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Related Concept Videos

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Functions of Thyroid Hormones

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The thyroid hormone (TH) plays a pivotal role in the intricate orchestration of physiological processes, exerting profound effects on development, metabolism, and homeostasis throughout different life stages.
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Low blood levels of the thyroid hormones — triiodothyronine (T3) and thyroxine (T4) — signal the hypothalamus to release the thyrotropin-releasing hormone (TRH). TRH then reaches the pituitary gland and stimulates the release of thyroid-stimulating hormone(TSH) into the bloodstream.
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Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but...
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Hormones, the biochemical messengers produced by endocrine glands, are pivotal in regulating bodily functions and maintaining homeostasis. Each hormone's balance is crucial; imbalances can lead to significant physiological disruptions. Major hormones include oxytocin, cortisol, epinephrine, estrogen, testosterone, thyroxine, growth hormone, insulin, and glucagon.
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The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
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An Ex vivo Culture System to Study Thyroid Development
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Insulin-Like Growth Factor Pathway and the Thyroid.

Terry J Smith1

  • 1Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States.

Frontiers in Endocrinology
|June 21, 2021
PubMed
Summary

The insulin-like growth factor (IGF) pathway impacts thyroid function and Graves' disease (GD). Targeting the IGF-I receptor (IGF-IR) with teprotumumab offers a new therapy for thyroid-associated ophthalmopathy (TAO).

Keywords:
Graves’ diseaseautoimmunegoitergrowth factorhormoneophthalmopathythyroid

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Area of Science:

  • Endocrinology and Molecular Biology
  • Investigates the intricate crosstalk between the insulin-like growth factor (IGF) pathway and thyroid function, particularly in autoimmune thyroid diseases.

Background:

  • The insulin-like growth factor (IGF) pathway, including IGF-I, IGF-II, IGF-IR, and IGF-IIR, plays crucial roles in growth and metabolism, intersecting with thyroid hormone regulation.
  • IGF-I supports normal thyroid gland function, volume, and hormone synthesis, influencing TSH sensitivity and potentially impacting thyroid pathologies like Graves' disease (GD).
  • In Graves' disease (GD) and thyroid-associated ophthalmopathy (TAO), the IGF-I receptor (IGF-IR) is overexpressed in orbital tissues and immune cells, suggesting its involvement in disease pathogenesis.

Purpose of the Study:

  • To elucidate the role of the IGF pathway in thyroid function and its specific involvement in Graves' disease (GD) and thyroid-associated ophthalmopathy (TAO).
  • To explore the therapeutic potential of targeting the IGF-IR in the context of TAO, leveraging the understanding of its interaction with the TSH receptor (TSHR).

Main Methods:

  • Review and synthesis of existing literature on the IGF pathway, thyroid hormone regulation, and the molecular mechanisms underlying GD and TAO.
  • Analysis of findings related to IGF-IR overexpression in GD/TAO tissues and the functional consequences of autoantibodies binding to the TSHR/IGF-IR complex.
  • Examination of preclinical and clinical data supporting the efficacy of IGF-IR targeted therapies, such as teprotumumab.

Main Results:

  • IGF-IR is overexpressed in GD and TAO, and autoantibodies in GD patients can activate signaling through a TSHR/IGF-IR complex.
  • Inhibition of IGF-IR signaling, demonstrated with monoclonal antibody inhibitors, can attenuate TSHR and IGF-IR signaling pathways.
  • Teprotumumab, a β-arrestin biased agonist targeting IGF-IR, has emerged as the first FDA-approved medication for TAO treatment, now in wide clinical use.

Conclusions:

  • The IGF pathway, particularly IGF-IR, is a critical player in the pathogenesis of Graves' disease and thyroid-associated ophthalmopathy.
  • Targeting IGF-IR with specific therapies like teprotumumab represents a significant therapeutic advancement for TAO, offering a novel treatment strategy.
  • The findings underscore the importance of understanding receptor crosstalk and developing targeted therapies for complex autoimmune conditions.