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THYROID HORMONES
Thyroid gland (weighs about 30 g in adults) is located on either side of the trachea below the larynx. It produces two principal hormones — thyroxine (T4; 3,5,3’,5’-tetraiodo thyronine) and 3,5,3’-triiodothyronine (T3) — which regulate the metabolic rate of the body. Thyroid gland also secretes calcitonin, a hormone concerned with calcium homeostasis
Biosynthesis of thyroid hormones
Iodine is essential for the synthesis of thyroid hormones. More than half of the body’s total iodine content is found in the thyroid gland
Uptake of iodide : The uptake of iodide by the thyroid gland occurs against a concentration
gradient (about 20 : 1). It is an energy requiring process and is linked to the ATPase dependent Na+-K+ pump. Iodide uptake is primarily controlled by TSH. Antithyroid agents such as thiocyanate and perchlorate inhibit iodide transport.
Formation of active iodine : The conversion of iodide (I–) to active iodine (I+) is an
essential step for its incorporation into thyroid hormones. Thyroid is the only tissue that can oxidize I– to a higher valence state I+. This reaction requires H2O2 and is catalysed by the enzyme thyroperoxidase (mol. wt. 60,000). An NADPH dependent system supplies H2O2. TSH promotes the oxidation of iodide to active iodine while the antithyroid drugs (thiourea, thiouracil, methinazole) inhibit
Thyroglobulin and synthesis of T3 and T4 :
Thyroglobulin (mol. wt. 660,000) is a glycoprotein and precursor for the synthesis of T3 and T4. Thyroglobulin contains about 140 tyrosine residues which can serve as substrates for iodine for the formation of thyroid hormones. Tyrosine (of thyroglobulin) is first iodinated at position 3 to form monoiodotyrosine (MIT) and then at position 5 to form diiodotyrosine (DIT). Two molecules of DIT couple to form thyroxine (T4). One molecule of MIT, when coupled with one molecule of DIT, triiodothyronine (T3) is produced. The mechanism of coupling is not well understood. The details of synthesis of T3 and T4 are given under tyrosine metabolism. As the process of iodination is completed, each molecule of thyroglobulin contains about 6- 8 molecules of thyroxine (T4). The ratio of T3 to T4 in thyroglobulin is usually around 1 : 10
Storage and release of thyroid hormones
Thyroglobulin containing T4 and T3 can be stored for several months in the thyroid gland. It is estimated that the stored thyroid hormones can meet the body requirement for 1-3 months. Thyroglobulin is digested by lysosomal proteolytic enzymes in the thyroid gland. The free hormones thyroxine (90%) and triiodothyronine (10%) are released into the blood, a process stimulated by TSH. MIT and DIT produced in the thyroid gland undergo deiodination by the enzyme deiodinase and the iodine thus liberated can be reutilized.
Transport of T4 and T
Two specific binding proteins—thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA)—are responsible for the transport of thyroid hormones. Both T4 and T are more predominantly bound to TBG. A small fraction of free hormones are biologically active. T4 has a half-life of 4-7 days while T3 has about one day
Biochemical functions of thyroid hormones
Triiodothyronine (T3) is about four times more active in its biological functions than thyroxine (T4). The following are the biochemical functions attributed to thyroid hormones (T3 and T4).
1. Influence on the metabolic rate : Thyroid hormones stimulate the metabolic
activities and increases the oxygen consumption in most of the tissues of the body (exception—brain, lungs, testes and retina).
Na+-K+ ATP pump : This is an energy depen dent process which consumes a major
share of cellular ATP. Na+-K+ ATPase activity is directly correlated to thyroid hormones and this, in turn, with ATP utilization. Obesity in some individuals is attributed to a decreased energy utilization and heat production due to diminished Na+-K+ ATPase activity.
2. Effect on protein synthesis : Thyroid hormones act like steroid hormones in promoting
protein synthesis by acting at the transcriptional level (activate DNA to produce RNA). Thyroid hormones, thus, function as anabolic hormones and cause positive nitrogen balance and promote growth and development.
Regulation of insulin secretion
About 40-50 units of insulin is secreted daily by human pancreas. The normal insulin concen tration in plasma is 20-30 U/ml. The important factors that influence the release of insulin from the - cells of pancreas
1 )Factors stimulating insulin secretion : These include glucose, amino acids and
gastrointestinal hormones.
Glucose is the most important stimulus for insulin release. A rise in blood glucose level is a
signal for insulin secretion.
Amino acids induce the secretion of insulin. This is particularly observed after the ingestion
of protein-rich meal that causes transient rise in plasma amino acid concentration. Among the amino acids, arginine and leucine are potent stimulators of insulin release
Gastrointestinal hormones (secretin, gastrin, pancreozymin) enhance the secretion of
insulin.
