All Metabolism Handouts (3) PDF

INTRODUCTION TO ENDOCRINE PHYSIOLOGY Reading: Vander et al., Human Physiology, 14th ed. pp. 318-337. Learning Objectives 1. Identify the chemical class for each hormone. 2. Describe how hormones are transported in the blood, know which hormones are bound to proteins and know how...

INTRODUCTION TO ENDOCRINE PHYSIOLOGY Reading: Vander et al., Human Physiology, 14th ed. pp. 318-337. Learning Objectives 1. Identify the chemical class for each hormone. 2. Describe how hormones are transported in the blood, know which hormones are bound to proteins and know how protein binding affects hormone action. 3. List the types of hormone receptors and identify which hormones bind to each type of receptor. 4. List the components of the hypothalamic-pituitary axis. 5. List the hormones secreted by the hypothalamus, anterior pituitary and posterior pituitary. 6. Describe the negative feedback regulation of the release of anterior pituitary hormones. I. Overview of Endocrinology A. Major Communication system B. Endocrine system is not anatomically connected C. Hormones secreted by endocrine glands and travel to target via blood The specificity of the hormone action is due to the expression of receptors on the target tissue D. Responses to hormones take seconds to days. E. Hormone concentrations in plasma are very low – 10-9 M to 10-12 M  F. Hormones from previous lectures 1. Autonomic nervous system - epinephrine, norepinephrine 2. Cardiovascular system - atrial natriuretic peptide 3. Gastrointestinal system - gastrin, secretin, cholecystokinin, motilin 4. Renal system - renin-angiotensin, aldosterone, parathyroid hormone, vitamin D, ADH G. Hormone secreting tissues 1. Glands Pituitary gland, thyroid gland, parathyroid gland, testes, ovaries, adrenal gland, pancreas 2. Other tissues Central nervous system (hypothalamus), GI tract, liver, heart, kidneys, placenta, adipose tissue, bone 3. Neoplasms- lung cancers commonly secrete hormones including parathyroid hormone, antidiuretic hormone and ACTH. 4. Glands may secrete multiple hormones but normally one type of cells in the gland will secrete a single hormone (an exception are the gonadotrophs in the anterior pituitary which release luteinizing hormone and follicle stimulating hormone) II. Chemical classification of hormones A. Amines - derivatives of amino acid tyrosine 1. Catecholamines – dopamine (hypothalamus), norepinephrine, epinephrine (adrenal medulla)  2. Thyroid hormone B. Steroids 1. Cholesterol - precursor to all steroid hormones 2. Steroid Hormones a. mineralocorticoid - aldosterone b. glucocorticoids - cortisol c. sex steroids i. androgens - testosterone ii. estradiol iii. progesterone 3. Steroid secreting glands (details will be covered in the following lectures) a. Adrenal gland - located above the kidneys Divided into two parts: cortex (outer) and medulla (inner) Adrenal cortex produces: § Mineralocorticoids (aldosterone) § Glucocorticoids (cortisol) § Androgens (DHEA) b. Gonads § Testes - testosterone § Ovaries - estrogen, progesterone c. Placenta § Estrogen and progesterone C. Peptide hormones Synthesis – polypeptide chain Examples – Proopiomelanocortin (POMC), insulin List of peptide hormones: corticotrophin releasing hormone (CRH), thyrotropin releasing hormone (TRH), growth hormone- releasing hormone (GHRH), somatostatin, gonadotropin releasing hormone (GnRH), adrenocorticopic hormone (ACTH), growth hormone (GH), insulin-like growth factor 1 (IGF-1), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, human chorionic gonadotropin (hCG), human placental lactogen (hPL), oxytocin, antidiuretic hormone (ADH), inhibin, atrial naturetic peptide (ANP), angiotensin, insulin, glucagon, parathyroid hormone, calcitonin Summary of classes of hormones: Amines - catecholamine and thyroid hormone Steroids - aldosterone, cortisol and sex steroids Peptides – ACTH, CRH, insulin III. Hormonal transport in blood A. Water soluble hormones travel as free form in blood e.g. Catecholamines and peptides (except growth hormone and IGF-1) B. Protein bound hormones All steroid hormones, thyroid hormone, growth hormone & insulin-like growth factor-1 (IGF-1) are bound to binding proteins in the blood. Hormones bind to specific binding proteins (TBG for thyroid hormone, CBG for cortisol. TBG and CBG are produced and secreted by the liver) as well as nonspecific proteins (e.g. albumin). Many of the hydrophobic hormones (e.g. steroids) are bound to proteins in blood to increase their solubility. The free form of the hormone is the active form. The hormone must dissociate from the binding protein to be active. Most of the hormone is in the bound state (90-99%) with very little free. hormone + binding protein hormone-binding protein Functions of bound hormone 1. Bound hormone serves as a reservoir of hormone and minimizes fluctuations in levels of hormone in blood. 2. Extends the half-life of hormone. Only the free form of hormone is metabolized and excreted by the kidney. e.g. free thyroid hormone (T4) half-life is several minutes, bound T4 half-life is 7- 8 days. In general, hormones that have chronic long-term effects (e.g. protein synthesis) are bound to proteins. Hormones with acute short-term effects circulate in the free form. IV. Biotransformation A. Metabolism 1. Function a. Inactivation – most of the metabolites have lower activity or are not biologically active b. Activation Renin-angiotensin I-angiotensin II T4 to T3 Testosterone to dihydrotestosterone and estradiol c. Elimination – the metabolites are more soluble in water and are excreted in bile or kidney.  2. Sites of metabolism a. Liver b. Kidney c. Plasma - catecholamines, peptides B. Excretion – bile, urine, feces V. Hormone receptors A. Membrane bound receptors 1. Hormones - Catecholamines, peptides 2. Signal transduction pathways - binding of hormones to receptors on the plasma membrane causes activation of cell signaling pathways that ultimately produce the biological effects. The activation of the signaling pathways can produce rapid effects (seconds to minutes). The signaling pathways can also alter gene expression and can have a slow response (hours to days). Examples: G-protein coupled receptors, insulin receptor B. Intracellular receptors 1. Steroid hormones, thyroid hormone, vitamin D 2. The intracellular hormone receptors are transcriptional factors. Hormone binding to receptor activates the receptor to alter gene expression (increase or decrease). C. Integration of hormone action 1. Complementary actions – two hormones have similar effects. e.g. epinephrine and cortisol increase circulating lipid and carbohydrate levels during stress 2. Antagonistic actions – two hormones having opposite effects. e.g. insulin and glucagon 3. Permissive actions The effect of one hormone requires the presence of a second hormone. Thus, the effect of the second hormone permits the actions of the first hormone. Example: thyroid hormone has permissive effects in that it is needed for epinephrine to have its maximum effects VI. Control of hormone secretion A. Pattern of secretion 1. release in pulses - every 90 minutes, prevents down regulation caused by continuous stimulation of receptor 2. cyclical release a. circadian patterns - light-dark - cortisol sleep - growth hormone B. Monthly cycles - menstrual cycle C. Regulation of Hormone Secretion 1. Plasma concentrations of mineral ions or nutrients e.g. insulin secretion regulated by plasma glucose levels, parathyroid secretion regulated by plasma Ca2+ levels 2. Physical stimuli a. mechanoreceptors – ANP 3. Neuronal control a. Autonomic nervous system (sympathetic and parasympathetic) b. Central nervous system - hypothalamus-pituitary axis  4. Hormonal control - tropic hormones (CRH, GHRH, TRH, GnRH) Tropic hormone: a hormone that stimulates the release of another hormone. VII. Anatomy of Hypothalamus and Pituitary A. Hypothalamus Major center for control of homeostasis including temperature, cardiovascular functions, feeding and hormone secretion. The hypothalamus regulates the release of hormones from the pituitary gland by neuronal and hormonal mechanisms. Anatomy: 1. Nuclei in Hypothalamus Neurons project to posterior pituitary or median eminence 2. Median eminence - base of hypothalamus, contain capillaries of the hypothalamic-pituitary portal system. 3. Hypothalamic-pituitary portal vessels (Hypophyseal portal system) This portal circulatory system travels from capillary beds in the median eminence to capillary beds in the anterior pituitary via the infundibulum or pituitary stalk. These vessels transport hormones released by hypothalamic neurons from the median eminence to the anterior pituitary. The capillary bed in the anterior pituitary is highly fenestrated and allows the hormones to move out of the capillaries into the interstitial fluid of the anterior pituitary. B. Pituitary Gland Consists of posterior lobe and anterior lobe. 1. Location 2. Posterior pituitary (neurohypophysis) outgrowth of hypothalamus - neuronal tissue contains nerve terminals of neurons projecting from the hypothalamus 3. Anterior pituitary (adenohypophysis) Adjacent to posterior pituitary. 