The Endocrine Physiology Introduction to HORMONES PDF

The Endocrine Physiology Introduction to HORMONES Homeostasis ◆ Maintenance of internal conditions even when the external conditions are changing ◆ Body in dynamic equilibrium ◆ Endocrine system and nervous system adjust to changes occurring in the body to return it to within...

The Endocrine Physiology Introduction to HORMONES Homeostasis ◆ Maintenance of internal conditions even when the external conditions are changing ◆ Body in dynamic equilibrium ◆ Endocrine system and nervous system adjust to changes occurring in the body to return it to within narrow limits ◆ Positive and negative feedback systems control Endocrine System ◆ A system of ductless glands that produce hormones ◆ Helps to regulate all the body functions ◆ Controls the rate at which we grow, hunger, body temperature, fluid retention, sexual development, menstruation and much more ◆ Could be called the rhythm section of life Endocrine System: Overview Endcocrinology: It is study of homeostatic functions of substances called HORMONES, that are released from glands called endocrine glands distributed throughout the body. Hormones: Are secretions of ductless glands that are directly released into the blood stream. They can act on cells in the vicinity or on distant target cells. Endocrine system – the body’s second great controlling system which influences metabolic activities of cells by means of hormones ◆ 1889: Von Mering and Menkowski experimented on dogs ◆ They opened up a dog and removed an organ they didn’t know ◆ The dog got sick and died ◆ Before dying the dog urinated a lot ◆ Ants were attracted to the urine ◆ One of the Doctors tasted the urine and found that it was sweet ◆ They concluded that the organ had something to do with carbohydrate metabolism ◆ 1922: Banting and Best continued experiments on dogs ◆ Removed the same organ which is called the pancreas ◆ Dog got sick ◆ Replaced pancreas ◆ Dog got better ◆ Produced a pancreatic extract and used it on a dog with its pancreas removed ◆ Dog got better ◆ Work on the extract isolated a single protein ◆ 1948 to 1958: Sanger worked on isolating and identifying protein ◆ Protein was Insulin ◆ This was the first protein ever sequenced. Sanger recieved a Nobel prize. ◆ When an animal doesn’t have a pancreas or the pancreas doesn’t function properly they have an illness called Diabetes Mellitus ◆ This can be translated into Sweet Water. Why? Negative Feedback ◆ Most controls use negative feedback. ◆ A stimulus causes a change - the feedback system reduces the change ◆ Blood sugar increases, insulin is produced to reduce blood sugar Positive Feedback ◆ Stimulus causes change, the feedback increases change ◆ Clotting of blood ◆ Birth of a baby Glands ◆ A gland is any organ that produces a secretion ◆ Endocrine glands: are organized groups of tissues which use materials from the blood to make new compounds called hormones. Endocrine glands are also called glands of internal secretion. Hormones ◆ Biochemicals produced by endocrine glands ◆ Informational molecules Glands of Internal Secretion ◆ Types: ◆ Exocrine - has a duct that it releases its products into, this duct carries the secretion to a body surface or organ. ◆ Sweat ◆ Salivary ◆ Lacrimal - Crying ◆ Pancreas Glands of Internal Secretion ◆ Endocrine - no duct, products are secreted into the bloodstream ◆ Pineal (brain) ◆ Pituitary (brain) ◆ Parathyroid ◆ Thyroid Examples of Endocrine Glands ◆ Thymus (chest) ◆ Adrenal (kidneys) ◆ Pancreas ◆ Ovary ◆ Testes Glands of Internal Secretion ◆ Products of the endocrine glands ◆ Hormones ◆ Produced only when needed (quantity is important) ◆ Target cells somewhere in the body that are stimulated ◆ Optimum quantity range Endocrine System: Overview Endocrine glands – pituitary, thyroid, parathyroid, adrenal, pineal, and thymus The pancreas and gonads produce both hormones and exocrine products The hypothalamus has both neural functions and releases hormones Other tissues and organs that produce hormones – adipose cells, pockets of cells in the walls of the small intestine, stomach, kidneys, and heart The Endocrine System Autocrines and Paracrines Autocrines – chemicals that exert their effects on the same cells that secrete them Paracrines – locally acting chemicals that affect cells other than those that secrete them These are not considered hormones since hormones are long-distance chemical signals Types of Hormones Amino acid based – most hormones belong to this class, including: Amines (Tyrosine: Caecholamines and Thyroid hormones, Tryptophan: Melatonin) Polypeptide hormones protein hormones Steroids – Derived from Cholesterol, gonadal and adrenocortical hormones Fatty acid derived: Eicosanoids, derived from