WordPress.com



ENDOCRINE VIVASTHYROID2009-1, 2005-1Describe the steps in the synthesis of thyroid hormonesThyroid hormone are made by thyroid epithelial cells called thyrocytesThey have 4 functions:Collect and transport iodine: via Na+/I- symport (NIS), secondary active transport (Na/K ATPase)Synthesise thyroglobulin and secrete it into the colloid: Contains 134 tyrosine residuesFix the iodine to the thyroglobulin to generate thyroid hormones: Via thyroid peroxidase in a multistep process w/ iodotyrosines MIT => DIT => T4 (2xDIT) and some T3 (MIT+DIT), creating a reservoir of thyroid hormones (in the colloid), nb some (inactive) reverse T3 also madeRemove the thyroid hormones from the thyroglobulin and secrete then into the circulation: Colloid internalized by endocytosis => lysosomal degradation => lysis of colloid releases hormoneAll steps TSH controlledT3 also made peripherally by deiodination of T4 (D1 deiodinase in periphery, kidneys, liver, thyroid)2010-2, 2009-2 (+symtpoms), 2009-1 (T4), 2008-1, 2007-1, 2005-1Outline the physiological effects of thyroid hormones The free thyroid hormones enter cells and bind to thyroid receptors in the nuclei and alter gene expressionT3 3-5x the affect of T4 b/c more is free and it has a higher affinity with the TR (RT3 is inert)TissueEffectMechanismHeartChronotropicInotropic -adrenergic receptors responses to catecholamines -myosin heavy chain (higher ATPase activity)AdiposeCatabolic LipolysisMuscle Protein breakdownGutMetabolic Carbohydrate absorptionLipoprotein LDL receptorsOther metabolically active tissues (except: testes, uterus, lymph nodes, spleen, anterior pituitary) Calorigenic O2 consumption Metabolic rate (mobilize FFA, increase Na/K ATPase),BSL/insulin resistanceBoneDevelopmentalPromote normal growth and development (cretinism)Nervous systemWhat are the effects of thyroid hormones on nervous and vascular systems? 2009-2CNSDevelopment CNS : cerebral cortex, basal ganglia, cochlea↑ activity, mentation speed and agitation (via catecholamines on RAS, dopamine and direct brain effects)↑ refexesCVSHeat generation => vasodilation => decreased PR => Na+ retention and expanded blood volume↑HR and contractility => ↑COT3 not formed in myocytes, but enters from circ and increases expression of certain genes (drecreases other)Increases: -adrenergic receptors, -myosin heavy chain (higher ATPase activity), sarcoplasmic reticulum Ca2+ ATPase, Na/K ATPase2011-2, 2010-2, What factors are involved in regulating thyroid hormone secretion?Predominant factor controlling thyroid secretion is the circulating level of TSH released from the anterior pituitaryTRH from hypothalamus serves to increase TSH secretionNegative feedback: T3 (and T4) block the increase in TSH secretion produced by TRHThyroid hormones inhibit TSH secretion before they inhibit synthesisTSH receptor on thyrocytes: G-protein and activates adenylyl cyclase via GsThyrocytes also have receptors for:IGF-1 and EGF => promote growthTNF- INF- => inhibit growth (?chronic inflammation -> weight loss and cachexia)Other Inhibitors of TSHStressWarmth in exp. animals (cold stimulates TSH secretion in exp animals and human infants)Dopamine, somatostatin and glucocorticoids (but physiological role in regulation of TSH secretion is not known)PANCREAS2010-2, 2008-2, 2008-1, 2006-1, 2005-1 (describe the synthesis and receptor)What happens when insulin binds to an insulin receptor?Formed in B cells as a precursor hormone w/ C peptide and stored in membrane bound granules t? 5 mins => binds to receptors => endocytosed and destroyed by proteases in the endosomes Insulin receptorTetramer: 2 and 2 glycosolated subunits subunits extracellular + bind insulin subunits span membrane, intracellular parts have tyrosine kinase activityInsulin binding triggers tyrosine kinase activity of subunits → autophosphorylation of subunits on tyrosine residuesPhosphorylation and de-phosphorylation of proteinsEffectors and secondary mediators: Insulin receptor substrate (IRS-1), phosphoinositol 3-kinase (PI3K)Once bound, insulin receptors aggregate in patches and are endocytosed => enter lysosomes => broken down or recycled (t? of receptors is 7 hours)What are the principal actions of insulin?Net effect: storage