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ANPS Anatomy & Physiology

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Presentation on theme: "ANPS Anatomy & Physiology"— Presentation transcript:

1 ANPS Anatomy & Physiology
Endocrinology III

2 Stress - anything that perturbs homeostasis Bad
Emotional – exams, bills, bad job Physical – drugs, hard labor, wound Metabolic – starvation, cold, heat Combination – car accident, combat, rape Good Exercise Nervous system activation Sympathetic stimulation - adrenal chromaffin release of epinephrine (E) β1 receptor - heart; increase rate and pulse pressure β2 - vasodilation in muscles (more blood to do work) - fiber release of norepinephrine (NE) α1 – vasoconstriction in peripheral tissues and gut Endocrine system activation Hypothalamic-pituitary-adrenal (HPA) axis stimulation – cortisol release - redistribution of fuel - enhances sympathetic E function - activates genes for stress adaptation Both types of stressors turn on same systems Epinephrine binds to GPCRs on B1, B2, A1 receptors

3 ACTH and Hypothalamic- Pituitary-Adrenal (HPA)
Axis Responses Stress, pain, circadian drive activate hypothalamic CRH release CRH binds GPCRs on anterior pituitary corticotroph cells Corticotrophs release ACTH ACTH binds to adrenal cortical GPCRs for cortisol release Cortisol binds to steroid receptors Cortisol has long feedback to hypothalamus and pituitary gland

4 Pro-opiomelanocortin (POMC)
Precursor to adrenocorticotropin (ACTH) and -endorphin ACTH -endorphin Anterior pituitary Not on test* Hypothalamus brain (anorexic peptide suppresses appetite)

5 Adrenal gland cortex – 3 contiguous layers medulla – sympathetic
Aldosterone Cortisol Androgens Epinephrine (adrenalin) cortex – 3 contiguous layers medulla – sympathetic -chromaffin cells (E) Adrenal glands Adrenal gland sits on top of kidneys in posterior wall, buried in fat Medulla composed of adrenal cells that produce epinephrine

6 Cholesterol ACTH Cortisol Corticosterone Glucocorticoids
zona glomerulosa zona fasciculata zona reticularis All 3 zones use Cholesterol ACTH activates zona fasciulata that produces Coritsol (humans), Corticosterone (other species) Glucocorticoids: lipophilic Aldosterone Cortisol Corticosterone Androgen Glucocorticoids

7 glucocorticoid receptor
Cortisol cortisol is lipophilic and enters cells cortisol binds to cytosolic glucocorticoid (steroid) receptors (GR) associated with chaperone heat-shock protein (HSP90) bound GR complex translocates into nucleus complex acts as transcription factor to activate or repress genes on a variety of tissues (-) cortisol glucocorticoid receptor (GR) (+)

8 Cortisol actions: metabolic vascular
anti-inflammatory/immunosuppressive Metabolic: “gluco” in glucocorticoids implies increased blood glucose levels liver – stimulates gluconeogenesis fat – stimulates lipolysis, inhibits glucose uptake muscle – stimulates protein catabolism; amino acids for gluconeogenesis, inhibits glucose uptake net effect – diabetogenic (important in fasting) Cortisol increases level of glucose available to use (kidneys: glucose production, fat/muscle: breakdown to fuel) **raise blood glucose levels Vascular: enhances epinephrine function to maintain vascular tone and pressure

9 Anti-inflammatory / immunosuppressive:
**cortisol inhibits inflammatory mediators (prostaglandins, interleukins, thromboxane, TNF, etc) reduces T lymphocytes / interferon production* decreases antibody production (long term)* * important in transplants to inhibit rejection But ... in excess (chronic stress or medication): centripetal (trunk) obesity muscle wasting and thin skin from connective tissue loss – poor wound healing increased infections from immune suppression bone resorption/loss – osteoporosis sodium retention and potassium loss from binding to mineralocorticoid receptors Stress increases inflammatory mediators  tissue damage Our body was never made to maintain stress response, used to turn on/off Increase of glucose in body = increase in body fat in trunk (chest to belly) Coritsol activates the breaking down of CT, matrix, tissue  muscle wasting, loss of calcium

