Endocrinology short notes

Compare the source, release and actions of vasopressin and oxytocin

Both oxytocin and vasopressin (ADH) are peptide hormones secreted by the posterior pituitary. Oxytocin acts on a membrane G protein coupled receptor which is coupled to PLC in breast and uterine muscle. It causes contraction of the uterine myometrium in childbirth and contraction of breast myoepithelium to eject milk. It also has a role in social behaviour, Release is controlled by stretch of cervix/vagina during parturition. ADH however acts on V2 receptors in the kidney with G proteins coupled to cAMP and V1 (PLC-coupled) receptors in vasculature. It acts to increase water reabsorption by acting in collecting ducts of kidney and has vasculopresssor effects through constricting peripheral arterioles and veins. Its release is controlled by blood osmolarity which is sensed by hypothalamic osmoreceptors. These are also sensitive to a decrease in blood volume and pressure.

Explain the physiological basis of what you would expect to find on the examination of a patient with Cushing's syndrome

Cushing's syndrome is caused by a prolonged elevation of cortisol levels. Overproduction of cortisol causes liberation of amino acids from muscle tissue which results in a weakening of protein structures (specific muscle and elastic tissue). The end result may include a protuberant abdomen with purple stria, poor wound healing, thinning of the skin, generalised muscle weakness and marked osteoporosis which is made worse by an excessive loss of calcium in the urine and by the inhibiting effects of cortisol on bone formation. Elevated cortisol also causes hypertension through intrinsic mineralocorticoid activity, activation of the renin-angiotensin system, enhancement of vasoactive substances and by suppressing vasodilatory systems. High circulating levels of cortisol lead to accumulation and storage of fat as a protection mechanism in response to the stress the body believes it is being exposed to.

How is energy intake controlled?

Energy intake is notoriously difficult to assess and is usually underestimated by about 30%. Different foods have different effects on energy intake with high fat foods having lower capacity to induce satiety than protein. The general controller is the ventromedial, paraventricular and arcuate nuclei of the hypothalamus. These have efferent controls through the autonomic nervous system to determine intake, distribution, storage and utilisation of energy substrates. Afferent signals can be sent from the controlled system to the general controlled and these can be in the form of sensory, metabolic, gut and other hormones as well as action through the sympathetic nervous system.

What do the different types of glucose transporters do?

GLUT1 transporters are in the plasma membranes of all cells and are associated with the basal uptake of glucose. It transports glucose, galactose and mannose. GLUT2 transporters however are found in the small intestine, renal tubules, hepatocytes, brain and β cells. They transport both glucose and fructose. GLUT3 transporters are ubiquitous and transport only glucose. GLUT4 transporters are found in skeletal and cardiac muscle as well as adipose tissue. They are the only transporter under insulin control and transport glucose. Finally, GLUT5 transporters are mainly found in the gut but possibly in the muscle and the brain. They are responsible for transporting fructose. Active co-transport can also move glucose against a concentration gradients and this can be carried out by SGLT-1 and SGLT-2 which reabsorb glucose in the kidney.

Write short notes on the actions of glucocorticoids

Glucocorticoids are steroid hormones produced in the zona fasciculate of the adrenal cortex and are part of the feedback mechanism in the immune system which reduces certain aspects of immune function such as inflammation. They are therefore used to treat disease caused by an overactive immune system but due to their many diverse effects on the body can have potentially harmful side effects. They affect cells by binding to the glucocorticoid receptor which up-regulates the expression of antinflammatory proteins in the nucleus and represses the expression of proinflammatory proteins in the cytosol. Cortisol is the most important human glucocorticoid and is essential for life as it regulates and supports important cardiovascular, metabolic, immunologic and homeostatic functions

How is iron transported in the plasma?

Iron travels in the plasma bound to the transport protein transferrin which is essential because it is very oxidative and can cause problems on its own. Transferrin is a liver derived glycoprotein with binding sites for two Fe(III) atoms. Serum transferrin concentration rises in response to iron deficiency and is often quantified as total iron binding capacity. Free serum iron levels are variable and alone are rarely a good index of iron status. Transferrin saturation (serum iron/TIBC x 100) is usually around 20-30% and is often used as an index of iron availability. This gives you a percentage of the full iron binding sites in the bloodstream.

Describe the importance of fatty acids and amino acids

Neurons don't use fatty acids as fuel. They diffuse across the blood brain barrier and into cells where they can be esterified to fatty acyl-CoA and integrated into the intracellular acyl-CoA pool. From here they can be used in mitochondrial β oxidation to produce ATP or they can be incorporated into phospholipids. Fatty acids are important in modulating the conductance of a variety of ion channels in the plasma membrane. These include Cl- channels, K+ channels and Ca2+ channels therefore consumption of fatty acids can affect neuronal transmission in this way. Amino acids are essential and cannot be produced by the body therefore they must be taken up by eating. Their presence therefore reflects food intake. Leucine, for example, selectively activates mTOR. This is a Ser/Thre kinase involved in gene transcription. Stimulation reduces food intake and increases metabolism. Leptin and insulin are thought to ultimately activate mTOR. It is inhibited by AMP kinase, the activity of which is increased by ghrelin and decreased by leptin and insulin.

Write short notes on the composition of oral contraceptive pills and their mechanism of action

The combined oral contraceptive pill consists of oestrogen and progesterone. It acts by preventing ovulation, thickening the cervical mucus and thus making it harder for sperm to move and by thinning the lining of the uterus making it harder for the egg to attach there. They can be monophasic and have an even amount of hormone throughout the month or have varied hormones doses through the month (triphasic). The progesterone only oral contraceptive also exists which thickens cervical mucus and thins the lining of the uterus. These were developed for women who are sensitive to oestrogen.

Write short notes on insulin resistance, dyslipidaemia and inflammation

Fatty acids cause insulin resistance by directly interfering with GLUT4 activation by insulin. They do this by decreasing Pl3K activation. Under certain conditions such as adipocyte dysfunction, lipolysis and/or the release of chemokines from adipose tissue promotes a macrophage activation and inflammation. Decreased permeability of the blood brain barrier leads to loss of feeding behaviour control and basal insulin regulation.

What is the biological importance of iron?

Iron can occupy multiple oxidation or transition states, including the most biologically important ferrous (Fe2+) and ferric (Fe3+) forms. It can therefore participate readily in reduction-oxidation reactions. Iron is a vital constituent of haemoproteins (e.g. haemoglobin) and iron-sulphur proteins (e.g. electron transport chain), and its redox properties make it an important co-factor for many enzymes. However, iron can be very toxic in excess, participating in intracellular Fenton reactions that can generate harmful free radical compounds. Homeostatic mechanisms must therefore balance the requirement of the body fir sufficient iron against the risk of cellular iron overload.

What are the inputs and outputs of the hypothalamus?

It receives input from the retina through the retinohypothalamic tract which terminates in the SCN. It also receives input from the olfactory receptors in the medial forebrain bundle and the cutaneous receptors. It also receives an inpit from higher limbic systems including the hippocampal formation with the fornix projecting to the mammillary bodies and from the amygdala where the stria terminalis projects to the medial hypothalamus. The output of the hypothalamus however is to the thalamus. This is via the mammillothalamic tract (Papez circuit: cingulate gyrus - hippocampal formation - mammillary bodies - anterior thalamic nucleus - cingulate gyrus). It is also projects from the medial hypothalamus to the midbrain amygdalia and the midbrain PAG which is responsible for aggression, rage and fight. It also has output to the frontal and parietal lobes, habenular nucleus and the midbrain as well as the blood stream via the pituitary.

How does the arcuate nucleus regulate appetite?

The arcuate nucleus contains two populations of neurons with completely antagonists properties. As their names suggest, POMC/CART neurons expression pro-opiomelanocortin and cocaine and amphetamine regulated transcript. POMC is converted into α-MSH which is released into neurons in the PVN that express MC4R which α-MSH is an agonist to. It also projects to the DMN, LHA and the VMN. NPY/AgRP neurons however express neuropeptide Y and agouti-related peptide. AgRP is released onto neurons in the PVN that express MC4R and it inhibits them, acting as an antagonist. NPY also projects to DMN, VMN and LHA. Stimulation of POMC/CART neurons decreases food intake and increase metabolism through its action of the PVN which produces TRH while the NPY/AgRP neurons increase food intake and decreases metabolism. The NPY/AgRP neurons also inhibit oxytocin-producing neurons in the PVN which is important because oxytocin administration induces weight loss. Loss of these neurons is therefore implicated in Prader Willi Syndrome

How does glucose regulate insulin secretion?

The primary stimulus for insulin secretion is the beta cell response to changes in ambient glucose. Glucose is transported into beta cells through facilitated diffusion of GLUT2 glucose transporters. Intracellular glucose is then metabolised through glycolysis and the krebs cycle to produce ATP. This results in an elevation of the ATP:ADP ratio which induces closure of the cell-surface ATP-sensitive K+ channels leading to cell membrane depolarisation. Cell surface voltage depdendent calcium channels are then opened which facilitates the influx of extracellular calcium into the beta cell. A rise in free cytosolic calcium triggers the exocytosis of insulin-containing granules via SNARE proteins which results in release of insulin into the bloodstream.

What role does bone have in insulin secretion?

Embryonic stem-cell phosphatase (ESP) osteoblast knock-out mice died perinatally from severe hypoglycaemia, linking bone to insulin for the first time. Embryonic stem-cell phosphatase is expressed only in embryonic stem cells, Sertoli cell of the testes and osteoblasts. These findings lead to the discovery of osteocalcin. Insulin signalling in osteoblasts decreases OPG expression. This decreases the ratio of OPG to RANKL and therefore increases bone resorption by osteoclasts. The acidic pH in resorption lacunae decarboxylates and activates osteocalcin stored in the bone matrix. Active osteocalcin stimulates insulin secretion by pancreatic β cells through an unknown mechanism. ESP counters insulin effects on bone. It inhibits insulin receptor activation is osteoblasts by insulin and therefore prevents insulin-mediated release of osteocalcin.

Write short notes on the endocrine control of appetite

Endocrine control of appetite involves the action of hormones from adipose tissue, the pancreas and the GI tract regulating the neural appetite centres in the brain such as the arcuate nucleus. Leptin is released from adipose tissues and is responsible for decreasing food intake and increasing metabolism to provide a long term regulation of body weight. It acts on its tyrosine kinase receptor in order to stimulate POMC/CART neurons and inhibit the NPY/AgRP neurons. Insulin is released from the β cells of the pancreas and also reduces food intae and increases metabolism through actions on the same neurons of the arcuate nucleus but this occurs more over the short term. Also released from the pancreas, pancreatic pepetide has a similar action but works through Y4 receptors on the brainstem and hypothalamus. Ghrelin is the only gastric messenger that stimulates food intake and decreases metabolism through its action on receptors on the NPY/AgRP neurons that make GABAergic contacts with POMC/CART neurons. PYY decreases food intake and CCK decrease meal size but increases meal frequency.