4. Infundibulum (pituitary stalk) - connects the hypothalamus to the posterior pituitary gland. VIII. Posterior Pituitary The posterior pituitary consists of unmyelinated axons and nerve terminals of neurons with cell bodies in the hypothalamus. Activation of these neurons causes release of hormones into capillaries in the posterior pituitary which then pass into the systemic circulation. Posterior pituitary hormones: 1. Antidiuretic hormone (ADH, Vasopressin) regulates water reabsorption in collecting ducts. 2. Oxytocin stimulates milk ejection reflex and stimulates uterine contractions. IX. Hypothalamus - Pituitary Axis A. Hypophysiotropic hormones Neurons in the hypothalamus project to the median eminence. Activation of these neurons causes the release of hypophysiotropic (Tropic) hormones from the hypothalamus which regulate release of hormones from anterior pituitary. 1. Control of release of hypophysiotropic hormones Tropic neurons in the hypothalamus receive synaptic input from all areas of the nervous system. These synapses are both excitatory and inhibitory. Various stimuli can result in excitatory input into these hypothalamic nuclei and cause release of tropic hormones. e.g. stress causes release of CRH which causes the release of ACTH from the pituitary which stimulates release of cortisol from the adrenal cortex. Hypophysiotropic hormones released from the hypothalamus travel to the anterior pituitary via hypothalamo-pituitary portal vessels. Hypophysiotropic hormones bind to receptors on specific cells in the anterior pituitary. Binding of the hypophysiotropic hormone to its receptor stimulates (CRH, GnRH, GHRH, TRH) or inhibits (somatostatin and dopamine) secretion of anterior pituitary hormones into circulation. 2. Hypophysiotropic hormones: Gonadotropin releasing hormone (GnRH) – stimulates release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) Growth Hormone Releasing Hormone (GHRH) – stimulates release of growth hormone. Somatostatin (SS) - inhibits release of growth hormone. Thyrotropin releasing hormone (TRH) – stimulates release of thyroid stimulating hormone (TSH) Dopamine (DA) - inhibits release of prolactin. Corticotropin releasing hormone (CRH) – stimulates release of adrenocorticotropin hormone (ACTH) All of the hypothalamic hormones are peptides except dopamine. B. Anterior Pituitary Hormones The anterior pituitary is highly vascularized with capillaries from the hypothalamic-pituitary portal system and contains epithelial cells that secrete hormones. Hormones released into the capillaries in the anterior pituitary enter the systemic circulation. The type of cells in the anterior pituitary are named for the hormones they produce. Lactrotrophs - prolactin Corticotrophs - adrenocorticotropin (ACTH) Thyrotrophs - thyroid stimulating hormone (TSH) Gonadotrophs - luteinizing hormone (LH) and follicle stimulating hormone (FSH) Somatotrophs - growth hormone. 1. Actions of anterior pituitary hormones a. Anterior pituitary hormone stimulates secretion of hormone by an endocrine gland or tissue. b. Anterior pituitary hormone can also have direct effects on target tissues (e.g. prolactin, growth hormone) 2. Anterior Pituitary Hormones E - 18 X. Hormonal Feedback Control Systems A. Negative feedback loops Hormones inhibit the release of releasing and trophic hormones to help dampen hormone response. This negative feedback keeps the hormone levels within a certain range. Example: CRH-ACTH-cortisol feedback loop B. Mechanism of feedback loops 1. Down-regulation – adaptation of a hormone system to decrease the response of the cell due to excessive stimulation by a hormone. (more common) The response can be due to decreased number of receptors or uncoupling of the receptor from the signal transduction mechanism (or both). 2. Up regulation – adaptation of a hormone system to increase the response of the system due to a lack of stimulation by a hormone. (less common) The response can be due to either an increase in receptor number or enhanced coupling of the receptor to the signal transduction system (or both). V. Endocrine disorders A. Terminology Primary disorder is a problem with the function of the gland. Secondary disorder is a problem with the regulation of the gland. B. Hypo-secretion 1. Primary hyposecretion – decreased hormone secretion due to abnormality of the gland a. destruction of the gland (e.g., Type I diabetes: autoimmune destruction of beta cells) b. defects in hormone biosynthesis 2. Secondary hyposecretion - decreased hormone secretion. Gland is normal but there is too little stimulus from tropic hormone or pituitary hormone (e.g., trauma to infundibulum preventing hypophysiotropic hormones from reaching pituitary) B. Hyper-secretion 1. Primary hypersecretion - increased hormone secretion due to abnormalities of the gland. A common cause is presence of a hormone-secreting cell tumor. 2. Secondary hypersecretion - increased hormone secretion due to abnormality in regulation or secretion from secondary site. The gland is normal but there is too much stimulus from pituitary or trophic hormone. (e.g., hormone secreting tumor in pituitary) C. Spillover effects - excess concentrations of hormone can result in the hormone binding to and activating other classes of receptors. e.g., excess cortisol can activate aldosterone receptors and cause hypertension. D. Hypo-responsiveness hormone secretion is normal, but target cell does not respond to hormone. 1. Deficiency or lack of hormone receptors (e.g., androgen insensitivity syndrome)  2. Receptor-signal transduction is impaired (e.g., Type II diabetes, target cells have reduced response to insulin stimulation) 3. Metabolic activation is abnormal (conversion of testosterone to dihydrotestosterone) E. Hyper-responsiveness up regulation of hormone receptors e.g., hyper-response to epinephrine with hyperthyroidism due to up regulation of adrenergic receptors (permissiveness  INTRODUCTION TO METABOLISM Reading: Vander et al., Human Physiology, 14th ed. pp. 565-570. Learning Objectives 1. Define postprandial state and fasting state. 2. Identify anabolic processes for glucose, triglyceride and amino acids in liver, muscle and adipose tissue during postprandial state and understand how these processes contribute to metabolic homeostasis when dietary nutrients are in excess. 3. Identify catabolic processes of glucose, triglyceride and amino acids in liver, muscle and adipose tissue during fasting state and understand how these processes contribute to energy homeostasis when dietary nutrients are limited. I. Overview of Cellular Metabolism A. Metabolic Processes 1. Anabolism - synthesis of new macromolecules to store and build up 2. Catabolism - breakdown of macromolecules to generate energy B. Organs Involved in Regulation of Metabolism 1. Liver 2. Skeletal muscle 3. Adipose tissue 4. Brain C. Nutrient Macromolecules 1. Carbohydrates 2. Lipids 3. Protein D. Carbohydrates 1. Monosaccharides - glucose, galactose, fructose primary energy source of body Synthesis - gluconeogenesis Catabolism - glycolysis 1  2. Polysaccharides – glycogen Storage form of carbohydrates, found in all tissues, but highest amounts are in the liver (75-100 g) and skeletal muscle (300-400 g). Total body glycogen is approximately 700 g and can provide approximately 3000 kcal of energy Anabolism – glycogen synthesis Catabolism - glycogenolysis, release of glucose Liver glycogenolysis can occur quickly to release glucose into the circulation to help maintain blood glucose levels. Skeletal muscle glycogenolysis produces G-6-P for muscle energy needs (Muscle does not release glucose into circulation). C. Lipids 1. Triglycerides (triacylglycerols) synthesized from glycerol and fatty acids, primary storage form of lipids 2. Lipolysis – complete hydrolysis of a TG molecule produces 1 glycerol molecule and 3 molecules of fatty acid Lipolysis Glycerol Fatty Acids 2  D. Proteins - polymers of amino acids In addition to the roles of proteins in cell structure and function, proteins can also be used as a source of fuel. Proteins are metabolized to free amino acids which are then further metabolized to α-keto acids after losing the amino group. E. Overview of metabolic pathways (major energy generating pathways) II. Introduction to metabolism A. Absorptive state (fed state, postprandial state) - ingested nutrients are entering the blood from the GI tract (broadly defined as the 3-5 h period after a meal) B. Postabsorptive state - GI tract is empty and energy is supplied by body stores. (broadly defined as fasting state) C. Starvation: a severe deficiency in caloric energy intake below the level needed to maintain an organism's life (not a major focus of the lecture). 3 III. Absorptive state (Postprandial state) Following absorption from GI tract, some nutrients are utilized for immediate energy requirements. The remainder are processed and added to the body energy stores. The body’s energy stores are able to withstand a fast of many weeks providing adequate supply of water. A. Nutrient composition 1. Carbohydrate - primary source of immediate energy from a meal. Carbohydrates are absorbed from GI tract as monosaccharides. 