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Lect E4 - Endocrine insulin Growth, Metabolism & Calcium Endocrine System Summary Lect # 4 Glucose & Metabolism 1. Growth Hormone & Somatomedins (IGF’s) Prof Kumlesh K. Dev Department off Physiology h l 2. Thyroid hormones (T3 & T4) 3. Oestrogens & Testosterone 4. Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids 5. Insulin & Glucagon 6. Calcitonin, PTH & Vit D CRH TRH PRH PIH GnRH dopamine ThyrotropinReleasing hormone Prolactinreleasing hormone Prolactininhibiting hormone (LH releasing hormome LHRH) CorticotropinReleasing hormone GHRH Gonadotropinreleasing hormone GHIH somatostatin Growthhormone inhibiting hormone Growthhormone releasing hormone ACTH TSH Prolactin FSH LH GH AdrenoAdrenocorticotropic hormone Thyroid stimulating hormone (non(non-tropic) FollicleFolliclestimulating hormone Luteinising hormone Growth Hormone Adrenal cortex Thyroid gland mammary glands cortisol Thyroid Hormone (T3.T4) breast growth, milk secretion Chapter 4 Principles of Neural and Hormonal Communication Human Physiology by Lauralee Sherwood ©2007 Brooks/Cole-Thomson Learning many target organs Ovaries /Testes progesterone & estrogen ovulation & luteinisation estrogen (develop ovarian follicles) testosterone sperm production growth, anabolic actions y The Glands Anabolic Steroids – Testosterone Summary Testosterone • Testosterone is best known anabolic steroid • anabolic steroids promote: – cellll growth h & di division i i – protein synthesis – muscle mass and strength – appetite – bone remodeling and growth – production of red blood cells • side effects of estrogen receptor activation: – accelerated bone maturation in children – elevated blood pressure & cholesterol levels – mood change, acne, reduced sexual function, infertility, testicular atrophy, baldness 1 Lect E4 - Endocrine insulin Testosterone vs Estradiol Feedback Loops of Estrogen/Testosterone Testosterone Testosterone Testosterone ‘male’ hormone Hypothalamus ─ fetal: for development of reproductive organs Gonadotroping releasing hormone ─ puberty: to stimulate bone growth and secondary sexual characteristics GnRH Testosterone masculinizing hormone Long Loop Estradiol ‘female’ hormone Short Loop ─ aged: delay bone loss during menopause Estradiol feminizing hormone Gonads Estrogen/testosterone Growth, Metabolism & Calcium FSH LH Follicle-Follicle stimulating hormone Luteinising hormone Ovaries /Testes progesterone & estrogen ovulation & luteinisation estrogen (develop ovarian follicles) testosterone sperm production The Glands Summary Summary 1. Growth Hormone & Somatomedins (IGF’s) 2. Thyroid hormones (T3 & T4) 3. Oestrogens & Testosterone 4. Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids 5. Insulin & Glucagon Calcitonin, PTH & Vit D Ant. Pituitary LH/FSH ─ young: stimulate growth of uterus, sex organs, follicular growth, bone growth 6. GnRH (LH releasing hormome LHRH) CRH TRH PRH PIH GnRH dopamine ThyrotropinReleasing hormone Prolactinreleasing hormone Prolactininhibiting hormone (LH releasing hormome LHRH) CorticotropinReleasing hormone GHRH Gonadotropinreleasing hormone GHIH somatostatin Growthhormone inhibiting hormone Growthhormone releasing hormone ACTH TSH Prolactin FSH LH GH AdrenoAdrenocorticotropic hormone Thyroid stimulating hormone (non(non-tropic) FollicleFolliclestimulating hormone Luteinising hormone Growth Hormone Adrenal cortex Thyroid gland mammary glands cortisol Thyroid Hormone (T3.T4) breast growth, milk secretion many target organs Ovaries /Testes progesterone & estrogen ovulation & luteinisation estrogen (develop ovarian