Metabolism and Homeostasis Theme 2

How are peptide hormones secreted?

By exocytosis as they cannot cross the phospholipid bilayer

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What occurs when peptide hormones activate the cAMP pathway?

Adenylate cyclase --> cAMP --> PKA. PKA phosphorylates enzymes, activating/inactivating them. ADH, TSH, ACTH and LH operate this way.

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What occurs when peptide hormones activate the phosphoinositide pathway?

IP3 and DAG generated, activate intracellular pathways. TRH, adrenaline, ADH and PTH operate this way.

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What occurs when peptide hormones activate the tyrosine kinase pathway?

Tyrosine kinases activated to cross-link, then phosphorylate each other. Tyrosine kinase complexes then able to phosphorylate other molecules (often activating transcription factors). Insulin operates this way.

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How are steroid hormones transported in the blood?

Bound to proteins (albumin) as they aren't water soluble

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What are biogenic amines?

Derived from the amino acid tyrosine. Only two - thyroxine is hydrophobic so is released from secreting cells by diffusion, adrenaline is hydrophilic so released from secreting cells by exocytosis.

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What is homeostatic endocrine control?

When a hormone regulates housekeeping (regular) functions within the body

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What is adaptive endocrine control?

When a hormone regulates specific changes in response to stimuli

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What ooccurs in a complex endocrine response?

Involves action of more than one endocrine gland. Hypothalamus is triggered by a neuronal stimulus to release a tropic hormone which acts on the anterior pituitary, stimulating it to release another tropic hormone that activates an endocrine gland.

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What examples of feedback occur in a complex endocrine response (by the desired hormone)?

Long, direct loop on the anterior pituitary or a long, indirect loop on the hypothalamus or a short loop on the hypothalamus

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What is the hypothalamus sensitive to?

Blood bourne stimuli, olfactory stimuli, light/day length, infection, temperature, stress (in trauma or pregnancy) and sensory inputs from the heart, stomach and respiratory tract

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What is TRH (TSH releasing hormone)?

Peptide hormone from hypothalamus, acts on anterior pituitary to stimulate TSH release

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Describe the adenohypophsis

Anterior pituitary; secretes ACTH, FSH, LH, GH, TSH and prolactin (most of these are tropic so it is the master gland). Functionally connected to the hypothalamus via portal vessels (into which nuclei of the hypothalamus secrete neurohormones).

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What are ganadotrophs?

Cells of anterior pituitary which secrete LH and GH. Stimulated by GnRH (gonadotropin releasing hormone) from hypothalamus.

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What are somatotrophs

Cells of anterior pituitary whiich secrete growth hormone. Stimulated by GHRH (GH releasing hormone), inhibited by GIH (GH inhibiting hormone); both from hypothalamus.

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What are thyrotrophs?

Cells of the anterior pituitary which secrete TSH. Stimulated by TRH from the hypoothalamus.

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What are lactotrophs?

Cells of the anterior pituitary responsible for secreting prolactin. Inhibited by PIH (prolactin inhibiting hormone) from the hypothalamus

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What are corticotrophs?

Cells of the anterior pituitary responsible for secreting ACTH. Stimulated by CRH (corticotroph releasing hormone) from the hypothalamus.

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Describe the neurohypophsis

Posterior pituitary, secretes ADH from supraoptic nuclei and ocytocin from paraventricular nuclei (together termed magnocellular nuclei) of hypothalamus

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What is the action of ACTH (adrenocorticotropic hormone)?

Acts to control the adrenal glands; stimulates cortisol (involved in catabolism) and aldosterone secretion (acts to increase renal Na+ reabsorption)

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What are the actions of the gonadotropins?

FSH stimulates gametogenesis, LH causes testosterone release in malea and ovulation in females

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How does GH stimulate growth?

Stimulates carbohydrate and lipid metabolism alongside protein synthesis - therefore NOT tropic

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What does TSH do?

Stimulates thyroxine release from the thyroid gland (involved in anabolic metabolism)

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What is the action of prolactin?

Acts on the mammary glands (so not tropic) to stimulate milk PRODUCTION; also causes renal Na+ reabsorption

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What are the actions of ADH?

