MBC 101 Unit IV Part 1 PDF

11/7/24 1 Hormones are chemical messengers that are secreted directly into the blood, which carries them to organs and tissues of the body to exert their functions. There are many types of hormones that act on different aspects of bodily functions and processes. Hormones are...

11/7/24 1 Hormones are chemical messengers that are secreted directly into the blood, which carries them to organs and tissues of the body to exert their functions. There are many types of hormones that act on different aspects of bodily functions and processes. Hormones are secreted by Endocrine glands Some glands also have non-endocrine regions that have functions other than hormone secretion. the pancreas has a major exocrine portion For example, that secretes digestive enzymes and an endocrine portion that secretes hormones. The ovaries and testes secrete hormones and also produce the ova and sperm. 2 1  11/7/24 Exocrine Vs Endocrine glands Exocrine Endocrine hormone Main differences between endocrine and exocrine glands. 3 Chemical messenger are delivered from the cell of origin to their targets cells by one of several routes: 1) Endocrine: chemical messengers/hormones are transported through blood (the classical definition of a hormone) and act on distant cells 2) Neuroendocrine: when the hormone released by a nerve is bloodborne 4 2  11/7/24 3) Autocrine: when chemical messenger/hormone binds to receptor present on the same cells leading to changes in the cell. 4) Paracrine: released hormone diffuses to its adjacent target cells through the immediate extracellular space and affects the nearby cell 5) Neurocrine: where a neuron contacts its target cells by axonal extensions and then releases the hormone into a synaptic cleft between two cells 5 Endocrine glands 6 3  11/7/24 7 8 4  11/7/24 Hormones Classification There are three general classes of hormones (chemical classes ) Proteins and peptides Steroids Amines ( derivatives of amino acid tyrosine) 9 1. Proteins and peptides hormones Most of the hormones in the body are polypeptides and proteins. These hormones range in size from small peptides with as few as 3 amino acids (thyrotropin-releasing hormone) to proteins with almost 200 amino acids (growth hormone and prolactin). In general, polypeptides with 100 or more amino acids are called proteins, and those with fewer than 100 amino acids are referred to as peptides. 10 5  11/7/24 Synthesis of protein hormones Protein and peptide hormones are synthesized on the rough end of the endoplasmic reticulum of the different endocrine cells. They are usually synthesized first as larger proteins that are not biologically active (preprohormones) and are cleaved to form smaller prohormones in the endoplasmic reticulum. These are then transferred to the Golgi apparatus for packaging into secretory vesicles. In this process, enzymes in the vesicles cleave the prohormones to produce smaller, biologically active hormones and inactive fragments. The vesicles are stored within the cytoplasm, and many are bound to the cell membrane until their secretion is needed. 11 Synthesis of protein hormones The peptide hormones are water soluble, allowing them to enter the circulatory system easily, where they are carried to their target tissues. 12 6  11/7/24 Protein hormone synthesis However, in some cases, Prohormone molecules may be secreted themselves, and then processed to yield a mature hormone in the blood or even in a target tissue Angiotensinogen (prohormone) Angiotensin I Renin (enzyme) Angiotensin II Angiotensin-converting enzyme 13 Example 2: kininogens kinins (Large precursor plasma protein) Kallikreins e.g. bradykinins (Serine Protease peptide that causes (released in blood as prohormone) Inhibitor) blood vessels to dilate 14 7  11/7/24 2. Steroid hormones The chemical structure of steroid hormones is similar to that of cholesterol All of the steroid hormones are derived from cholesterol. They are lipid soluble and consist of three cyclohexyl rings and one cyclopentyl ring combined into a single structure 15 Steroid hormones are primarily produced by the adrenal cortex and the gonads (testes and ovaries) as well as by the placenta during pregnancy. Much of the cholesterol in steroid-producing cells comes from the plasma, but there is also de novo synthesis of cholesterol in steroid- producing cells. 16 8  11/7/24 Synthesis of Steroid Hormones 1. In both the gonads and the adrenal cortex, the cells are stimulated by the binding of a pituitary gland hormone to its receptor 2. These receptors are linked to G proteins, which activate adenylyl cyclase and thus cAMP production 3. The subsequent activation of protein kinase A results in phosphorylation of numerous cytosolic and membrane proteins 4. When the cell is stimulated, free cholesterol is released from the lipid droplet by the action of the enzyme cholesterol esterase, which is activated by protein kinase A 5. Carrier proteins then transport the free cholesterol to the mitochondria. 17 Synthesis of Steroid Hormones The cholesterol is transported to the inner mitochondrial membrane, which contains the enzymes required to process cholesterol into steroid hormones. These enzymes, called cytochrome P450s, attach hydroxyl groups to carbon atoms As the P450 enzymes modify cholesterol, intermediates are formed further modified in mitochondria and in the smooth endoplasmic reticulum. 