2. Protein - absorbed from GI tract as amino acids and dipeptides. Dipeptides are hydrolyzed into amino acids in the epithelial cells which are transported to the blood. 3. Fatty acids - Absorbed into lymph as triglycerides in chylomicrons. B. Glucose 1. All cells - take up glucose where it is utilized as primary energy source. It is the major source of energy during postprandial state. There are several isoforms of glucose transporters (GLUT) that mediate glucose entry into cells for metabolic needs. 2. Skeletal muscle a. Catabolizes glucose for energy Skeletal muscle is the majority of body mass and a major consumer of glucose for energy even at rest. b. Converts excess glucose to glycogen for storage. 4 3. Adipose tissue (adipocytes) a. Adipose tissue is not quantitatively a major glucose consuming organ (compared to muscle) b. Glycolysis generates glycerol-3-P, which is used for triglyceride synthesis. 4. Liver – net uptake of glucose during postprandial state (uptake > gluconeogenesis) a. Glucose is converted into glycogen for storage. b. Glucose also enters glycolysis and TCA to produce ATP. A significant amount of TCA intermediate citrate is converted to fatty acids and then triglycerides. Some of the triglycerides are stored inside the cells in lipid droplets, and some triglycerides are incorporated to Very Low Density Lipoproteins (VLDL). VLDLs are secreted into the blood to deliver fatty acids to other tissues. (Fatty acid oxidation is not very active in postprandial state since the cells are under energy surplus). c. Triglycerides in VLDL is broken down into fatty acids and glycerol by lipoprotein lipase located in the membranes of capillaries in adipose tissue. Fatty acids enter the adipocytes where they are used to synthesize triglycerides and stored as fat. (b and c: this is how high sugar intake leads to obesity) 5 C. Fat metabolism 1. Stored as triglycerides or used in beta oxidation to generate ATP Triglycerides in chylomicrons are metabolized into fatty acids and glycerol by lipoprotein lipase in endothelial cells in adipose tissue and other tissues that use fatty acid as fuel. Fatty acids enter the cells and are used to synthesize triglycerides for storage (adipose) or produce energy via beta oxidation (i.e. cardiac muscle, skeletal muscle). 2. Sources of fatty acids in adipose tissue a. Ingested triglycerides via chylomicrons b. VLDL synthesized in the liver c. Glucose that is converted to glycerol-3-P 3. Oxidation of Fatty Acids Some fatty acid is catabolized by beta oxidation immediately for energy. The amount used depends on the glucose and fat content of the meal and cellular metabolic need. 6 D. Amino acids 1. All cells - most amino acids absorbed by the GI tract are used to synthesize proteins. During growth and training exercise, amino acids are also used to produce new protein and to increase muscles mass. 2. Liver – Amino acids taken up by liver are used for protein synthesis, energy production, and synthesis of other molecules. Breakdown of amino acids generates ammonia (toxic) which is converted to urea (less toxic, via urea cycle) and excreted by the kidneys. BUN (blood urea nitrogen) is used clinically to evaluate kidney function. Higher BUN indicates impaired kidney function. 7 IV. Fasting state (post-absorptive state) A. Overview In fasting state absorption of nutrients from the GI tract is mostly completed and the nutrients have been processed and stored in various tissues. During this period the body needs to maintain blood glucose levels, especially for the central nervous system that cannot use fatty acid as energy source, and has to draw from the store of nutrients. There are 2 mechanisms for maintaining plasma glucose 1) producing glucose 2) shifting fuel source from glucose to fat (glucose sparing) B. Source of glucose 1. Glycogenolysis a. Liver Glycogen is hydrolyzed to glucose which then enters the blood. There is only enough glycogen in the liver to maintain glucose levels for a few hours. b. Skeletal muscle Glycogen is hydrolyzed to glucose-6-phosphate in skeletal muscle. Muscle does not have the enzymes required to convert this molecule to glucose. Most of the glucose-6-phosphate derived from glycogen in skeletal muscle goes to muscle metabolic needs (glycolysis). Glucose-6-phosphate undergoes glycolysis to produce pyruvate and lactate. The pyruvate is used by the muscle to produce ATP (via TCA). Some lactate converted from pyruvate enters the blood and is taken up by the liver. In the liver lactate is used for gluconeogenesis to produce glucose. 2. Gluconeogenesis (primarily liver, to less extent kidney) a. Lipolysis In adipose tissue, lipolysis of triglyceride produces glycerol and fatty acids. These products enter the blood and are taken up by the liver. In liver glycerol is used for gluconeogenesis to produce glucose. 8 b. Protein A few hours after the beginning of the fasting state, protein begins to break down to produce amino acids. Amino acids, especially alanine, are metabolized to α-keto acids and then converted to glucose by gluconeogenesis. 9 C. Fat Utilization (glucose sparing) Body requires 1500-3000 kcal/day. However, glycolysis and gluconeogenesis provide only 750 kcal/day. During fasting state the body shifts from utilizing glucose to fat utilization (glucose sparing). Thus, the glucose produced by the liver can be used by the CNS. 1. Lipolysis Fatty acids produced by lipolysis circulate in the blood bound to albumin. Fatty acids enter cells undergo b oxidation to produce energy. 2. Ketones (ketone bodies) Liver - fatty acids are metabolized to ketones (β-hydroxybutyrate and acetone). These ketones are released into the blood where they are taken up by cells and used as a source of energy, especially for the brain during periods of fasting. 10 Summary 11 REGULATION OF METABOLISM Reading: Vander et al., Human Physiology, 14th ed. pp. 570-576. Learning Objectives 1. List effects of insulin on glucose, protein and lipid metabolism in liver, muscle and adipose tissue during postprandial state. 2. Describe the mechanism by which glucose stimulates insulin secretion. 3. Describe how GI incretins potentiate insulin secretion. 4. Describe the metabolic events that occur in liver, muscle and adipose during fasting. 5. List the major effects of glucagon on glucose metabolism and know the target organs. 6. List the effects of the sympathetic nervous system in preventing hypoglycemia and the 4 counterregulatory hormones and their effects in glucose metabolism. 7. Compare/contrast Type 1 and Type 2 diabetes mellitus. 8. List symptoms of Type 1 diabetes mellitus and describe their mechanisms. 9. List symptoms of Type 2 diabetes mellitus and major risk factors. I. Introduction Questions: What controls the anabolic events during the postprandial state and the catabolic events in the fasting state? What promotes glucose utilization during the postprandial state and fat utilization during the fasting state? What controls the transition from the postprandial state to the fasting state? Normal fasting glucose levels – 70-110 mg/dl Minimal glucose levels required by brain – 40 mg/dl Tm of renal proximal tubules for glucose – 180 mg/dl Regulators of metabolism Insulin Counter-regulatory hormones 1. glucagon 2. epinephrine 3. cortisol 4. growth hormone II. Insulin The most important hormone involved in the control of plasma glucose concentrations. A. Plasma levels of insulin Elevated in postprandial state Low in fasting state B. Pancreas - insulin is synthesized and secreted from β-cells in Islets of Langerhans in the pancreas. Islets of Langerhans contain α cells (glucagon), β cells (insulin), δ cells. β Cells make up 60-80% of cells in Islets. C. Synthesis of Insulin Insulin is synthesized as a prehormone consisting of A, B and C chains. The prehormone is processed in the Golgi. The C chain is cleaved and the A and B chains are linked by disulfide bridges to form the mature insulin. Insulin and the C chain secreted together. First pass metabolism – 60% of insulin released is metabolized when it passes through the liver. Insulin half-life is 5-6 minutes. C-chain (C-peptide, connecting peptide) is released with insulin and slowly metabolized (half-life is 30 min.). Since C-chain has a longer half-life than insulin, C-chain is measured in the blood as an indicator of insulin secretion. This can be used to distinguish exogenous insulin that diabetic patients use to lower glucose. Insulin binds to receptors located on the surface of cells and through its signal transduction system stimulates the storage of nutrients (anabolism). Islets of Langerhan D. Metabolic effects of insulin Summary of major insulin effects by tissue a. Liver promotes synthesis of glycogen and triglycerides, and protein inhibits glycogenolysis, gluconeogenesis and protein degradation. b. Muscle increases glucose and amino acid transport into muscle promotes glycogen formation and protein synthesis inhibits protein degradation c. Adipose tissue increases glucose uptake increases synthesis of triglycerides inhibits lipolysis E. Regulation of insulin secretion 1. Plasma glucose - the primary regulator of insulin secretion Elevated plasma glucose concentrations stimulate the secretion of insulin from the pancreatic beta cells. As glucose levels decline, insulin secretion decreases. 