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Endocrinology and Diabetes

In the conception of this book, we used our teaching experience to cover the main topics in
endocrinology and diabetes in a simple and easy-to-understand style.

We have tried to discuss the basic anatomy and physiology of the endocrine system, which is fundamental to the understanding of pathophysiology and presentation of endocrine diseases. Lecture Notes: Endocrinology and Diabetes also contains detailed sections on the practical management of diabetes and endocrine disorders.
Therefore we believe that this book is suitable for medical students and doctors training in endocrinology, and can be used for exam revision as well as rapid consultation in the clinic. *mercy health diabetes and endocrine center*

Thyroid anatomy and physiology

Anatomy

The thyroid gland consists of left and right lobes connected by a midline isthmus. The isthmus lies below the cricoid cartilage, and the lobes extend upward over the lower half of the thyroid cartilage. The thyroid is covered by the strap muscles of the neck and overlapped by the sternocleidomastoids. The pretracheal fascia encloses the thyroid gland and attaches it to the larynx and the trachea. *diabetes doctor specialist near me*

This accounts for the upward movement of the thyroid gland on swallowing. The thyroid gland develops from the floor of the pharynx in the position of the foramen caecum of the adult tongue as a down growth that descends into the neck. During this descent, the thyroid gland remains connected to the tongue by the thyroglossal duct, which later disappears. However, aberrant thyroid tissue or thyroglossal cysts (cystic remnants of the thyroglossal duct) may occur anywhere along the course of the duct. Such thyroid remnants move upward when the tongue
is protruded. The thyroid gland is composed of epithelial spheres called follicles, whose lumens are
filled with a proteinaceous colloid containing thyroglobulin. Two basic cell types are present in the follicles. *children’s diabetes and endocrinology*

The follicular cells secrete thyroxine (T 4 ) and triiodothyronine (T 3) and originate from a downward growth of the endoderm of the floor of the pharynx (see above). The parafollicular or C cells secrete calcitonin and arise from neural crest cells that migrate into the developing thyroid gland. The follicles are surrounded by an extensive capillary network. *mercy health diabetes and endocrine center*

Physiology

Thyroid hormones act on many issues. They regulate:
● organogenesis, growth, and development (central nervous system, bone)
● energy expenditure
● protein, carbohydrate, and fat metabolism
● gut motility
● bone turnover
● heart rate and contractility, and peripheral vascular resistance
● beta-adrenergic receptor expression
● muscle contraction and relaxation
● the menstrual cycle
● erythropoiesis. Iodine is essential for normal thyroid function. It is obtained by the ingestion of foods such as seafood, seaweed, kelp, dairy products, some vegetables, and iodized salt. The recommended iodine intake for adults is 150 μg per day (250 μg per day for pregnant and lactating women). Dietary iodine *children’s diabetes and endocrinology*

Thyroid anatomy and physiology

Thyroid gland
Possible sites of remnants of the thyroglossal duct.

Thyroid hormone synthesis

● Thyroglobulin is synthesized in the rough endoplasmic reticulum and is transported into the follicular lumen by exocytosis.
● Iodide is transported into the thyroid follicular cells via a sodium–iodide symporter on the basolateral membrane of the follicular cells. Iodide transport requires oxidative metabolism.
● Inside the follicular cells, iodide diffuses to the apical surface and is transported by pendrin (a membrane iodide – chloride transporter) into the follicular lumen.
● The thyroid peroxidase (TPO) enzyme catalyzes the process of oxidation of the iodide to iodine and its binding (organification) to the tyrosine residues of thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT).
● DIT and MIT molecules are linked by TPO to form thyroxine (T 4) and triiodothyronine (T 3) in a process known as coupling.
● Thyroglobulin containing T 4 and T 3 is resorbed into the follicular cells by endocytosis and is cleaved by lysosomal enzymes (proteases and peptidases) to release T 4 and T 3. T 4 and T 3 are then secreted into the circulation.
● Uncoupled MIT and DIT are deiodinated, and the free tyrosine and iodide are recycled. *children’s diabetes and endocrinology*

The thyroid gland stores T 4 and T 3 incorporated in thyroglobulin, and can therefore secrete T 4 and T 3 more quickly than if they had to be synthesized. *mercy health diabetes and endocrine center*

Extra – t thyroidal T 3 production


T 4 is produced entirely by the thyroid gland. The production rate of T 4 is about 100 μg per day.
However, only 20% of T 3 is produced directly by the thyroid gland (by coupling of MIT and DIT).
Around 80% of T 3 is produced by the deiodination of T 4 in peripheral extra-thyroidal tissues (mainly
liver and kidney). The total daily production rate of T 3 is about 35 μ g.
T 4 is converted to T 3 (the biologically active metabolite) by 5 ′ – deiodination (outer-ring deiodination). 5 ′ – Deiodination is mediated by deiodinases type 1 (D1) and type 2 (D2). D1 is the predominant

deiodination enzyme in the liver, kidney, and thyroid. D2 is the predominant deiodination enzyme in muscle, brain, pituitary, skin, and placenta. Type 3 deiodinase (D3) catalyzes the conversion of T 3 to reverse T 3 (the inactive metabolite) by 5 – deiodination (inner ring deiodination), as shown in Fig. 1.5.
Changes in T 3 concentration may indicate a change in the rate of peripheral conversion and may not be an accurate measure of the change in thyroid hormone production. For example, the rate of T 3 production (by 5 ′ – deiodination of T 4) is reduced in acute illness and starvation. *diabetes doctor specialist near me*