18 9  11/7/24 Synthesis of Steroid Hormones The final product depends upon the cell type and the types and amounts of the enzymes it expresses. Cells in the ovary, for example, express large amounts of the enzyme needed to convert testosterone to estradiol, whereas cells in the testes do not express significant amounts of this enzyme and thus make primarily testosterone. Once formed, the lipophilic steroid hormones are not stored in the cytosol, but instead diffuse out through the lipid bilayer of the plasma membrane into the interstitial fluid and from there into the circulation. Because of their lipid nature, steroid hormones are not highly soluble in blood, and thus they are largely transported in plasma bound to carrier proteins such as albumin 19 3. Amine hormones The amine hormones are all derivatives of the amino acid tyrosine. They include the Thyroid hormones (T4 and T3) Epinephrine and norepinephrine (produced by the adrenal medulla), Dopamine (produced by the hypothalamus) 20 10  11/7/24 Amine hormone synthesis: Amine hormones are formed by the action of enzymes in the cytosolic compartment of the glandular cells The thyroid hormones are synthesized and stored in thyroid gland incorporated into macromolecules of the protein thyroglobulin, which is stored in large follicles within the thyroid gland. H Thyroglobulin stored in large follicles in thyroid glands 21 Hormone secretion: Thyroid Hormones TH Split or Thyroglobulin Thyroglobulin TH released Free hormones released into the blood stream In blood, thyroid hormones Thyroid hormones combine with plasma are slowly released proteins: in the target Thyroxine-binding globulin tissues 22 11  11/7/24 Transport of Hormones in the Blood 1. Water-soluble hormones (peptides and catecholamines i.e. epinephrine and norepinephrine) These hormones are dissolved in the plasma and transported from their sites of synthesis to target tissues. In target tissues, they diffuse out of the capillaries, into the interstitial fluid, and ultimately to target cells. 23 Transport of Hormones in the Blood 2. Steroid and thyroid hormones These hormones are fat soluble hormones and are transported in blood mainly bound to plasma proteins. Generally, less than 10 per cent of steroid or thyroid hormones in the plasma exist in free form. For example, more than 99 per cent of the thyroxine in the blood is bound to plasma proteins. These protein-bound hormones cannot easily diffuse across the capillaries and gain access to their target cells. These hormones are biologically inactive until they dissociate from plasma proteins. The relatively large amounts of hormones bound to proteins serve as reservoirs, replenishing the concentration of free hormones when needed. Binding of hormones to plasma proteins greatly slows their clearance from the plasma. 24 12  11/7/24 In plasma, free hormone is in equilibrium with the bound hormone Total hormone concentration = free hormone + hormone bound to protein concentration of the free hormone is what is biologically important rather than the concentration of the total hormone 25 Physiological roles of Hormones: 1. Hormones affect cellular synthesis and secretion of other biologically active molecules such as hormones within other endocrine glands or neurotransmitters in neurons. They affect secretion of digestive tract products such as enzymes, hydrochloric acid, bile salts. They also affect epithelial mucus and milk synthesis and secretion. 2. Hormones affect metabolic processes in most cells. The synthesis and degradation of carbohydrates, lipids, and proteins are controlled by hormones to meet the specific energy or growth need of the individual. 3. Hormones affect contraction, relaxation and metabolism of muscle. They cause contraction and relaxation od vascular and gastrointestinal smooth muscle. Hormones also affect cardiac and skeletal muscle contractile properties. Some steroid hormones profoundly affect anabolic and catabolic processes with the muscle. 26 13  11/7/24 Physiological roles of Hormones: 4. Hormones control reproductive processes, such as gonadal differentiation, maturation and gametogenesis. 5. Hormones stimulate or inhibit cellular proliferation, thus affecting growth. 6. The excretion and reabsorption of inorganic cations and anions from kidney is regulated by hormones. Sodium, potassium, calcium and phosphate ions are particularly affected. 7. Hormones play important roles in animal behaviour like sexual or aggressive behaviour. 27 Endocrine Glands, Hormones, and their functions and structure Hypothalamus 28 14  11/7/24 Endocrine Glands, Hormones, and their functions and structure Anterior pituitary 29 Endocrine Glands, Hormones, and their functions and structure Posterior pituitary 30 15  11/7/24 Endocrine Glands, Hormones, and their functions and structure Thyroid 31 Endocrine Glands, Hormones, and their functions and structure 32 16  11/7/24 Endocrine Glands, Hormones, and their functions and structure Pancreas 33 Endocrine Glands, Hormones, and their functions and structure Parathyroid The parathyroid glands are four tiny glands, located in the neck, that control the body's calcium levels. Each gland is about the size of a grain of rice (weighs approximately 30 milligrams and is 3-4 millimeters in diameter). The parathyroids produce a hormone called parathyroid hormone (PTH). 34 17  11/7/24 Endocrine Glands, Hormones, and their functions and structure 35 Endocrine Glands, Hormones, and their functions and structure 36 18  11/7/24 Mechanisms of Action of Hormones Hormone Receptors and Their Activation The first step of a hormone’s action is to bind to specific receptors at the target cell. Cells that lack receptors for the hormones do not respond. Receptors for some hormones are located on the target cell membrane, whereas other hormone receptors are located in the cytoplasm or the nucleus. When the hormone combines with its receptor, this usually initiates a cascade of reactions in the cell, with each stage becoming more powerfully activated so that even small concentrations of the hormone can have a large effect. Hormonal receptors are large proteins, and each cell that is to be stimulated usually has some 2000 to 100,000 receptors. Each receptor is usually highly specific for a single hormone; this determines the type of hormone that will act on a particular tissue. 37 Mechanisms of Action of Hormones Location of Hormone Receptors On the surface of The membrane receptors are specific mostly for the cell membrane the protein, peptide and catecholamine In the cell The primary receptors for the different steroid hormones are found mainly in the cytoplasm cytoplasm In the cell The receptor for the thyroid hormones are found in the nucleus nucleus 38 19  11/7/24 Hormone receptors Types of hormone receptors present on the surface of the cell membrane : 1. G Protein–Linked Receptors 2. Receptors that are ligand-gated ion channels 3. Receptors that themselves function as enzymes 4. Enzyme-Linked Hormone Receptors 39 1. G Protein–Linked Receptors Many hormones receptors are coupled with groups of cell membrane proteins called heterotrimeric GTP-binding proteins (G proteins). There are more than 1000 known G protein–coupled receptors, all of which have seven transmembrane segments that loop in and out of the cell membrane. Some parts of the receptor that protrude into the cell cytoplasm (especially the cytoplasmic tail of the receptor) are coupled to G proteins that include three (i.e., trimeric) parts—the α, β, and ƴ subunits. 