arachidonic leukotrienes and prostaglandins  Classification of hormone Hormones are classified A.Onthe basis of chemical nature B.Onthe basis of mechanism of hormone action Group I hormone Group II hormone A.On the basis of chemical nature: Protein hormones: insulin, glucagon Steroid hormone: sex hormones, glucocorticoids Aminoacidsderivatives hormones: epinephrine, nor epinephrine etc  B.On the basis of mechanism of hormone action 1.Group I hormone (lipophilic hormone): These hormones are lipophilic in nature. They are mostly derivatives of cholesterol. These hormones binds to intracellular receptors Example: Steroid hormones, Estrogen, androgen, glucocorticoids, cholcalciferol, thyroxine etc 2. Group II hormones (water soluble hormone): These hormones binds to cell surface receptors and stimulates the release of certain molecules (secondary messengers) to perform biochemical functions  On the basis of secondary messengers group II hormones are of 3 types; i. Secondary messenger is cAMP: eg. Adrenocorticotropic hormone, FSH, LH, PTH,ADH, calcitonin, glucagon, ii. Secondary messenger is phosphotidylinocitol/calcium or both: eg. Acetylcholine, vasopressin, cholecystokinin, gastrin, gonadotropin releasing hormone, thyrotropin releasing hormone, Insulin, chorynoicsomatomamotropin, epidermal growth factors, fibroblast growth factors, GH, Prolactin iii. Secondary messenger is cGMP: Atrial natriuretic peptide (ANP) Amine Hormone Structure Figure 7-8: Tyrosine-derived amine hormones Steroid Hormones: Structure Figure 7-6: Steroid hormones are derived from cholesterol A Structural Classification of Hormones Correlation of Plasma Half-Life & Metabolic Clearance of Hormones with Degree of Protein Binding Hormone Protein Plasma half-life Metabolic clearance binding (%) (ml/minute) Thyroid Thyroxine 99.97 6 days 0.7 Triiodothyronine 99.7 1 day 18 Steroids Cortisol 94 100 min 140 Testosterone 89 85 min 860 Aldosterone 15 25 min 1100 Proteins Thyrotropin little 50 min 50 Insulin little 8 min 800 Antidiuretic hormone little 8 min 600 MCR = (mg/minute removed)/(mg/ml of plasma) = ml cleared/minute Circulating Transport Proteins Principle Hormone Transport Protein Transported Specific Corticosteroid binding globulin Cortisol, aldosterone (CBG, transcortin) Thyroxine binding globulin (TBG) Thyroxine, triiodothyronine Sex hormone-binding globulin Testosterone, estrogen (SHBG) Nonspecific Albumin Most steroids, thyroxine, triiodothyronine Transthyretin (prealbumin) Thyroxine, some steroids Determinants of Free Hormone Receptor Binding Carrier-bound hormone Endocrine Free Hormone cell Hormone receptor Hormone Biological degradation effects Hormone Action Hormones alter target cell activity by one of the following mechanisms: Ion Channel–Linked Receptors. G Protein–Linked Hormone Receptors. Enzyme-Linked Hormone Receptors. Intracellular Hormone Receptors and Activation of Genes (steroid and thyroid hormones) Hormone Action Hormones circulate to all tissues but only activate cells referred to as target cells Target cells must have specific receptors to which the hormone binds Peptide Hormones PeptideHormones: Peptide hormones are hydrophylicand lipophobic(fat-hating) –meaning they cannot freely cross the plasma membrane They bind to receptors on the surface of the cell, which are typically coupled to internally anchored proteins (e.g. G proteins) The receptor complex activates a series of intracellular molecules called second messengers, which initiate cell activity This process is called signal transduction, because the external signal (hormone) is transduced via internal intermediaries Examples of second messengers include cyclic AMP (cAMP), calcium ions (Ca2+), nitric oxide (NO) and protein kinases The use of second messengers enables the amplification of the initial signal (as more molecules are activated) Peptide hormones include insulin, glucagon, leptin, ADH and oxytocin Location of receptors: 1. In or on the surface of the cell membrane. The membrane receptors are specific mostly for the protein, peptide, and catecholamine hormones. 2. In the cell cytoplasm. The primary receptors for the different steroid hormones are found mainly in the cytoplasm. 