follicles) testosterone sperm production growth, anabolic actions y 2 Lect E4 - Endocrine insulin Release of ACTH Adrenal Gland Adrenal Gland Adrenal Gland • • ─ hypothalamus neurons in paraventricular nucleus (PVN) also release CRF (41 amino acid peptide) in portal system Adrenal cortex: outer part CRF • • • ─ CRF controls ACTH production and release from anterior pituitary ─ ACTH controls release of corticosteriods from adrenal cortex • • Corticosteriods adrenal glands embedded above each kidney in a capsule of fat adrenals have two divisions: cortex and medulla ACTH Catecholamines similar origin to gonads make steriods hormones derived from cholesterol Mineralocorticoids (outer, glomerulosa) – aldosterone Glucocorticoids (middle, fasciculata) – cortisol (corticosterone) Androgen sex steroids (inner, reticularis) – DHEA (dehydroepiandrosterone) Adrenal medulla: inner part • • composed of chromaffin cells (originate from sympathetic nervous system) Catecholamines – epinephrine (adrenaline) – norepinephrine (noradrenaline) Role of Adrenal Hormones in Metabolism Adrenalectomy Adrenal Gland ¾ adrenaline ¾ works in concert with sympathetic nervous system ¾ increases fat mobilisation ¾ response to stress ("fight or flight" response) ¾ cortisol released in response to ACTH ¾ stimulates hepatic gluconeogenesis ¾ inhibits tissue glucose uptake What happens if you have no adrenal glands? Adrenal Gland ¾ Loss of ability to respond to “stress” ¾ Loss of steroid hormones ¾ Circulatory collapse - heart beat is less effective - decreased peripheral resistance - reduced cerebral blood flow ¾ Skeletal muscle fatigue ¾ Apathy 3 Lect E4 - Endocrine insulin Mineralocorticoids – Aldosterone Glucocorticoids – Cortisol Adrenal Gland Aldosterone • is major mineralocorticoid • Mineralocorticoids maintain body’s electrolyte balance Adrenal Gland Low Na+ and/or high K+ • Feedback: Angiotensin II – 1. low plasma Na++ or high K+ – 2. activates renin-angiotensin system – 3. Angiotensin II increases aldosterone release from adrenal glands – 4. acts on distal renal tubules • increase Na++ & water retention • increase excretion of K+ & H+ ions Adrenal cortex Aldosterone Sex Hormones/Androgen – DHEA Adrenal Gland DHEA (Dehydroepiandrosterone) • overpowered by testosterone in males • physiologically significant in females • supplement to gonad hormone secretion • identical/similar to those produced by gonads Cortisol (hydrocortisone) • is major glucocorticoid in humans • secretion regulated (diurnal rhythm) – plays role in adaptation to stress – alter glucose metabolism (inhibit glucose uptake/use, raise blood glucose) – alter protein & lipid metabolism (stimulates protein breakdown, fatty acid & lipid release in e.g. g muscles)) – control water and electrolyte balance – anti-inflammatory/immunosuppressive Feedback: • negative feedback on hypothalamus (CRH) & anterior pituitary (ACTH) CRH Corticop tropinReleasing hormone ACTH Adreno-Adreno corticotropic hormone Adrenal cortex Cortisol Catecholamines – Nor/Adrenaline Adrenal Gland Epinepherine and Norepinerphrine • Adrenal medulla is a modified part of sympathetic nervous system • Primary stimulus: activation of sympathetic nervous system by stress • Epinephrine – Secreted into blood by exocytosis of chromaffin g granules – Reinforces sympathetic system in mounting general systemic “fight-or-flight” responses – Maintenance of arterial blood pressure – Increases blood glucose and blood fatty acids 4 Lect E4 - Endocrine insulin Adrenaline and Glucocorticoids Glucocorticoids (Cortisol) - Therapy Adrenal Gland Adrenal Gland ¾ Adrenal medulla – adrenaline, stored