40 20  11/7/24 When the receptor is activated, it undergoes a conformational change This causes the GDP-bound trimeric G protein to associate with the cytoplasmic part of the receptor and to exchange GDP for guanosine triphosphate (GTP). Displacement of GDP by GTP causes the α subunit to dissociate from the trimeric complex and to associate with other intracellular signaling proteins these proteins, in turn, alter the activity of ion channels or intracellular enzymes 41 Ion channel enzyme Change in membrane potential Second messenger Cell’s Response Cell’s Response 42 21  11/7/24 The signaling event is rapidly terminated when the hormone is removed and the α subunit inactivates itself by converting its bound GTP to GDP The α subunit once again combines with the β and ƴ subunits to form an inactive, membrane-bound trimeric G protein. Some hormones are coupled to inhibitory G proteins (denoted Gi proteins), whereas others are coupled to stimulatory G proteins (denoted Gs proteins). 43 2. Receptors that are ligand-gated ion channels They are particularly prevalent in the plasma membranes of nerve cells 44 22  11/7/24 3. Receptors that themselves function as enzymes Most of the receptors with intrinsic tyrosine kinase activity bind first messengers that typically influence cell proliferation and differentiation 45 4. Enzyme-Linked Hormone Receptors The receptor is associated with an enzyme. The binding of a first messenger to the receptor causes a conformational change in the receptor that leads to activation of the enzyme. Activated enzyme (kinases) further phosphorylates downstream proteins and results in a cell’s response to the chemical messenger. 46 23  11/7/24 Example of an enzyme-linked receptor is the leptin receptor Leptin is a hormone secreted by fat cells In the case of the leptin receptor, one of the signaling pathways occurs through a tyrosine kinase of the janus kinase (JAK) family, JAK2 The leptin receptor exists as a dimer (i.e., in two parts) Binding of leptin to the receptor alters its conformation, enabling phosphorylation and activation of the intracellular associated JAK2 molecules The activated JAK2 molecules then phosphorylate other tyrosine residues within the receptor–JAK2 complex to mediate intracellular signaling. 47 Example of an enzyme-linked receptor is the leptin receptor Phosphorylation of signal transducer and activator of transcription (STAT) proteins occur which activates transcription by leptin target genes to initiate protein synthesis. Some of the effects of leptin occur rapidly as a result of activation of these intracellular enzymes Some actions occur more slowly and require synthesis of new proteins. 48 24  11/7/24 Intracellular Hormone Receptors and Activation of Genes Mechanisms of interaction of lipophilic hormones, such as steroids, with intracellular receptors in target cells. 49 Thyroid hormone activation of target cells 50 25  11/7/24 Second messenger system Second messengers are molecules that relay signals received at receptors on the cell surface to target molecules in the cytosol and/or nucleus. In addition to their job as relay molecules, second messengers serve to greatly amplify the strength of the signal. Binding of a ligand to a single receptor at the cell surface may end up causing massive changes in the biochemical activities within the cell. 51 Second messenger system 1. cAMP 2. Diacylglycerol (DAG) 3. Inositol Trisphosphate (IP3) 4. Calcium 52 26  11/7/24 1. cAMP second messenger system 1. Binding of the hormones with the receptor allows coupling of the receptor to a G protein 2. Stimulation of adenylyl cyclase, a membrane-bound enzyme, by the Gs protein 3. Adenylyl cyclase converts a small amount of cytoplasmic adenosine triphosphate (ATP) into cAMP inside the cell. 4. This then activates cAMP dependent protein kinase, which phosphorylates specific proteins in the cell. 5. This triggers biochemical reactions that ultimately lead to the cell’s response to the hormone. 53 Regulation of cAMP level in the cell Increase in the cAMP concentration in cell Increase activity of Adenylyl cyclase Decrease activity of phosphodiesterase Decrease in the cAMP concentration in cell Decrease activity of Adenylyl cyclase Increase activity of phosphodiesterase Example: Caffeine and theophylline present in coffee and tea They inhibit the phosphodiesterase activity Thus prolong the action of cAMP 54 27  11/7/24 cAMP Amplification cascade This explains how hormones and other messengers can be effective at extremely low extracellular concentrations. For example, one molecule of the hormone epinephrine can cause the liver to generate and release 108 molecules of glucose. 55 Role of cAMP in the cell 56 28  11/7/24 Activation of PKA by cAMP Protein kinase A Target protein Target protein phosphorylated 57 Feedback inhibition of cAMP Activated PDE 58 29  11/7/24 2. Diacylglycerol and Inositol Trisphosphate Phosphatidylinositol bisphosphate (PIP2) à diacylglycerol (DAG) and inositol trisphosphate (IP3) DAG activates protein kinase C, which then phosphorylate a large number of other proteins, leading to the cell’s response. IP3, in contrast to DAG, does not exert its second messenger role by directly activating a protein kinase. IP3, binds to ligand-gated Ca2+ channels located on the endoplasmic reticulum. When bonded to IP3, the channels open. This increase in the calcium level then continues the sequence of events leading to the cell’s response to the first messenger. 59 Diacylglycerol and Inositol Trisphosphate phosphatidylinositol bisphosphate (PIP2) à diacylglycerol (DAG) and inositol trisphosphate (IP3) 60 30  11/7/24 3. Calcium as a Second Messenger On entering a cell, calcium ions bind with the protein calmodulin. This protein has four calcium binding sites When three or four of these sites have bound with calcium, the calmodulin changes its shape and initiates multiple effects inside the cell, including activation or inhibition of protein kinases. 