Nanopeptide which is stimulated for release in low blood pressure/increased blood osmolarity; induces water reabsorption in the collecting duct of the kidney and induces contraction of smooth muscle of the vascular system (causing negative feedback)

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What are the actions of oxytocin?

Nanopeptide which induces milk secretion from the mammary glands (let-down reflex) or uterine contraction during childbirth (the ferguson reflex - this experiences positive feedback after first contraction stimulates release)

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What patterns may be expressed in endocrine pathology?

Hormone deficiency (diabetes type I), abnormal responsiveness (diabetes type II), hormone excess (hyperthyroidism/Graves disease)

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What are the main causes of hormone excess?

Benign tumour and hypoplasia (hypoplastic tissue which shows excessive growth)

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What causes primary hyposecretion?

Oversecretion of the desired hormone due to an issue with the target gland. Neurohormone and tropic hormone low but desired hormone high.

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What causes secondary hyposecretion?

Issue with anterior pituitary (neurohormone low, tropic and desired high) or the hypothalamus (all high as negative feedback negated by increased hypothalamic drive)

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What is Graves disease (primary hyperthyroidism)?

Autoimmune disorder due to excess thyroxine from the thyroid gland when the body generates excess antibodies against its own thyroid, enlarging it. Symptoms are bulging eyes, increased osteoclast activity, oedema, hand tremors and red skin of shins.

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What is Graves disease managed?

Anti-thyroid drugs, ingestion of radioactive iodine (only accumulates in thyroid) or thyroidectomy (full/partial thyroid removal)

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What occurs when Ca2+ is below normal?

Neuronal system becomes more excitable as Na+ VGC's become active at lower voltage (since no Ca2+ bound to them which normally increases voltage needed); causes uncontrolled hypocalcaemic tetany/Trosseau's sign

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In what forms may Ca2+ exist?

In its filterable form (as a free ion or anion-complexed) or its non-filterable form (protein-complexed)

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What is the rapidly exchangable calcium pool?

Occurs at the surface of bones, is the site of bone remodelling (occurs in trabecular - spongy - bone as greater surface area). Organises fast non-hormonal changes to calcium concentration, but not regulated.

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What is osteoid?

Organic bone matrix secreted by osteoblasts - comprised of collagen, later matures to hydroxyapetite

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What are osteocytes?

Mature bone cells in the bone matrix - connected to surface cells and each other by canaliculi

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What are osteoclasts?

Large mulit-nucleate cells derived from monocytes; resorb bone by releasing lipases, proteases and DNAases (hydrolyse it, releasing Ca2+)

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What occurs in osteoporosis?

Reduced bone density and mass through equal loss of organic and inorganic bone matrix (bone formed is therefore normal, just not enough of it as high turnover (too much resorption) or low turnover (too little formation)).

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Why is osteoporosis more common in women?

Already small bone mass, suffer postmenopausal oestrogen loss (oestrogen being a stimulator of bone formation)

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How is osteoporosis treated?

Calcium rich diet, habitual exercise (normal weight on bones promotes formation), oestrogen replacement (females), androgens (makes) and anti-resorptive drugs (bisphosphates and salmon calcitonin)

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What is osteomalacia (rickets)?

Caused by vitamin D deficiency (through lack from diet/sunlight or inability to convert to 1,25-DHCC; inability for 1,25-DHCC to act on target tissue also possible). Causes inadequate mineralisation so more osteoid than inorganic bone (so bow-legs).

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Hoow is osteomalacia treated?

Vitamin D analogs (synthetic 1,25-DHCC like calcitriol) or increased dietary Ca2+; any malabsorption should be treated

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What is the passive paracellular method of gut Ca2+ transport?

Occurs in ileum. Ca2+ from lumen inbetween cells of gut lining along conc grad into blood (but lumen conc varies from 0.3-9mM, must be above 2.5mM (though has no rate limiting step)).

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What is the active transcellular method of gut Ca2+ transport?

Occurs in duodenum and jejunum. Ca2+ from lumen into epithelia via facilitated diffusion, then assocaites with CaBP (sequesters so conc grad maintained, then slowly releases for active tranport at basolateral membrane).