2. Incretins - hormones that enhance insulin release and help buffer changes in plasma glucose concentrations Two peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon- like-peptide-1 (GLP- 1) enhance the glucose-dependent stimulation of insulin. a. Glucose-dependent insulinotropic peptide (GIP) GIP is secreted from the duodenum. GIP secretion is stimulated by food intake, particularly carbohydrates and fats, and occurs within minutes of food intake (feed forward regulation). GIP stimulates glucose-dependent insulin secretion in normal individuals. b. Glucagon-like-peptide-1 (GLP-1) GLP-1 is released from cells in distal small intestine and colon Effects of GLP-1 Stimulates glucose-dependent insulin secretion, increases proinsulin gene expression Decreases gastric emptying and GI motility Decreases glucagon secretion Enhances β-cell proliferation. This effect is not dependent on glucose Promotes satiety, decreases food intake III. Glucose Counter-regulatory systems The systems are called “counter-regulatory” because they act counter to insulin and increase blood levels of glucose. Glucose levels are maintained in the post-absorptive period by hormonal and neuronal control systems. A. Glucagon - major glucose counter-regulatory hormone (post-absorptive state) 1. Secreted by α-cells in pancreatic islets 2. Target organ – liver 3. Metabolic effects - overall effect is to increase liver glucose output to prevent blood glucose decrease and hypoglycemia during the post-absorptive state increase glycogen breakdown increase gluconeogenesis 4. Regulation of glucagon release a. decreased plasma glucose levels cause secretion of glucagon b. transition from postprandial state to fasting state due to increase in glucagon: insulin ratio in plasma c. Autonomic nervous system regulation of glucagon secretion - sympathetic activation and epinephrine stimulate glucagon release. B. Sympathetic control of plasma glucose 1. Regulation - sympathetic nervous system can directly affect plasma levels of glucose, fatty acid and glycerol. Sympathetic stimulation can affect glucose levels by two mechanisms: Neural activity in liver and adipose tissue. Plasma epinephrine affects skeletal muscle, liver and adipose tissue (major). The sympathetic system contributes to control of plasma nutrients, but to a lesser degree than insulin and glucagon. 2. Metabolic effects glycogenolysis (liver and skeletal muscle) gluconeogenesis (liver) lipolysis (adipose tissue) – stimulates hormone-sensitive lipase (HSL) 3. Regulation Decreased plasma glucose levels (hypoglycemia) cause increase sympathetic neural activity to liver and adipose tissue and release of epinephrine from adrenal medulla. During long periods of fasting the sympathetic nervous system adapts and decreases activity. Stress can stimulate the sympathetic nervous system and lead to increased circulating levels of nutrients (covered in detail in Stress lecture) C. Cortisol Under normal concentrations the cortisol plays a permissive role in adjustments during post- absorptive periods and fasting. Normal levels of cortisol maintain enzymes required for gluconeogenesis and lipolysis (permissive effects). D. Growth Hormone – primarily responsible for stimulating protein synthesis and bone growth GH has minor effects on carbohydrate and lipid metabolism at normal levels in adults. GH can affect carbohydrate and lipid metabolism when plasma GH levels are high in response to hypoglycemia. GH has “anti-insulin” effects. It makes adipocytes more sensitive to lipolytic stimuli, increases gluconeogenesis by the liver and decreases sensitivity muscle and adipocytes to insulin. E. Summary IV. Fasting a. Insulin levels are low and glucagon levels are elevated b. Glycogen stores in liver and skeletal muscle are depleted, thus plasma glucose levels decline c. Metabolic substrates shift to lipolysis products: fatty acids, glycerol and ketones Glucose uptake by liver, adipocytes and skeletal muscle decreases, but brain glucose uptake remains normal glycolysis is decreased in liver and skeletal muscle Lipolysis increases (decreased insulin levels removes any constraints) tissues shift to use fatty acid for metabolic substrates Net breakdown in protein Glycerol from lipolysis and amino acids from protein catabolism in muscle provide substrate for gluconeogenesis V. Hypoglycemia A. Symptoms Central effects due to lack of glucose in the brain 1) headaches 2) confusion 3) dizziness 4) incoordination 5) slurred speech 6) convulsions 7) coma Effects of sympathetic stimulation in response to low blood glucose 1) tachycardia 2) trembling 3) nervousness 4) sweating 5) anxiety B. Mechanisms 1. Increased blood insulin 1) overdose of insulin by a diabetic 2) drugs causing insulin secretion 3) drugs (beta adrenergic antagonists)  4) insulin secreting tumors 2. Defect in glucose counter-regulatory systems 1) inadequate glycogenolysis or gluconeogenesis due to liver disease 2) glucagon deficiency 3) cortisol deficiency VI. Diabetes Mellitus Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Deficient action of insulin on target tissues results in abnormalities in carbohydrate, fat and protein metabolism. § “Diabetes” refers to increased urinary volume § “Mellitus” means sweet, due to glucose content in urine o Criteria for diabetes: Fasting plasma glucose > 125 mg/dl (measured twice more than a week apart) Symptoms of diabetes plus random plasma glucose > 200 mg/dl Plasma glucose > 200 mg/dl 2 hrs after an oral glucose load (measured twice more than a week apart). HbA1c > 6.5% o Prevalence of Diabetes: In 2014 29.1 million Americans (9.3% of population) had diabetes (21 million diagnosed, 8.1 million undiagnosed) 10.9% of Oklahomans suffer from diabetes. o Diabetes Classification Type 1 and Type 2. 1. Type 1 Diabetes Mellitus (T1DM): 9% of diabetic patients peaks of incidence: first peak at puberty, second peak around 40 years of age  Mechanism: β-cell destruction and absolute insulin deficiency. 90% of total β-cell mass loss before symptoms occur Insulin and C-peptide is low Etiologies: autoimmune destruction of β-cells 2. Type 2 Diabetes Mellitus (T2DM) 90% of diabetic patients, usually in overweight adults, starting at middle age, 80% of T2DM patients are obese Symptoms: Polyuria, thirst, blurred vision, and fatigue Patients may be asymptomatic initially and diabetes may be picked up during routine medical exam Mechanism - 1. Insulin resistance – Initially target tissues are unresponsive to insulin. Cells have decreased glucose uptake and decreased glycogen synthesis. Insulin resistance is thought to be related to obesity. A continuous exposure to elevated glucose levels causes a continuous release of insulin to maintain normal plasma glucose levels (hyperinsulinemia). 2. In later stages, there can be loss of insulin secretion due to decreased β-cell function 3. Pathophysiology of diabetes Glucose does not enter target cells that depend in insulin for glucose uptake, these cells are in a fasting state. Elevated plasma glucose. The liver and skeletal muscle continually make and release glucose via glycogenolysis and gluconeogenesis (due to decreased insulin repression of these pathways) Increased lipolysis generating fatty acids and glycerol. There is no insulin to inhibit lipolysis causing elevated plasma fatty acids. Elevated plasma triglyceride levels (hyperlipidemia). Increased liver production of VLDL and possibly decreased peripheral clearance of VLDL-triglycerides. Glycosuria – excess glucose in glomerular filtrate saturates renal transporters causing glucose to spill into urine. More prevalent in uncontrolled T1DM than T2DM. Polyuria – excess glucose in glomerular filtrate causes hyperosmotic filtrate resulting in osmotic diuresis and loss of electrolytes and nutrients causing dehydration.  