61 How do stimuli cause the cytosolic calcium concentration to increase? Plasma-membrane calcium channels open in response to a first messenger 1. Receptor activation Calcium is released from the endoplasmic reticulum by secondary messenger IP3 Active calcium transport out of the cell is inhibited by a second messenger 2. Opening of voltage-gated calcium channels. 62 31  11/7/24 Major mechanisms by which an increase in the Cytosolic Ca2+ concentration induces the Cell’s responses: 1. Calcium binds to calmodulin. On binding calcium, the calmodulin changes shape, which allows it to activate or inhibit a large variety of enzymes and other proteins. Many of these enzymes are protein kinases. 2. Calcium combines with calcium-binding intermediary proteins other than calmodulin. These proteins then act in a manner analogous to calmodulin. 3. Calcium combines with and alters response proteins directly, without the intermediation of any specific calcium-binding protein. 63 64 32  11/7/24 Endocrine Glands, Hormones, and their functions and structure Thyroid 65 Thyroid gland is one of the largest of the endocrine glands, normally weighing 15 to 20 grams in adults. They secrete two major hormones, thyroxine and triiodothyronine, commonly called T4 and T3 Both of these hormones profoundly increase the metabolic rate of the body Complete loss of thyroid secretion Basal metabolic rate to fall 40 to 50 per cent below normal Basal metabolic rate increases by Excesses of thyroid secretion 60-100 per cent above normal The thyroid gland also secretes calcitonin, an important hormone for calcium metabolism Thyroid secretion is controlled primarily by thyroid-stimulating hormone (TSH) secreted by the anterior pituitary gland. 66 33  11/7/24 Physiologic Anatomy of the Thyroid Gland. The thyroid gland is composed of large numbers of closed follicles (100 to 300 micrometers in diameter) filled with a secretory substance called colloid and lined with cuboidal epithelial cells that secrete into the interior of the follicles. The major constituent of colloid is the large glycoprotein thyroglobulin, which contains the Microscopic appearance of the thyroid thyroid hormones within its molecule. gland, showing secretion of thyroglobulin into the follicles. 67 93 % Thyroxine Thyroid gland secretion 7% Triiodothyronine However, almost all the thyroxine is eventually converted to triiodothyronine in the tissues T4 T3 The functions of these two hormones are the same, but they differ in rapidity and intensity of action Triiodothyronine is about four times as potent as thyroxine Triiodothyronine is present in the blood in much smaller quantities and persists for a much shorter time than does thyroxine. 68 34  11/7/24 blood Thyroid cellular mechanisms for iodine transport, thyroxine and triiodothyronine formation, and thyroxine and triiodothyronine release into the blood. 69 Formation of thyroid hormones 70 35  11/7/24 Formation of thyroid hormones 1. Transport of iodides from the blood into the thyroid glandular cells and follicles The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell. This is called iodide trapping. In a normal gland, the iodide pump concentrates the iodide to about 30 times its concentration in the blood ( and upto 250 times when fully active) The concentration of TSH is one of the most important factor that controls the iodide trapping by thyroid glands 71 2. Formation and secretion of Thyroglobulin by the Thyroid Cells The endoplasmic reticulum and Golgi apparatus synthesize and secrete thyroglobulin (Mol wt. 335,000) into the follicles. Each molecule of thyroglobulin contains about 70 tyrosine amino acids These tyrosine residues are the major substrates that combine with iodine to form the thyroid hormones Thus, the thyroid hormones form within the thyroglobulin molecule. 72 36  11/7/24 3. Iodination of Tyrosine and Formation of the Thyroid Hormones The binding of iodine with the thyroglobulin molecule is called organification of the thyroglobulin Oxidized iodine binds directly to the amino acid tyrosine. Reaction is slow in absence of enzyme In the thyroid cells, an iodinase enzyme is present that causes the process to occur within seconds or minutes 73 74 37  11/7/24 Storage of Thyroglobulin The thyroid gland has the ability to store large amounts of hormone *unusual among the endocrine glands Each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules. In this form, the thyroid hormones are stored in the follicles Supply of thyroid hormones for 2 to 3 months Even after the synthesis of thyroid hormone is stopped, the physiologic effect of deficiency is not observed for several months. 75 Transport of Thyroxine and Triiodothyronine to Tissues Thyroxine and Triiodothyronine are bound to plasma proteins when transported Around 99 per cent of the T4 and T3 combines immediately with several of the plasma proteins (E.g. thyroxine-binding globulin). Thyroxine and Triiodothyronine are released slowly to Tissue Cells. Half the T4 in the blood is released to the tissue cells about every 6 days, whereas half the T3 is released to the cells in about 1 day (because of its lower affinity) On entering the tissue cells Both T4 and T3 again bind with intracellular proteins (T4 binding more strongly than the T3). They are again stored in the target cells and are used slowly over a period of days or weeks. 76 38  11/7/24 Physiologic Functions of the Thyroid Hormones 77 1. Thyroid Hormones increase the transcription of large numbers of Genes Before acting on the genes to increase genetic transcription, one iodide is removed from almost all the thyroxine, thus forming triiodothyronine T4 T3 Intracellular thyroid hormone receptors have a very high affinity for triiodothyronine (T3). More than 90 per cent of the thyroid hormone molecules that bind with the receptors is triiodothyronine. 78 39  11/7/24 Thyroid hormone activation of target cells 79 TSH (from the Anterior Pituitary Gland) Increases Thyroid Secretion. TSH, also known as thyrotropin, increases the secretion of T3 and T4 by the following effects: 1. Increased proteolysis of the thyroglobulin stored in the follicles, with resultant release of the thyroid hormones into the circulating blood. 