What happens in Beckwith-Wiedemann

Excessive IGF2 production results in somatic overgrowth. The IGF2 gene is closely linked to the H19 gene which encodes a non-coding RNA and regulates IGF2 expression through a mechanism which is still unclear. IGF2 is expressed only from the paternal allele and H19 is expressed only from the maternal allele. Development of this syndrome therefore results from a parallel pattern and timing of expression during foetal life. Parental alleles are differentially marked by DNA methylation during germ cell generation.

Why is it important that levels of extracellular and intracellular calcium are controlled

Extracellular calcium is tightly controlled within a narrow range to allow proper functioning of tissues. Total plasma concentration is 2.4mM and it is important in excitation-contraction coupling, synaptic transmission and platelet aggregation and coagulation. Intracellular calcium is controlled at levels 10,000 fold lower than extracellular calcium. Calcium is an important intracellular second messenger in the regulation of cell division, muscle contraction, cell motility, membrane trafficking and cell secretion. It is also important in the activation of SNARE proteins which are important for exocytosis.

Describe the storage of iron in cells

Ferritin is the key protein for intracellular iron storage and detoxification. Pasma ferritin is sometime a good indicator of body iron stores, but is also an acute phase protein so levels rise with inflammation or infection. This occurs to stash iron away from invading pathogen but low ferritin is however the best marker of iron deficiency. The protective outer shell of ferritin has 24 protein subunits with up to roughly 4500 iron atoms stored in its crystalline core. Smaller amounts of iron can be stored in cells as insoluble haemosiderin.

Write short notes on the unimolecular polypharmacy based on gut hormone receptors

GLP-1 derivates are approved by the FDA for the treatment of diabetes, often associated with obesity. There has been a long term prescription of neuroglutide in diabetic patients and this has been found to also produce weight loss. The drug is currently injectable but oral formulations are being created. Chimeric peptides, which are petites of the glucagon family, act as unimolecular, dual and triple agonists targeting GLP1, GIP and glucagon receptors. Different combinations of peptides have different effects on metabolic parameters. The GLP-1/glucagon co-agonist mostly improves body weight while the GLP-1/GIP co-agonist most improves glycaemic control. The GLP-1/GIP/Glucagon triagonist however has large effects on body weight but also greatly improves glycaemic control, hepatosteatosis and cholesterol levels and therefore has the greatest overall effect.

How do hormones released from the cells of the pancreatic islets regulate food intake and metabolism?

Insulin is released from pancreatic β cells and circulating levels are proportional to body adipose mass. It has a similar central action to leptin in that it reduces food intake and increases metabolism. It acts by binding to the insulin receptors which tyrosine kinase receptors expressed in POMC?CART and NPY/AgRP neurons in the arcuate. Insulin binding stimulates POMC/CART neurons but inhibits NGY/AgRP neurons. Pacreatic polypeptide is released from the PP cells in the islets of Langerhans in response to a meal. Release is in proportion to the caloric intake. It can then bind the g-protein coupled Y4 receptors in the NTS of the brainstem and the arcuate and PVN of the hypothalamus. It may also act avia the vagus nerve. Like insulin, it acts to reduce food intake and increase metabolism.

How are phosphate levels regulated and what is their effect on calcium?

Phosphate is not strictly regulated like calcium. It is produced from hydroxyapatite crystals. Both FGF23 and PTH promote phosphate excretion by the kidneys. Active vitamin D3 enhances the absorption of phosphate by the kidneys. FGF23 explains the regulatory effect of serum phosphate levels on vitamin D3 metabolism, especially the lowering of the active vitamin D3 levels in blood. PTH acts to prevent hypocalcaemia and therefore promotes phosphate loss.The main role of active vitamin D3 is to promote mineralisation of new bone and therefore increase absorption of calcium and phosphate. Phosphate is secreted by osteocytes in bone to regulate active vitamin D3 levels in the kidney and thyroid. There is therefore an inverse relationship between phosphate levels and the amount of active vitamin D3.

How do leptin levels alter bone mass?

Plasma levels of leptin reflect total white fat mass. Leptin inhibits feeding through action in the hypothalamus via POMC neurons and it also inhibit insulin secretion. Ob/ob knock-out mice lack leptin. The action of the brain upregulates sympathetic tone. The sympathetic nervous system acts via β2 adrenergic receptors on osteoblasts to increase EPS expression in osteoblasts which, in turn, inhibits osteoclastic activity and therefore bone formation and also osteocalcin release. Mice lacking this receptor in the osteoblasts are hypoglycaemic and hyperinsulinemic as ESP cannot be made and osteocalcin activity cannot be inhibited. Ob/ob mice lacking an osteocalcin gene have normal insulin levels for longer when compared to wildtype.

Describe the cause and symptoms of Prader Willi syndrome

Prader Willi syndrome is a rare disorder related to an abnormality on the 15th chromosome. It occurs in males and females equally and in all ethnic groups. The incidence is between 1 in 10,000 and 1 in 25,000 live births. It typically causes low muscle tone, short stature if not treated with growth hormone and an incomplete sexual development. It is also associated with a chronic feeling of hunger and a down-regulated metabolism. This can result in excessive eating which can lead to life-threatening obesity.

Name the two parts of the pituitary gland and explain their different developmental origins. What cell types are found in each?

Rathke's pouch grows up from the oropharyngeal ectoderm (roof of the mouth) to form the anterior pituitary. The infundibular process grows down from the forebrain vesicle to form the posterior pituitary. The portion of Rathke's pouch in contact with the posterior pituitary froms the intermediate. The lobe remains intact in some species but in humans its cells becomes interspersed with those of the anterior pituitary. The posterior pituitary is formed by the axons and terminals of the magnocellular neuosecretory neurons originating in the hypothalamus. The posterior pituitary largely consists of the para nervosa which is the storage site of oxytocin and vasopressin. It includes the Herring bodies which are the neurosecretory terminals and pituicytes which are specialised glial cells that assist in the storage and release of hormones. See handwritten notes for a table

What is stress?

Stress is any change/event that either disrupts or threatens to disrupt homeostasis to an unusual degree. It is therefore any change that threatens a negative rewards. A stressor can be almost any severe disturbance and acute stressors can be physical such as extreme heat/cold, blood volume depletion, hypoglycaemia, toxins from infection or sleep deprivation. They can also be psychic in the from of anything that causes a fear reaction. Chronic stressors however may be obvious or more subtle and include chronic infections, finantial worries, difficulties at work or martial problems. The complexity of the human cerebral cortex means that, unlike most animals, some humans may be stressed by some situations that do not affect others such as phobias. If any stress is sufficient, it can trigger a general adaptation stress response. This involves many body systems and is largely independent of the stressful stimulus.

Write short notes on the structure and function of the posterior pituitary

The posterior pituitary is a collection of axonal projections from the hypothalamus that terminate behind the anterior pituitary and serve as a site for the secretion of oxytocin and vasopressin directly into the blood. It consists mainly of the neuronal projections of magnocellular neurosecretory cells extending from the supraoptic and paraventricular nuclei of the hypothalamus. These axons store and release neurophysial hormones oxytocin and vasopressin into the neurohypophyseal capillaries and from there they get back into the systemic circulation. The pars nervosa is the region that constitutes the majority of the posterior pituitary and is the storage site of oxytocin and vasopressin. It includes the Herring bodies which are the neurosecretory terminals and the pituicytes which are specialised glial cells that assist in the storage and release of hormones. The infundibular stalk bridges the hypothalamic and hypophyseal systems.

Summarise the control of pituitary gonadotrophin (LH and FSH) release in males

The principal regulator of LH and FSH secretion is the gonadotropin-releasing hormone (GnRH), a ten amino acid peptide that is synthesised and secreted from the hypothalamic neurons and binds to receptors on the gonadotrophs. GnRH stimulates secretion of LH, which stimulates gonadal secretion of the sex steroid testosterone. In a classic negative feedback loop, sex steroid inhibit secretion of GnRH and also appear to have direct negative effects on gonadotrophs. This regulatory loop leads to a pulsatile secretion of LH and, to a much lesser extent, FSH. The number of pulse of GnRH and LH varies from a few per days to one or more per hour. Lack of LH or FSH pulses would cause infertility. FSH also stimulates Sertoli cells to produce inhibin which provides negative feedback to the anterior pituitatry to decrease FSH secretion. See handwritten notes for diagram

Describe the regulation of thirst

The regulation of thirst can occur at the cellular level due to cellular dehydration stimuli which include hypertonic NaCl and hypertonic glucose which both elicit drinking. It is also regulated by receptors in the anterior hypothalamus/preoptic area and subfornical organ. Lesions abolish hypertonic NaCl-induced drinking whereas local infusion of hypertonic NaCl elicit drinking behaviour. Infusions of hypertonic sucrose also elicit drinking while lesions of the SFO prevents drinking. 24 hour water deprivation raises plasma osmolarity from 280 mOsm/l to 290 with the osmotic threshold for stimulation of thirst being only 2-3 mOsm/l . Stimuli which cause thirst also switch on ADH to conserve body water. Angiotensin II is a very potent stimulus to drinking. Low pressure receptors induce thirst via vagus (x) and NTS projections to hypothalamus. Drinking is maintained by reward as the hypothalamic and orbitofrontal neurons respond to the taste of water if thirsty. We do not need a change in plasma osmolarity before we stop drinking therefore preabsorptive mechanisms must be important for thirst satiation.

Write short notes on the acute alarm reaction

The short term stress response is counter-homeostatic to prepare the body to meet an emergency situation. It has evolved in order to allow the individual to survie the emergency and return to normal homeostasis when the stress is no longer present. This acute alarm reaction involves hypothalamic control by activation of CNS outputs which involves neurohormones controlling the pituitary which has actions on the respiratory centre for example to produce the arousal reaction. It also activates the sympathetic nervous system which can have whole body effects depending on the terminals of the nerves. Finally the adrenal medulla can also be activate to have widespread effects via the action of adrenaline and some noradrenaline. The responses are immediate but can be relatively short-lived. They mobilise the body's resources for immediate physical activaty and cause arousal of the cerebral cortex.

How does the hypothalamus regulate circadian rythms?