Polydipsia - excessive thirst due to increased urine flow and loss of water. Untreated patients are thirsty and consume large quantities of water. Weight loss due to loss of glucose and nutrients (in T1DM) Polyphagia - excessive food consumption, probably due to loss of glucose in urine (T1DM) Diabetic ketoacidosis - in untreated or poorly controlled T1DM, increased ketones in blood cause decrease in pH. In T2DM ketoacidosis seldom occurs spontaneously and when it occurs it is usually associated with stress from trauma or infections. Blurred vision due to lenses and retina exposure to hyperosmotic fluids (T1DM). Diabetic retinopathy occurs in T2DM and poorly controlled T1DM. 4. Therapy 1. Type 1 Diabetes - insulin administration Injection Insulin pump MiniMed Real-Time Insulin pump and continuous glucose monitor 2. Type 2 Diabetes Weight reduction with exercise - insulin responsiveness increases with long-duration type exercise. Exercise increased the number of glucose transporters in skeletal muscle. Drugs 1) Metformin (GLUCOPHAGE®) – inhibit hepatic gluconeogenesis 2) Secretagogues - stimulate secretion of insulin from pancreas (Sulfonylureas) 3) Incretins - GLP-1 agonist (exenatide, BYETTA®) – enhances glucose-stimulated insulin release, decreases release of nutrients from stomach, decreases food intake 4) SGLT-2 inhibitors – block reabsorption of glucose in kidney and increase glucose excretion Canagliflozin (INVOKANA®) 5) Insulin administration – when insulin secretion from pancreas becomes inadequate Clinical Features of Diabetes Clinical Features of Diabetes Type 1 Diabetes Type 2 Diabetes Polyuria and thirst ++ + Weakness or fatigue ++ + Polyphagia with weight loss ++ - Recurrent blurred vision + ++ Vulvovaginitis or pruritus + ++ Peripheral neuropathy + ++ Nocturnal enuresis ++ + Often asymptomatic - ++ From Greenspan and Gardner, Basic Clinical Endocrinology, 9th ed. 2011 5. Diabetic complications: Chronic abnormalities of Type I and Type II Diabetes Mellitus Abnormalities are due to non-enzymatic glycosylation of proteins caused by chronic elevated glucose levels. Many of the problems are the result of damage to vasculature and narrowing of the capillaries. Atherosclerosis (macrovascular complication) peripheral vascular disease – leads to amputations (macrovascular complication) nephropathy (microvascular complication) neuropathies (microvascular complication) infections retinopathy leading to blindness (microvascular complication) 6. Diagnostic tests Fasting glucose levels Glucose tolerance test: 75 gm glucose given to individual then blood glucose is measured for several hours. Insulin C-peptide – used for evaluating insulin secretion rate Glycosylated hemoglobin – HbA1c (normal range 4-6)  RESPONSE TO STRESS Reading: Vander et al., Human Physiology, 14th ed. pp. 342-345, 337-341. Learning Objectives 1. List the neuronal and endocrine components involved in the stress response. 2. List effects of the stress-induced stimulation of the sympathetic nervous system. 3. List effects of stressed-induced cortisol release. 4. Describe the negative feedback of the HPA Axis. 5. List the symptoms of hypercortisolism (Cushing’s disease) and hypocortisolism (Addison’s disease) and understand the causes of the symptoms. 6. Describe how hypercortisolism (Cushing’s disease) and hypocortisolism (Addison’s disease) affect the hypothalamus-pituitary-adrenal (HPA) axis. I. Response to Stress A. Stressors 1. Stress: definition Stress is a state where homeostasis is challenged or actually threatened or perceived to be threatened by internal or external adverse forces (stressors). Homeostasis is re-established by physiological and behavioral responses to the stressor. The response to the stress is normally proportional to the magnitude of the stress and can be specific to the stressor or non-specific and generalized. A generalized response usually occurs when the stress reaches a threshold level. 1. Physical stress Disease, trauma, medical procedures, infection, shock, pain, ↓ O2 supply, prolonged exercise, hypoglycemia  2. Environmental cold (prolonged exposure), heat 3. Psychological fear, anxiety B. Responses 1. 2 limbs of stress response: a. Neuronal response Central nervous system Peripheral Nervous System – Sympathetic Nervous System b. Hormonal response Sympathetic Nervous System – adrenal medulla HPA Axis 2. Function of stress response: Short term adaptation to threats on homeostasis and survival Chronic stress may become maladaptive and can cause pathology 3. Stress response a. Increase arousal, alertness, increased vigilance, focused attention, increased cognition, anxiety/fear, aggression b. Promote redirection of energy Oxygen and nutrients are directed to CNS and stressed organ systems. Increased cardiovascular tone (heart rate, cardiac output, blood pressure), increased respiratory rate. Increased gluconeogenesis, glycogenolysis, and lipolysis to enhance availability of energy substrates c. Inhibit digestive and reproduction systems through withdrawal of parasympathetic activity and inhibition of the hypothalamic-pituitary-gonad axis.  4. Molecules of the stress response norepinephrine, epinephrine, CRH, ACTH, cortisol II. Sympathetic nervous system activation - fight, flight or fright The sympathetic nervous system (SNS) has neural and hormonal components to the response to stress. The SNS directly innervates various organs to release norepinephrine. The SNS also innervates the adrenal medulla to stimulate the release of epinephrine and norepinephrine into the systemic circulation. The SNS response is very rapid, seconds-minutes, and is activated in the initial stress response. Sympathetic syndrome associated with response to stress: Tachycardia Systolic hypertension (increased contractility) Skeletal muscle vasodilation Pallor (shift of blood supply away) Sweating (norepinephrine stimulation of apocrine glands) Pupillary dilation Hyperglycemia Hyperventilation Piloerection Agitation Physiological Effects of Stress-Induced Sympathetic Activity a. Increased cardiac output (↑ contractility, ↑ heart rate) b. Increased ventilation c. Shunting of blood from viscera to skeletal muscles d. Decreased GI motility e. Renal retention of sodium and water f. Increased glycogenolysis in muscle and liver (for fast source of glucose) g. Increased gluconeogenesis in liver h. Increased lipolysis, increases circulating glycerol and free fatty acids III. Hypothalamic-Pituitary-Adrenal Axis A. Steps in cortisol (glucocorticoid) release Input from various brain regions, especially the limbic system, stimulates secretion of corticotropin releasing hormone (CRH) from the hypothalamus into capillaries in the median eminence. CRH travels to anterior pituitary and releases adrenocorticotropic hormone (ACTH). ACTH enters the systemic circulation and travels to adrenal medulla and releases cortisol from the zona fasciculata and zona reticularis. 1. Regulation of cortisol secretion – negative feedback Cortisol inhibits release and synthesis of CRH in hypothalamus and ACTH in anterior pituitary. A. Hormones in HPA Axis 1. Corticotropin releasing hormone (CRH) CRH is synthesized in neurons in the paraventricular region of the hypothalamus. CRH is a neurotransmitter in several regions of the brain including several that are involved in the stress response. The hormone is released from the nerve terminals into the interstitial fluid of the median eminence in a pulsatile manner, and diffuses into the hypothalamic-pituitary portal vessels. 2. Adrenocorticotropic Hormone (ACTH) ACTH is released from corticotrophs in the anterior pituitary and also may be released from small cell carcinomas in the lung. ACTH is synthesized as part of a large preprohormone, proopiomelanocortin (POMC). In addition to ACTH, POMC cleavage also produces several other hormones including α-MSN, γ-MSH and β- endorphin. α- MSN and γ-MSH stimulate melanin production in melanocytes. ACTH has low affinity for their receptors, but at high concentrations ACTH (such as those that can occur in certain diseases) can stimulate melanin synthesis and pigmentation. ACTH action - When released from the pituitary, ACTH will enter the systemic circulation and stimulate the synthesis and release of cortisol from the zona fasciculata and reticularis in the adrenal cortex. Other actions – ACTH receptors are also present in the zona glomerulosa and have mild stimulator effects on aldosterone release. However, aldosterone release is primarily under the control of the renin-angiotensin system and aldosterone can be released in the absence of ACTH. ACTH receptors are also located on cells in the zona fasciculata and reticularis that synthesize and release androgens.  3. Cortisol Synthesized in the zona fasciculata and reticularis of the adrenal gland. Steroid hormones are not stored, but rather synthesized and released on demand. Once released, it binds to several proteins in the systemic blood including corticosteroid binding protein (approx. 90%) and albumin (approx. 7%) with 3-4% free. Basal cortisol - released in a circadian rhythm. Levels peak in early morning after waking up. Stress will increase cortisol release above the cyclical basal levels B. Effects of basal levels of cortisol (non-stress) 1. Permissive effects on response to catecholamines through expression of adrenergic receptors. Cortisol helps maintain normal blood pressure. Cortisol also regulates the synthesis of enzymes that synthesize epinephrine. 2. Maintain liver enzymes involved in gluconeogenesis and is needed to maintain normal glucose levels during the fasting state. 3. Fetal development - cortisol is required for proper development of CNS, skin, GI tract and lungs. Cortisol stimulates Type II alveolar cells in the fetus which produce surfactant in late gestation. C. Effects of increased cortisol levels during stress Cortisol causes mobilization of fuels - amino acids, glucose, glycerol and free fatty acids. 1. Stimulation of protein catabolism - provides amino acids for gluconeogenesis in the liver and amino acids for tissue repair if needed. Excessive cortisol will cause muscle weakness due to proteolysis. 