2)Factors inhibiting insulin secretion : Epinephrine is the most potent inhibitor of
insulin release. In emergency situations like stress, extreme exercise and trauma, the nervous system stimulates adrenal medulla to release epinephrine.
Degradation of insulin
In the plasma, insulin has a normal half-life of 4 - 5 minutes. A protease enzyme, namely insulinase (mainly found in liver and kidney), degrades insulin
Metabolic effects of insulin
Insulin plays a key role in the regulation of carbohydrate, lipid and protein metabolisms.
1.Effects on carbohydrate metabolism : In a normal individual, about half of the
ingested glucose is utilized to meet the energy demands of the body (mainly through glycolysis). The other half is converted to fat (~ 40%) and glycogen (~ 10%). The net effect is that insulin lowers blood glucose level (hypoglycemic effect) by promoting its utilization and storage and by inhibiting its production. L
Effect on glucose uptake by tissues : Insulin is required for the uptake of glucose by
muscle (skeletal, cardiac and smooth), adipose tissue, leukocytes and mammary glands. Surprisingly, about 80% of glucose uptake in the body is not dependent on insulin. Tissues into which glucose can freely enter include brain, kidney, erythrocytes, retina, nerve, blood vessels and intestinal mucosa.
Effect on glucose utilization : Insulin increases glycolysis in muscle and liver. The
activation as well as the quantities of certain key enzymes of glycolysis, namely glucokinase (not hexokinase) phosphofructokinase and pyruvate kinase are increased by insulin. Glycogen production is enhanced by insulin by increasing the activity of glycogen synthetase.
Effect on glucose production : Insulin decreases gluconeogenesis by suppressing the
enzymes pyruvate carboxylase, phosphoenol pyruvate carboxykinase and glucose 6 phosphatase. Insulin also inhibits glyco-genolysis by inactivating the enzyme glycogen phosphorylase.
2 .Effects on lipid metabolism :
The net effect of insulin on lipid metabolism is to reduce the release of fatty acids from the stored fat and decrease the production of ketone bodies.
Effect on lipogenesis : Insulin favours the synthesis of triacylglycerols from glucose by
providing more glycerol 3-phosphate (from glycolysis) and NADPH (from HMP shunt). Insulin increases the activity of acetyl CoA carboxylase, a key enzyme in fatty acid synthesis.
Effect on lipolysis : Insulin decreases the activity of hormone-sensitive lipase and thus
reduces the release of fatty acids from stored fat in adipose tissue.
Effect on ketogenesis : Insulin reduces ketogenesis by decreasing the activity of HMG CoA
synthetase
3.Effects on protein metabolism : Insulin is an anabolic hormone. It stimulates the entry
of amino acids into the cells, enhances protein synthesis and reduces protein degradation.
2. Insulin-mediated glucose transport :
The binding of insulin to insulin receptors signals the translocation of vesicles containing glucose transporters from intracellular pool to the plasma membrane. The vesicles fuse with the membrane recruiting the glucose transporters. The glucose transporters are responsible for the insulin–mediated uptake of glucose by the cells. As the insulin level falls, the glucose transporters move away from the membrane to the intracellular pool for storage and recycle
3. Insulin mediated enzyme synthesis :
Insulin promotes the synthesis of enzymes such as glucokinase, phosphofructokinase and pyruvate kinase. This is brought about by increased transcription (mRNA synthesis), followed by translation (protein synthesis)
Biochemical functions of catecholamines
Catecholamines cause diversified biochemical effects on the body. The ultimate goal of their action is to mobilize energy resources and prepare the individuals to meet emergencies (e.g. shock, cold, low blood glucose etc.).
1. Effects on carbohydrate metabolism : Epinephrine and norepinephrine in general
increase the degradation of glycogen (glycogenolysis), synthesis of glucose (gluconeogenesis) and decrease glycogen formation (glycogenesis). The overall effect of catecholamines is to elevate blood glucose levels and make it available for the brain and other tissues to meet the emergencies.
2. Effects on lipid metabolism : Both epinephrine and norepinephrine enhance the
breakdown of triacylglycerols (lipolysis) in adipose tissue. This causes increase in the free fatty acids in the circulation which are effectively utilized by the heart and muscle as fuel source. The metabolic effects of catecholamines are mostly related to the increase in adenylate cyclase activity causing elevation in cyclic AMP
3. Effects on physiological functions : In general, catecholamines (most predominantly
epinephrine) increase cardiac output, blood pressure and oxygen consumption. They cause smooth muscle relaxation in bronchi, gastro intestinal tract and the blood vessels supplying skeletal muscle. On the other hand, catecholamines stimulate smooth muscle contraction of the blood vessels supplying skin and kidney. Platelet aggregation is inhibited by catecholamines.