The suprachiasmatic nucleus is responsible for producing circadian rythms which control the sleep-wake cycle, feeding, temperature control and hormone release. It receives direct input from light-sensitive melanopsin ganglion cells in the retina through the retinohypothalamic tract. This cells are activated by a phototransduction cascade similar to the invertebrate one which involves TRPC channels. Repeated jet-lag exposure and rotating shift work increases the risk of life-style related diseases such as cardiovascular problems and metabolic insufficiencies. This is due to the mismatch between the SCN clock signals and environmental cues. Knockout of the vasopressin V1a and V1b receptors causes resistance to jet lag in mice.

Write short notes on the roles of the ventromedial hypothalamus and the lateral hypothalamus in the control of appetite

The ventromedial hypothalamus is an additional direct leptin-sensing centre with stimulation decreasing food intake. It is associated with satiety which was shown by VMN lesions causing hyperphagia in rats. When activated it would produce the feeling of having had too much. More than the mere absence of hunger, this would be a drive to avoid further consumption of food, even if it continued to taste good. The lateral hypothalamus however is thought to function as a hunger centre with lesions resulting in aphagia. When the LH is activated, the individual feels hungry and becomes motivated to seek out and consume food.

Write short notes on intrauterine growth retardation

Nutritional restriction leads to decreased endocrine and paracrine IGF1. This results in a resetting of the foetal development to accommodate the nutritionally deprived environment. Insulin, IGF1 and GH resistance results in slower growth rate and a smaller, but otherwise normal baby with reduced nutritional demands

What are the metabolic adapatations to short term fasting?

In short term fasting, there are very limited glucose stores and some obligatory requirements for glucose but there are also unlimited fat stores. To maintain blood glucose for the essential needs, there is an increased use of fatty acids and ketones. There is also increased production of glucose from glycerol, lactate and amino acids as well as reduced glucose utilisation, especially by the brain. This minimalizes the need to mobilise body protein as an energy source. The main hormonal control of this are increase glucagon and corticosteroids as well as decrease insulin.

Draw a diagram to show how insulin is secreted. Provide one example of an oral hypoglycaemic drug

Sulfonylureas - inhibit K+ channel leaking to reduce K+ efflux See handwritten notes for diagram

How does vitamin D3 inhibit PTH synthesis?

Increased serum levels of calcium leads to an inhibition of PTH secretion. Activation of the calcium sensing receptor by increased calcium levels causes the generation of arachidonic acid metabolites which inhibit the release of PTH. These also increase expression of VDR increasing the cells sensitivity to the negative feedback exerted by active vitamin D.

How does inflammation relate to obesity?

Obesity is associated with chronic inflammation in adipose tissue, and to a less extent, other organs. It is metabolic in origin as it is induced by nutrients including saturated fatty acids. The inflammation is of a moderate severity, is low grade and is local. It also involves a wide range of inflammatory cytokines.

Give two examples of disorders that affect adrenal medulla function

Phaeochromocytoma is caused by a tumour arising from chromaffin cells. This results in uncontrolled secretion of adrenaline and noradrenaline. It produces symptoms that include hypertension and tachycardia. These are however rare and usually found post-mortem in the elderly. Another disorder is adrenal medulla exhaustion which causes autonomic failure as plasma adrenaline falls. This results in a profound fall in blood glucose, loss of vascular tone and a profound fall in blood pressure. In extreme cases it can result in renal failure and death.

How does cellular uptake of iron occur?

Target cell such as erythroid cells express the cell surface transferrin receptors TfR1, which bind and internalize the Fe(III)-transferrin complex. Liver cells also express TfR2 which may be important in sensing iron availability. Iron uptake forms an endosome which is acidified.

What is the structure of the hypothalamus?

The hypothalamus is a structure derived from the diencephalon. It makes up the base of the forebrain and forms the floor and ventral walls of the 3rd ventricle. It makes up 0.3% of the total mass of the brain.

Compare and contrast the hormones ACTH and cortisol. What are the consequences of dysregulation of these hormones?

ACTH is a polypeptide tropic hormone produced and secreted by the anterior pituitary. ACTH related to the circadian rhythm in many organisms and is an important component of the HPA axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol by the cortex of the adrenal gland. Cortisol however is a steroid hormone produced by the zona fasciculata of the adrenal cortex in the adrenal gland. Like ACTH it is released with a diurnal cycle and release is increased in response to stress and low blood glucose concentration. Unlike ACTH, it acts to promote gluconeogenesis, to supress the immune system and also to decrease bone formation. Dysregulation of ACTH such as in a hypopituitarism can directly dysregulate cortisol levels and lead to a secondary adrenal insufficiency for example. Addison's and Cushing's disease are diseases related to dysregulation of cortisol secretion from the adrenal cortex. These can however be caused by ACTH dysregulation. A lack of cortisol, as in Addison's can cause hypotension, anaemia, muscle weakness and poor bone growth. Excess cortisol such as in Cushing's disease however will cause hypertension, polycythaemia, osteoporosis, muscle weakness and an abnormal fat distribution.

How is vitamin D3 formed, converted to its activated product and regulated?

Active vitamin D3 is formed by exposure to sunlight and dietary intake of animal base cholecalciferol or plant-based ergocalciferol. In the plasma, it is bound to the vitamin D binding protein, DBP. In the liver, it is hydroxylated at the C25 position to give 25-hydroxyvitamin D3 which is the major circulating vit D3 derivative. This reaction is catalysed by cytochrome P450 dependent hydroxylase, CYP27R1, localized to microsomes. Active vit D3 is made in the kidney catalysed by 1α hydroxylase . The kidney is the only endocrine organ that produces 1,25 vit D3, in reponses to calcium and phosphate regulating hormones. Vitamin D controls its own negative feedback through transcriptional regulation of 1α hydroxylase. VDR down regulates expression of this enzyme through a negative response element in its promoter region.

What is acylation stimulating protein, TNF-α and adiponectin?

Acylation-stimulating protein is a derivative of complement factor 3 and acts locally on adipocytes to increase triglyceride formation by increasing glucose uptake and triglyceride synthesis. It therefore has an additive effect with insulin. It also suppresses lipolysis and fatty acid release and levels are increased in obese humans and fall after fasting which results in weight loss. The regulatory role of ASP may be lost as a result of metabolic disturbances in obesity and diabetes as increased levels do not counteract metabolic abnormalities TNFα acts locally to inhibit lipogenesis and increase lipolysis. It may act as a feedback loop to limit excessive triglyceride storage. It partially blocks insulin signalling via interference with intracellular signal transduction pathways and decreased expression of GLUT4 transporters. It is produced in obese humans mainly by adipose tissue macrophage infiltrates. Adiponectin is a large protein which is related to TNFα and collagen. It reduces hepatic glucose production and increase muscle glucose utilisation. Levels are reduced in obesity but are increased by thiazolidenediones such as agonists of PPARγ. There may be a mechanism by which these agents increase whole body insulin sensitivity.

Write short notes on the origin and mechanisms of action of two hormones that modify potassium homeostasis

Aldosterone is a steroid hormone produced by the cortex of the adrenal glands. It mediates its effect in responsive cells by binding cellular nuclear receptors which are then stimulated to transcribe a variety of specific target genes. The most important aldosterone target genes are a NaK ATPase which is typically directed toward the basolateral surface of the response cell and a potassium channel which is typically directed toward the luminal surface of the responsive cell. This allows it to stimulate sodium reabsorption and potassium secretion by principal cells of the late distal tubule and collecting duct and thus contribute to potassium homeostasis. Insulin however is a peptide a hormone that is released from the beta cells of the pancreatic islet. It acts to increase the permeability of many cells to potassium, magnesium and phosphate ions. The effect on potassium is clinically important. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentration

What is the role of the hypothalamus in thermoregulation?

Alert consciousness and patterned motor activities only occurs when the CNS temperature is 36-39oC. The hypothalamus can stimulate thermogenesis which results in shivering, piloerection, skin vasoconstriction and other behaviours that increase body temperature or minimise heat loss. The hypothalamus can also stimulate heat loss through the actions of sweating and skin vasodilation as well as behaviours that promote body temperature cooling. Controlled elevation of body temperature in a fever reduces pathogen viability and boosts immune system function. Lesions to the anterior hypothalamus causes hyperthermia as here there are endogenous temperature sensors which are warm-sensitive neurons. The temperature set-point can be changed by pyrogens through PGE2 acting on EP3 receptors. This causes an elevated core temperature. Lesions to the posterior hypothalamic area however cause hypothermia. This is responsible for a dilation or contraction of the cutaneous circulation and the control of sweat glands. It also receives cutaneous temperature information. There are two current models for the central temperature sensor with the first being that heat directly opens ion channels that depolarise the neurons and result in action potential firing. This is the same principal as peripheral temperature sensing through TRP channels. The other model is that heat indirectly promotes depolarisation as increased K+ channel inactivation at a high temperature results in decreased hyperpolarisation due to loss of K+ so the background depolarisation can now effectively depolarise the cell to threshold levels for action potential firing.

What is the effect of pH levels and protein concentration on plasma calcium?

Alkalosis increases the negative charge on plasma proteins. This means that more calcium binds to the protein and as a result plasma calcium falls. This produces a hypocalcaemia tetany. Acidosis however decreases the negative charge of plasma proteins which means that less calcium binds to proteins. This results in a hypercalcaemia in the blood. Normally, 45% of total plasma calcium is associated with protein. Excess protein is produce in multiple myeloma which is a tumour of plasma cells in the bone marrow that therefore reduces free calcium levels. Loss of protein occurs in nephrotic syndrome and this therefore increases free Ca2+.

Write short notes on the endocrine cell types of the pancreatic islets of Langerhans, other than the beta cell, and the actions of the hormones produced

Alpha cells makes up 20% of the human islet cells and are responsible for synthesising and secreting the peptide hormone glucagon which elevates the glucose levels in the blood. It does this by binding to receptors on hepatocytes and some other cells to activate glycogen phosphorylase and promote glycogenolysis. In rodents alpha cells are located largely at the periphery but in humans there is a more random distribution. Delta cells produce somatostatin and are also found in the periphery of rodent islets but in a less well organised fashion in humans. Somatostatin is an inhibitory peptide hormones that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with its G-protein coupled receptors. It therefore inhibits insulin and glucagon secretion in a paracrine fashion. The pancreatic islets also have a small number of epsilon cells which produce ghrelin, a hormone which increases hunger prior to consumption of a meal. Finally PP cells produce pancreatic peptide which self-regulates pancreatic secretion activities and also has effects on hepatic glycogen levels and gastrointestinal secretion.