in secretory granules ¾ Adrenal cortex – cortisol, aldosterone & testosterone/oestrogens, little storage ¾ Both are important for regulation of fuel metabolism Adrenaline Glucocorticoids ─ ─ Control of intermediate metabolism esp gluconeogenesis ─ NOT important for rapid mobilization of fuel ─ Important for cardiac/skeletal muscle function ─ Anti inflammatory ─ ─ ─ Stimulates gluconeogenesis and glycogenolysis Activates hormone sensitive lipase to promote fatty acid release. I Increases cardiac di muscle l contractility Arousal of higher centres Glucocorticoids: hydrocortisone, prednisolone, dexamethasone, betamethasone Replacement therapy: in adrenal failure (Addison’s disease) A ti i fl Anti-inflammatory/immunosuppressive t /i i disorders: di d reduce T cell proliferation, release of IL-2, TNF-a, IL-1 – asthma (Inhaler) – eczema (topical cream) – arthritis (systemic injections) – ulcerative colitis (rectal suppositories) – prevent graft rejection of the transplant – cancer patients (anti-emetic; reduce oedema in brain tumours) Benefit > Risk of glucocorticoid use – Immune system limited (delay tissue repair, increase gastric acidity, peptic ulcers) – Cushinoid symptoms – Osteoporosis (alter function of bone cells osteoblasts/osteoclasts) – Acute adrenal insufficiency due to sudden withdrawl (patient card – ”do not stop my steroid treatment abruptly”) Mineralocorticoids (Aldosterone) - Therapy Addison’s disease Adrenal Gland Adrenal Gland • • fludrocortisone has g glucocorticoid and mineralocorticoid activity • used in mineralocorticoid replacement therapy (eg) in Addison’s disease. • Kidneys Kidneys, bladder and colon are the major targets of mineralocorticoids (low corticoids) glucocorticoid (cortisol) & mineralocorticoid (aldosterone) deficiency Causes • Primary Addison’s: damage of adrenal gland (TB or autoimmunity); low cortisol and aldosterone • Secondary Addison’s: low ACTH release (when glucocorticoids are given for long periods); low cortisol only Symptoms • hypoglycaemia • decreased liver glucogen • fatigue, anorexia, nausea, weight loss, dizziness, hypotension, psychiatric • death if untreated Treatment • Steroid replacement therapy 5 Lect E4 - Endocrine insulin Cushing’s disease (high glucocorticoids) Conn’s Syndrome (high mineralocortocoids) Adrenal Gland • adrenal Hyperactivity and excess secretion of glucocorticoids (cortisol) Adrenal Gland • Excessive secretion of mineralocortocoids (aldosterone) from adrenal gland Causes • ACTH secreting tumor in pituitary Causes • primary - tumour • secondary - excessive renin-angiotensin action in kidney disease, cirrhosis of liver, congestive heart failure Symptoms • hyperglycemia • elevated blood pressure • obesity (abdominal fat, thin arms & legs) • muscle wasting, osteoporosis, cataracts • poor wound healing • buffalo hump, moon face, red cheeks • psychiatric symptoms (depression, euphoria, hallucinations) Hyperplasia of Adrenal Cortex Treatment • surgically remove adenoma, treat with antiglucocorticoids or surgical adrenalectomy Symptoms • sodium and water retention • increase in extracellular hypertension fluid Treatment • antagonist of aldosterone lactone) • unilateral adrenalectomy Hyperplastic Normal Stress and Depression and (spirono- Cortisol Feedback Hypothalamus-Pituitary-Adrenal (HPA) Axis Adrenal Gland Stress generalised stress response • ↑ epinephrine secretion from adrenal medulla Higher brain centers (chromaffin cells) for fight-or-flight response • ↑ CRH-ACTH-cortisol CRH ACTH cortisol (HPA axis) that mobilises CRH metabolic resources • ↓ insulin & ↑ glucagon secretion to raise blood