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What are the advantages/disadvantages of active transcellular Ca+ transport?

Ca2+ pumps may be saturated (limiting rate), but always continual through action of CaBP and can be regulated by Vit D metabolites

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Where is Ca2+ reabsorbed?

60% of filtered actively reabsorbed in proximal tubule, 30% passively down loop of Henle, 9% actively at distal tubule (most important as regulated, since PTH stimulates and requires Vit D metabolites), 1-2% excreted in urine.

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Describe the action of PTH (parathyroid hormone)

Released from parathyroid chief cells, tanslated as pre-prohormone but matures via cleavage in secretory vesicles. In low Ca2+ increases number/activity of osteoclasts, stimulates distal tubule Ca2+ reabsorption, indirectly allows active gut uptake.

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How does PTH indirectly increase active transcellular Ca2+ uptake?

Stimulates 1-alpha-hydroxylase in kidney which catalyses 1,25-DHCC formation

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How is 1,25-DHCC formed?

Metabolite of vitamin D3 (from fish/eggs/cereal or via UVB radiation from cholesterol). Enzyme adds hyroxyl group to Vit D3 in hepatic circulation forming 25-HCC, travels to kidney where 1-alpha-hydroxylase adds another hydroxyl giving 1,25-DHCC.

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What are the actions of 1,25-DHCC?

Increases plasma Ca2+ by increasing number of CaBP's for active transcellular gut transport (also stimulates active uptake by Ca2+ pumps into blood here).Less profoundly increases tuubular Ca2+ reabsorption and promotes the action of PTH upon bone.

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Wht does stimulation of PTH and 1,25-DHCC by each other not cause overwhelming positive feedback?

1,25-DHCC also acts to inhibit PTH gene expression (so only increases action of PTH already formed)

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What is the action of calcitonin?

Synthesised and secreted by thyroid C cells, not very potent in humans. Stimulated by rise in Ca2+ levels; acts to reduce osteoclast mobility and changes their cell shape (so they become inactive). Also slightly decreases tubular Ca2+ reabsorption.

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What is primary hyperparathyroidism?

Hypercalcaemia through excessive PTH release (as tumour/hypoplastic tissue of parathyroid). May cause neuromuscular supression (as Na+ VCG's require greater voltage to open) or deposits in soft tissue. Treated by anti-resorptive drugs/surgery.

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What is osteosarcoma?

Bone cancer, where malignant cells destroy bone material so Ca2+ released (causing hypercalcaemia)

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What is Vitamin D depedant hypercalcaemia?

High levels of Vit D/1,25-DHCC occur due to overdosing on Vit D supplements or granulomatous diseases (leprosy/TB, cause WBC's to synthesise 1,25-DHCC)

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What is acromegaly?

Autoimmune disorder where 1-alpha-hydroxylase stimulated by excess GH release (so increased 1,25-DHCC causing hypercalcaemia)

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Why does hypercalcaemia only become more exaggerated in humans?

Due to the limited ability of relatively impotent calcitonin to rectify it.

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How is hypocalcaemia (low Ca2+) treated?

Long term Ca2+ or calcitriol (synthetic 1,25-DHCC) supplements (given intravenously if malabsorption severe - this should also be treated if present)

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What are the types of hypoparathyroidism?

PTH-deficient (through excess parathyroid removal), PTH-ineffective (inactive PTH released), PTH-resistant (target tissue unresponsive) and secondary (decreased Vit D absorption so little 1,25-DHCC; PTH replaces but causes bone resorption)

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Describe the arrangements of Islets of Langerhans

Alpha-cells (comprise 25%, secrete glucagon) in cortical/outer region, D-cells (comprise 10%, secrete somatostatin) in middle region, beta-cells (comprise 60%, secrete insulin) in centre region

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What activates/inactivates insulin?

Acctivated by = high blood glucose, amino acids , gastrin, secretin, CCK, sympathetic to alpha-receptors, parasympathetic to cholinergic neurones. Inhibited by = low blood glucose, somatostatin, symapthetic to beta receptors and stress.