2. Increased activity of the iodide pump, which increases the rate of “iodide trapping” in the glandular cells. 3. Increased iodination of tyrosine to form the thyroid hormones. 4. Increased size and increased secretory activity of the thyroid cells. 5. Increased number of thyroid cells plus a change from cuboidal to columnar cells and increase in the infolding of the thyroid epithelium into the follicles. In summary, TSH increases all the known secretory activities of the thyroid glandular cells. 80 40  11/7/24 Diseases of the Thyroid Hyperthyroidism Hypothyroidism 81 Hyperthyroidism Causes of Hyperthyroidism 1. Graves’ Disease (autoimmune disease) In most patients with hyperthyroidism, the thyroid gland is increased by two to three times normal size. A tremendous hyperplasia (enlargement of gland) is observed and infolding of the follicular cell lining into the follicles leading to an increase in the number of cells. Rate of hormone secretion by cells increases drastically. Radioactive iodine uptake studies indicate that some of these hyperplastic glands secrete thyroid hormone at rates 5 to 15 times normal. 82 41  11/7/24 The changes in the thyroid gland in most instances are similar to those caused by excessive TSH. However, the plasma TSH concentrations in these patients are found to be less than normal. These conditions are characterized by presence of antibodies that bind with the same membrane receptors that bind TSH. These antibodies are called thyroid-stimulating autoimmunity against thyroid immunoglobulin (TSI). tissue. TSI induce continual activation of the cAMP system of the cells, with resultant development of hyperthyroidism. TSI stimulate thyroid glands for longer period of time (12 hours) in contrast to a little over 1 hour for TSH. The high level of thyroid hormone secretion caused by TSI in turn suppresses anterior pituitary formation of TSH. 83 2. Thyroid Adenoma Hyperthyroidism occasionally results from a localized adenoma (a tumor) that develops in the thyroid tissue and secretes large quantities of thyroid hormone. There is no evidence of involvement of any autoimmune disease. Adenoma secreting large quantities Production of TSH by of thyroid hormone pituitary gland Secretory function in the remainder of the thyroid gland is almost totally inhibited 84 42  11/7/24 Symptoms of Hyperthyroidism 1) A high state of excitability 2) Intolerance to heat (3) Increased sweating (4) Mild to extreme weight loss (sometimes as much as 100 pounds) (5) Varying degrees of diarrhea (6) Muscle weakness (7) Nervousness or other psychic disorders (8) Extreme fatigue but inability to sleep (9) Tremor of the hands. 85 Exophthalmos Most people with hyperthyroidism develop some degree of protrusion of the eyeballs. This condition is called exophthalmos. The cause of the protruding eyes is edematous swelling (accumulation of fluid) of the retro-orbital tissues and degenerative changes in the extraocular muscles. Caused due to presence of antibodies that react with eye muscles an autoimmune process The concentration of these immunoglobulins is usually highest in patients who have high concentrations of TSIs. The exophthalmos usually is greatly ameliorated with treatment of the hyperthyroidism. 86 43  11/7/24 Hypothyroidism 1. Hypothyroidism caused by autoimmune disease (E.g. Hashimoto's disease): Hypothyroidism is probably initiated by autoimmunity against the thyroid gland. This autoimmune disease destroys the gland rather than to stimulates it. The thyroid glands of most of these patients first have autoimmune thyroiditis (thyroid inflammation). This causes progressive deterioration and finally fibrosis of the gland, with resultant diminished or absent secretion of thyroid hormone. 87 2. Endemic Colloid Goiter caused by dietary iodine deficiency The term “goiter” means a greatly enlarged thyroid gland. The mechanism for development of large endemic goiters: Lack of iodine prevents production of both T3 and T4 Production of TSH by the anterior pituitary is not inhibited Excessive secretion of TSH from pituitary The TSH then stimulates the thyroid cells to secrete tremendous amounts of thyroglobulin colloid into the follicles The thyroid gland grows larger and larger But because of lack of iodine, T3 and T4 production does not occur in the thyroglobulin molecule. The normal suppression of TSH production by the anterior pituitary does not occur The thyroid gland may increase to 10 to 20 times normal size. 88 44  11/7/24 3. Idiopathic Nontoxic Colloid Goiter Enlarged thyroid glands similar to those of endemic colloid goiter can also occur in people who do not have iodine deficiency. The secretion of hormone is depressed due to unknown reason Most of these patients show signs of mild thyroiditis Thyroiditis causes slight hypothyroidism, which then leads to increased TSH secretion and progressive growth of the noninflamed portions of the gland. These glands usually become nodular, with some portions of the gland growing while other portions are being destroyed by thyroiditis 89 In some persons with colloid goiter, the thyroid gland has an abnormality of the enzyme system required for formation of the thyroid hormones. Some abnormalities often encountered are : 1. Deficient iodide-trapping mechanism, in which iodine is not pumped adequately into the thyroid cells 2. Deficient peroxidase system, in which the iodides are not oxidized to the iodine state 3. Deficient coupling of iodinated tyrosines in the thyroglobulin molecule, so that the final thyroid hormones cannot be formed 4. Deficiency of the deiodinase enzyme, which prevents recovery of iodine from the iodinated tyrosines that are not coupled to form the thyroid hormones (this is about two thirds of the iodine), thus leading to iodine deficiency 90 45  11/7/24 Physiologic Characteristics of Hypothyroidism Hypothyroidism may be caused by factors like thyroiditis, endemic colloid goiter, idiopathic colloid goiter, destruction of the thyroid gland by irradiation, or surgical removal of the thyroid gland. However, the physiologic effects are the same. 1. Fatigue and extreme sleeping (up to 12 to 14 hours a day) 2. Extreme muscular sluggishness, slowed heart rate, decreased cardiac output, and decreased blood volume. 