Hypothalamus Cortico-ve tropinglucose & fatty acids Releasing hormone • ↑ renin-angiotensin-aldosterone system & from neurons vasopressin secretion to maintain blood volume released into blood vessels and blood pressure chronic stress • causes heart disease disease, hypertension hypertension, atherosclerosis, immune-suppression • prolonged release of CRH (HPA axis activation) causes anxiety & depression • CRF1 receptor antagonists may treat anxiety, depression, drug dependence and irritable bowel syndrome Anterior Pituitary ACTH Adreno-Adreno corticotropic h hormone Adrenal Gland Stress Time of Day Hypothalamus CRH Cortisol CRH is released by hypothalmic neurosecretory cells Long Loop cortisol acts on CRH neurons in hypothalamus stops CRH release -ve Ant. Pituitary ACTH Short Loop Adrenal cortex CRH CorticotropinReleasing hormone cortisol acts on anterior pituitary cells stops ACTH release CRH carried by portal vessels into anterior pituitary where ACTH is released ACTH stimulates cortisol ti l release l by b adrenal cortex ACTH Adreno-Adreno corticotropic hormone Adrenal cortex Adrenal Cortex cortisol Cortisol 6 Lect E4 - Endocrine insulin Growth, Metabolism & Calcium Summary on Corticoids (Adrenal Cortex) Adrenal Gland Type Glucocorticoids Mineralocorticoids N Name C ti l Cortisol Ald t Aldosterone Adreno-corticotropic Hormone (ACTH) Angiotensin II Upstream Hormones Hypersecretion Hyposecretion Cushing’s disease ((high g g glucocorticoids)) Conn’s Syndrome (high mineralocortocoids Summary 1. Growth Hormone & Somatomedins (IGF’s) 2. Thyroid hormones (T3 & T4) 3. Oestrogens & Testosterone 4. Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids 5. Insulin & Glucagon 6. Calcitonin, PTH & Vit D Addison’s disease (low corticoids) CRH TRH PRH PIH GnRH dopamine ThyrotropinReleasing hormone Prolactinreleasing hormone Prolactininhibiting hormone (LH releasing hormome LHRH) CorticotropinReleasing hormone GHRH GHIH somatostatin Growthhormone inhibiting hormone Growthhormone releasing hormone Gonadotropinreleasing hormone ACTH TSH Prolactin FSH LH GH AdrenoAdrenocorticotropic hormone Thyroid stimulating hormone (non(non-tropic) FollicleFolliclestimulating hormone Luteinising hormone Growth Hormone Adrenal cortex Thyroid gland mammary glands cortisol Thyroid Hormone (T3.T4) breast growth, milk secretion many target organs Ovaries /Testes progesterone & estrogen ovulation & luteinisation estrogen (develop ovarian follicles) testosterone sperm production growth, anabolic actions y The Glands Metabolism Summary Body Fuel ─ energy requirements vary during sleep, exercise, illness, starvation ─ energy expenditure dit and d ffuell supply l regulated by endocrine system ─ protein, carbohydrate, and fat in diet are broken down into intermediates that are convertible ─ used for two purposes Carbohydrate Protein Fat Glucose Amino Acids Fatty Acids Pyruvate Oxaloacetate AcCoA ─ 1. energy production ─ 2. tissue growth & repair ─ Krebs cycle i.e. hormones control normal fuel supply, growth and development ATP 7 Lect E4 - Endocrine insulin Hungry vs. Fed Starvation Body Fuel protein glycogen Hungry State Muscle glucose (in) glycogen amino acids (out) glycerophosphate ketoacids triglyceride (in) amino acids (in) glucose (in) fatty acid glycerophosphate triglycerides (in) pyruvate (in) starvation reduces energy expenditure/metabolic rate glucose ─ circulating glucose, glucose fatty acid and triglycerides in body provide energy for ~ 1-2 hrs C l ifi value Calorific l off substrates b t t are: • Glucose 17.6 kJ/g • Amino acids 18.0 kJ/g • Fatty acids 39.0 kJ/g ─ glycogen store in liver