2. Stimulation of lipolysis and release of fatty acids and glycerol to provide glycerol to the liver for gluconeogenesis. Hypercortisolism (pathological or pharmacological) causes a redistribution of body fat to the trunk and face. 3. Stimulation of hepatic gluconeogenesis 4. Inhibition of glucose uptake except brain Elevated cortisol levels – effects are opposite of insulin Individuals with abnormally high cortisol levels develop symptoms similar to that of insulin deficiency. 5. Enhanced vascular reactivity to norepinephrine 6. Inhibition of inflammation and immune responses Cortisol also inhibits phospholipase A2 (thus inhibiting production of prostaglandins and leukotrienes) at pharmacological doses and at levels that occur during extreme stress. Cortisol decreases production of proinflammatory cytokines and stimulates anti-inflammatory cytokines. 7. Reproductive system - cortisol inhibits the reproductive system by inhibiting GnRH-induced release of luteinizing hormone. 8. Bone metabolism - cortisol increases bone resorption. It also decreases the absorption of calcium from the GI tract and reabsorption of calcium by the kidney. Cortisol also directly inhibits osteoblast activity. 9. Connective Tissue - Cortisol inhibits fibroblast formation and collagen formation and excess cortisol causes thinning skin. This will lead to increased bruising since there is less support for capillaries. 10. CNS effects - Acutely, glucocorticoids produce a feeling of well-being and enhance memory. Chronic exposure to elevated levels can cause emotional lability and depression. Chronic cortisol may decrease memory. IV. Diseases of the Hypothalamus-Pituitary-Adrenal (HPA) Axis A. Hypercortisolism – Cushing’s syndrome Symptoms: 9 times more common in women than men Muscle weakness due to wasting of muscle - catabolism of protein Osteoporosis - due to demineralization of bone and loss of Ca++ Glucose intolerance – elevated glucose levels with glucose challenge Redistribution of fat from extremities (arms and legs) to face (moon facies) and trunk (above waist and between shoulders, buffalo hump) Hypertension – due to weak aldosterone-like actions (reabsorption of Na+) Spillover effects Decreased immune function Emotional disturbances - depression, neurosis and psychosis Growth retardation in youth 1. Cushing’s disease - hypercortisolism due to excess secretion of ACTH by the anterior pituitary, most common type of hypercortisolism. Secondary hypersecretion. The most common cause is a basophil adenoma in the anterior pituitary. The elevated cortisol inhibits the release of CRH from the hypothalamus and the ACTH from the normal corticotrophs in the anterior pituitary. However, the release of ACTH from adenoma is not inhibited by the negative feedback from cortisol and the plasma ACTH will be elevated. Cushing’s Disease (1) Ectopic ACTH (2)  2. Hypercortisolism due to secretion of ACTH by ectopic loci Small cell carcinomas in the lung may secrete ACTH as well as other carcinomas. Secretion of ACTH from these ectopic sites is not inhibited by cortisol. B. Cortisol Hyposecretion - Addison’s disease uncommon - 4 to 6 per 100,000 cause - autoimmune disease, tuberculosis slight predominance in females over 90% of adrenocortical tissue must be loss to observe clinical signs of adrenocortical insufficiency 1. Clinical signs of Addison’s Disease § Weakness and fatigue § Hypotension § Weight loss/loss of appetite § Decreased plasma sodium & increased plasma potassium (occurs in total adrenocortical destruction, due to loss of aldosterone) § Hyperpigmentation (less feedback, high ACTH stimulates melanocytes) Normal Addison’s disease 2. Therapy for Addison’s disease Replacement of cortisol and sometimes mineralocorticoids Cortisol is taken twice daily: 2/3 of dose is taken in the morning, 1/3 in the late afternoon to match circadian rhythm of cortisol release  ENERGY BALANCE AND THYRIOD PHYSIOLOGY Reading: Vander et al., Human Physiology, 14th ed. pp. 342-345, 337-341. Objectives 1. Know the anatomy of thyroid gland and steps involved in the synthesis and release of thyroid hormone. (know the function of Thyroglobulin, TPO, and iodine.) 2. Know thyroid hormone blood transport and target organ activation (Difference between T4 and T3). 3. Describe the HPT axis and feedback regulation. 4. List the actions of thyroid hormone on nutrient metabolism (glucose, lipid, protein). 5. Describe the effect of thyroid hormone on adrenergic response. 6. List the major causes of hyperthyroidism (Grave’s disease) and hypothyroidism (Hashimoto’s disease). 7. List symptoms of hyperthyroidism (Grave’s disease) and hypothyroidism (Hashimoto’s disease) and understand the causes of these symptoms. 8. Describe the treatments for hyperthyroidism and hypothyroidism. I. Metabolic rate The total energy output by the body per time is the metabolic rate. Metabolic rate is the rate that body expends energy doing external and internal work. External work – work of skeletal muscles to move Internal work – work done by heart, smooth muscle, transporters and other cellular processes A. Factors affecting metabolic rate In a physiological system, total work consists of two components 1) external work such as the movement of skeletal muscles to move objects and 2) internal work which includes the contraction of cardiac and smooth muscle, transport of solutes and various other cellular processes that require energy. 1. Physical activity affects both external work and internal work. Skeletal muscles and internal organs such as the heart and smooth muscle will have to use energy during physical activity. 1 2. Diet – food thermogenesis - digestion and assimilation of food produces heat 3. Body surface area (height, weight) 4. Body composition – lean muscle has higher energy consumption than fat 5. Gender – men have a higher metabolic rate than women 6. Age – metabolic rate decreases with age 7. Environmental temperature – a hot or cold environment can increase metabolism to activate systems to either remove or retain heat 8. Genetics 7. Hormones – thyroid hormone, catecholamines, growth hormone 2  B. Basal Metabolic Rate (BMR) In the absence of physical activity, there is a basal metabolism required to keep organs functioning and maintain life. Basal metabolic rate is thought to be the metabolic cost of living. BMR is measured during mental and physical rest, comfortable temperature, and after a 12 fast. II. Hormones influencing metabolic rate Thyroid - most important hormone influencing basal metabolic rate 1. Thyroid hormone actions a. Increases basal metabolic rate Hyperthyroidism causes increased sensitivity to heat. Hypothyroidism causes increased sensitivity to cold. Mechanism of action – still unknown, several mechanisms possible depending on tissue. Thyroid hormone increases futile cycles of energy utilization and production. 1. Thyroid hormone stimulates Na+/K+ ATPase. While Na/K ATPase activity is increased, there is no change in Na + or K+ concentrations in the cell and no changes in membrane potential. 2. Thyroid hormone increases Ca-ATPase activity in skeletal muscle sacroplasmic reticulum 3. Thyroid hormone increases a mitochondrial uncoupling protein b. Metabolism Carbohydrate metabolism - increases hepatic glucose production through gluconeogenesis and glycogenolysis. Plasma glucose levels remain normal if the pancreas can respond by increasing insulin secretion. Lipid metabolism - increases lipolysis in adipose tissue and makes glycerol available for gluconeogenesis in the liver. Thyroid hormone also increases lipogenesis. Triglyceride synthesis in the liver is dependent of normal thyroid hormone levels. If the thyroid hormone is 3  elevated, lipolysis will dominate lipogenesis causing mobilization of fat and loss of body fat stores. Protein metabolism - thyroid hormone will promote proteolysis primarily in skeletal muscle. The amino acids released are used by the liver for gluconeogenesis. Thyroid hormone also produces protein synthesis. Excess thyroid hormone can produce muscle wasting and weakness. The thyroid hormone-induced increase in catabolism and anabolism of carbohydrates, lipids and protein produces futile cycles and causes an overall consumption of energy and O2. Hyperthyroidism can exacerbate diabetes mellitus due to increased gluconeogenesis and lipolysis. Effects of Thyroid Hormone Levels on Metabolism Hypothyroidism Hyperthyroidism BMR ↓ ↑ Carbohydrate metabolism ↓ gluconeogenesis & ↑ gluconeogenesis & glycogenolysis. Normal serum glycogenolysis. Normal serum glucose glucose Protein metabolism ↓Synthesis & proteolysis ↑Synthesis & proteolysis, muscle wasting Lipid metabolism ↓ lipogenesis & lipolysis, ↑ ↑lipogenesis & lipolysis, ↓ serum cholesterol serum cholesterol Thermogenesis ↓ ↑ Autonomic nervous system Normal serum catecholamines ↑ β-adrenergic receptors, normal catecholamine levels c. Stimulates synthesis of β-adrenergic receptors This action increases heart contractility. Increases in β-adrenergic receptors also increase the sensitivity of the heart to sympathetic activity and circulating catecholamines. 