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What are the actions of insulin?

Binds to target cells (all except liver) to increase GLUT-4 tranporter number and stimulate glycogenesis in muscles and lipolysis in adipose. Acts to decrease blood glucose (reducing secretion by negative feedback).

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How does somatostatin act?

Another name for GIH. Activates cAMP pathway to inhibit both insulin and glucagon.

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What occurs after a carbohydrate rich meal?

Plasma glucose increase causes rise in insulin; this decreases levels, inducing negative feedback on itself (as part of direct endocrine reflex arc)

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What occurs after a protein rich meal/arginine infusion?

Insulin levels rise as AA's increased alongside glucagon (as rise in insulin decreases blood glucose). Overall effect is small increase in glucose levels before they settle at a normal level.

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What are the symptoms of diabetes?

Hyperglycaemia, excessive urination and thirst (as glucose decreases renal water reabsorption), weight loss (as fasted state metabolism since glucose can't enter cells) and blurred vision (as glucose deposits in soft tissues)

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What do the adrenal glands secrete?

Mineralocortcoids (aldosterone) and glucocorticoids (cortisol) from the adrenal cortex and catecholamines (adrenaline, nor-adrenaline, dopamine) from the adrenal medulla

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What are the layers of the adrenal cortex?

Zona glomerulosa (synthesises/secretes mineralocorticoids), zona fasciculata (synthesises/secretes glucocorticoids) and zona reticularis (secretes glucocorticoids and sex hormones)

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What is the role of aldosterone (a mineralocorticoid)?

Increases Na+ reabsorption in the principal cells of the collecting duct, increasing blood volume/pressure

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Describe the renin-angiotensin pathway

Decrease in blood volume/pressure --> slower GFR picked up by macula densa --> juxtaglomerular cells of kidney stimulate renin release --> angiotensinogen to angiotensin I --> in pulmonary circulation ACE converts angiotenin I to angiotensin II

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What are the actions of angiotensin II?

Vasoconstriction, release of aldosterone and ADH, increase in cardiac output (all increase blood pressure)

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Describe the action of cortisol (glucocorticoid)

Acts in circadian rhythm, peaks before breakfast to prevent hypoglycaemia (overidden in long term stress). It increases gluconeogenesis, protein catabolism, lipolysis and supresses the immune system. Attached to albumin/transcortin (liver degrades).

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Why must cortisol be used carefully as an exogenous immunosupressant?

Excess cortisol will shut down hypothalamic-pituitary-adrenal axia (stop CRH, ACTH and endogenous cortisol release) so dosage must be monitored then decreased steadily so axis can reactivate

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Why does cortisol have a permissive effect on glucagon?

Cotisol must be present to ensure full responsiveness to glucagon (why death occurs if adrenal glands removed)

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What is Addison's disease?

Reduced production of aldosterone (making dehydrated) and cortisol (reducing ability to deal with stress)

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What is Cushing's syndrome?

Caused by excess cortisol, results in red rounded face (as fat redistributed after excess lipolysis), thin/weak limb muscles (as excess protein catabolism), hypoglycaemia (as excess gluconeogensis) ans susceptibilty to infection (as immunosupressed).

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What are the causes of Cushing's syndrome?

Adrenal tumour (causing primary cortisol hypersecretion), a pituitary tumour (causing secondary ACTH and cortisol hypersecretion) and overdoses of exodgenous cortisol.

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How is Cushing's syndrome treated?

Surgical removal of pituitary/adrenal tumour (though supplements needed if both adrenal glands removed), pituitary irridation/cytotoxic chemotherapy or adrenal enzyme inhibitors

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What is the action of progesterone?

A steroid (progestrogen) hormone secreted from the ovaries to inhibit LH release (ensuring only one apropriate ovulation) and maintain uterus lining in pregnancy

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What is the action of testosterone?

A steriod (androgen) hormone secreted from the testis of males which stimulates male reproductive development, induces sperm production, enhances libido, stimulates erythrocyte production and stimulates maintenance of bone mass (like oestrogen)

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Metabolism and Homeostasis Theme 2

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