Endocrinology (Part B) 2024 PDF

Endocrinology (Part B) Cortisol, stress & metabolism Growth Hormone & metabolism Exercise & energy Eating, fasting & starving  Cortisol, stress and metabolism  Adrenal cortex (80%) Zona glomerulosa aldos...

Endocrinology (Part B) Cortisol, stress & metabolism Growth Hormone & metabolism Exercise & energy Eating, fasting & starving  Cortisol, stress and metabolism  Adrenal cortex (80%) Zona glomerulosa aldosterone Zona fasciculata and reticularis Adrenal medulla (20%) adrenaline & noradrenaline B&B Fig 50-1  Steroid Hormones Classes of steroid hormone Gonadal or sex steroids e.g. progesterone, testosterone, oestradiol Glucocorticoids e.g. cortisol, corticosterone Mineralocorticoids e.g. aldosterone  Steroid Hormone Synthesis Precursor is cholesterol Cholesterol Progestagen Glucocorticoid Mineralocorticoid Androgen Oestrogen  Steroid Hormone Synthesis Zona glomerulosa Zona fasciculata and zona reticularis B&B Fig 50-2  Secreted Adrenal Steroids Aldosterone = mineralocorticoid named because of effects on minerals/electrolytes Cortisol (95%) and Corticosterone = glucocorticoids named because they increases blood glucose DHEA and androstenedione = androgens No other steroid producing tissue secretes glucocorticoids or mineralocorticoids  Regulation of Glucocorticoids hypothalamus Corticotrophin the HPA axis releasing hormone hypothalamo-pituitary- (CRH) adrenal gland axis Anterior Pituitary gland Adrenocorticotrophic hormone (ACTH) adrenal cortex ACTH has little or no effect on zona glomerulosa and cortisol aldosterone secretion target cells Rate-limiting Side chain cleavage step enzyme P-450scc Zona glomerulosa 11beta-hydroxylase Essential P-450c11 for GC CYP 11B1 activity Zona fasciculata and zona reticularis B&B Fig 50-2  Regulation of Glucocorticoids ACTH = adrenocorticotrophic hormone Binds to plasma membrane receptors on cortical cells ACTH-receptor is “melanocortin type 2 receptor” (MC2-R) Increases cholesterol uptake and trafficking Increases pregnenolone production Increases expression key enzymes P-450scc (side chain cleavage) P-450c11 (11-beta hydroxylase)  Effects of ACTH B&L Fig 47-5  Regulation of Glucocorticoids psychological or physical e.g. hypoglycaemia starvation Negative feedback Maintain/preserve blood glucose Hiller-Sturmhöfel S and Bartke, A (1998). Alcohol Health Res World. 22(3):153-164.  Effects of Glucocorticoids 1. Fuel metabolism Increase hepatic glucose output & peripheral catabolism 2. Permissive effects required for metabolic reactions & vascular reactivity 3. Water Excretion necessary normal water excretion 4. Resistance adaptation to stress preserves blood glucose 5. Reduce response to inflammatory stimuli & immunosuppression – a pharmacological effect.  Fuel Metabolism Increase peripheral catabolism & hepatic glucose output Adipose ↑ Lipolysis FAs used as alternative E substrate Plasma Muscle ↑ Protein breakdown ↓ AAs uptake utilized for energy supplement Liver ↑ Gluconeogenesis Growth Hormone and metabolism  BIOM2011/3 Actions of GH GH is a major determinant of growth Its actions are generally anabolic increases number & size of cells in soft tissues increases thickness & length of long bones + Metabolic actions distinct from effects on growth  BIOM2011/3 GH metabolic actions Muscle < stimulates AA uptake < decreases glucose uptake, < inhibits protein breakdown increases muscle mass Adipose tissue < decreases glucose uptake < increases fat breakdown (lipolysis) decrease in fat deposits Liver < increase protein synthesis, < increase gluconeogenesis Overall increase blood glucose  BIOM2011/3 Summary of GH actions In general GH acts to redistribute nutrients towards production processes such as growth Growing person/child (open epiphyses) GH causes true growth + Metabolic effects stimulates protein synthesis, decrease protein catabolism stimulates lipolysis (anti-insulin effect) increases blood glucose (anti-insulin effect) Adult (closed epiphyses) No major growth but metabolic functions as above, particularly important in maintaining muscle mass  Lipolysis is a key GH metabolic effect Plasma GH concentrations inversely correlate with abdominal fat Endotext  Metabolic Effects of Growth Hormone Counteracts the actions of insulin That is, causes insulin insensitivity - is “diabetogenic” leads to hyperglycaemia Role defense against hypoglycemia i.e. maintain blood glucose (ignores insulin signal to lower blood glucose) development of "stress" diabetes during fasting and inflammatory illness BUT in relation to glucose homeostasis….. Normally plasma GH does not cause such metabolic effects. But is critical in starvation response & exercise (next slide). Also important in patients under hGH treatment.  