3. In the cell nucleus. The receptors for the thyroid hormones are found in the nucleus and are believed to be located in direct association with one or more of the chromosomes. Cyclic Adenosine Monophosphate (cAMP) Second Messenger Mechanism Hormone (first messenger) binds to its receptor, which then binds to a G protein The G protein is then activated as it binds GTP, displacing GDP Activated G protein activates the effector enzyme adenylate cyclase Adenylate cyclase generates cAMP (second messenger) from ATP cAMP activates protein kinases, which then cause cellular effects Cyclic Adenosine Monophosphate (cAMP) Second Messenger Mechanism Cell Membrane Phospholipid: Second Messenger System Hormone binds to the receptor and activates G protein G protein binds and activates a phospholipase enzyme Phospholipase splits the phospholipid PIP2 into diacylglycerol (DAG) and IP3 (both act as second messengers) DAG activates protein kinases; IP3 triggers release of Ca2+ stores Ca2+ (third messenger) alters cellular responses Cell Membrane Phospholipid: Second Messenger System Cytokine Receptors & Tyrosine Kinase Receptors The Insulin Receptor & Mechanisms of Insulin Action Protein Hormones - Mechanisms of Action Tyrosine Adenylyl Cyclase Phospholipid Guanylate Cyclase Kinase/Cytokine Mechanism Mechanism Mechanism Receptor Mechanism ACTH GnRH ANP Insulin LH TRH IGF-1 FSH PTH GH TSH Angiotensin II Prolactin GHRH ADH (V1 receptor) Somatostatin Oxytocin ADH (V2 receptor) HCG MSH CRH Calcitonin PTH Glucagon Steroid and Thyroid Hormones Steroid hormones and thyroid hormone diffuse easily into their target cells Once inside, they bind and activate a specific intracellular receptor The hormone-receptor complex travels to the nucleus and binds a DNA-associated receptor protein This interaction prompts DNA transcription to produce mRNA The mRNA is translated into proteins, which bring about a cellular effect Streroid Hormones Steroid Hormones Steroid hormones are lipophilic (fat-loving) –meaning they can freely diffuse across the plasma membrane of a cell They bind to receptors in either the cytoplasm or nucleus of the target cell, to form an active receptor-hormone complex This activated complex will move into the nucleus and bind directly to DNA, acting as a transcription factor for gene expression Examples of steroid hormones include those produced by the gonads (i.e. estrogen, progesterone and testosterone) Steroid & Thyroid Hormones - Mechanism of Action  Amine Hormones Amine Hormones Amine hormones are derived from the amino acid tyrosine and include adrenaline, thyroxin and triiodothyronine Amine hormones do not all share identical properties and have properties common to both peptide and steroid hormones Target Cell Activation Target cell activation depends on three factors Blood levels of the hormone Relative number of receptors on the target cell The affinity of those receptors for the hormone Up-regulation – target cells form more receptors in response to the hormone Down-regulation – target cells lose receptors in response to the hormone Hormone Concentrations in the Blood Hormones circulate in the blood in two forms – free or bound Steroids and thyroid hormone are attached to plasma proteins Hormone Concentrations in the Blood Concentrations of circulating hormone reflect: Rate of release Speed of inactivation and removal from the body Hormones are removed from the blood by: Degrading enzymes The kidneys Liver enzyme systems Interaction of Hormones at Target Cells Three types of hormone interaction Permissiveness – one hormone cannot exert its effects without another hormone being present Synergism – the total effect of two hormones together is greater than the sum of their individual effects Antagonism – one or more hormones opposes the action of another hormone Hormonal Rhythms 12 GH (G/L) PLASMA 8 4 0 8 12 16 20 0 4 8 500 400 CORTISOL PLASMA (nmol/L) 300 200 100 0 8 12 16 20 0 4 8 CLOCK TIME Control of Hormone Release Blood levels of hormones: Are controlled by negative and positive feedback systems Vary only within a narrow desirable range Hormones are synthesized and released in response to humoral, neural, and hormonal stimuli Feedback Control Negative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretion Positive feedback is less common: examples include LH stimulation of estrogen which stimulates LH surge at ovulation Feedback Mechanisms Negative Feedback Positive Feedback + + Target Endocrine Target Endocrine cell cell cell cell _ + Biological effects Biological effects Negative feedback Measurement of Hormone Concentrations Radioimmunoassay (RIA) Enzyme-Linked Immunosorbentm Assay (ELISA) Hypothalamus (Floor of the Brain) ◆ Drive centers are located here and the subconscious control center ◆ Hypothalamus secretes releasing factors or inhibiting factors into the blood supply of the infundibulum which is connected to the anterior lobe of the pituitary. They stimulate or inhibit hormone production. Each hormone from the anterior lobe will have its own specific set of control factors from the hypothalamus. Hormone Functions ◆ Pituitary gland (AKA hypophysis) ◆ 2 lobes (anterior and posterior) ◆ Anterior adenohypophysis ◆ 7 different hormones ◆ Posterior neurohypophysis ◆ 2 different hormones Hormone from the