4  d. Required for maturation of fetus and infant Thyroid hormone is required for brain development and maturation of the skeleton. Absence of thyroid hormone will result in cretinism (mental retardation and dwarfism) e. Pulmonary system Thyroid hormone maintains normal hypoxic and hypercapnic drive in the respiratory centers in the brain. The increased respiration maintains normal plasma O2 levels needed for increased metabolism. In severe hypothyroidism, hypoventilation can occur. f. Gastrointestinal system Thyroid hormone stimulates gut motility. Increased bowel movement occurs in hyperthyroidism and constipation occurs in hypothyroidism. g. Required for normal alertness and reflexes at all ages Thyroid hormone affects the nervous system and muscles. Hyperthyroidism results in hyperactivity while hypothyroidism results in sluggishness. h. Facilitates secretion and response of growth hormone 2. Anatomy of thyroid gland i. follicle ii. follicular epithelial cells iii. colloid - proteinaceous material, primarily comprised of thyroglobulin 5 3. Synthesis of thyroid hormone a. Iodide is actively taken up by follicular cells in thyroid gland via I-/Na+ cotransporter on the basolateral membrane (facing the blood). b. Iodide is transported into follicle possibly through the Cl--HCO3- anion exchanger. c. Thyroglobulin and thyroid peroxidase are synthesized by follicular cells and placed into secretory vesicles. The thyroid peroxidase is located on the inner membrane of the secretory vesicle. The secretory vesicles release thyroglobulin into the lumen of the follicle and the tyrosine peroxidase is incorporated into the apical membrane of the epithelial cells facing the lumen of the follicle. d. Iodide is oxidized to iodine in follicle by thyroid peroxidase located on the apical membrane of the epithelial cells. e. Thyroid peroxidase iodinates tyrosine residues on thyroglobulin (~ 20/ thyroglobulin molecule) making monoiodotyrosine (MIT) and diiodotyrosine (DIT). f. Thyroid peroxidase conjugates MIT and DIT within the thyroglobulin molecule to make predominantly tetraiodothyronine (T4) (DIT and DIT) and some triiodothryonine (T3) (MIT and DIT). g. Thyroid hormone (T3 and T4) is stored on thyroglobulin in the follicles of the thyroid gland. 6  Reverse T3 (rT3) has no known biological activity and is formed in non-thyroid tissues through deiodination of T4. Summary of thyroid hormone synthesis reactions catalyzed by thyroid peroxidase I- I0 I0 + tyrosine Monoiodotyrosine (MIT) or Diiodotyrosine (DIT) MIT + DIT Triiodothyronine (T3) DIT + DIT Tetraiodothyronine (Thyroxine, T4) 7 4. Secretion of thyroid hormone a. Circulating TSH activates receptors on the follicle cells to endocytose some thyroglobulin from the lumen of the follicle. Endosomes containing thyroglobulin fuse with lysosomes to form endolysosomes. In the endolysosomes, the thyroglobulin is degraded releasing amino acids, MIT, DIT, T3 and T4. The T3 (10%) and T4 (90%) are released out of the cell into the blood and the MIT, DIT and amino acids are recycled. b. T3 and T4 bind to proteins in plasma (thyroid-binding globulin (TBG), albumin and transthretin) and are distributed to target tissues throughout the body. More than 99% of T4 and T3 circulate in bound form. 5. Intracellular mechanism of action of thyroid hormone T3 and T4 enter tissues and T4 is converted to T3 by deiodinase. T3 then diffuses into the nucleus where it binds to its receptor, binds to DNA and alters gene expression. 8  6. Regulation of thyroid hormone secretion (the HPT axis) a. TRH (thyrotropin releasing hormone) - released by hypothalamus continuously b TRH stimulates release of TSH (thyroid stimulating hormone, or thyrotropin) and stimulates synthesis of TSH. c. TRH also stimulates the release of prolactin although it is not the primary prolactin releasing hormone. Elevated TRH can cause elevated prolactin levels. Prolactin inhibits the release of GnRH. Thus, elevated TRH can cause disruptions of the reproductive system. 7. Actions of TSH § Increases the uptake of thyroglobulin into the epithelial cells and release of T3 and T4 § Increases the size of thyroid cells and increases vascularization of thyroid gland. § Increases iodine metabolism – increases uptake of iodide, increases oxidation and iodination of thyroglobulin Increases synthesis of thyroglobulin Increases overall metabolism of thyroid gland. 9 III. Thyroid Diseases Goiter is enlargement of the thyroid gland and can occur in both hyperthyroid and hypothyroid conditions. A. Hyperthyroidism - hyperplasia of thyroid gland, iodide levels are usually normal, but TSH levels are low Symptoms: increase in BMR with weight loss and increased food intake enlarged thyroid gland (goiter) intolerance to heat excessive sweating increased adrenergic activity emotional lability Difficulty swallowing or breathing due to compression of esophagus or trachea by enlarged thyroid gland. Causes: Grave’s disease - autoimmune disease, antibodies bind to the TSH receptor and cause constant stimulation of TSH receptor Toxic multinodular goiter (benign neoplasm acquired activating mutation of TSH receptor, hyperfunctional) 10 B. Hypothyroidism Symptoms: low BMR weight gain without increased food intake lowered body temperature and intolerance to cold decreased sweating dry skin decreased adrenergic activity lethargy slowing of movement and speech in childhood retardation of growth in neonates developmental and mental retardation Causes: § Hashimoto’s disease - autoimmune disease § injury or removal of thyroid gland § iodine deficiency – nontoxic goiter (normal or hypofunctional) 11 12  CALCIUM HOMEOSTASIS AND CONTROL OF GROWTH Reading: Vander et al., Human Physiology, 14th ed. pp. 346-354. Learning Objectives 1. List the functions of osteoclasts and osteoblasts in bone resorption and bone formation 2. List the hormones responsible for calcium regulation. 3. Describe the synthesis of 1,25-dihydroxy vitamin D3 4. Describe the mechanisms by which parathyroid hormone regulates calcium homeostasis. 5. List factors that affect growth. 6. List effects and mechanisms of growth hormone on growth. 7. Describe the regulation of growth hormone release. 8. List effects of IGF-1 on growth. 9. List other hormones that affect growth and know what effects they have on growth. I. Calcium Regulation A. Organs involved in Ca2+ regulation 1. GI tract Ca2+ is absorbed from the small intestine. Approximately 1 gm of Ca2+ is ingested each day and the GI tract absorbs about 1/3 of the ingested Ca2+. The absorption of Ca2+ is regulated by 1,25- dihydroxy-vitamin D3. 2. Kidneys The kidneys reabsorb 99% of the filtered Ca2+. 90% is reabsorbed in the proximal tubule and loop of Henle. Nine percent (9%) is reabsorbed in the distal segment and this portion is regulated by parathyroid hormone. The kidneys also play an indirect role in Ca2+ regulation though the synthesis of 1,25- dihydroxy-vitamin D3 3. Bone - the major storage site for Ca2+ and phosphate 1  B. Hormones involved in Ca2+ regulation 1. Parathyroid hormone (PTH) - primary hormone responsible for Ca2+ homeostasis 2. 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol, calcitrol) 3. Calcitonin - minor role in regulating plasma levels of calcium C. Sources of body Ca2+ Total body calcium - 1 - 2 kg Bone - 99% of total Ca2+ Extracellular - 0.1%, In plasma, 50% of Ca2+ is bound to serum proteins (primarily albumin) and inorganic anions. Intracellular - 0.9% II. Bone structure A. Compact bone (cortical bone) 80% of bone mass Long bones Very dense and provides much of the tensile strength for weight bearing Low turnover - relatively metabolically inactive B. Spongy bone (trabecular bone) 20% of total bone mass Vertebral bodies, ends of the long bones Composed of a lattice of connecting bone trabeculae which can withstand compressive forces Very rapid turnover – relatively metabolically active 2 C. Extracellular bone composition 1. osteoid - 40% of the bone matrix. Makes up the organic matrix. Consists of collagen and other proteins 2. hydroxyapatite (Ca10(PO4)6(OH)2)- 60% of the bone matrix. Hydroxyapatite crystals form the mineral matter of bone. The hydroxyapatite crystals precipitate on the osteoid. D. Bone Cells 1. osteoclasts - cells that resorb bone 2. osteoblasts - cells that form bone 3. osteocytes - cells in the interior of bone 3 III. Bone remodeling Osteoclasts are located on the surface of bone. They secrete acid and enzymes that dissolve bone and release Ca2+ and phosphate into the extracellular fluid (bone resorption). This Ca2+ and phosphate can be picked up by the blood vessels or taken up by neighboring osteoblasts. Osteoblasts are adjacent to the osteocytes. These cells synthesize and secrete osteoid into the extracellular matrix. They also secrete Ca2+ and phosphate to form hydroxyapatite crystals on the osteoid. The balance between the bone reabsorption by the osteoclasts and the bone formation by the osteoblasts determine the plasma Ca2+ concentrations. Bone remodeling is always occurring. http://www.youtube.com/watch?v=78RBpWSOl08 Osteocytes - As the bone is formed around the osteoblasts, they are trapped in the bone matrix and become osteocytes. Osteocytes are connected to other osteocytes and osteoblasts through gap junctions. These cells communicate to the other cells and transport Ca2+ and phosphate to the osteoblasts. 