Metabolic Effects of Growth Hormone During fasting GH is the only “anabolic hormone” to increase (insulin and IGF-I levels decrease) GH acts together with increased levels of the catabolic hormones (glucagon, adrenaline and cortisol) Thought that key role of GH is to preserve muscle mass During moderate exercise protein and glucose metabolism remain unaffected GH stimulates of lipolysis - FA as alternative energy source  BIOM2011/3 Hypothalamus = integrated response Metabolic Neural High AA, Low FAs, hypoglycemia Stress, exercise, deep sleep malnutrition Hormonal Sex steroids GHRH and/or Somatostatin GH Exercise & Energy  Energy Sources for Muscle Immediate e.g. power events source ATP or phosphocreatine (PCr) ADP + PCr ATP + Cr Non-oxidative e.g. sprint anaerobic glycolysis glycogenolysis provides glucose fastest pathway Oxidative (e.g. >2 min) oxidation of glucose & fat most efficient pathway Nutrients stored in muscle provide energy eg. glycogenolysis Plus mobilised from liver & adipose tissue stores (carbohydrate and fat) Energy Sources: Exercise B&B Fig 60-5  Energy Sources: Exercise A. Endocrine control increased adrenaline & glucagon decreased insulin increased cortisol & GH Muscle activity itself moves GLUT4 to cell membrane plasma glucose important after muscle glycogen depleted Lactate from type IIb muscle fibres is converted by other muscle fibres to pyruvate and oxidised. also taken up by liver and converted to glucose B&B Fig 60-5  Energy Sources: Exercise B. Hepatocytes Gluconeogenesis “Cori cycle” - lactate - G - lactate impt prolonged exercise (>1 h) Fats Lipolysis, FA mobilisation and beta oxidation to yield E impt prolonged exercise B&B Fig 60-5  Glucose Intense prolonged excercise 180 min cycling Lactate Glycerol FFA Blood glucose decreases during prolonged exercise ie. regulation of hypoglycemia by glucagon & other hormones. Grego et al. 2004 Neurosci Lett 364:76-80  Exercise Endocrine decreased insulin increased cortisol (& GH not shown) increased SNS - adrenaline (& Glucagon not shown) Metabolic increased G uptake & oxidation increased FFA due to lipolysis increased glycerol – gluconeogenesis Grego et al. 2004 lactate no change – used in muscle & gluconeogenesis Neurosci Lett 364:76-80 Eating - anabolism  Energy storage after meal: CHO * * 25-30% of G * * * * Note: some G is oxidised * * * Insulin stimulates * B&B Fig 58.8  Energy storage after meal: Protein * * * * * Insulin stimulates Note: some G is oxidised B&B Fig 58.8  Energy storage after meal: Fat * Insulin stimulates * * * B&B Fig 58.8 Impt: insulin inhibits hormone-sensitive lipase (HSL) & prevents lipolysis Fasting & Starvation  Let’s expend energy catabolism Glycogen Proteins Triacylglycerides glycogenolysis proteolysis lipolysis glucose, lactate, amino acids, fatty acids, ketone bodies Energy - ATP You need to comprehend the biochem in this figure. Is covered in BIOC2000 the recommended pre-req Silverthorn: Human Physiology. Fig 22-3.  When not eating Priorities 1. Maintain blood glucose for brain function CNS main energy source, but CNS can utilize ketone bodies over time. Other tissues are capable of oxidation of Fas. 2. Maintain protein reserves Contractile proteins, enzymes, signalling etc  Energy Sources: Overnight Fast Endocrine control increased glucagon decreased insulin Metabolism Reduced G uptake muscle & adipose tissue increased Glycogenolysis increased Gluconeogenesi s increased Lipolysis Maintenance of G homeostasis by decreasing G uptake + some G production B&B Fig 58-13  Moving from fast to starvation After a few days of not eating metabolism shifts from enhanced gluconeogenesis in liver and utilization of amino acids as precursors to ketogenesis of fat stores ketone bodies provide fuel for the CNS, muscles and other tissues Endocrine control decreased insulin & thyroxine increased glucagon, SNS (Adrenaline), cortisol and GH from gluconeogenesis to ketogenesis Am J Nephrol. 2021;52(6):467-478. doi:10.1159/000517305  Energy Sources: Starvation Note gluconeogenesis in liver & kidney, & ketogenesis in liver B&B Fig 58-14  Gluconeogenesis & Ketogenesis Ketogenesis Precursors Fatty acids Gluconeogenesis beta oxidized Acetyl CoA can enter CAC OR combine to produce ketones Precursors Glycerol + amino acids (like alanine) B&B Fig 58-14 Beta-oxidation of fatty acids to acetyl CoA & then energy yield Silverthorn: Human Physiology. Fig 22-3.  Ketogenesis Acetoacetate, b-hydroxybutyrate, Acetone produced by liver enter circulation can be used as alternative energy source Muscle and CNS can utilise Acetoacetate or b-hydroxybutyrate to yield 2 molecules of Acetyl-CoA (reversible) Acetone is volatile so mainly blown off in respiration Symptoms of ketosis Fruity smell to breath due to acetone Metabolic acidosis – ketoacidosis – mild acids  Summary: Starvation Ketone bodies are converted back to acetyl CoA then enter TCA cycle to provide energy yield increased ketosis in liver decreased gluconeogenesis in liver enhanced/shift to gluconeogenesis in kidney After 3 days, brain gets 30% of its energy from ketone bodies. After 40 days, ketone bodies supply 70% of energy.  Starvation Glycogen is only a very short-term fuel source. The bulk of stored metabolic fuel is in the form of TAGs in adipose tissue which is sufficient to prolong life for 3 months. Protein is the second most abundant stored fuel @ about 14 days of energy, which is spared for as long as possible to permit mobility.