10 Glucocorticoids: the good vs bad in therapeutics
the anti-inflammatory/immunosuppressive effects of glucocorticoids (hydrocortisone, dexamethasone) are used therapeutically to blunt severe inflammation, allergic reactions, autoimmune responses and transplant rejections The bad: long term use can lead to immunosuppression (bad for infections), muscle wasting, osteoporosis, hyperglycemia, obesity, neural/psychiatric disorders Good for short term, bad for long term

11 Pancreas, Islets and Glucose Homeostasis
Insulin is the key regulator of blood glucose Insulin actions are opposed and balanced by glucagon β-islet cells – insulin (green) α-islet cells – glucagon (red) exocrine/endocrine pancreas endocrine Islets of Langerhans High glucose in blood would coat rbc and everything in blood stream, damages capillaries (retna, kidneys) 90g of glucose in blood from a normal meal 5 gram: amount body tries to keep of glucose in blood How to get rid of all the glucose in blood? Store in muscle or fat Pancreas- mostly exocrine (amylase, tripsin), produce Islet cells Most cells produced by pancreas are Beta Islet cells: more insulin that glucagon from pancreas

12 Glucose transporters (GLUT): the other key players
, brain Know GLUT 2, 4 GLUT 2: brain! (20% glucose used by brain), beta islet cells GLUT4: insulin dependent, muscle/fat

13 Triggering insulin release
increase in blood glucose (after a meal) result in glucose entry into β-cells via GLUT2 cellular glucose metabolism result in increased ATP increase in ATP inhibits intracellular K+ efflux (KATP channels) increase in cellular K+ results in cell depolarization and calcium entry increased calcium stimulates insulin release from secretory granules Islet β-cells Net positive charge in islet cells Opens up calcium channels, allows insulin release from B islet cells depolarization

14 Islet β-cell insulin production
synthesized as 84 amino acid chain 3 disulfide bonds intervening connecting peptide (also called C-peptide) is removed by dibasic RR/KR cleavage

15 Insulin-receptor signaling
insulin binds to tyrosine receptor kinase in muscle, fat and other tissues different signaling pathways from scaffold increase cell survival/proliferation, decrease glucose synthesis, and increase GLUT4 transporter insertion to enhance cell glucose entry P IRS PI3K Sos Ras Raf Akt MEK ERK increase cell survival/proliferation decrease gluconeogenesis increase GLUT4 translocation into membrane (muscle/fat) glucose entry insulin receptor dimerization α β Shc Grb2 *insulin receptor translocation of GLUT4 to allow glucose entry to muscle/fat

16 **study this slide GLUT2 GLUT4 Triglycerides (muscle / liver
(fat storage) (muscle / liver storage)

17 Elevated glucose levels will:
increase insulin-depdendent GLUT4 insertion into tissues for glucose entry increase tissue glycogen production and storage (from excess glucose) in liver and muscle increase fatty acid/triglyceride synthesis/storage in fat increase amino acid into tissues for protein synthesis inhibit glycogen breakdown (inhibits glycogenolysis) inhibit new glucose synthesis (inhibits gluconeogenesis) inhibit lipolysis and reduce circulating free fatty acids net result is glycogen and triglyceride storage (i.e., fuel storage) Body tries to maintain 100 mg/dL If <100mg, glucagon released from alpha cells If>100 mg, insulin released

18 From decreased in blood glucose levels (between meals, fasting):
glucagon is released from islet α-cells glucagon binds to target tissue G protein-coupled receptors receptor activation of cAMP/PKA pathways result in enzyme phosphorylation and activity Glucagon effects are (opposite to insulin): increased glycogenolysis (breakdown of glycogen) to release glucose increased gluconeogenesis in liver increased lipolysis to free fatty acids and keto acids increased protein breakdown to amino acids net effect is fuel mobilization to serve metabolic demands

19 Diabetes – 2 types Type I diabetes mellitus (juvenile onset diabetes)
About 5% of all cases Genetic predisposition – autoimmune disease attacking beta cells Pancreatic beta cells fail Environmental factors Type II diabetes mellitus (adult onset diabetes) About 95% of all cases Genetic predisposition (many genes from genome studies) Body responds poorly to insulin (tissue insulin resistance likely because of fat) Eventual pancreatic beta cell “burn-out” - can’t keep up Biggest culprit: overeating / obesity Type 1: people are dependent on insulin for metabolism Type 2: excess fat inhibits role of Insulin receptors, beta cells constantly turned on

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