4 IV. Hormone regulation of calcium A. Vitamin D 1. Synthesis Vitamin D3 (cholecalciferol) can be obtained through diet or through conversion from 7-dehydrochoesterol by UV light. Vitamin D3 must be converted to the active form, 1,25-dihydrovitamin D3, by a 2 step synthesis. The first step occurs in the liver with the 25-hydroxylation. The second step occurs in the kidney with the 1-hydroxylation. 2. Physiological effects a. 1,25-vitamin D3 stimulates Ca2+ absorption from the intestine 5 B. Parathyroid hormone 1. Synthesis and release - parathyroid hormone (PTH) is synthesized and released from PTH glands located embedded in the posterior surface of the thyroid gland. low plasma Ca2+ concentrations stimulate the synthesis and release of PTH high plasma Ca2+ concentrations inhibits PTH release and synthesis 2. Physiological effects - increases plasma Ca2+ concentrations a. promotes resorption of bone by osteoclasts and releases Ca2+ and phosphate from bone to the extracellular fluid PTH binds to receptors on osteoblasts and stimulates the synthesis of a protein called RANK ligand (RANKL). RANK ligand binds to the RANK receptor on osteoclasts to stimulate bone resorption activity. RANK ligand also binds to RANK receptors on osteoclast progenitor cells to cause differentiation into mature osteoclasts. http://www.youtube.com/watch?v=GpMV197xZXc 6  b. stimulates the reabsorption of Ca2+ and inhibits the reabsorption of phosphate in the kidneys c. stimulates the 1-hydroxylation of 25-hydroxylvitamin D3 in the kidneys C. Calcitonin 1. synthesis and release Calcitonin is synthesized in C cells associated with thyroid gland. Calcitonin release is stimulated by increased plasma Ca2+ above normal. 2. Physiological effects Decreases plasma Ca2+ by inhibition of osteoclasts Calcitonin does not regulate Ca2+ on a minute-to-minute basis, only regulates plasma Ca2+ when Ca2+ is high. 7  D. Other Hormones affecting calcium and bone metabolism 1. Sex steroids - decrease bone resorption 2. Thyroid hormone - increases bone resorption 3. Growth Hormone - increases bone synthesis and growth 4. Glucocorticoids - increase bone resorption, decreases bone synthesis V. Disorders in Ca2+ regulation A. Rickets and osteomalacia Disease that causes soft bones that easily fracture. The diseases are caused by a deficiency of bone mineralization primarily due to lack of vitamin D3. In children the disease is called Rickets and the child often has bowed legs. In adults the disease is called osteomalacia. Affected adults do not have legs because the disease occurs after the long bones have fully developed. Rickets B. Osteoporosis Loss of compact and spongy bone that occurs in the elderly. Bone maintenance also requires sex steroids, estrogen and testosterone. Osteoporosis occurs more often in elderly women because of the sudden loss of estrogen after menopause. Osteoporosis is less common in men because they have a larger skeletal mass and testosterone gradually declines with age. 8 VI. Control of Growth - Factors influencing growth Genetics, Endocrine function, Environmental factors nutrition illness stress Growth requires cell division & protein synthesis throughout the body. Height is specifically determined by bone growth primarily of the vertebral column and legs A. Bone growth 1. Anatomy of long bone a. epiphysis – end of bone b. shaft c. epiphyseal growth plate – area where epiphysis contacts shaft. It is the location of proliferating cartilage. d. chondrocytes - located in interior of epiphyseal growth plate, these cells form new cartilage e. osteoblasts - located at shaft edge of epiphyseal growth plate. Osteoblasts convert cartilaginous tissue into bone. 2. Linear growth Growth continues as long as epiphyseal growth plate exists. Chondrocytes in the middle of growth plate lay down cartilage. Osteoblasts convert cartilage to bone at edge of growth plate. Growth continues until the epiphyseal plate is converted to bone. This is referred to as “closure of the epiphyseal plate” and occurs late in puberty. 9  3. Growth patterns a. organs brain growth occurs early bone growth occurs late b. development i. fetal ii. postnatal iii. puberty B. Environmental factors controlling growth 1. Nutrients Essential amino acids, essential fatty acids, vitamins and minerals are necessary for normal growth. Nutrients providing energy (carbohydrates, protein) must also be available for growth. Growth retardation is most severe when malnutrition occurs early in life. Maternal malnutrition can cause low birth weight, and increased numbers of prenatal and postnatal deaths. Malnutrition during infancy and early childhood can lead to decreased growth and intellectual development. 10  2. Sickness - can stunt growth, but is temporary. After recovery the child usually has a growth spurt to catch up to normal size. 3. Stress - impairs growth C. Hormonal factors controlling growth (Table 11-6) 1. Growth hormone a. Actions i. Most important hormone for postnatal growth, stimulates cell division (mitogenic), promotes bone lengthening ii. Stimulates release of insulin-like growth factor-1 (IGF-1, also called somatomedin-C) from liver and other cells. IGF-1 is the factor that mediates most of growth hormone’s activities. iii. Stimulates protein synthesis by increasing the uptake of amino acids in tissues and synthesis of RNA and ribosomes iv. Anti-insulin effects – acute effects (minutes to hours) stimulates lipolysis stimulation of gluconeogenesis by liver reduces insulin-induced glucose uptake b. Control of growth hormone release release stimulated by growth hormone releasing hormone (GHRH) release inhibited by somatostatin Negative feedback – GH inhibits GHRH release and stimulates somatostatin release. IGF-1 inhibits GH release, GHRH release and stimulates somatostatin release. 40% of growth hormone in plasma is bound to GH-binding protein 11 c. Patterns of release pulses - diurnal pattern, elevated during slow wave sleep 12 2. IGF-1 a. Stimulates differentiation of prechondrocytes to chondrocytes in epiphyseal plates b. Stimulates secretion of IGF-1 from chondrocytes c. Stimulates division of chondrocytes 3. Other hormones affecting growth a. Thyroid hormone T3 and T4 are essential for growth. They are required for secretion of growth hormone and the growth promoting effects of growth hormone (permissive) Thyroid is required for normal development of the central nervous system in the fetus. Lack of thyroid hormone during pregnancy (usually due to iodine deficiency) causes mental retardation. Hypothyroidism can also affect mental functions (sluggishness and mental confusion) throughout life. This can be corrected with thyroid hormone supplements. b. Insulin Adequate insulin levels are required during growth to supply the cells with glucose. Also, the stimulation of amino acid uptake by cells is needed for protein synthesis. Insulin promotes cell differentiation and division in the fetus. Insulin is needed for the production of IGF-1. c. Sex Hormones Production of sex hormones increases during puberty and last for 5-10 years. Growth during puberty requires the increased levels of sex hormones. The major effect is to increase GH and IGF-1 secretion. Cause closure of epiphyseal plates and stop bone growth Testosterone has anabolic effects which increase muscle mass in males 13  d. Growth factors - over 60 growth factors presently known autocrine or paracrine actions. e.g. nerve growth factor (NGF) & epidermal growth factor (EGF) also growth inhibiting factors Growth factors and growth inhibiting factors also may be important in cancer. e. Cortisol – anti-growth effects at high doses inhibits DNA synthesis stimulates protein catabolism inhibits bone growth causes bone resorption inhibits release of growth hormone 4. Growth Hormone Diseases a. Excess GH Gigantism - excess GH before puberty and closure of epiphyseal growth plates. Causes increase lengthening of long bones. 14 Acromegaly - excess GH after closure of epiphyseal growth plates, no increase in length of long bones. Increase thickness of bones and increase soft tissues such as head, hands and feet. b. GH Deficiency Dwarfism - if deficiency occurs before puberty there is a inhibited growth. If deficiency occurs in adults, there is little clinical illness. 5. Age dependent release highest during adolescence & declines with age 6. Pharmacological Treatment with Growth Hormone a. Children b. Elderly patients c. Athletes 15 Hormone Influence on Growth and Bone Maturation Hormonal State Growth Rate Bone Maturation Mature Height Thyroid deficiency Very slow Very retarded Reduced Thyroid excess Mild acceleration Mild advancement Normal GH deficiency Slow Retarded Reduced GH excess Accelerated Normal Increased Sex steroid deficiency Normal prepubertal Low for pubertal age Tall-eunichoid Sex steroid excess Accelerated Marked advancement Reduced Summary of Metabolism Regulation Insulin Glucagon Epinephrine Cortisol Growth Hormone (elevated levels) (elevated levels) Carbohydrates Glucose uptake + - - Glycogen synthesis + Glycogenolysis - + + Gluconeogenesis + + + + Ketone synthesis + Amino Acids Amino acid uptake + Protein synthesis + Protein catabolism - + Lipids Triglyceride synthesis + Lipolysis - + + + Lipoprotein lipase + + stimulate, - inhibit 16