltimore Md: 1950) (2002) 168:94250. Both basal and pulsatile TSH secretion are often reduced while thyroxine levels can remain unaffected (47). This results in the release of the IGF ligand from the complex and a consequent increase in IGF ligand available for binding to the IGF-1R . Insulin-like growth factors (IGFs) are key growth-promoting peptides that act as both endocrine hormones and autocrine/paracrine growth factors. Reprinted with permission. Grassadonia A, Tinari N, Fiorentino B, Nakazato M, Chung HK, Giuliani C, et al. Careers. The major regulator of hepatic IGF-I biosynthesis is growth hormone (GH); insulin and nutrients are also important determinants of liver IGF-I . Moreno B, Rodrguez-Manzaneque JC, Prez-Castillo A, Santos A. Thyroid Hormone Controls the Expression of Insulin-Like Growth Factor I Receptor Gene At Different Levels in Lung and Heart of Developing and Adult Rats. IGFBP-5 is expressed in diverse cell types, and its expression level is regulated by a variety of signaling pathways in different contexts. doi: 10.1074/jbc.M501129200, 91. 2.1. Potential effectiveness of teprotumumab in vision threatening TAO resulting from compressive optic neuropathy is unknown since patients with signs of impending vision loss were excluded from both trials. J Clin Endocrinol Metab (1996) 81:117983. 61. Growth Factors (1990) 2:99109. At week 24, considerable bilateral reductions in proptosis (5 mm) and CAS (4 points). J Biol Chem (1991) 266:783441. At baseline, the patient exhibits substantial proptosis (left eye, 29mm and right eye, 27mm) as well as multiple inflammatory signs (left eye Clinical Activity Score of 7 and right eye 5). Although very similar to insulin and its receptor; the modus operandi of the insulin-like growth factors (IGFs) within the body is very different from that of the traditional peptide hormone. The vast majority of hyaluronan synthesis occurs in CD34- orbital fibroblasts. The concept of IGF-IR playing an important role in the development of TAO or targeting the protein as a strategy for treating the disease had been met with overwhelming skepticism when it was first proposed (9, 10). doi: 10.1074/jbc.271.46.29400, 106. Endocr J (2012) 59:7916. Westermark K, Alm J, Skottner A, Karlsson A. The C-domain contains six conserved cysteine residues, a RK-rich sequence (red) important for IGF binding, ALS binding, nuclear localization, and a thyroglobulin-like fold and other sites of interaction with ECM components. Teprotumumab is now in wide clinical use in North America. doi: 10.1210/er.2018-00066, 9. Despite its evolutionary conservation and numerous biological activities, knockout of IGFBP-5 in mice produced only a negligible phenotype. Inactivating IL34 promotes regenerating muscle stem cell expansion and attenuates Duchenne muscular dystrophy in mouse models. 2023 Feb 13;26(3):106198. doi: 10.1016/j.isci.2023.106198. Novartis Foundation Symposium (2004) 262:16071. (F) Change from baseline in transformed GO-QOL score (least squares mean standard error). Gland volume in acromegaly correlates with serum GH and IGF-I levels. 30. In general, teprotumumumab (AKA R1507) was well-tolerated in those earlier studies, frequently involving fragile patients; however, the drug was not devoid of adverse events which were more severe in younger patients (125). A Phase I Study of Weekly R1507, a Human Monoclonal Antibody Insulin-Like Growth Factor-I Receptor Antagonist, in Patients With Advanced Solid Tumors. J Immunol (Baltimore Md: 1950) (2008) 181:576874. Milford H, editor. Figure 4 Cartoon proposed model of Graves disease and thyroid-associated ophthalmopathy (TAO) pathogenesis. Mechanisms of Thyroid Hormone Action on the Insulin-Like Growth Factor System: All Thyroid Hormone Effects Are Not Growth Hormone Mediated. (2) BCAA, especially isoleucine, play a major role in enhancing glucose consumption and utilization by up-regulating intestinal and muscular glucose transporters. Endocrinology (2019) 160:146879. Tools 3GF1 insulin-like growth factor macromolecular structure The insulin-like growth factors ( IGFs) are proteins with high sequence similarity to insulin. Roberts CT Jr. Control of Insulin-Like Growth Factor (IGF) Action by Regulation of IGF-I Receptor Expression. J Korean Med Sci (2007) 22:88390. doi: 10.1530/acta.0.1180415, 81. IGFBP-5 is expressed in dive Thyrospheres derived from healthy tissue express both isoforms of IR, namely IR-A and IR-B, as well as IGF-IR, IGF-I and IGF-II, levels which decline following cell differentiation. Teprotumumab for the treatment of active thyroid eye disease. Nnt-Salonen K, Muller HL, Hoffman AR, Vu TH, Rosenfeld RG. doi: 10.1210/en.2008-0878, 102. 10.1007/PL00000744 The differences between the two treatment groups emerged at week 6 of treatment (p<0.001). doi: 10.1097/MED.0b013e32833c8942, 89. J Endocrinol Invest (2010) 33:41421. Some of these effects are mediated through enhancement of sensitivity to the actions of TSH while others may be independent of pituitary function. Clin Endocrinol (2007) 67:62936. 31. Extensive crosstalk of the multiple downstream signal transduction pathways utilized by the two receptors has been identified (101104). An important goal of this medical therapy is to lessen reliance on either routine surgical rehabilitation for chronic disease or urgent surgical intervention in sight-threatening TAO. The effects of hyaluronan on proliferation of these fibroblasts was found to involve differential effects on membrane polarization, where high molecular weight hyaluronan results in depolarization and low molecular weight hyaluronan causes membrane hyperpolarization and inhibits proliferation. doi: 10.1210/jcem-66-6-1227, 54. The Effect of Altered Thyroid Status on Pituitary Hormone Messenger Ribonucleic Acid Concentrations in the Rat. Kawanami T, Takiguchi S, Ikeda N, Funakoshi A. Endocr Rev (2019) 40:23667. doi: 10.1210/en.2007-1443, 43. These receptor classes share scaffolding proteins, namely -arrestin 1 and 2. Endocrinology (2010) 151:553749. Patients with acromegaly are at increased risk for a variety of cancers besides those of the thyroid. This finding theoretically confirms the high capacitance of brain neurotrophic factors even in old ages, to boost neuronal plasticity, neurogenesis and cognitive functions [37 . Crosstalk Between Epidermal Growth Factor Receptor- and Insulin-Like Growth Factor-1 Receptor Signaling: Implications for Cancer Therapy. Among these, IGFs impact the thyroid and the hormones that it generates. Copyright (2020) Massachusetts Medical Society. Accessibility Endocrinology (1986) 119:12049. Teprotumumab, an IGF-1R Blocking Monoclonal Antibody Inhibits TSH and IGF-1 Action in Fibrocytes. doi: 10.1210/endo-121-2-749, 26. Physiologic Effects of Growth Hormone A critical concept in understanding growth hormone activity is that it has two distinct types of effects: Direct effects are the result of growth hormone binding its receptor on target cells. IGFs are part of a complex system that cells use to communicate with their physiologic environment. IGF-I and cAMP appear to differentially activate the PI3 kinase pathway in FRTL-5 cells, leading to G1 cyclin-cyclin dependent kinase activation and DNA synthesis (42). Eggo MC, Bachrach LK, Burrow GN. Endocrinology (2007) 148:350717. Endocrinology. For those with systemic exposure, a uniform steroid washout period of 6 weeks was required prior to study enrolment. 10.1210/endo.140.11.7151 Krieger CC, Boutin A, Jang D, Morgan SJ, Banga JP, Kahaly GJ, et al. 10.1016/j.ygcen.2004.12.022 IGFBP-5 consists of 3 structurally domains: a highly conserved, Proposed modes of IGFBP-5 actions. was followed by doses of 20 mg/Kg B.W. IGFBP-5 consists of 3 structurally domains: a highly conserved globular N-terminal domain, a central non-conserved linker domain, and a conserved C-terminal globular domain.

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