3. Sometimes increased body weight 4. Constipation 5. Mental sluggishness 6. Failure of many trophic functions in the body evidenced by depressed growth of hair and scaliness of the skin. 7. In severe cases, development of an edematous appearance throughout the body called myxedema. 91 Myxedema Myxedema develops in the patient with total lack of thyroid hormone function Hyaluronic acid and chondroitin sulfate bound with protein form excessive tissue gel in the interstitial spaces. Total quantity of interstitial fluid is increased. Caused bagginess under the eyes and swelling of the face. 92 46  11/7/24 Cretinism Cretinism is caused by extreme hypothyroidism during fetal life, infancy, or childhood. This condition is characterized especially by failure of body growth and by mental retardation. Failure of the thyroid gland to produce Congenital thyroid hormone because of a genetic cretinism defect of the gland Cretinism Endemic Failure of the thyroid gland to produce cretinism thyroid hormone due to lack of iodine in the diet The severity of endemic cretinism varies greatly, depending on the amount of iodine in the diet 93 94 47  11/7/24 The pancreas is composed of two major types of tissues (1) The acini, which secrete digestive juices (2) The islets of Langerhans, which secrete insulin and glucagon The human pancreas has 1 to 2 million islets of Langerhans The islets contain three major types of cells, 1) Alpha cells 2) Beta cells 3) Delta cells 95 60 % of all the cells of the islets lie mainly in the middle of each islet and Beta cells secrete insulin and amylin (a hormone that is often secreted in parallel with insulin, function unknown) Alpha cells about 25 % of the total cells of the islets secrete glucagon about 10 % of the total cells of the islets Delta cells secrete somatostatin is present in small numbers in the islets PP cell secretes a hormone of uncertain function called pancreatic polypeptide 96 48  11/7/24 Insulin and Its Metabolic Effects 97 Insulin was first isolated from the pancreas in 1922 by Banting and Best Insulin secretion is associated with energy abundance Insulin Excess carbohydrates Stored as glycogen mainly in the Insu liver and muscles li n All the excess carbohydrates that cannot be stored as glycogen are converted into fats and stored in the adipose tissue. Insulin promotes amino acid Insulin Excess amino acids uptake by cells and conversion of these amino acids into protein. It also inhibits the breakdown of the proteins that are already in the cells. 98 49  11/7/24 Insulin Chemistry and Synthesis Insulin is a small protein Human insulin has a molecular weight of 5808. It is composed of two amino acid chains connected to each other by disulfide linkages. Insulin functional activity is lost when two amino acid chains are split apart. 21 aa 30 aa 99 Insulin is synthesized in the beta cells by the usual cell machinery for protein synthesis Cleaved in Preproinsulin cleaved in the ER Proinsulin the Golgi and insulin (11,500) (9000) packed into (5808) vesicles Transport: Insulin is circulated almost entirely in an unbound form It has a plasma half-life of about 6 minutes Cleared from the circulation within 10 to 15 minutes Enzyme insulinase degrade unbound insulin mainly in liver and to a lesser extent in kidney and muscles followed by other tissues. 100 50  11/7/24 Insulin Receptor: Insulin binds with and activates a membrane receptor protein (MW 300,000). It is the activated receptor, not the insulin, that causes the subsequent effects. The insulin receptor is a combination of four subunits held together by disulfide linkages: 1) two alpha subunits 2) two beta subunits enzyme-linked receptor 101 Activation of insulin receptor: The insulin binds with the Beta subunits protruding into the cell alpha subunits become autophosphorylated Autophosphorylation of the beta subunits activates a linked tyrosine kinase causes phosphorylation of multiple other intracellular enzymes including a group called insulin-receptor substrates (IRS). In this way, insulin regulates carbohydrate, fat, and protein Activation/deactivation of enzymes metabolism. 102 51  11/7/24 Mechanisms of Insulin Secretion from Beta cells: High Glucose concentration in the blood. Glucose transporter (GLUT-2) allows intake of glucose in the cell (more glucose more intake) Glucose is converted to glucose-6-phosphate by glucokinase enzyme. The glucose-6-phosphate is subsequently oxidized to form ATP, which inhibits the ATP-sensitive potassium channels of the cell. Closure of the potassium channels depolarizes the cell membrane, thereby opening voltage-gated calcium channels Intracellular Ca 2+ increases that stimulates fusion of the docked insulin-containing vesicles with the cell membrane and secretion of insulin into the extracellular fluid by exocytosis. 103 104 52  11/7/24 105 1. Effect of Insulin on Carbohydrate Metabolism 2. Effect of Insulin on Fat Metabolism 3. Effect of insulin on protein metabolism 106 53  11/7/24 Effect of Insulin on Carbohydrate Metabolism 1. Insulin promotes muscle glucose uptake and metabolism The insulin causes rapid transport of glucose into the muscle cells. Glucose transported inside is converted to glycogen and stored. This muscle glycogen can be used for energy by the muscle. 107 2. Insulin promotes Liver uptake, storage, and use of Glucose Glucose Glucose in Stored as Taken up by liver glycogen glycogen liver synthase liver phosphorylase In presence of Insulin Glucose 1. Insulin inactivates liver phosphorylase, enzyme that causes liver glycogen to split into glucose. This prevents breakdown of the glycogen that has been stored in the liver cells. 2. Insulin causes enhanced uptake of glucose from the blood by the liver cells. By increasing the activity of the enzyme glucokinase Glucokinase initiates phosphorylation of glucose and hence glucose is trapped in the liver 3. Insulin increases the activities of the enzymes that promote glycogen synthesis (E.g. glycogen synthase) The net effect of all these actions is to increase the amount of glycogen in the liver. 