Write short notes on genetic obesity syndromes

At least 10% of children with severe obesity have chromosomal abnormalities, nonsense mutations or missense mutations that strongly determine obesity. Those that occur without developmental delay include leptin or leptin receptor deficiency. There can also be a POMC deficiency which results in severe early-onset obesity, adrenal insufficiency and red hair pigmentation. This can however be treated with recombinant hormone therapy. MC4R deficiency results in hyperphagia, accelerated linear growth, increased bone density, adipose and lean tissue mass. KSR2 mutations are associated with obesity, insulin resistance and impaired cellular fuel oxidation. Finally prohormone convertase-1-deficiency results in defective prohormone processing which leads to abnoral glucose levels, very low insulin levels and elevated plasma pro-insulin and pro-POMC concentrations as well as them being hypogonadotropic. Obesity syndrome with developmental delay is caused by Prader-Willi syndrome which results from a deletion or disruption of a paternally imprinted region of chromosome 15. It leads to hypotonia in infancy, hyperphagia, ghrelin levels 4.5-fold higher than weight matched controls, hypogonadism and small hands and feet. They also have a growth hormone deficiency therefore GH treatment decrease body fat and increases liner growth, lean mass, fat oxidation and energy expenditure.

What is BMR and what factors affect it?

BMR is the minimum calorific requirement needed to sustain life in a resting individual. It is therefore the amount of energy your body would burn if you slept all day. It is a major contributor of total energy expenditure whether you are resting or working. It can be affected by many factors with aging lowering it, tall and thin people having a higher metabolic rate as well as it being increased during growth so children and pregnant women have a higher BMR. Fasting/starvation lowers BMR as well as fat while lean muscle increases it. BMR can also be raised by the cold because if BMR increases, heat production also increases. The cellular reactions that make up BMR sustain ventilation and circulation in minimal state and maintain a stable core body temperature. They do this by increasing ATP usage and reducing efficiency of ATP synthesis by increasing the expression of uncoupling proteins to a large extent in skeletal muscle and brown adipose tissue.

What is the result of bariatric surgery?

Bariatric surgery results in a perioperative calorie restriction with a doubling of hepatic insulin sensitivity. It creates an unretarded passage of nutrients into the small intestine. An abnormally high exposure of the distal small intestine, which has high L-cell density, to digested nutrients and secretions results in an exaggerated release of GLP-1 and PYY. The final result of this is weight loss with time and diabetes resolution in about 50%.

How is bone resorption and formation matched?

Bone resorption by the osteoclasts takes about 3 weeks while bone formation by osteoblasts takes 3-4 months. 5-10% of bone is remodelled each year which means that the skeleton is replaced once every 10 years. The need for remodelling is recognized at a site where the lining cell is separate from bone to form a raised canopy over the site. New bone formation therefore occurs at bone resorption sites in each bone remodelling compartment. In the bone matrix TGF-β1 and IGF1 act as the primary coupling factors and are released in response to osteoclastic bone resorption. TGF-β1 and IGF1 induce the migration of osteoblastic cells so that the new bone formation is spatiotemporally coupled with resorption through this mode of matricellular signalling. RANK-RANKL mediates communication to induce differentiation of osteoclast progenitors. Sema4D is secreted from osteoclasts and regulates osteoblast differentiation. Osteoclastic production of Sema4D is stimulated by increased osteoblastic RANKL. Sema4D then inhibits osteoblast differentiation to balance the supply of osteoclasts and osteoblasts, thus functioning in a negative feedback loop.

How could obesity be tackled?

Brown adipose tissue provides the thermoregulation of mammals by burning calories and it has recently been found that this is also true for adult humans. The amounts of detectable brown adipose tissue is inversely correlated with age, BMI, fat mass and insulin sensitivity. BAT activity is under direct sympathetic control and is activated following exposure to a cold environment. Evidence suggests that white adipocytes may be turned into brown (beige) adipocytes. Studies have shown that exposing individuals to cold environments leads to BAT activation and therefore weight loss but this may not be very safe. It has also been found that microbiota are different in lean and obese individuals. This was shown that gut microbiota from twins discordant for obesity modulate metabolism in mice. Lean microbiota produce more short-chain fatty acids and digest more of the plant fibre. Short-chain fatty acids inhibit fat accumulation in adipose tissue, raise energy expenditure and enhance production of satiety signals. Fecal transplants could therefore be used to treat obesity as they have already been used to treat a number of distinct ailments. Transfer from lean to obese individuals to the obese has improved insulin sensitivity in some but not all obese patients and is also very risky as can transfer pathogenic microbiota.

Explain, giving example, the cellular and molecular effects of circulating catecholamines

Catecholamines exert their effects via two classes of receptors, α and β. Adrenergic receptors interact with catecholamines on the extracellular side of the plasma membrane, and with G proteins within the cell membrane. Stimulation of the α class of receptors by norepinephrine results in vasoconstriction, blood pressure elevation, pupillary dilatation and bladder sphincter contraction. Epinephrine also stimulates α receptors as well as β which results in actions such as vasodilation, acceleration of the heart rate, bronchodilation, glycogenolysis and lipolysis. These actions are part of the physiological response to stressful stimuli. In liver, catecholamines promote glucose output by activating glycogenolysis, accelerating gluconeogenesis and inhibiting glycogen synthesis. Stimulation of adrenergic receptors by catecholamines increases activity of adenyl cyclase and conversion of glycogen phosphorylase from the inactive to the active form. In adipose tissue, catecholamines also stimulate lipolysis by increasing activity of hormone-sensitive lipase, and the cleavage of triglycerides into fatty acids and glycerol for increase gluconeogenesis and energy availability. Some drugs like tolcapone raise the levels of catecholamines.

What are the systemic effects of circulating catecholamines and what intracellular messenger systems do they activate?

Circulating catecholamines are adrenaline and noradrenaline. They increase chronotropy and inotropy by acting on β1 receptors in the heart. It also causes vasoconstriction in most systemic arteries and veins through α1 and α2 receptors. Activation of β2 receptors causes relaxation of smooth muscle such as in the lungs where it results in bronchodilation. Α1 receptors act through the Gq signalling pathway which activates protein light-chain kinase and this stimulates the second messengers of IP3 and DAG. All of the β receptors are Gs coupled and therefore activate adenyl cyclase to increase cAMP levels. Α2 however is Gi coupled which means that it inhibits adenyl cyclase to decrease cAMP production.

How does adipose tissue act as a dynamic buffer of circulating fatty acids and triglycerides?

Control of storage and mobilisation is required to maintain insulin sensitivity. As with glucose, there is only a modest rise in plasma FFA and TG after meals. Distribution of fatty acids between intake and storage and circulation is constantly regulated. After overnight fasting, there is no fatty acid trapping. 1-2 hours after a meal, 90% of fatty acid is trapped. Control is mediated through fatty acid release, clearance of chylomicron and VLDL triglyceride, and VLDL production in the liver

Write short notes on cortisol

Cortisol is a glucocorticoid hormone produced by the zona fasciculata of the adrenal cortex within the adrenal gland. It is release in response to stress and low blood glucose. Blood levels of cortisol vary throughout the day following a diurnal rhythm. The secretion of cortisol is mainly controlled by the interaction of the hypothalamus, the pituitary and the adrenal gland which is called the HPA axis and has a negative feedback control. Cortisol functions to increase blood sugar through gluconeogenesis, suppress the immune system and to aid in the metabolism of fat, protein and carbohydrate in the liver and peripheral tissues. It also decrease bone formation. Cortisol increases the sensitivity of blood vessels t vasoconstrictors and prevents increased capillary permeability as well as maintaining the contractility of cardiac muscle. Prolonged elevated levels of cortisol however can lead to Cushing's syndrome.

In what way does the skeleton act as an endocrine organ?

ESP osteoblast knockout mice died perinatally from severe hypoglycaemia which linked bone to insulin for the first time. There is a surge of osteogenesis following head injuries. There has also been found to be an inhibitory effect of leptin on bone formation with a surprisingly high bone mass phenotype in leptin-deficient ob/ob mice. See handwritten notes for diagram

Describe the source, release and actions of gastrin and CCK

Gastrin is a peptide hormone released by G cells in the pyloric antrum of the stomach, duodenum and the pancreas. It is produced from preprogastrin which is cleaved by enzymes in posttranslational modification to produce progastrin and then gastrin in various forms. It is released in response to stimuli including distension, vagal stimulation, digested proteins in the stomach and hypercalcaemia but release is inhibited by the presence of acid or somatostatin. Gastrin stimulates the parietal cells to secrete hydrochloric acid both directly and indirectly via ECL cells. CCK however is a peptide hormone synthesized and secreted by the enteroendocrine cells in the duodenum. CCK is released rapidly into the circulation in response to a meal and therefore the greatest stimulator is the presence of fatty acids and amino acids in the chyme entering the duodenum. The release of CCK is inhibited by somatostatin and pancreatic peptide. CCK has important physiological actions as both a neuropeptide in the central nervous system and as a peptide hormone in the gut. It participates in a number of processes such as digestion, satiety and anxiety.

Describe the regulation of gastrin secretion

Gastrin stimulates gastric acid and pepsinogen secretion and motility. Release is stimulated by protein digestion products (esp tryptophan, phenylalanine) and by the vagus nerve through acetylcholine and gastrin-releasing peptide. It can also be stimulated by distension of the stomach and hypercalcaemia. Release however is inhibited by a stomach pH<2.5 and alkali which has little short term effect but in the long term causes hyperplasia. Somatostatin is released from the δ cells of the stomach and also provides a local negative feedback of secretion. (see Wikipedia page for more)

Describe genomic imprinting and foetal programming

Genomic imprinting is a system evolved in mammals where femals solely support foetal growth and early post-natal development. The mother needs to trade off size of indivduals offspring and number of offspring. Expression of the H19 gene therefore regulates the response to paternal IGF2 to limit its growth stimulatory effect. Programming however involves foetal events leading to abnormal physiological response and predisposing to later diseases. It could be related to altered hormonal sensitivity with a resetting of homeostatic circuits to a different levels. This means that something that happens in development can predetermine disease later on. For example, the writings about the Dutch Famine described how babies born after gestation in this winter had impaired insulin secretion as adults. These were however small effects and there was no consequence on their glucose curves so they were not diabetic.

What is ghrelin and how does it relate to obesity?