of CHO, protein and fat, i.e. anabolicWhat is the time frame for these effectsRapidSeconds transport of glucose, amino acids and K+ into insulin-sensitive cellsIntermediateMinutes simulation synthesis degradation of proteinsActivation of glycolysis and glycogen synthesis (enzymes)Inhibition of gluconeogenesis (enzymes)DelayedHoursIncrease lipogenesis (via transcription)2008-1Describe the effects of insulin on various tissuesAdiposeGlucose, K+ uptakeFatty acid and glycerol synthesisTriglyceride depositionMuscleGlycogen and protein synthesisAmino acids and ketone uptakeLiver*Glycogen, protein and lipid synthesisDecreases ketone productionGeneralCell growth What metabolic effects does insulin have on the liver? 2010-2*↑glycogen synthesis, ↑protein synthesis, ↑lipid synthesis↓ketogenesis↓glucose output due to ↓gluconeogenesis and↑glycolysis 2003-1What happens to the insulin secretion when?a person is injected with 50ml of 50% Dextrose?It would go upDescribe the mechanism of insulin secretionGlucose => GLUT2 in B cells => glycolysis to pyruvate => ATP via citric acid cycleRapid phase of release (3-5mins): ATP inhibits ATP sensitive K+ channels, depolarizing the B cell and Ca2+ enters => exocytosis of readily available secretory granulesProlonged phase of release (2-3hr): metabolism of pyruvate via citric acid cycle => increased glutamate which acts as an intracellular second messenger to release these granules2011-2, 2009-2, 2007-1What factors determine the plasma glucose level?Concept: ?Balance between glucose entering the bloodstream and glucose leaving the bloodstreamDietary intakeCellular uptake (Esp. muscle/fat/ hepatic)Hepatic?glucostatic activity: (glycogenisis, glycogenolysis, gluconeogenisis)Renal: freely filtered but PT reabsorbed to?TmaxHormonal effects on theseList the ?hormones which effect plasma glucose levels? 2009-2BSLInsulin => by glucose uptake, glycogenesis, liver glucose to fat NSILA (nonsupressible insulin-like activity), esp. IGF 1and 2 (< activity than insulin)BSLCatecholamines (NA/Adrenaline): receptor => cAMP => glycogenolysis/gluconeogenesisGlucagon: cAMP => glycogenolysis/gluconeogenesisGH: anti-insulin effect, increases liver outputCortisol: permissive effect on catecholamines and glucagon, some glucogenesisThyroid: absorption + glycogenolysis (esp. liver)Nb: -adrenergic stimulators and somatostatin inhibit insulin secretionExplain how the blood glucose is maintained during fasting. 2011-2Prolonged fasting: Glycogen depleted => increase gluconeogenesis from glycerol and amino acids in liverThere is also increase in FFA => tissues directly and => ketones via liverHormones: glucagon, cortisol and GHWhat are the potential pathways for glucose metabolism in the body? 2007-1Aerobic: glucose + 2ATP (or glycogen + 1ATP) + 6O2 => 6CO2 + 6H2O + 40ATPAnaerobic: glucose + 2ATP (or glycogen + 1ATP) O2 => 2 lactic acid + 4ATPGlycolysis: glucose => pyruvate + H+ + energy for ATP productionPrepatory/investment phase followed by the pay-off-phaseCan occur in aerobic and anerobic environmentsAerobic: pyruvate ultilised via the Krebs/citric acid cyclePentose-phosphate pathway: for NADPH productionGlycogenesis: glucose => glycogen for storage (prevents excessive osmotic pressure)2011-1, 2010-2, 2005-1What are the effects of insulin deficiency?Intracellular glucose deficiency w/ extracellular?excessDerangement of the glucostatic function of the liverHyperglycaemia with no decrease in gluconeogenesis Secondary osmotic diuresis with dehydrationElectrolyte and calorie lossCatabolism of protein and fatKetosis => acidosis2011-1Please name the principal Ketone bodies.Acetoacetate, β hydroxybutyrate, AcetoneHow are the Ketone bodies produced and how are they metabolised?Fatty acids (β oxidation) => acetyl-CoA => citric acid cycle => high output of energy (c.f. CHOs)Occurs in the mitochondria in the liver and other tissuesAcetyl-CoA will condense => acetoacetyl-CoA (and aceyl-CoA + acetoacetyl-CoA = HMG-CoA)In the liver from these (via deacyclase and HMG-CoA) acetoacetate <=> β hydroxybutyrate (irreversible, the enzyme for acetoacetate => acetyl-CoA is not found in liver cells)These products are water soluble (unlike fatty acids and triglycerides) and are exported from