Pituitary Gland 1. Thyroid-stimulating hormone (TSH) 2. Adrenocorticotropic hormone (ACTH) 3. Follicle-Stimulating hormone (FSH) 4. Luteinizing Hormone (LH) 5. Prolactin (PRL) 6. Growth Hormone (GH) 7. Melanocyte-Stimulating hormone (MSH) Thyroid Stimulating Hormone (TSH) ◆ Target tissue is the thyroid (indirect) ◆ Releases thyroid hormones ◆ Influenced by stress (increases production) Adrenocorticotropic Hormone (ACTH) ◆ Stimulates the release of steroid hormones by the adrenal glands. ◆ ACTH specifically targets cells producing hormones called glucocorticoids which affect glucose metabolism. ◆ Influenced by stress Follicle-Stimulating Hormone (FSH) ◆ Promotes egg development in women and stimulates the secretion of estrogens (steroid hormones) produced by ovarian cells ◆ In men, FSH production supports sperm production in the testes Luteinizing Hormone (LH) ◆ It induces ovulation in women and promotes the ovarian secretion of estrogens, which prepare the body for the possibility of pregnancy FSH & LH are aka as Gonadotropic Hormones ◆ Follicle stimulating hormone (FSH) ◆ Gonads (direct and indirect) ◆ Direct - stimulates sex cell production ◆ Indirect - stimulates hormone production in females ◆ Luteinizing hormone (LH) ◆ Gonads ◆ Direct - stimulates ovulation in females ◆ Indirect - stimulates hormone production in males (testosterone) Prolactin ◆ Stimulates the development of the mammary glands and the production of milk ◆ Has no effect on human male Prolactin ◆ Breast tissue (mammary glands - direct) ◆ Works with 6 other hormones to stimulate breast development ◆ Limited to women ◆ Inhibited by sex hormones ◆ Causes sensitivity to breast tissue prior to flow phase of the menstrual cycle ◆ Mechanical stimulation of breast tissue causes increase in prolactin production (nursing) Growth Hormone ◆ Stimulates cell growth and replication by the rate of protein synthesis. ◆ GH breaks down glycogen reserves and the release of glucose into the circulation causing the blood glucose levels to rise. Growth Hormone ◆ Hyposecretion: ◆ Children - pituitary dwarf (normal body proportions) usually no taller than 4 feet tall. ◆ Adults - Simmond's disease (atrophy and premature aging) Growth Hormone ◆ Hypersecretion ◆ Children - pituitary giants (8 –9 feet tall) ◆ Adults – acromegaly ◆ Widened bones and thick fingers ◆ Lengthening of the jaw and cheek bones ◆ Thick eyelids, lips, tongue, and nose Melanocyte Stimulating Hormone (MSH) ◆ Epidermis, basal cell layer (direct) ◆ Stimulates the melanocytes of the skin, increasing their production of melanin. ◆ MSH is important in the control of skin and hair pigmentation. Posterior Pituitary (Neurohypophysis) 2. Antidiuretic Hormone (ADH) 3. Oxytocin Hormone (Neurohypophysis) Composed of Nervous Tissue ◆ Hormones are made by the hypothalamus ◆ Stored and released in the posterior lobe ◆ Oxytocin (birth hormone) ◆ Target organs are the uterus and mammary glands. ◆ Stimulate muscles in the uterine wall to contract in labor and delivery processes ◆ baby suckles - sensory information is sent from the breast to the hypothalamus. The hypothalamus responds by sending nerve impulses to the pituitary gland, causing the release of oxytocin. Antidiuretic Hormone (ADH) ◆ Is secreted by the posterior pituitary gland. ◆ The primary target organ is the Kidneys ◆ Causes reabsorption of water and returns it to the blood ◆ Decreases the amount of urine excreted ◆ Inhibited by alcohol ◆ Hyposecretion is called diabetes insipidus (note this is not diabetes mellitus) Antidiuretic Hormone (ADH) ◆ Increased by or responds from conditions: ◆ Pain ◆ Stress ◆ Drugs (morphine and nicotine) ◆ The absence of ADH will will cause an increase in diuresis up to 25 liters/day ADH (aka Vasopressin) ◆ Decreases the amount of water lost through the kidneys and causes vasoconstriction, both mechanisms serve to increase the BP Vasopressin ◆ Vasopressin can be used to treat certain types of cardiac arrest, (Ventricular Fibrillation) and GI bleeding (especially esophageal varices). In women it can cause uterine contraction. ◆ It’s properties increase blood flow to the brain and heart Thyroid ◆ Only 1 gland ◆ Located in the anterior throat ◆ Stores its own hormones 1. Triiodothyronine T3 2. Tetraiodothyronine T 4 or thyroxine Thyroid Glands ◆ They regulate the metabolism of: 1. Carbohydrates 2. Proteins 3. Fats Thyroid Glands ◆ Thyroid hormones increase the rate of metabolism of most cells. Thyroxin ◆ Hyposecretion ◆ Child - cretinism (a form of dwarfism) ◆ Retarded and sluggish ◆ Lower temperature and heart rate ◆ Adult - myxedema (slow and puffy) ◆ Is a slowed down metabolic state ◆ Retains water (increasing blood pressure) ◆ Low temperature and slow heart rate ◆ No retardation Thyroxin ◆ Hypersecretion: (Grave's disease) ◆ Mostly in adults and women ◆ Speeds up metabolic state ◆ Exophthalmic goiter (thyroid 2-3X normal size) ◆ Bulging eyes, forced forward by fat deposits ◆ Increased metabolism and decreased weight ◆ Opposite of hyposecretion (increased temperature and heart rate) ◆ Wide emotional swings Calcitonin ◆ Bone ◆ Increases rate of Ca++ deposit in bone ◆ Hyposecretion - hypercalcemia - increased Ca++ in the blood ◆ Hypersecretion - hypocalcemia - decreased Ca++ in the blood Parathyroid Hormones (PTH) ◆ Four, small, posterior thyroid surface ◆ Parathyroid hormone ◆ PTH has 3 target organs ◆ Bone ◆ Kidneys ◆ GI tract Parathyroid Hormones ◆ Activates vitamin D (works in the intestine) (Ca++ absorption) ◆ Increases blood Ca++ level ◆ In the kidneys it helps with reabsorption of Ca++ and magnesium with phosphate being lost Parathyroid Hormones ◆ Hyposecretion ◆ Surgery or damage to the thyroid ◆ Causes hypocalcemia ◆ Causes muscle tetany ◆ Trousseau's sign - causes contracture of the hand if the BP cuff is applied Parathyroid Hormones (PTH) ◆ Hypersecretion ◆ Usually associated with tumor (VonRecklinghausen's disease) ◆ Hypercalcemia ◆ Increase in urine production and increase in kidney stones ◆ Deformity and pain in bones Adrenal Glands (Suprarenal) ◆ Paired and double structures ◆ Adrenal cortex: makes 28 steroid hormones and is linked with cholesterol ◆ Aldosterone (mineralocorticoid) ◆ Causes Na+ absorption and excretion of K+ ◆ Conserves water, Cl-, and bicarbonate ◆ Kidney, distal convoluted tubule Adrenal Cortex (Outer Region) The adrenal cortex secretes 3 steroids: 1. Glucocorticoids 2. Mineralocorticoids 3. Sex Hormones Glucocorticoid ◆ Cortical (hydrocortisone) ◆ Decreases inflammation response ◆ Slows the healing process, decreases resistance to some diseases ◆ They assist to ensure a steady supply of glucose for the brain and other cells Adrenal Cortex (Outer Region) ◆ Hyposecretion - cortex degeneration ◆ Addison's disease (adrenal insufficiency) ◆ A. generalize weakness ◆ B. muscle atrophy ◆ C. severe fluid loss ◆ D. bronzing of the skin ◆ E. must be tx with steroids & fluids Adrenal Cortex ◆ Hypersecretion of glucocorticoids ◆ Cushing's syndrome ◆ Obesity ◆ Buffalo hump - fat deposited across the shoulders ◆ Moon faced - often flushed ◆ Abdominal striations - stretch marks ◆ Heavy abdomen and skinny legs ◆ Thin skin that bruises easily Mineralocorticoids ◆ The chief mineralocorticoid is Aldosterone ◆ It’s role is regulation of: A. blood volume B. blood pressure Mineralocorticoids ◆ The primary targeted organ is the kidney ◆ Aldosterone conserves sodium and water and eliminates potassium Sex Hormones (Gonadocorticoids) ◆ Not secreted until puberty ◆ Of the gonad hormones, testosterone is dominant ◆ Normally production is small Sex Hormones (Gonadocorticoids) ◆ When secreted the female hormone is called estrogens ◆ When secreted the male hormone is called androgens Adrenal Medulla ◆ Secretes 2 hormones ◆ 1. Epinephrine (adrenalin) ◆ 2. Norepinephrine ◆ known as catecholamines ◆ secreted in stress situations Adrenal Medulla ◆ Classified as Amine type hormones, 80% of secretion is epinephrine ◆ Production stimulated by stress ◆ Related to the sympathetic half of the autonomic nervous system Epinephrine (Adrenalin) and Norepinephrine ◆ Functions ◆ Increases blood pressure, heart output and respiratory rate ◆ Increases blood sugar Epinephrine (Adrenalin) and Norepinephrine ◆ Dilation of bronchial tubes ◆ Inhibits digestion response ◆ Prolongs sympathetic nerve response by 10X Epinephrine (Adrenalin) and Norepinephrine ◆ Increase metabolic rate of most cells, thereby making more energy ◆ Causing bronchodilation to increase the flow of air into the lungs ◆ Changing blood flow patterns, causing dilation of the blood vessels to the heart and muscles and constriction of the blood vessels to the GI tract Epinephrine (Adrenalin) and Norepinephrine ◆ Hypersecretion ◆ Usually caused by a tumor ◆ Cause of increased blood pressure and hyperglycemia ◆ Prolonged stress response  Epinephrine Signals Impending Activity Animal confronted with a stressful situation that requires increased activity (fighting or fleeing) Extreme case - neuronal signals from brain trigger release of epinephrine & norepinephrine (adrenal medulla) Both hormones 1. dilate respiratory passages to facilitate uptake of O2 2. increase rate & strength of heartbeat 3. raise blood pressure 4. promote flow of O2 & fuels to tissues (Table 23-6) This is “fight or flight” response Epinephrine acts primarily on muscle, adipose, liver  Activates glycogen phosphorylase & inactivates glycogen synthase by cAMP- dependent phosphorylation of enzymes Thus stimulating conversion of liver glycogen to blood