Ghrelin is a 28 amino acid peptide secreted by the stomach. It stimulates appetite by activating orexigenic NPY and AgRP neurons in the arcuate nucleus of the hypothalamus via GHS-R1a receptor. It inhibits anorexigenic POMC neurons and its effects involve AMPK. Ghrelin levels rise before meals and is suppressed after meals in proportion to calorie load. Ghrelin levels show an inverse correlation with BMI. It therefore has both reduction in concentration and reduced sensitivity to action in obese subjects. Post-prandial suppression of ghrelin secretion is also reduced in the obese. In Prader-Willi syndrome Ghrelin levels are 3-4x higher than weight-matched controls the peripheral effects of Ghrelin include decreased glucose-stimulated insulin secretion, impaired glucose tolerance and enhanced gluconeogenesis. It also results in decreased use of fatty acids as fuel and increase adipose tissue and bodyweight.

How do ghrelin, PYY and CCK regulate food intake and metabolism?

Ghrelin is the only gastric messenger that stimulates food intake and decreases metabolism. The plasma concentration of ghrelin rises shortly before a meal and falls on feeding. The circulating concentration of this is chronically elevated in people with Prader Willi syndrome. Its receptor is expressed on NPY/AgRP neurons in the arcuate nucleus and therefore the action of ghrelin is abolished in animals with a knockout of these neurons. Ghreli stimulates NPY.AgRP and inhibits POMC/CART neurons beucase the NPY/AgRP neurons make GABAergic contacts with POMC/CART neurons. PYY is produced by the ilium and colon in response to food intake, mainly in the form of fat. It is low in the fasted state and increases following food intake. PYY binds to the G-protein coupled Y receptors in the arcuate nucleus and brainstem to decrease food intake. CCK was the first hormone to be implicated in appetite and increases after a meal. AA high plasma concentration of CCK decreases meal size but increases meal frequency.

Write short notes on the clinical uses of glucocorticoids

Glucocorticoids have an important use in the treatment of inflammatory disorders such as arthritis and asthma. They also inhibit transplant rejection and can be an important anti-growth drug in chemotherapy. Their antenatal use is to mature the lungs in the foetus of women threatening preterm labour by producing surfactant to prevent respiratory distress. They work by decreasing PLA2 and increasing annexin 1 which is an anti-inflammatory protein. The downside of their use however is that cortisol effects multiple systems in the body and therefore can produce unwanted side effects. This means that treatment with cortisol can only be for a short time.

How is glucose sensed and what is its action in the different cell types involved?

Glucose sensing can be achieved by 2 pathways. Metabolism of glucose to produce ATP involves the GLUT2 glucose transporter, glucokinase, KATP channels and AMP-activated kinase. The KATP channels close in response to ATP binding which produces a depolarisation. AMPK is activated when the ratio of AMP/ATP increases. There is also an allosteric modification of enzymes by glucose. Some cells are glucose-excited cells which fire action potentials when glucose rises. They require glucose metabolism for excitation and switching off the KATP channels. It is however unclear If this is the only mechanisms and whether they overlap with POMC/CART. Glucose inhibited neurons however stop firing action potentials when glucose rises. It is unclear how glucose inhibits firing but it is likely to be a mix of pathways which could include activation of Cl- channels and a Na+/K+ pump. It is also unclear if there is overlap with NPY/AgRP neurons. Glucose sensing neurons are found in the LHA, VMN and NTS therefore the arcuate nucleus is not the only glucose sensor.

Write short notes on the determinants of post natal growth

Growth hormone is an important determinant of post-natal growth both via its direct action and via IGF1 and 2, thyroid hormone, and sex steroids. Genetic factors can also be important such as the relationship to mid parental height. Nutrition influences post-natal growth as it is highly dependent on diet and can be severely stunted by malnutrition. This links into the importance of socio-economic factors. Psychological factors also have a key role. In chronic disease such as cardiac failure and respiratory disease, post-natal growth can be altered.

Write short notes on hereditary haemochromatosis?

Hereditary haemochromatosis is a relatively common group of genetic disease characterised by excessive dietary absorption or cellular iron retention. Most of these are due to inadequate hepcidin expression. Type 1 is due to a recessive HFE mutation which results in inadequate hepcidin expression. The C282Y mutation is seen in up to 10% of Caucasians but other genes may also play a role. Type 2 is caused by a recessive hepcidin or hemojuvelin mutation. Type 3 is caused by a transferrin receptor 2 recessive mutation. Finally type 4 is caused by a dominant ferroportin mutation which creates an overactivity that is equivalent to Hepcidin loss. The presenting features of these disorders are due to iron deposition in parenchymal tissues and these include liver cirrhosis, hypogonadism, diabetes, arthropathy of the joints, cardiomyopathy and skin hyperpigmentation. Diagnosis involves blood tests which measure elements such as transferrin saturation and ferritin levels as well as genetic testing and sometimes a liver biopsy. Treatment may include therapeutic phlebotomy or iron chelation which involves compounds being infused to make iron soluble so it can pass out of the kidney.

Write short notes on hormonal abnormalities affecting foetal growth

Hormonal abnormalities can arise from a number of causes including if infants have diabetic mothers. This is the most common endocrine abnormality affecting foetal growth. Maternal hyperglycaemia results in foetal hyperinsulinemia. Increase fetal insulin secrection leads to increased body weight, mainly fat deposits as well as some increase in length and lean body mass. Another hormonal abnormality is pancreatic agenesis which causes neonatal diabetes and this produces a 50% reduction in body weight. Finally, leprechaunism is a failure of the insulin receptor activity which results in sever dwarfism.

Write short notes on the physiology of bone

Hydroxyapatite crystals (HAP) are embedded in the fibrous protein phase of tropocollagen. Tropocollagen assembles as mineralised collagen fibrils with hydroxyapatite crystals forming in the gaps between staggered tropocollagen fibres. Osteoid provides a site for nucleation of hydroxyapatite crystals. The crystals are arranged with their long axis aligned to the long axis of collagen fibres. The collagen fibres therefore align with the crystals to be laid down in a very specific direction. Bone consists of osteoblasts, osteocytes and osteoclasts which all play a role in forming, maintaining and remodelling bone. Remodelling of bone occurs throughout life and is dependent on reabsorption of bone via the osteoclasts over a period of about 3 weeks as well as formation via osteoblasts which is a much slower process that occurs over 3-4 months. The maturation and differentiation of osteoclast is driven by RANK which is activated by RANKL. Osteoprotegerin is a naturally occurring RANKL decoy. Osteoblasts which are never found in close proximity to osteoclasts provide the RANKL for osteoclasts to function. Mechanical stress stimulates bone formation while disuse causes a loss of bone. Osteocytes are osteoblasts that have become trapped in the bone matrix. They sense stimuli such as exercise and transmit this to osteoblasts via gap junction to stimulate new bone synthesis. Oestrogen and testosterone act on osteoblasts and precursors and deficits lead to osteoporosis, especially post-menopausal.

What happens when there is a dysregulation of calcium levels?

Hypocalcaemia occurs when plasma levels of calcium are too low. If it gets below levels of 1.2 mM, it can be very dangerous. It causes nerve hyperexcitability and muscle tetany due to a decrease in the threshold potential. This is because low calcium increase voltage-gated sodium channel activity. Hypocalcaemia is often the result of secondary hyperparathyroidism due to kidney disease. Hypercalcaemia however is the result of high levels of calcium and produces decreased excitability of nerves. It produces painful urinary stones, weakened bones and stomach pains. A concentration greater than 3mM can produce renal failure and a greater than 4mM causes cardiac failure. It is often the result of primary hyperparathyroidism which can occur due to MEN.

What are the neuroendocrine functions of the hypothalamus?

Hypothalamic neurons can act as neuroendocrine cells. The site of hormone release is the pituitary gland either via the anterior or posterior pituitary. Hypothalamic parvocellular neurons secrete releasing or inhibiting hormones into the hypothalamo-pituitary portal veins which carry them to the anterior pituitary. Responsive cells therefore secrete or stop secreting hormones into the systematic circulation as a result. Hypothalamic magnocellular neurons however release hormones directly into systemic veins that drain into the systematic circulation. This occurs through the hypothalamo-hypophyseal tract which contains the axons of the neuroendocrine magnocellular neurons. The magnocellular neurons are large to store a significant amount of hormone

Describe two different types of insulin-like growth factor

IGF1 is the major and the first determinant of foetal growth. It is expressed in all tissues including placenta. Its paracrine effects are as important or more important than endocrine effects. Its bioavailability and levels of IGF binding proteins are also important. The main determinants of IGF1 levels in the second half of pregnancy is nutrient status, especially glucose availability and its subsequent effect on foetal insulin release. IGF2 however is the predominant IGF in late foetal blood, but IGF1 has greater biological effect. IGF2 knockout mice have impaired foetal growth. IGF2 appears soon after organogenesis and acts through the IGF1 receptor. Its effects are not mediated through insulin however.

What are the metabolic adaptations to chronic malnutrition?

In chronic malnutrition, it is important to maintain substrate supplies for vital function. Protein synthesis is therefore diverted away from muscle to liver and general growth is suppressed to maximise function. Short term changes are mediated by glucagon, cortisol and insulin while long terms effects on growth are mediated through GH/IGF1 and thyroid hormone. Reduced fasting insulin and subnormal insulin response to a glucose load equates to a slight glucose increase which is related to the increased GH, cortisol and free fatty acids. Increased cortisol gives an increased supply of amino acids from muscle for hepatic gluconeogenesis and protein synthesis. This means that chronic malnutrition results in a relatively greater depletion of muscle than other tissues.

Write short notes on insulin resistance in obesity and lipodystrophy/lipoatrophy

In obesity, suppression of free fatty acid release by insulin is reduced. Activation of lipoprotein lipase is reduced. Increase insulin is insufficient to normalise adipose tissue metabolism. Buffering is ineffective and post-prandial free fatty acids and tryglycerides rise as adipocytes become full and resist further storage. Increased systemic lipid delivery leads to accumularion of TG in muscle, liver and β cells of the pancreas. This lipotoxicity results in insulin resistance and in β cells, eventual failure of insulin secretion. In lipodystrophy/lipoatrophy, there is insufficient fat tissue to buffer fluctuations in plasma lipids the consequences are the same.

How is the hypothalamus osmosensitive?