and muscle provide 800 kcal (~8 hrs fuel) pyruvate (out) glucose (out) fatty acid ─ glycogen protein glucose (in) Liver Factors affecting stores ─ growth ─ feeding - need energy for absorption, digestion ─ between meals, meals overnight ─ starvation, long term (weeks) or short term (days) ─ disease, trauma, infection, surgery ─ pregnancy Fed State amino acids (in) Adipose ─ fed state: store amino acids, glucose and triglycerides ─ hungry h state: t t mobilise bili stored t d reserves Body Fuel Adult body uses following per day: • Glucose 250g • Amino acids 150g • Fatty acids 100g glycerol glycogen amino acids (in) fatty acids (in) ketoacids ketones (out) triglycerides fatty acids (out) glycerol ─ ─ during g fasting g triglycerides gy metabolised; fat stores hold 100,000 kcal (30 days) when fat stores exhausted, protein breakdown provides 10,000 kcal; muscle wasting Feeding Total = 11MJ/day Starvation in 70kg adult ¾ 35kg muscle (7 kg protein) ¾ 20% body fat (14 kg) ¾ 400 g glycogen ¾ Resting Metabolic Rate 10MJ/d How long before death? ¾ Protein = 126MJ ¾ Fat = 546MJ ¾ CHO = 7.2MJ ¾ Total = 679 MJ = 68d Note: not all protein, fat can be used (cell memb) Exercise Body Fuel Body Fuel ─ feeding increases fat, g amino acids & glucose in blood ─ increases sympathetic stimulation ─ increases i glucagon l ─ decreases insulin ─ release insulin & decrease glucagon ─ increases adrenaline ─ increases glucose and fuel output ─ if meal is mostly protein then glucagon also i increases ─ takes several hours for hormonal response to subside ─ suppressed pp storage g ─ increases glucose uptake into muscle Well fed 2 wks starved 6μU/ml ¾ INSULIN 40μU/ml ¾ GLUCAGON 80 pg/ml 120 pg/ml ¾ GLUCOSE 6 mM 3.6 mM 8 Lect E4 - Endocrine insulin Hormones Regulating Metabolism Islets of Langerhans Body Fuel ─ Anterior Pituitary gland ─ Growth hormone, ACTH, TSH ─ Liver Insulin/Glucagon ─ pancreas exocrine and endocrine cells ─ exocrine cells secrete proteases into small intestine ─ Endocrine Islet of Langerhans ─ comprise 1 % of pancreas ─ rich blood supply for hormone drainage ─ clusters composed ~3000 endocrine secretory cells ─ surrounded d db by capsule l ─ scattered throughout pancreas ─ pancreas removal causes symptoms of diabetes ─ ↑ [glucose]plasma 20-30mM ─ Somatomedins (IGF’s) ─ Thyroid gland (T3 T4 ) ─ Thyroxine ─ Gonads ─ Sex steroids ─ Adrenal cortex ─ Glucocorticoids (cortisol) ─ Adrenal medulla ─ adrenaline (noradrenaline) ─ Pancreatic (Islets of Langerhans) ─ Insulin & glucagon Islets of Langerhans – Cell & Hormones Islets of Langerhans – Cell & Hormones Insulin/Glucagon ─ islets of Langerhans have 3 secretory cells producing peptide hormones Insulin/Glucagon Cell Type Hormone Role beta β cells insulin promotes glucose uptake decrease glucose in blood (see next slide) ─ α cells - glucagon - opposite effect to insulin alpha α cells glucagon ─ δ cells – somatostatin potentiates t ti t glycogen l breakdown b kd activity of glucagon opposite effect to insulin promotes blood glucose levels (see next slide) delta δ cells somatostatin potentiates glycogen breakdown activity of glucagon (see growth hormone inhibitory hormone) ─ β cells - insulin - promotes glucose uptake ─ insulin stored in & secreted from cytoplasmic granules VERY VERY IMPORTANT VERY VERY IMPORTANT 9 Lect E4 - Endocrine insulin Effects of Insulin & Glucagon Pro-Insulin & Insulin Insulin/Glucagon Insulin ¾ ¾ ¾ ¾ ¾ Insulin/Glucagon Glucagon fed state: anabolic hormone ¾ glucose to glycogen ¾ fatty acids to triglycerides ¾ amino acid to protein ↑ enzymes in liver & muscle to convert glucose to glycogen ↑ uptake of glucose