glucose, fuel for anaerobic muscular work Epinephrine also promotes anaerobic breakdown of muscle glycogen by lactic acid fermentation Stimulation of glycolysis accomplished by raising concentration of fructose 2,6-bisphosphate - a potent allosteric activator of phosphofructokinase-1 Epinephrine stimulates fat mobilization in adipose tissue, activating (by cAMPdependent phosphorylation) hormone-sensitive lipase, moving aside perilipin covering lipid droplet surface Epinephrine stimulates glucagon secretion & inhibits insulin secretion, reinforcing its effect of mobilizing fuels & inhibiting fuel storag Kidneys ◆ The kidneys are NOT primarily endocrine organs, but they release 3 hormones: 1. Calcitriol 2. Erythropoietin 3. Renin Renin ◆ Is released by the kidney cells in response to a decrease in blood volume or BP Pancreas ◆ One organ with a double function, half digestion (exocrine), half endocrine ◆ Islets of Langerhans - the endocrine half of the pancreas ◆ Pancreas secretes 2 hormones 1. Insulin 2. Glucagon ◆ Hormones are proteins Pancreas ◆ The islets of Langerhans have 2 types of cells: 1. Alpha cells (secrete glucagon) 2. Beta cells (secrete insulin) ◆ Both regulate blood glucose levels Pancreas ◆ The overall effect of insulin is to lower blood glucose levels ◆ The overall effect of glucagon is to increase blood glucose levels Insulin ◆ Beta cells produce this (represent 75% of the Islets) ◆ Removes glucose from the blood into the body cells ◆ Hypersecretion: ◆ Insulin shock (hypoglycemia) ◆ Can lead to seizures and unconsciousness Insulin ◆ Insulin helps to control carbohydrates, protein, and fat metabolism in the cell. Insulin stimulates the breakdown of glucose for energy. ◆ The liver and skeletal muscles store excess glucose as the form of glycogen Insulin ◆ Hyposecretion ◆ Diabetes mellitus ◆ Hyperglycemia and glucose in the urine ◆ Dehydration from excess urine production, Na+ loss, thirst ◆ Acidosis ◆ Retina deterioration, circulation problems, atherosclerosis, amputations Glucagon ◆ Producing cells are the alpha cells - 25% of the Islets ◆ Increase blood glucose level ◆ Hyposecretion: hypoglycemia ◆ Hypersecretion: hyperglycemia Other Pancreatic Hormones ◆ Somatostatin ◆ Produced by the delta cells of the Islets ◆ Suppresses insulin and glucagon release by other cells ◆ Pancreatic polypeptide ◆ Produced by the F cells of the Islets ◆ Inhibits gallbladder contractions Testes ◆ Two of them, double structure and double function ◆ Testosterone: stimulated by pituitary at puberty ◆ Produced by interstitial cells ◆ Produce the steroid androgens ◆ Responsible for secondary sex characteristics and the sex drive Ovaries (Female Sex Cells,Ova) ◆ Two - double structure and function ◆ Estrogen: comparable to testosterone and begins in quantity at puberty (sets the timing for the reproductive process) ◆ Produced by the follicle ◆ Responsible for secondary sex characteristics and sex drive ◆ Progesterone accelerates the movement of fertilized eggs along the uterine tubes an prepares the uterus for the arrival of a developing embryo Pineal Gland ◆ Located in the roof of the thalamus between the cerebellum and the cerebral hemispheres ◆ Secretes the hormone - Melatonin ◆ Works through the hypothalamus ◆ Inhibited by light, the more the light the more melatonin secreted ◆ Inhibits the hormone that stimulates the ovaries (slows the timing of sexual maturity) ◆ Involved in regulation of the menstrual cycle ◆ Influence on production of ACTH Thymus ◆ Endocrine gland in part ◆ Located in the membrane above the heart (in humans it is at its maximum size during puberty) ◆ Thymosin ◆ Target tissues - T cell lymphocytes ◆ Effect - stimulates production ◆ Net effect - stimulates cellular immunity Summary Most steroid and some amine hormones are lipophilic, can pass into cell, bind on cytoplasmic or nuclear receptors and activate DNA for protein synthesis Hypothalamus, pituitary trophic hormone pathways coordinate endocrine regulation Summary of the Endocrine System Figure 7-2-1: ANATOMY SUMMARY: Hormones Summary of the Endocrine System Figure 7-2-2: ANATOMY SUMMARY: Hormones Summary of the Endocrine System Figure 7-2-3: ANATOMY SUMMARY: Hormones  The Endocrine Pancreas Regulation of Carbohydrate Metabolism Pancreas Pancreatic Hormones, Insulin and Glucagon, Regulate Metabolism Production of Pancreatic Hormones by Three Cell Types Alpha cells produce glucagon. Beta cells produce the hormones insulin and amylin. Delta cells produce the hormones gastrin and somatostatin. F cells produce hormone pancreatic polypeptide  Islet of Langerhans Cross-section Three cell types are present, A (glucagon secretion), B (Insulin secretion) and D (Somatostatin secretion) A and D cells are located around the perimeter while B cells are located in the interior Venous return containing insulin flows by the A cells on its way out of the islets Pancreatic Hormones, Insulin and Glucagon, Regulate Metabolism Figure 22-8: Metabolism is controlled by insulin and glucagon Pancreas Secretes Insulin or Glucagon in Response to Changes in Blood Glucose  Parasympathetic (Stimulate) Sympathetic ( inhibit) Structure of Insulin Insulin is a polypeptide hormone, composed of two chains (A and B) BOTH chains are derived from proinsulin, a prohormone. The two chains are joined by disulfide bonds.  