the liver to extraheaptic tissues (esp. brain, skeletal and cardiac muscle) for ultilisationThey convert the β-HB => acetoacetate => acetoacetyl-CoA => acetyl-CoA for ulilisationThe acetone is formed from the spontaneous decarboxylation of acetoacetate cannot be converted back to acetyl-CoA and is excreted in urine and the lungsIn which clinical situations do they accumulate in the body?Insulin inhibits and glucagon stimulates there productionThis pathway is most active during extended periods of fastingA rise is seen during sleep, starvation, high fat/low carb dietAlso seen in diabetes when there is insulin deficiency and glucagon excessAlso alcoholic ketosis can occur: alcohol blocks the first step of gluconeogenesisNormally the levels of β-HB and acetoacetate will be much higher than acetone, but still very low due to utilization in the tissuesWhat are the physiological and clinical consequences of excess ketones?When production exceeds ultilisation (and excretion of acetone) there is a buildup (ketosis)Acetoacetate and β-HB are acids: normally buffered, but when the mechanisms are exceeded a metabolic acidosis developsThe kidneys and lungs initially compensateThe acidosis is exacerbated by the hyperglycaemia in DKA causing dehydration2010-2What are the physiologic actions of glucagon?Acts on Gs protein receptors => cAMP => Protein kinase A Also acts of different receptors to activate phospholipid C => Ca2+These lead to:Glycogenolysis in liver (not muscle)Gluconeogenesis from amino acids (only at very high levels)LipolysisKetogenesis+ve inotropic effect on heart (used in β-blocker OD b/c different receptor)Inc blood flow to kidneysStimulates secretion of GH, insulin and somatostatinWhat factors affect glucagon secretion?StimulatorsInhibitorsGlucogenic amino acidsGlucoseCCK, gastrinInsulinCortisolSomatostatinExercise, starvation, stress, protein mealSecretinInfectionFFAs, ketonesTheophyllinePhenytoinVagal stimulation (acetylcholine)α-adrenergic, GABAAdditionalInsulin secretionGlucose => GLUT2 in B cells => glycolysis to pyruvate => ATP via citric acid cycleRapid phase of release: ATP inhibits ATP sensitive K+ channels, depolarizing the B cell and Ca2+ enters => exocytosis of readily available secretory granulesProlonged phase of release: metabolism of pyruvate via citric acid cycle => increased glutamate which acts as an intracellular second messenger to release these granules by exocytosisStimulatorsInhibitorsGlucose, mannoseK+ depletionGlucagon, GIP (gastrin,secretin,CCK), AChSomatostatin, insulinAmino acids, b-keto acids2-deoxyglucose, mannoheptoseβ-adrenergic stimulationα-adrenergic stimulationTheophylline, sulphonureasPhenytoin, thiazides, diazoxideADRENAL2010-1, 2008-1, 2005-2What are the physiological effects of glucocorticoids?Metabolic (Intermediary metabolism of carbohydrate, protein, fat)Increased protein catabolismElevate blood glucose: hepatic glycogenesis and (permissive effect on) gluconeogenesis Raise peripheral tissue insulin resistanceMake DM worse, and Cushings -> IGT in 80%, and DM in 20%If deficient then hypoglycaemia (if fasting)Permissive effects on other reactionsAre required for catecholamines to produce calorigenic and lipolytic effects, pressor responses (vascular reactivity) and bronchodilationInhibit ACTH secretion (feedback)Allow water excretion (mechanism unclear)Blood and lymphatics: lymphocytes, lymph glands and eosiniphilsRBC, neutophils and plateletsRequired for stress responseCNS w/ effects on EEG waveforms (mild personality, irritable, poor concentration, apprehensive)How is glucocorticoid secretion regulated?Basal secretion and stress response both dependent on ACTHOther substances may stimulate adrenal directly but no evidence of role in physiologic regulationFree glucocorticoids produce negative feedback on ACTH secretion at both hypothalamic and pituitary levels (effect mediated by action on DNA)Stress response ACTH secretion mediated almost exclusively via hypothalamic release of? corticotrophin releasing hormoneCircadian rhythm: ACTH released in irregular bursts throughout day but much more common in early morning. 