Intrinsically osmosenstivie neurons in the OVLT, SFO, and NTS directly project to the surpraoptic and paraventricular nuclei. Most cells do not behave in this way but in osmosensitive cells, a change in osmolarity causes the cell swelling or shrinking which results in increase or decreased stretch of the plasma membrane. This stretch can gate non-selective ion channels which are called TRPV channels. TRPV1 opens in response to hypertonic stimuli via an N-terminal variant whereas TRPV4 opens in esponse to hypotonic stimuli through an indirect effect. TRPV1 knockout mice lose the ability to fire action potential in response to hypertonic solutions and ADH release is impaired. TRPV4 knockout mice drink significantly more when infused with the ADH-analogue dDAVP than wildtype. Increased blood osmolarity therefore causes osmosensitive neurons to shrink which oepns TRPV1 channels and causes depolarisation which eventually leads to firing of the OVLT neurons in a graded response. These neurons make monosynaptic glutamatergic contacts with supra-optic nuclei neurons. This promotes firing of ADH releasing neurons and hence ADH release. As these neruons are also intrinsically osmosensitive the firing rate of these neurons is therefore dependent on central and peripheral inputs as well as their own intrinsic osmosensitivity.

What are the causes of iron deficiency?

Iron deficiency can be caused by inadequate dietary intake but this is actually relatively rare as not much iron is taken up from the gut. Another cause is a malabsorption such as in coeliac disease where there is a problem with the duodenum which means it loses its brush border. Excessive use of iron such as in pregnancy or growth can also reduce iron which means that it is important to screen Hb levels in pregnancy. Hookworm infection reduces iron and is common worldwide. Blood loss is key in iron deficiency and this can be from blood donation or menstrual loss in young women which is a more powerful cause of anaemia than lack of iron uptake. Gastrointestinal bleeding is a less obvious causes in which one can lose small amounts of blood over a long time without noticing. Unexplained iron deficiency can therefore suggest an underlying more serious health problem.

What causes iron overload?

Iron overload can be caused by a primary genetic disease such as maemochromatosis. It is also seen in alcoholic cirrhosis in which there is an excess deposition of iron in the liver. Excessive oral intake of iron can cause overload, but this is not common. In some diseases, repeated blood transfusions are necessary, but this can cause iron overload. A final cause of iron overload can be excessive but ineffective erythropoiesis.

What happens in the cellular iron homeostasis?

Iron regulatory proteins (IRPs) coordinate cellular iron uptake and storage by controlling expression of important proteins according to iron levels. When cellular iron rises, IRPs are inactivated, leading to increased ferritin expression, reduced transferrin receptor expression and a protective shift towards iron storage and reduced iron uptake. When cellular iron levels are low, ferritin mRNA translation is inhibited and transferring mRNA is stabilised to encourage iron uptake

What inputs into the hypothalamus influence its response to stress?

It is largely influence by ascending catecholaminergic projections to the NTS which communicates arousal signals. The suprachiasmatic nucleus signals the light/dark cycle and therefore communicates the diurnal pattern of hormone secretion. At the 3rd ventricle of the OVLT, the blood-brain barrier is leaky and therefore this allows the hypothalamus to respond to circulating hormones and osmotic changes as the CRH neurons are close to the 3rd ventricle. The hypothalamus also receives input from the arcuate nucleus which contains POMC and opioids that control feeding. This allows the hypothalamus to respond to the stress of starvation and preserve glucose for the brain. Important inputs from the hippocampus and the amygdala allow cognition, mood, perception and phobias to influence the stress response and memory therefore also contributes to this. In this area there is some glucocorticoid feedback in which cortisol monitors stress inputs through glucocorticoid receptors.

Describe the source, release and actions of LH and FSH

LH and FSH are secreted by the gonadotroph cells of the anterior pituitary and act on G protein receptors coupled to cAMP in the ovaries and testes. Hypothalamically, LH and FSH release is stimulated by hourly pulses of gonadotrophin releasing hormone during reproductive life. Systemically it is inhibited by oestrogen via negative feedback however switch to positive feedback triggers LH surge at ovulation in females. In males however, LH release is inhibited by negative feedback from testosterone and ovarian peptides inhibit FSH. In females, these hormones act to control growth and development of follicles, ovulation, synthesis of sex steroid by the ovary and growth and secretion of the sex steroid progesterone by the corpus luteum. In males, LH control testosterone production by the Leydig cells and FSH stimulates the Sertoli cells and sperm production. Deficiencies of LH and FSH or receptor dysfunction as a result of genetic mutations causes infertility in adult life and lack of sexual maturation in children.

Write short notes on leptin

Leptin is a 167 amino acid peptide produced by adipocytes of white adipose tissue, the circulating levels of which mirror body adipose mass. Receptors of leptin are located in the arcuate nucleus of the hypothalamus. In obesity, a decreased sensitivity to leptin occurs resulting in an inability to detect satiety despite high energy stores and high levels of leptin, this is also why mutations in the leptin pathway can cause obesity. Leptins actions don't act meal to meal but are long term, decreasing food intake, increasing metabolism and inhibiting insulin secretion which allows it to regulate adipose tissue mass through central balance. Outside the brain, in the periphery of the body, leptin's secondary functions are modulation of energy expenditure, modulation between foetal and maternal metabolism and that of a permissive factor in puberty, activator of immune cells, activator of beta islet cells and growth factor.

Compare the general principles underlying the synthesis and release of steroid hormones with those for peptide hormones

Peptide hormones are synthesised in the rough endoplasmic reticulum via transcription of specific mRNA. They are synthesised as larger proteins (prehormones) then cleaved in the endoplasmic reticulum to form prohormones, and finally cleaved in the storage vesicles to form active fragments (hormones). Steroid hormones are synthesised from pregnenolone, a steroid precursor. There is minimal storage of the hormone itself, however large stores of cholesterol esters in the cytoplasm can be rapidly mobilised in response to a stimulus. Steroid hormones bound to plasma proteins also act as a reservoir. Peptide hormones are transported dissolved in the plasma and then diffuse into interstitial tissues at the target site while steroid hormones circulate bound to plasma proteins.

Describe the source, release and actions of leptin

Leptin is a 167 amino acid peptide produced by the adipocytes of white adipose tissue which was discovered by the parabiosis experiments of Coleman as an appetite supressing substance in the bloodstream. Its production is regulated by nutritional status with increased stored triglyceride resulting in greater leptin production. The regulation of leptin production by body fat stores means circulating levels of the hormone mirror body adipose tissue thus, in times of inadequate energy stores leptin levels decrease which enhances appetite and decreases energy use. Leptin is synthesised and extruded into the secretory pathway for release by mass action. Thus, although there is a modest diurnal variation in circulating leptin concentrations, secretion and circulating concentrations depend primarily on the rates of transcription and translation of the leptin mRNA dictated by adipose energy stores. Circulating leptin concentrations therefore vary little on a minute to minute or hour to hour basis. It carries out its action of decreasing long term food intake, increasing metabolism and inhibiting insulin secretion by crossing the blood brain barrier and acting on receptors located in the arcuate nucleus of the hypothalamus.

Describe the origins, mechanisms of release and the actions of leptin and ghrelin

Leptin is a 167 amino acid peptide produced by the adipocytes of white adipose tissue. Its production is regulated by nutritional status with increased stored triglyceride resulting in greater leptin production. Leptin is synthesised and extruded into the secretory pathway for release by mass action. It carries out its actions of decreasing long term food intake, increasing metabolism and inhibiting insulin secretion by crossing the blood brain barrier and acting on receptors located on the arcuate nucleus of the hypothalamus. Ghrelin is a small peptide which stimulates feeding and is produced by stomach parietal cells in fasting conditions. Levels rise 1-2h before a meal and decline to a minimum afterwards. It is a powerful stimulator of feeding by action in the hypothalamus and brainstem

How can the brainstem alter food intake?

Leptin receptors in the NTS decrease food intake while the ghrelin receptors here promote it. PYY3-36receptors on the NTS decrease food intake as do glucose sensing neurons. Gastric distention acts via the vagus nerve to decrease food intake. The brain stem projects to hypothalamus, particularly the arcuate nucleus from which it receives projections.

What are the physiological conseqeunces of a low concentraction of thyroxine in plasma? Name two possible causes.

Low concentrations of thyroxine in plasma leads to hypothyroidism. This produces the physiological consequences which can include lethargy, fatigue, cold intolerance, weakness, hair loss and reproductive failure. If these signs are severe, the clinical condition is called myxedema. The most severe form of hypothyroidism is seen in young children with congenital thyroid deficiency. If not corrected by supplemental therapy soon after birth, the child will suffer from cretinism, a form of irreversible growth and mental retardation. One possible cause of low thyroxine could be iodine deficiency due to the need for iodide to produce T4. Another cause could be as a result of primary thyroid disease which is an inflammatory disease of the thyroid that destroys parts of the gland meaning the follicular cells can no longer produce T4.

What are marasmus and kwashiorkor disorders and how are they are treated?

Marasmus is a more common form of protein-calorie malnutrition which results in a weight that is <60% of the median. It results in muscle wasting but no oedema as well as loss of adipose tissue, heart brain and liver but the liver is least affected. Low blood glucose results in ketosis and they have a reduced BMR as well as plasma insulin level. This condition also results in impaired immunity. Kwashiorkor however results in generalised oedema and areas of altered pigmentation. Children with this condition are withdrawn and will not eat. They also have thin hair which is red, blonde or grey. They also have hepatomegaly with fatty degeneration and diarrhoea. There is reduced albumin and VLDL synthesis as well as reduced plasma branched chain fatty acids. Patients with the condition are not necessarily underweight. The differences between the disorders may be related to a different composition of food. Kwashiiokor is associated particularly with relatively high carbohydrate intake and foods with a very low protein/energy ratio. Carbohydrate stimulates insulin secretion and promotes muscle protein synthesis but at the expense of the liver and other viscera. The disorders are treated acutely by correcting dehydration, electrolyte imbalances, low blood glucose and body temperature as well as treating infection. Re-feeding is important to gradually increase energy and protein intake as well as vitamins. There is usually an improvement after roughly 3 weeks in which they become more mentally alert but are still below body weight. They then catch up growth with adequate nutrition but mortality is still about 20%, even in good hospitals.

How does iron uptake from the diet occur?

Meat and fish contain haem iron while green vegetables, tofu, beans and pulses are rich in non-haem iron. Most dietary iron is found as Fe(III) but is converted to Fe(II) in the gut. Absorption of non-haem iron in the gut is promoted by vitamin C which promotes the conversion from Fe(III) to Fe(II). Total dietary uptake of iron is usually only 1-2mg per day but this can rise when we need more iron. Iron is then taken up by the duodenal enterocytes via the DMT-1 transporter. Following uptake, iron may be stored as ferritin in enterocytes and is subsequently lost via cell shedding or absorbed via the ferroportin transporter. Ferroportin is the only pathway for iron export from enterocytes and macrophages which take up and break down red blood cells to release iron. The body has no pathway for iron excretion so absorption is the key regulatory step in controlling total body iron.