Roles of Insulin Acts on tissues (especially liver, skeletal muscle, adipose) to increase uptake of glucose and amino acids. - without insulin, most tissues do not take in glucose and amino acids well (except brain). Increases glycogen production (glucose storage) in the liver and muscle. Stimulates lipid synthesis from free fatty acids and triglycerides in adipose tissue. Also stimulates potassium uptake by cells (role in potassium homeostasis). Specific Targets of Insulin Action: Carbohydrates Increased activity of glucose transporters. Moves glucose into cells. Activation of glycogen synthetase. Converts glucose to glycogen. Inhibition of phosphoenolpyruvate carboxykinase. Inhibits gluconeogenesis. Specific Targets of Insulin Action: Lipids Activation of acetyl CoA carboxylase. Stimulates production of free fatty acids from acetyl CoA. Activation of lipoprotein lipase (increases breakdown of triacylglycerol in the circulation). Fatty acids are then taken up by adipocytes, and triacylglycerol is made and stored in the cell. lipoprotein lipase Regulation of Insulin Release Major stimulus: increased blood glucose levels: - after a meal, blood glucose increases - in response to increased glucose, insulin is released - insulin causes uptake of glucose into tissues, so blood glucose levels decrease. - insulin levels decline as blood glucose declines  Insulin Action on Cells: Dominates in Fed State Metabolism  glucose uptake in most cells (not active muscle)  glucose use and storage  protein synthesis  fat synthesis Activation of glycogen synthase by insulin. Transmission of the signal is mediated by PI-3 kinase (PI-3K) and protein kinase B (PKB). Insulin Counters High Blood Glucose The well-fed state: the lipogenic l Insulin: Summary and Control Reflex Loop Other Factors Regulating Insulin Release Amino acids stimulate insulin release (increased uptake into cells, increased protein synthesis). Keto acids stimulate insulin release (increased glucose uptake to prevent lipid and protein utilization). Insulin release is inhibited by stress-induced increase in adrenal epinephrine - epinephrine binds to alpha adrenergic receptors on beta cells - maintains blood glucose levels Glucagon stimulates insulin secretion (glucagon has opposite actions). Structure and Actions of Glucagon Peptide hormone, 29 amino acids Acts on the liver to cause breakdown of glycogen (glycogenolysis), releasing glucose into the bloodstream. Inhibits glycolysis Increases production of glucose from amino acids (gluconeogenesis). Also increases lipolysis, to free fatty acids for metabolism. Result: maintenance of blood glucose levels during fasting.  Mechanism of Action of Glucagon Main target tissues: liver, muscle, and adipose tissue Binds to a Gs-coupled receptor, resulting in increased cyclic AMP and increased PKA activity. Also activates IP3 pathway (increasing Ca++) Glucagon Action on Cells: Dominates in Fasting State Metabolism Glucagon prevents hypoglycemia by  cell production of glucose Liver is primary target to maintain blood glucose levels Glucagon Counters Low Blood Glucose FIGURE 17–3 Mobilization of triacylglycerols stored in adipose tissue Fasting state: Glucogenic liver After some hours without a meal Glucagon Action on Cells: Dominates in Fasting State Metabolism  Targets of Glucagon Action Activates a phosphorylase, which cleaves off a glucose 1-phosphate molecule off of glycogen. Inactivates glycogen synthase by phosphorylation (less glycogen synthesis). Increases phosphoenolpyruvate carboxykinase, stimulating gluconeogenesis Activates lipases, breaking down triglycerides. Inhibits acetyl CoA carboxylase, decreasing free fatty acid formation from acetyl CoA Result: more production of glucose and substrates for metabolism  Regulation of Glucagon Release Increased blood glucose levels inhibit glucagon release. Amino acids stimulate glucagon release (high protein, low carbohydrate meal). Stress: epinephrine acts on beta-adrenergic receptors on alpha cells, increasing glucagon release (increases availability of glucose for energy). Insulin inhibits glucagon secretion. Other Factors Regulating Glucose Homeostasis Glucocorticoids (cortisol): stimulate gluconeogenesis and lipolysis, and increase breakdown of proteins. Epinephrine/norepinephrine: stimulates glycogenolysis and lipolysis. Growth hormone: stimulates glycogenolysis and lipolysis. Note that these factors would complement the effects of glucagon, increasing blood glucose levels. During Fasting and Starvation, Metabolism Shifts to Provide Fuel for the Brain Glycogen ( Muscle, Liver), TAG ( adipose tissues), tissue proteins Fuel metabolism (liver) during prolonged fasting or in uncontrolled diabetes mellitus Epinephrine Signals Impending Activity Animal is confronted with a stressful situation increased activity—fighting or fleeing, Neuronal signals from the brain trigger release of epinephrine and norepinephrine (adrenal medulla) Dilate the respiratory passages (uptake of O2) ↑ rate and strength of the heartbeat raise the blood pressure promoting the flow of O2 and fuels to the tissues Muscle, adipose, and liver tissues Activate : Glycogen phosphorylase : (liver glycogen to blood glucose , fuel for anaerobic muscular work ) Inactivates: Glycogen synthase Anaerobic breakdown of muscle glycogen, stimulating glycolytic ATP formation F- 2,6-bisphosphate, a potent allosteric activator of PFK-1 Fat mobilization in adipose tissue, (cAMP-dependent phosphorylation) both perilipin & TAG lipase Stimulates glucagon secretion & inhibits insulin secretion, reinforcing its effect of mobilizing fuels & inhibiting fuel storage Cortisol (adrenal cortex) , Signals Stress, Low Blood Glucose Anxiety, fear, pain, hemorrhage, infections, ↓ blood glucose, starvation Muscle, liver, and adipose tissue Slow-acting hormone ; kinds and amounts of certain enzymes In adipose tissue, TAGs, ↑ release of fatty acids ( fuel) glycerol is used for gluconeogenesis in liver Stimulates the breakdown of muscle proteins and the export of amino acids to the liver( gluconeogenesis) , PEP carboxykinase Glucose- glycogen or exported immediately to tissues Restore blood glucose to its normal level Increase glycogen stores, fight-or-flight response commonly Effects of cortisol ; counterbalance effects of insulin Diabetes Mellitus - Defects in Insulin Production or Action deficiency in the secretion or action of insulin, common disease Type I diabetes, Insulin dependent diabetes mellitus (IDDM) Begins early in life and quickly becomes severe Responds to insulin injection, inability to produce sufficient insulin. Insulin therapy & careful, lifelong control of the balance between dietary intake and insulin dose Type II diabetes, Non-insulin-dependent diabetes mellitus (NIDDM) Insulin-resistant diabetes. Characteristic symptoms of type I (and type II) diabetes Excessive thirst & frequent urination (polyuria), Intake of large volumes of water (polydipsia) “Diabetes mellitus” excessive excretion of sweet urine Large amounts of glucose in urine, glucosuria. Type II diabetes is slow to develop (older, obese ) symptoms are milder and often go unrecognized at first Type II Diabetes Group of diseases , regulatory activity of insulin is defective: insulin is produced but Some feature of the insulin-response system is defective- insulin-resistant. The connection between type II diabetes and obesity is an active area of research Individuals – unable to take up glucose efficiently from the blood Insulin triggers the movement of GLUT4 to the plasma membrane of muscle and adipose tissue Excessive but incomplete oxidation of fatty acids in liver. ACETYL-COA produced by oxidation cannot be completely oxidized by CAC, ↑[NADH]/[NAD] ratio inhibits CAC Acetyl-CoA leads to overproduction of ketone bodies acetoacetate , Acetone& β-hydroxybutyrate Acetone: volatile & exhaled, uncontrolled diabetes, breath has a characteristic odour sometimes mistaken for ethanol. Mental confusion due to high blood glucose is occasionally misdiagnosed as intoxicated, an error that can be fatal. Overproduction of ketone bodies, called ketosis, ↑concentrations of ketone bodies in blood (ketonemia) & urine (ketonuria). Ketone bodies- H+, can overwhelm capacity of buffering system, ↓ blood pH called acidosis or, in combination with ketosis, ketoacidosis, a potentially life-threatening condition. Biochemical measurements on blood and urine essential in the diagnosis and treatment of diabetes Glucose-tolerance test. Overnight fasting, drinks 100 g of glucose in water Blood glucose concentration – before test dose & 30 min intervals for several hours thereafter A healthy individual assimilates the glucose readily, 9 or 10 mM; little or no glucose appears in the urine. Diabetic individuals assimilate test dose of glucose poorly; their blood glucose level far exceeds the kidney threshold (about 10 mM), causing glucose to appear in the urine