Total and free T 4 and T 3

Approximately 99.97% of circulating T 4 and 99.7% of circulating T 3 are bound to plasma proteins:
thyroid-binding globulin (TBG), transthyretin (also

known as thyroid-binding pre-albumin), albumin and lipoproteins. Only the unbound thyroid hormone is available to the tissues. T 3 is less strongly bound and therefore has a more rapid onset and offset of action. The binding proteins have both storage and buffer functions. They help to maintain the serum-free T 4
and T 3 levels within narrow limits, and also ensure the continuous and rapid availability of the hormones
to the tissues. Free thyroid hormone concentrations are easier to interpret than total thyroid hormone levels. This is because the level of bound hormone alters with changes in the levels of thyroid-binding proteins, even though free T 4 (and T 3) concentrations do not change and the patient remains euthyroid. Box 1.1summarizes factors that may
alter TBG levels. *diabetes doctor specialist near me*

The conversion of T 4 to T 3 by 5 ′ – deiodination and to reverse T 3 by 5 – deiodination.

Other causes of increased serum total T 4 and T 3 levels include familial dysalbuminaemic hyperthyroxinaemia (due to the presence of abnormal albumin with a higher affinity for T 4) and the presence of anti – T 4 antibodies. Patients with these conditions are euthyroid, have normal serum thyroid-stimulating hormone (TSH) levels, and usually, have normal serum-free T 4 and T 3 levels when measured by appropriate methods. *diabetes doctor specialist near me*

Thyroid hormone metabolism


T 4 is degraded at a rate of 10% per day. Around 40% of the T 4 is deiodinated to T 3 and 40% to reverse T 3.
The remaining T 4 is conjugated with glucuronide and sulfate, deaminated and decarboxylated, or cleaved between the two rings. T 3 is degraded (mostly by deiodination) at a rate of 75% per day. Reverse T 3 is degraded even more rapidly than T 3, mostly by deiodination

Regulation of thyroid hormone production and release

T 3 and T 4 synthesis and secretion are stimulated by the thyroid-stimulating hormone (TSH) released from
the anterior pituitary gland (Fig. 1.7 ). TSH production and release are increased by hypothalamic thyrotrophin-releasing hormone (TRH). *mercy health diabetes and endocrine center*

Thyrotrophin – releasing hormone

TRH is a tripeptide synthesized and released by the hypothalamus. TRH content is highest in the
median eminence and paraventricular nuclei of the hypothalamus. TRH stimulates TSH secretion
by activating a G – protein-coupled receptor and the phospholipase C – phosphoinositide pathway,
resulting in mobilization of calcium from intracellular storage sites.

Chronic TRH stimulation also increases the synthesis and glycosylation of TSH, which increases its biological activity.

Thyroid-stimulating hormone

TSH is a glycoprotein secreted by the thyrotroph cells of the anterior pituitary. TSH is composed of

alpha and beta subunits that are non – covalently bound. The alpha subunit is the same as that of luteinizing hormone, follicle-stimulating hormone, and human chorionic gonadotrophin. However, the beta subunit is unique to TSH. TSH binds to specific plasma membrane receptors and activates adenylyl cyclase. TSH also stimulates phospholipase C activity. TSH stimulates every step in thyroid hormone synthesis and secretion. It also stimulates the expression of many genes in thyroid tissue and causes thyroid hyperplasia and hypertrophy.

T 4 and T 3 inhibit TSH synthesis and release both directly (by inhibiting transcription of the TSH
subunit genes) and indirectly (by inhibiting TRH release). T 4 and T 3 also decrease the glycosylation
and hence bioactivity of TSH. TSH secretion is regulated by very small changes in serum T 4 and T 3 concentrations. However, an important exception is that the reduced T 3 levels in patients with the non – thyroidal illness have little effect on TSH secretion. This may be due to a greater contribution of serum T 4 to the nuclear T 3 content of the pituitary than other tissues. Box 1.2shows a list of the causes of increased and decreased TSH concentration.

Mechanism of a ction of thyroid hormones

T 3 formed from the deiodination of T 4 and T 3 that enters the cells from the serum is transferred to the
nucleus. The thyroid hormone receptors (TRs) heterodimerize with the retinoid X receptor and act as nuclear transcription factors. TRs bind thyroid hormone response elements in the promoter region of thyroid hormone-responsive genes. In the absence of T 3, TRs bind co-repressor proteins that repress transcription. On T 3 binding, corepressors are displaced and coactivator proteins bind the TRs, resulting in histone acetylation, generation of a permissive chromatin structure, and induction of gene transcription. There are two T 3 nuclear receptors — alpha and
beta — encoded by separate genes located on chromosomes 17 and 3. Two forms of each TR are generated by alternative splicing. Only the beta – 1, beta – 2, and alpha – 1 receptor bind T 3. The liver predominantly expresses beta receptors, whereas the heart and bone express alpha receptors. The hypothalamus and pituitary express beta – 2 receptors which mediate the negative feedback regulation. *children’s diabetes and endocrinology*

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