75% of cortisol secreted at this timeHow are they metabolised 2005-2Cortisol is metabolised in the liverCongugated to glucuronic acidExcreted in the urine (15% in stool, via enterohepatic circulation)2010-2, 2009-2, 2008-2, 2007-1What is the physiological role of aldosteroneCauses retention of Na+ (and therefore H2O) expanding the ECFIncreases absorption of Na+ from urine, sweat, saliva and colonOn kidney is acts on principal cells in CD -> ENaC (rapid insertion & slower synthesis)The Na+ will be exchanged for H+ and K+ -> K+ diuresis and acidification of the urineBy expansion of the ECF -> increased renal perfusion -> negative feedback on rennin productionAldosterone is only one of the mechanisms for defense of ECF volumeWhat conditions increase aldosterone secretionPrimary adrenal disease 70% bilateral adrenal hyperplasia (idiopathic)Adrenal adenoma (Conn syndrome)Secondary hyperaldosteronismOveractivity of the RASeg. CCF, cirrhosis & nephrosisRenal artery constrictionDescribe the typical serum / urine effects in hyperaldosteronism1. Na/Cl mild ↑, fluid retention (follows Na),2. ↓K, alkalosis (alkalaemia only if K+ depletes)3. Urine K+/ H↑Clinical picture: usually without edema (due to escape phenomenom b/c ANP) , but weakness, hypertension, tetany, polyuria and hypokalemic alkalosisList the stimuli that increase aldosterone secretionRenin from kidney via angiotensin II (diaglycerol and protein kinase C)ACTH from anterior pituitary (cAMP, protein kinase A)Stimulatory effect of rise in plasma K+ conc. on adrenal cortex (Ca2+ via voltage gated channels)Clinical causes: Surgery, haemorrhage, standing, anxiety, physical trauma, high K intake, low Na+ intake, constriction of IVC in thorax, hyperaldosteronism (eg CCF, cirrhosis, nephrosis)Describe the feedback regulation of aldosterone secretionFall in ECF / blood volume -> reflex in renal nerve discharge & in renal artery pressure Increase in renin secretion -> increase -> in angiotensin II -> increase in aldosterone secretionNa+ & water retention -> expanded ECF volume -> decrease in stimulus that initiated renin secretion2006-1What hormones are secreted by the adrenal medullaThe catecholamines: Adrenaline, noradrenaline and dopamineWhat are the major effects of these hormones? and effectsCardiovascular as per table and diagramIncrease in blood glucose via:Glycogenolysis in liver ( effect)Stimulation of B cells Insulin, glucagon ( effect)Increased lipolyis (FA and TGs) via 3Hypokalaemia (K+ into cells) via 2Metabolic acidosisIncreased metabolismIncrease alertnessBronchodilation 2Mydriasis Increased renninLeucocytosisGastric, uterine, bladder SMC relaxationNoradrenaline1=2, 1>>2Vasoconstricts, positive inotrope (minimal chronotropy), COAdrenaline1=2, 1=2Vasoconstricts except skeletal m, positive inotrope/chronotropeDopamineD1=D2>>>>Vasodilation of renal and mesentery, vasoconstriction elsewhere (?NA release), inotropic (CO)CALCIUM2010-2, 2009-1, 2006-1, 2004-2What hormones are involved in serum calcium regulation.HormoneSecreted fromMain actionsPTHParathyroid Ca2+, mobiles from bone, urinary reabsorption in DT, urinary excretion of PO43-, 1,25 DHCCSun/skin/GI – liver/kidneys Ca2+, increases GI absorption, urinary reabsorption in PTCalcitoninThyroid (parafollicular cells) Ca2+, inhibits bone resorption, urinary excretion2011-2, 2010-2, 2009-2, 2009-1, 2006-1, 2004-2Describe the role of parathyroid hormone in calcium metabolism.Bone: Directly increases bone resorption and mobilises Ca2+ causing increased serum calciumOver longer timeframe will stimulate osteoblast and oseteoclast activityKidney:Directly increases Ca2+ reabsorption by the distal renal tubules although increased filtered Ca2+ may cause increased excretion (overwhelms absorbtion)Also causes increase PO43- excretion in PT (NaPi-IIa) i.e. phosphaturicGI:Indirectly increases gut absorption of Ca2+ by increasing formation of calcitriolHow is parathyroid hormone secretion regulated?Serum Ca2+ exerts negative feedback on PTH secretion via a membrane Ca2+ receptorCalcitriol exerts negative feedback by reducing preproPTH mRNASerum PO43- stimulates PTH secretion by decreasing Ca2+ and inhibiting calcitriol formationMg2+ is required for PTH secretionPTrHParathyroid related hormoneProbable role in fetal cartilage growth, teeth, breast, skin and placental Ca2+ transportHypercalcaemia