108 54  11/7/24 Glucose is released from the Liver between meals Concentration of glucose Insulin is not released is less Low blood glucose level Synthesis of glycogen is Stored liver glycogen is stopped converted to glucose glucose phosphorylase phosphatase glycogen Glucose phosphate glucose glucose diffuses back into the blood Enzyme phosphorylase is activated in the absence of insulin and in the presence of glucagon The enzyme glucose phosphatase is also inhibited by insulin 109 3. Insulin also promotes conversion of excess glucose into Fatty Acids and inhibits gluconeogenesis in the Liver Insulin decreases the quantity as well as activity of the liver enzymes required for gluconeogenesis. Insulin decreases the release of amino acids from muscle and other extrahepatic tissues and in turn the availability of these necessary precursors required for gluconeogenesis 110 55  11/7/24 Effect of Insulin on Fat Metabolism Insulin Promotes Fat synthesis and storage 1. Insulin increases the transport of glucose into the liver cells. After the liver glycogen concentration reaches 5 to 6 per cent, this in itself inhibits further glycogen synthesis. Then all the additional glucose entering the liver cells becomes available to form fat. Glucose Pyruvate acetyl coenzyme A fatty acids synthesis 2. An excess of citrate and isocitrate ions is formed by the citric acid cycle when excess of glucose are being used for energy. These ions activate acetyl-CoA carboxylase, the enzyme required to carboxylate acetyl-CoA to form malonyl-CoA, the first stage of fatty acid synthesis. 111 3. Most of the fatty acids are then synthesized within the liver itself and used to form triglycerides, the usual form of storage fat. Triglycerides Released from liver cells to Triglycerides the blood in lipoproteins (reaches adipose tissue) Triglycerides fatty acids absorbed into the adipose cells (adipose tissue) converted to Triglycerides Insulin activates lipoprotein lipase in the capillary walls of the adipose tissue Stored 112 56  11/7/24 Effect of insulin on protein metabolism 1. Insulin stimulates transport (uptake) of many of the amino acids into the cells. (Among the amino acids most strongly transported are valine, leucine, isoleucine, tyrosine, and phenylalanine) 2. Insulin increases the translation of messenger RNA, thus forming new proteins. in insul ON ribosomal machinery insulin OFF 3. Insulin also increases the rate of transcription of selected DNA genetic sequences It leads to increased formation of enzymes responsible for storage of carbohydrates, fats, and proteins. 113 4. Insulin inhibits the catabolism of proteins How ? Insulin diminishes the normal Less amino acids are released from the cell degradation of proteins by cellular lysosomes 5. In the liver, insulin depresses the rate of gluconeogenesis. It does this by decreasing the activity of the enzymes that promote gluconeogenesis. Insulin Lack Causes Protein Depletion and Increased Plasma Amino Acids. Virtually all protein storage comes to a halt when insulin is not available. 114 57  11/7/24 Glucagon and Its Functions Alpha cells about 25 % of the total cells of the islets secrete glucagon 115 Glucagon, a hormone secreted by the alpha cells of the islets of Langerhans Glucagon is a large polypeptide (peptide hormone) It has a molecular weight of 3485 and is composed of a chain of 29 amino acids. Glucagon has several functions that are diametrically opposed to those of insulin 116 58  11/7/24 Effects on Glucose Metabolism The major effects of glucagon on glucose metabolism are (1) breakdown of liver glycogen (glycogenolysis) (2) increased gluconeogenesis in the liver. Both of these effects greatly enhance the availability of glucose to the other organs of the body. 117 The most dramatic effect of glucagon is its ability to cause glycogenolysis in the liver, which in turn increases the blood glucose concentration within minutes. 118 59  11/7/24 2. Glucagon increases Gluconeogenesis Glucagon to increase the rate of amino acid uptake by the liver cells and then the conversion of many of the amino acids to glucose by gluconeogenesis. Glucagon activates multiple enzymes that are required for amino acid transport and gluconeogenesis. E.g. Activation of the enzyme system for converting pyruvate to phosphoenolpyruvate, a rate-limiting step in gluconeogenesis. 119 Other effects of Glucagon glucagon activates adipose cell lipase, making increased quantities of fatty acids available to the energy systems of the body. Glucagon also inhibits the storage of triglycerides in the liver, which prevents the liver from removing fatty acids from the blood this also helps make additional amounts of fatty acids available for the other tissues of the body. 120 60  11/7/24 Regulation of Glucagon Secretion 1. Increased Blood Glucose Inhibits Glucagon Secretion. The effect of blood glucose concentration on glucagon secretion is in exactly the opposite direction from the effect of glucose on insulin secretion. 121 2. Increased Blood Amino Acids Stimulate Glucagon Secretion. High concentrations of amino acids stimulate the secretion of glucagon This is the same effect that amino acids have in stimulating insulin secretion. Glucagon then promotes rapid conversion of the amino acids to glucose 3. Exercise Stimulates Glucagon Secretion. The blood concentration of glucagon often increases fourfold to fivefold during excessive exercising. What causes this is not understood, because the blood glucose concentration does not necessarily fall. A beneficial effect of the glucagon is that it prevents a decrease in blood glucose. 122 61  11/7/24 Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin. Diabetes Mellitus There are two general types of diabetes mellitus 1. Type I diabetes, also called insulin 2. Type II diabetes, also called non–insulin dependent diabetes mellitus (IDDM), dependent diabetes mellitus (NIDDM), is is caused by lack of insulin secretion. caused by decreased sensitivity of target tissues to the metabolic effect of insulin. This reduced sensitivity to insulin is often called insulin resistance. In both types of diabetes mellitus, metabolism of all the main foodstuffs is altered. 123 Type I Diabetes: cause by lack of Insulin production by Beta Cells of the Pancreas Injury to the beta cells of the pancreas or diseases that impair insulin production can lead to type I diabetes. Viral infections or autoimmune disorders may be involved in the destruction of beta cells in many patients Heredity also plays a major role in determining the susceptibility of the beta cells to destruction by these insults. In some instances, there may be a hereditary tendency for beta cell degeneration even without viral infections or autoimmune disorders. The usual onset of type I diabetes occurs at about 14 years of age in the United States, and for this reason it is often called juvenile diabetes mellitus. 