from blood into muscle and fat ↑ incorporation of amino acids into protein in muscle ↓ lipolysis & promotes lipogenesis in adipose tissue glycogenolysis/lytic gluconeogenesis lipolysis lipogenesis ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ hungry state: catabolic hormone ¾ glycogen to glucose ¾ triglycerides to fatty acids ↑ hepatic glycogen breakdown ↓ hepatic glycogen synthesis ↑ hepatic glucose synthesis ↓ amino acid uptake in muscle ↑ amino acid uptake by liver ↑ liver deaminates amino acids, converting ti to t glucose l ↑ glucose levels & insulin secretion ↑ adrenaline release ↑ lipolysis in liver & adipose tissue – glycogen breakdown – glucose synthesis – lipid/fat breakdown – lipid/fat synthesis Factors regulating insulin release ¾ insulin synthesised as prohormone which is cleaved to mature peptide in secretory granules ¾ insulin and glucagon have short half life so need sustained release to maintain serum concentration ¾ insulin glucagon t1/2 = 30 minutes t1/2 = 10 minutes Glucose Transporter Insulin/Glucagon Promoting secretion ¾ ¾ ¾ ¾ ↑ glucose ↑ parasymp’ activity ↑ amino acids (arginine) ↑ glucagon Inhibiting secretion ¾ ¾ ¾ ¾ ↓ glucose ↑ sympathetic activity ↑ somatostatin release ↑ cortisol Insulin/Glucagon ─ insulin causes glucose transporters to be inserted in plasma membrane ─ this increases glucose uptake by muscle and adipose tissue ─ reduces blood glucose levels 10 Lect E4 - Endocrine insulin Diabetes Mellitus Effects of severe diabetes Insulin/Glucagon Type II Diabetes ¾ symptoms develop rapidly symptoms develop slowly ¾ childhood onset adulthood onset ¾ affects 10-20% diabetics affects 80-90% diabetics ¾ loss of β cell function insulin insensitivity ¾ insulin secretion none/low insulin secretion normal or high ¾ insulin injections for treatment diet/exercise and oral drugs 1. excessive eating ¾ cells starved of carbohydrate ¾ hypothalamic center leads to excessive eating 2. dehydration and thirst ¾ low glucose uptake, blood glucose rises ¾ exceeds renal filtration capacity ¾ glucose appears in urine, increases urinary vol ¾ dehydration and thirst Glucose Tolerance Test Blood Sugar mg/dl Type I Diabetes Insulin/Glucagon 300 Diabetes 200 3. coma ¾ cells unable to use glucose increases 100 ¾ lipolysis to generate fatty acids ¾ fatty acids metabolism → acetyl CoA → ketoacids ¾ ketoacids lower blood pH ¾ hyperventilation to maintain blood pH ¾ decreased brain O2 and coma Normal 1 2 Hours 3 4. brain cells are glucose obligate cells ¾ low glucose, brain stops working ¾ coma and respiratory paralysis Growth, Metabolism & Calcium Insulin & Glucagon Feedback loops Summary Insulin/Glucagon 1. Growth Hormone & Somatomedins (IGF’s) 2. Thyroid hormones (T3 & T4) 3. Oestrogens & Testosterone 4. Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids 5. Insulin & Glucagon 6. Calcitonin, PTH & Vit D CRH TRH PRH PIH GnRH dopamine ThyrotropinReleasing hormone Prolactinreleasing hormone Prolactininhibiting hormone (LH releasing hormome LHRH) CorticotropinReleasing hormone GHRH Gonadotropinreleasing hormone GHIH somatostatin Growthhormone inhibiting hormone Growthhormone releasing hormone ACTH TSH Prolactin FSH LH GH AdrenoAdrenocorticotropic hormone Thyroid stimulating hormone (non(non-tropic) FollicleFolliclestimulating hormone Luteinising hormone Growth Hormone Adrenal cortex Thyroid gland mammary glands cortisol Thyroid Hormone (T3.T4) breast growth, milk secretion many target organs Ovaries /Testes progesterone & estrogen ovulation & luteinisation estrogen (develop ovarian follicles) testosterone sperm production growth, anabolic actions y 11