in cancer caused by it 80% of the time(20% by bone destruction – local osteolytic hypercalcaemia)Secreted by cancers of the breast, renal, ovary and skin2008-1, 2006-1, 2004-2What are the actions of vitamin D?Increased absorption of calcium from the intestine by induction of calbindin-D proteinsIncreased reabsorption of calcium in the kidneysIncreased osteoblast activity (w/ secondary osteoclastic activity)Aids calcification of bone matrixNote it also stimulates the uptake of PO43- from the GI (-ve FB on itself)How is the synthesis of vitamin D regulated?Sunlight or ingestion: VitD3 (cholecalciferol) => P450 in liver 25(OH)D (25-hydroxycholecalciferol = calciferol) => PT cells in kidney to active 1,25 (OH)2D (1,25-dihydroxycholecalciferol = calcitriol)Not closely regulated Ca2+ leads to PTH secretion => (via 1 hydroxylase) => calcitriol is produced Ca2+ inhibits PTH and the kidneys produce inactive metabolites (24,25DHCC)PO43- directly inhibits the 1 hydroxylase => calcitriol productionCalcitriol itself also inhibits the 1 hydroxylase and the release of PTH2008-1What factors influence the level of free calcium in plasma?Protein binding: Mainly to albumin, depends on plasma protein level and pH (less bound if acid)Total body calcium: 99% bound in bone w/ some bone readily exchangeable vs slowly exchangeable (resorption/deposition)Mobilisation from bone (PTH, calcitriol and calcitonin)Intake and subsequent GI absorption under influence of calcitriolRenal absorption by PTH (DT) and calcitriol (PT) and PO43- levels (decreases calcitriol)How does bone resorption occur?Osteoclasts are monocytes that develop from stromal cells under influence of RANKLAttach to bone via integrins in sealing zone of the membrane.Hydrogen dependent proton pumps move into cell and acidify the areaAcid dissolves hydroxyapatite and collagenProducts move across osteoclast into interstitial fluid2004-2What are the secondary hormones involved in calcium metabolism?GH: increases gut absorptionGlucocorticoids: increases bone reabsorptionOestrogens: inhibits osteoclastsPITUITARY2006-2Describe the changes in ACTH secretion that occur in response to stressIncreased ACTH secretionMediated through hypothalamus by CRHCRH produced in paraventricular nuclei, secreted in medial eminence and transported in portal hyperphysical vessels to anterior pituitaryMultiple nerve endings converge on paraventricular nucleiDestruction of median eminence means stress response is blockedWhat are the physiological consequences of sudden cessation of steroid therapy after prolonged treatment?Low glucorticoid levels with inability to increaseNormally a drop in resting corticoid levels stimulate ACTH secretion (feedback loop)Prolonged exogenous glucocorticoid inhibits ACTH Adrenal atrophic and unresponsiveInhibitory effect pituitary and hypothalamus due action on DNADegree of pituitary inhibition proportional to glucocorticoid level ACTH inhibiting activity parallels glucocorticoid potencyPituitary unable to secrete normal amounts of ACTH for one month, probably secondary to decreased ACTH synthesisAfter one month a slow rise in ACTH levels to supranormal levels, stimulates adrenal with increased glucocorticoid outputFeedback inhibition causes a gradual decrease in ACTH levels to normalAvoid by tapering dose over long period (or short dosing if possible)2005-1What hormones are produced by the?pituitary?Anterior pituitary (adenohypophysis):HormoneCell-typeAssociated syndromeFBasophilsFSHGonadotrophHypogonadism (lethargy, loss of libido, amenorrhoea), mass effect and hypopituitarismLLHAACTHCorticotrophCushing’s syndromeTTSHThyrotrophHyperthyroidPAcidProlactinLactotrophAmenorrhea, galactorrhea, loss of libido, and infertilityIIgnoreMammosomatotrophCombined features of GH and prolactin excessGGHSomatotrophGiantism (children), acromegaly (adults)Posterior pituitatry (neurohypophysis) – remember: Point-of-view => posterior has oxytocin and vasopressin.What are the physiologic effects of vasopressinAntidiuretic: renal retention of water in excess of solute?reducing body fluid osmolality insertion of aquaporins in CDPressor: increases peripheral vascular resistance => BP ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download