Write short notes on obesity

Obesity is co-morbid with a number of disease including diabetes, cardiovascular disease and hypertension. It is 45-85% genetically determined as we are genetically programmed to eat more than is need for daily output when food is available so that energy reserves can be stored in the body for times when food is scarce. A combination of genetic predisposition, continuous availability of food and reduced energy output are major factors contributing to the fact that 1/3 of the adult population in the UK are thought to be obese. It is likely that obesity is caused by a defence of elevated both weight rather than absence of regulation. The thrifty genotype concept states that we are genetically somewhat resistant to insulin and leptin in higher concentrations. This advantageous when food availability foes in cycles as leptin is not a hormone to prevent obsesity but to prevent starvation as it is set at a level of how much food is needed. It is however disadvantagoues when food is continuously available.

Write short notes on obesity and its models

Obesity is the most pressing health problem in the western world and currently causes roughly 5% of the total health costs. >50% of Europeans between 35 and 65 are overweight or obese and there is a corresponding increase in childhood and adolescent obesity. Obesity is associated with lower educational attainment and lower income. The consequences of obesity include increased risk of hypertension, heart disease, diabetes and some cancers as well as many other ailments. There are two models of obesity. One is that is caused by a lack of dietary discipline as diets fail in the majority of cases. 90% of people return to the original weight after weight loss. Another mode however is that weight is controlled physiologically. With a deviation from the set weight, the system reacts to restore weight towards normal. Family/twin studies and animal models have shown that obesity is 30-50% genetically determined and therefore has a heritability that is comparable to that of height.

How does optogenetics work?

Optogenetics involves an exogenous gene coding for a light-sensitive protein that is selectively expressed in target cells/tissues and illumination is therefore used to modify cell behaviour. Expressing a light-stimulated protein in neurons of interest can lead to the depolarisation or hyperpolarisation of neurons of interest thereby changing its action potential firing ability. Depolarisation occurs in channel-rhodopsin-2 which absorbs blue light and this induces a conformational change that opens the channel pore of this non-selective cation channel. Hyperpolarisation occurs in Halorhodopsin which absorbs yellow light and uses its energy to pump Cl- into cells. Optogenetics is therefore used to study the role of neurons in neuronal circuits and ultimately behaviour.

What are the peripheral and central effects of oxytocin and vasopressin?

Oxytocin is a pulsatile hormone therefore hormone replacement must be given in a diurnal rhythm for them to work well. The peripheral effect of oxytocin is that it produces the contraction of the uterus in labour. It is also responsible for the ejection of milk during lactation. Nipple stimulation therefore goes to the hypothalamus and increases the production of oxytocin. The peripheral effects of vasopressin are involved in controlling water balance and blood pressure. These hormones in females have an important role in maternal behaviour. In males however they are important for courtship, aggression, territorial defense, paternal care of the young and pair bonding.

Describe stem cell research for diabetes

Pancreatic β cells display functional heterogeneity. This means that they differ in size, glucose responsiveness, insulin secretion and precursor cell potential. Recent work subdivides β cells into two subpopulations and distinguishes proliferation-competent from mature β cells with distinct molecular, physiological and ultrastructural features. These advances might enable targeting of endocrine subpopulations for the regeneration of functional β cell mass in diabetic patients.

Write short notes on the origin and mechanism of action of three hormones involved in plasma calcium homeostasis

Parathyroid is synthesised, stored then released from the chief cells of the parathyroid glands and is released in response to a decrease in plasma calcium levels. It binds the PTHR1 receptor which is G protein coupled and found in bone and kidney. In bone it stimulates calcium release through activating osteoclasts and in the kidney it increase the reabsorption of calcium back into the blood. Calcitriol is produced from vitamin D3 and is hydroxylated to the active form in the kidney. Its role is to enhance the absorption of calcium in both the gut and kidney by upregulating important transporters and proteins including calbindin which facilitates calcium transfer through the gut. Finally, calcitonin is synthesised from a precursor produced by the parafollicular cells of the thyroid and is produced in response to increased circulating calcium levels. The physiological importance of calcitonin remains unclear because PTH is more potent so the changes produced by calcitonin could be offset by this and in a thyroidectomy, calcitonin replacement is not required. It could however have a protective function for bone in cases such as pregnancy where excessive bone resorption could be harmful.

What is leptin and how does it relate to obesity

Secretion of leptin is proportional to body fat content. It has central effects by acting on the hypothalamus which is mediated by the activation of POMC neurons and inhibition of NPY neurons. The peripheral effects is that it influences insulin secretion and action as well as energy metabolism in adipocytes and muscle. Fasting leptin level is proportional to body fat mass but circulating level falls on decreased energy intake to a much greater degree than expected from any decrease in adiposity. It's response is to increase energy intake long before body stores are compromised. The normal physiological role of leptin is to stimulate energy intake in response to need, not to restrain intake in obesity. Insulin promotes leptin secretion by adipocytes and is found at peak concentration 4-5 hours after meals. Primary leptin and leptin receptor deficiencies are extremely rare but result in morbid hyperphagia. Defects in leptin signalling pathway in the hypothalamus involve POMC neurons and melanococrtin-4 receptor. These also cause gross obesity. M4R mutations however are relatively common and do not always result in obesity. Heterozygotes for leptin deficiency are obese with relatively low leptin for their but leptin levels are usually increased in obesity as a result of leptin resistance. Diet induced weight loss results in lowering of leptin, stimulates eating and subsequent weight gain.

Draw a diagram to summarise calcium regulation

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Draw a diagram to summarise the differences between type 1 and type 2 diabetes

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Draw a diagram to summarise the osteoblast and osteoclast feedback loops

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Illustrate how the level of intracellular calcium is regulated

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Summarise the integration of the skeleton in mineral and energy homeostasis

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Draw an annotated figure of the cellular structure of the thyroid gland

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Write short notes on the HPA axis and the effects of glucocorticoids on body and brain

See handwritten notes for diagram HPA axis cortisol is switched on immediately in stress but acts slowly. Has genomic action with 10% of genes being regulated. In the body, it produces gluconeogensis in the liver, accelerates lipid and protein catabolism in the liver and peripheral tissues, increases red blood cell production and maintains circulation. It also reduces the inflammation and the immune response but can produce infertility. |n the brain, it produces reduced GnRH secretion from the hypothalamus to avoid the risk of pregnancy, a further drain on resources. It also effects appetite and glucocorticoids act on GR to modify emotional reactions such as inducing mild euphoria to diminish psychic effects of stress. This is beneficial in trauma and can reduce PTSD. Finally, it has been found to promote postsynaptic spine formation in the mouse cortex after motor skill learning.

Write short notes on i) the cell types of the anterior pituitary ii) the control of anterior pituitary hormone secretion

See handwritten notes for part i The endocrine cells of the anterior pituitary are controlled by regulatory hormones released by parvocellular neurosecretory cells in the hypothalamic capillaries leading to infundibular blood vessels, which in turn lead to a secondary capillary bed in the anterior pituitary. This vascular relationship constitutes the hypothalamo-hypophyseal portal system. Overall hypothalamic control is stimulating for all anterior pituitary hormones except PRL. The pulsatile release of hypothalamic stimulating factors stimulates pulses of anterior pituitary hormones. The systemic hormones produced also provide a negative feedback control and there are paracrine interactions within the anterior pituitary.

What are some of the complications that can occurs from diabetes and what causes them?

Some of the complications of poorly managed or long terms diabetes include gangrenous foot with foot and leg ulcers that are caused by poor blood and nerve supply which means that capillaries thicken so nutrients can't cross. Neuropathy can also occur, particular in the retina which leads to blindness. As well as this, patients also suffer with kidney damage and renal failure is the primary cause of death in diabetics. This is because podocyte damage and apoptosis result in glomerular filtrate break-down meaning albumin can be detected in urine. All these conditions result from glycation of proteins in the presence of high plasma glucose, resulting in damage and ultimately apoptosis of cells. Glycated haemoglobin (HbA1c) is a form of haemoglobin that is measured to identify the average plasma glucose concentration over prolonged periods of time. HbA1c is formed in a non-enzymatic glycation pathway as a result of haemoglobins exposure to plasma glucose. In diabetes mellitus, higher amounts of glycated haemoglobin indicates poorer control of blood glucose levels over the test period. Glycation is a haphazard process that impairs the functioning of targets, whereas glycosylation occurs at defined sites and is required for correct function. Long-lived cells and long-lasting proteins may accumulate substantial damage over time and is the cause of many complications observed in diabetic patients.

Write short notes on the determinants of prenatal growth

Substrate delivery from the mother is the most important factor in determining prenatal growth. Embryo transfer experiments in multiple pregnancies have shown that placenta is the limiting factor in this. Intra-uterine growth retardation therefore results from placental malfunction which can be caused by maternal hypertension, placental disease or maldevelopment and maternal infection, drug ingestions and smoking. This results in a disproportionate pattern of impaired growth with slow catch-up rate after birth. Another determinant is hormonal control but the main growth promoting hormones of postnatal life appear to have little role as shown by growth hormone deficient, anencephalic, hypothyroid foetuses being near normal size at birth. Important pre-natal growth hormones are therefore insulin-like growth factors, insulin and placental growth hormone. Placenta is both a source of IGFs and their binding proteins and a target for IGF action. These determine the partitioning of nutrients from mother to placenta to foetus. Foetal pancreatectomy results in profound IUGR with low levels of IGF1 while maternal starvation results in low IGF1 and can be relieved by infusion of glucose insulin. Levels of growth hormone are very high in the foetus but they have few receptors in peripheral tissues. It is therefore thought that GH-v from placenta is transported into the maternal circulation where is suppresses maternal pituitary GH release and may regulate maternal IGF1. Insulin also has effects apart from stimulation of IGF1 such as promoting deposition of adipose tissue.

Write short notes on diabetes mellitus

Symptoms of diabetes is a marked increase in urine output with a urine that contains raised amounts of glucose. It is a disease caused by a lack of insulin and there are two different types with type 1 being a complete lack of insulin as a result of a destruction of the β cells whereas type 2 is a severe insulin resistance with a collapsing of β-cell function but some insulin remains. Normal fasting plasma glucose is 3.5-5.5 mM and diabetes is diagnosed when this is over 7.0 mM. It can also be tested for with a glucose tolerance test with a 250ml oral dose of glucose that would naturally be cleared in 2 hours but in diabetics glucose levels remain greater than 11.1 mM after 2 hours. Type 1 diabetes is caused by an immune destruction of β-cells whereas type 2 is observed as a metabolic syndrome in obese patients that impairs β cell function and reduces insulin signalling. Mutations in KATP channels are responsible for neonatal diabetes. Maturity-onset diabetes of the young has been linked to mutations of 6 different genes involved in β cell metabolism.

