Modulation of thyroxine (T4) prohormone secretion by the thyroid gland and. iodine uptake, decreased T4 production, an increased T3/T4 secretion ratio,.
Although fat and muscle are classic insulin-responsive tissues responsible for glucose disposal, we have found that other cell types (e.g., fibroblasts) also have an insulin-regulated trafficking pathway. One major difference between the pathways in fibroblasts and adipocytes is the magnitude of the response, with insulin stimulating an 10 fold translocation of GLUT 4 in adipocytes.
Studies on the MCT8 deficient mouse revealed that in the absence of functional MCT8, alternative thyroid hormone transporters play an important complementary role in neuronal T3 transport. In contrast, the lack of alternative pathways, for example, LAT2 in developing human neurons, might be involved in the devastating neurodevelopmental phenotype seen in MCT8-deficient patients with Allan-Herndon-Dudley.
Recent evidence on the direct paracrine impact of glial D2 on neuronal gene expression underlines the importance of glial-neuronal interaction in thyroid hormone regulation as a major regulatory pathway in the brain in health and disease.
Control at both levels is developmentally regulated and modified in serious nonthyroidal illness (trauma, infection, cancer, metabolic diseases). Racial and gender differences are of little significance except for the effects of placental estrogens and chorionic gonadotropin during pregnancy.
The effect on circulating T4 and T3 concentrations is not significant because of the large size of the extrathyroidal T4 pool. In healthy subjects there is no significant impact of body weight, physical training, body habitus, posture, immobilization, exercise, or ambulatory status on thyroid function, and no significant geographic environmental variation.
Excessive iodine intake can block thyroid hormone biosynthesis by inhibiting the enzymes involved in the biosynthetic process, resulting in reduced T4 secretion, increased TSH concentrations, goiter, and hypothyroidism if the iodine excess is chronic.
1Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083, Hungary 2Division of Endocrinology, Diabetes, and Metabolism, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
There is physical overlap between the general and specialized insulin-regulated trafficking pathways since GLUT 4 is internalized through clathrin-coated pits, the major endocytic uptake system in cells. Therefore, a key to understanding how insulin regulates GLUT 4 trafficking is to understand how this specialized pathway differs from the general endocytic pathway.
Although the magnitude is smaller, the pathways in the differentiated and undifferentiated cells share a number of similarities and I anticipate that understanding the pathway in the more experimentally amenable fibroblasts will a provide a context for analyzing the more complex pathway adipocytes.
2. Thyroid Hormone-Mediated Changes in Neuroglial Cells Brain development provides the best studied model of thyroid hormone.
In contrast to the glial D2, D3 expression in the brain is restricted to neurons 21. While historically glial elements of the brain were viewed as a type of connective tissue of the CNS without any real function, this view was overturned by the abundant data on the complex role of glial cells in brain.
However, only supraphysiological doses of T3 were sufficient to suppress pro-TRH mRNA in the hypothalamic paraventricular nucleus of hypothyroid rats 10 indicating that T4 uptake into the brain is important for normal function of T3-mediated processes in this tissue.