124 62  11/7/24 Type I diabetes may develop very abruptly, over a period of a few days or weeks, with three principal sequelae: (1) Increased blood glucose. (2) Increased utilization of fats for energy (3) Depletion of the body’s proteins. 125 Symptoms: 1. Blood Glucose concentration rises to very high levels in Diabetes Mellitus. Lack of insulin Glucose not utilized from blood Plasma glucose level rises up to 300 to 1200 mg/100 ml The increased plasma glucose then has multiple effects throughout the body. 126 63  11/7/24 2. Increased blood glucose causes loss of glucose in the urine The high blood glucose causes more glucose to filter into the renal tubules than can be reabsorbed, and the excess glucose spills into the urine This happens when blood glucose concentration rises above 180 mg/100 ml. “threshold” level 127 3. Increased Blood Glucose Causes Dehydration A Glucose level high in Glucose does not diffuse easily through the extracellular fluid pores of the cell membrane Increased osmotic pressure in the extracellular fluids causes osmotic transfer of water out of the cells B In addition to the direct cellular dehydrating effect of excessive glucose, the loss of glucose in the urine causes osmotic diuresis. The osmotic effect of glucose in the renal tubules massive loss of fluid in greatly decreases tubular reabsorption of fluid urine Thus, polyuria (excessive urine excretion), intracellular and extracellular dehydration, and increased thirst are classic symptoms of diabetes. 128 64  11/7/24 4. Chronic high glucose concentration causes Tissue injury Blood vessels in multiple tissues Blood glucose is poorly throughout the body begin to function controlled over long abnormally and undergo structural changes periods in diabetes mellitus that result in inadequate blood supply to the tissues. This in turn leads to increased risk for heart attack, stroke, end-stage kidney disease, retinopathy and blindness, and ischemia and gangrene of the limbs. 129 5. Diabetes Mellitus causes increased utilization of Fats and metabolic acidosis Carbohydrate Shift caused Fat metabolism metabolism by DM Increases the release of keto acids, such as acetoacetic acid and β-hydroxybutyric acid They are released more rapidly than they can be taken up and oxidized by the tissue cells Patient develops severe metabolic acidosis from the excess keto acids, which, in association with dehydration due to the excessive urine formation, can cause severe acidosis. This leads rapidly to diabetic coma and death unless the condition is treated immediately with large amounts of insulin. 130 65  11/7/24 6. Diabetes Causes Depletion of the Body’s Proteins Glucose is not utilized Increased utilization and decreased storage of for energy production proteins as well as fat Diabetes mellitus leads to rapid weight loss and asthenia (lack of energy) despite eating large amounts of food (polyphagia). Without treatment, these metabolic abnormalities can cause severe wasting of the body tissues and death within a few weeks. 131 Type II Diabetes (Resistance to the Metabolic Effects of Insulin) 132 66  11/7/24 Type II diabetes is far more common than type I, accounting for about 90 per cent of all cases of diabetes mellitus. Also called as adult-onset diabetes Onset usually occurs after age 30, often between the ages of 50 and 60 years, and the disease develops gradually. Obesity, Insulin Resistance, and “Metabolic Syndrome” usually precede development of Type II Diabetes. Type II diabetes, in contrast to type I, is associated with increased plasma insulin concentration (hyperinsulinemia) Hyperinsulinemia occurs as pancreatic beta cells try to compensate for diminished sensitivity of target tissues to the metabolic effects of insulin.. This condition is referred to as insulin resistance. 133 The decrease in insulin sensitivity impairs carbohydrate utilization and storage, raising blood glucose and stimulating a compensatory increase in insulin secretion. Development of insulin resistance and However, the mechanisms impaired glucose metabolism is usually a that link obesity with insulin gradual process, beginning with excess resistance are still uncertain. weight gain and obesity. Mechanism of Insulin Resistance: Some studies suggest that there are fewer insulin receptors, especially in the skeletal muscle, liver, and adipose tissue, in obese than in lean subjects. However, most of the insulin resistance appears to be caused by abnormalities of the signaling pathways that link receptor activation with multiple cellular effects. 134 67  11/7/24 Insulin resistance is part of a cascade of disorders that is often called the “metabolic syndrome.” Some of the features of the metabolic syndrome include: (1) Obesity, especially accumulation of abdominal fat (2) Insulin resistance (3) Fasting hyperglycemia (4) Lipid abnormalities such as increased blood triglycerides (5) Hypertension Excess weight gain (especially when it is associated with accumulation of adipose tissue in the abdominal cavity around the visceral organs) 135 Insulinoma—Hyperinsulinism Much rarer than diabetes Excessive insulin production occasionally occurs from an adenoma of an islet of Langerhans. About 10 to 15 per cent of these adenomas are malignant, and occasionally metastases from the islets of Langerhans spread throughout the body, causing tremendous production of insulin by both the primary and the metastatic cancers. More than 1000 grams of glucose is administered every 24 hours to prevent hypoglycemia in some of these patients. 136 68  11/7/24 Insulin shock and Hypoglycemia: Blood glucose level falls 50 to 70 mg/100 ml Excitation of Central nervous system Sometimes various forms of hallucinations result, but more often the patient simply experiences extreme nervousness, trembles all over, and breaks out in a sweat. Blood glucose level falls to 20 to 50 mg/100 ml Seizure/loss of consciousness As the glucose level falls still lower, the seizures cease and only a state of coma remains 137 69