ANPS Anatomy & Physiology

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

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. ACTH -endorphin Pro-opiomelanocortin (POMC) Precursor to adrenocorticotropin (ACTH) and -endorphin Anterior pituitary Hypothalamus brain (anorexic peptide suppresses appetite)

5. Aldosterone Cortisol Androgens Epinephrine (adrenalin) Adrenal gland • cortex – 3 contiguous layers • medulla – sympathetic • -chromaffin cells (E) Adrenal glands

6. Cholesterol ACTH zona glomerulosa zona fasciculata zona reticularis Cortisol Corticosterone Aldosterone Androgen Glucocorticoids

7. 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) • 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

10. Glucocorticoids: the good vs bad in therapeutics • The good: • 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

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

12. , brain Glucose transporters (GLUT): the other key players

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 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 α insulin receptor dimerization glucose entry β P P IRS Shc Sos Grb2 P P PI3K Ras Raf increase GLUT4 translocation into membrane (muscle/fat) P P P P MEK Akt P P ERK increase cell survival/proliferation decrease gluconeogenesis

16. GLUT2 GLUT4 Triglycerides (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)

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