What are the functions of the hormones made by the thyroid gland?

The 2 main thyroid hormones are T3 and T4, the secretion of which is controlled by thyroid stimulating hormone, which is released from the pituitary gland. T4 is metabolically inactive and converted to active T3 by deiodinase. T3 acts on nearly every tissue and increases basal metabolic rate, oxygen usage and heat production via increased production of the Na+/K+ ATPase. T3 acts by increasing production of myosin, β1 adrenergic receptors and Ca2+ ATPase which increase contractility and result in increased cardiac output, rate and force. The thyroid also secretes calcitonin by the parafollicular cells which is involved in blood calcium and phosphate level regulation which are both involved in the formation of bones. Calcitonin reduces calcium levels in the blood by inhibiting osteoclast activity and thus reducing the relase of calcium from bones into the bloodstream and decreasing the reasorption of calcium in the kidneys

How are calcium levels sensed?

The Ca2+ sensing receptor couples the calcium concentration to PTH secretion. It is not found exclusively in the parathyroid being found in skin, kidneys, stomach bones and colon as well. It also does not specifically bind calcium only. The calcium receptor has diverse functions throughout the body playing a role in both calcium homeostasis and fluid regulation via the kidney. It is a G protein coupled receptor dimer which activates the PLC pathway and inhibits the adenyl cyclase pathway in high calcium whereas the activity of these pathways is reversed in low calcium. The production of IP3 by the PLC pathway stimulates the opening of store operated calcium channels whereas the production of cAMP by adenyl cyclase results in exocytosis. Positive allosteric modulators of the calcium sensing receptor increase sensitivity to extracellular calcium and can be used to treat hyperparathyroidism.

Write short notes on the hypothalamo-pituitary-gonadal axis

The HPG axis plays a critical part in the development and regulation of a number of the body systems such as the reproductive and immune systems. The hypothalamus is located in the brain and secrete GnRH. This travels down to the anterior pituitary via the hypophyseal portal system and binds to receptors on the gonadotrophs to stimulates the release of LH and FSH into the bloodstream. In females, FSH and LH orimarily activate the ovaries to produce estrogen and inhibin to regulates the menstrual and ovarian cycle. Estrogen forms a negative feedback cycle by inhibiting GnRH production. In males, LH stimulates the interstitial cells located in the testes to produce testosterone and FSH plays an important role in spermatogenesis. See handwritten notes for diagram

Write short notes on the structure and function of the adrenal gland

The adrenal cortex is the outermost layer which contains three zones. The outermost zone is the zona glomerulosa which is the main site for the production of aldosterone, a mineralcorticoid, by the action of aldosterone synthase. Aldosterone plays an important role in the long term regulation of blood pressure. The middle zone is the zona fasciculata which produces glucocorticoids such as cortisol. It is the largest of the three layers, accounting for nearly 80% of the volume of the cortex. The Innermost layer is the zona reticularis which lies directly adjacent to the medulla and produces androgens. The adrenal medulla is at the centre of each adrenal gland and contains chromaffin cells which are the body's main source of the catecholamines adrenaline and noradrenaline. The adrenal medulla is driven by the sympathetic nervous system via preganglionic fibres originating in the thoracic spinal chord.

How is food intake associated with reward?

The brain areas involved in the perception of reward and taste are also involved in food intake. The orbitorfrontal cortex combines information on taste, smell and visual inputs such as texture representation. It is crticial for learning which foods to avoid and which foods to seek out. The ventral tegmental area is DA neurons which signal reward expectations projects to the nucleus accumbens. The VTA also has leptin receptors which decrease the concentration of DA released and increase DA reuptake. Ghrelin also increases DA release in this way. In the nucleus accumbens cues previously paired with calories elicit neuronal activation, reflecting the reinforcement of the value of food. Flavours paired with calories are therefore liked more than flavours not paired with calories which is why people don't like artificial sweeteners. Activity of the reward pathways in the brain therefore promote eating in the absence of an energetic requirement especially if the food is rich in sugar and it may even suppress pain sensation. The orexin and MCH neurons are populations of neurons that promote feeding and these can be tonically inhibited by reward pathway. The amygdala GABAergic neurons projects to the LHA glutamatergic neurons and inhibition of these neurons reduces food intake even in starved animals while activation increases food intake even in well fed animals.

Write short notes on stress related illness

The changes produced by the stress response have been honed by evolution to counter physical stressors. However, humans are often stressed by circumstances in which major physical activity is either inappropriate or counterproductive. Therefore the rise on blood pressure, plasma glucose and free fatty acids are not used by any physical exertion and remain counter homeostatic. People who have continuing psychological stress levels appear to be in a continuous state of mile resistance response. This could be a major factor for many stress related illness e.g heart disease and peripheral vascular disease and is why anxiolytic, β-adrenergic blockers and ACE inhibitors are used in treatment. People in highly stressed jobs are therefore advised to carry out substantial exercise and relaxation techniques. Animals in the wild do not obviously suffer such chronic stress-related illnesses as their stress response either saves them or they are killed. Animals in the zoo however cannot mount a physical reponse to the stress of inappropriate conditions and this can lead to similar problems to those found in humans.

Name the main hormones produced by the cortex and medulla of the adrenal gland and give their functions

The cortex produces corticosteroids with the main ones being the mineralocorticoids and the glucocorticoids. The mineralocorticoid aldosterone is important in the regulation of salt balance and blood volume. The main glucocorticoid is cortisol which influences the metabolism rates of proteins, fats and sugars. They also have anti-inflammatory effect and reduce bone formation. The medulla produces the catecholamine adrenaline and a small amounts of noradrenaline which can have widespread effects on the body. This occurs through their actions of the α and β adrenergic receptors which activates signalling cascades and produces actions such as increased heart rate, vasoconstriction, bronchodilation and increased sweat production

Describe how the hypothalamus acts as a feedback, feedforward and anticipation system?

The hypothalamus acts as a feedback system because it corrects deviation from a given set-point. It measures the current value and compares this with a supposed value. From this it makes adjustments to achieve a supposed value. In this way, it helps maintain body homeostasis. The feed-forward system however is based on the fact that the hypothalamus can over-ride feedback under special conditions. This includes in stress responses and in fever when the body temperature is changed to a higher set point. It is involved in anticipation because the hypothalamus adjusts its output to meet future needs. An example of this is increasing insulin secretion prior to food intake.

Describe the major physiological functions of the hypothalamus

The hypothalamus is parts of the diencephalon and lies at the base of the forebrain. It plays a major role in maintaining homoestaiss through the regulation of the endocrine system, ANS and visceral function. Control via the hypothalamus can be divided into non-endocrine control and neuroendocrine control. Non-endocrine control includes: · Control of circadian rhythms - implicating the timing and modulation of sleeping patterns · Food intake - controls the release of satiety signals and therefore appetite · Thermoregulation - maintains a constant core body temperature through PGE2 synthesis · Memory - mamillary. Bodes of the hypothalamus are connected with the hippocampus via fornix and fire at a frequencyes which elicits long term potentiation in the hippocampus Neuroendocrine control by the hypothalamus involves the secretion of hormones by hypothalamic neurons from the terminals in the posterior pituitary to stimulate particular functions which include: · Promoting water retention sin the kidneys through the stimulation of ADH release · Causing milk production in females and premoting social interaction through stimulating oxytocin secretion Korsakoff's syndrome is caused by a deficiency of thiamine and results in damage to components of the hypothalamus leading to anterograde and retrograde amnesia.

Write short notes on the mechanisms of insulin resistance

The impairment of insulin signalling pathways can occur by the accumulation of fatty acids and/or their metabolites, TNFα, IL-6 and other cytokines. A major effect may be the interferences with tyrosine phosphorylation of insulin receptors substrates 1 and 2. Leptin normally sensitise tisssues to insulin via CNS-neuroendocrine/neural pathways and via direct effects on muscle and β cells including increased fatty acid oxidation and reduces tryglyceride synthesis. These effects are reduces as a result of leptin resistance in obesity. Adiponectin promotes uptake and oxidation of fatty acids and reduction in triglyceride storage in muscle and liver but expression is reduced in obesity. The metabolic causes of insulin resistance link to the increased mobilisation of fatty acids from adipose tissue which leads to increased circulating free fatty acids that inhibit glucose uptake in muscle and adipose tissue and reduce the suppressive effects of inuslin on hepatic glucose output. Visceral fat is less sensitive to insulin and has a high lipolytic activity related to β-adrenergic receptors. This means it continues to relate fatty acids into the portal vein even after meals with a high flux of fatty acids to the liver stimulating glucose output. Endocrine and paracrine effects inhibit intracellular insulin signalling pathways which evidence the importance of adipose tisse infiltraton by inflammatory cells. Lipotoxicity is caused by increased release of fatty acids from adipose tissue, devreased glucose uptake by muscle and adipose tissue, decreased fatty acid oxidation in muscle and loss of the suppressive effect of insulin of hepatic glucose release. Effects are greater with visceral adipose tissue.

What is the role of the hypothalamus in food and drink intake?

The lateral hypothalamic area is a feeding centre which was shown by bilateral lesions producing aphagia. It receives olfactory input via the medial forebrain bundle. The ventromedial nucleus is a satiety centre as bilateral lesions of this produce hyperphagia. It contains receptors for glucose and free fatty acids. The arcuate nucleus contains receptors for leptin and insulin. The subfornical organ contains osmosensitive neurons which projects to the PVN, SON and POA. It is responsible for stimulation of drinking behaviour. Other cicumventriculae organs also contribute.

What do the mammillary bodies do?

The mammillary bodies have a significant role in memory. This is shown by Korsakoff's syndrome which is an alcohol-induced vitamin B1 deficiency that results in damage to the mammillary bodies but also the thalamus. It therefore produces symptoms of anterograde and retrograde amnesia and confabulation. The mammillary bodies contain several nuclei with distinct connections. The lateral nuclei contain head direction cells which fire selectively when animals face a specific direction in the horizontal plane and are therefore important for navigation. The medial nuclei are important for memory formation and are connect to the hippocampus via the fornix. They fire at a theta frequency (4-8Hz) which elicits long term potentiation in the hippocampus

Discuss the effects of excess thyroid hormones

The most common hyperthyroid condition is Graves. Excess thyroid hormones often result in a high BMR which will cause an individual to lose weight, despite sometimes an increased appetite and for them to be heat intolerant and always hot. They will also exhibit increased sensitivity to sympathetic stimulation and thus an increased heart rate as well as increased fat burn, which also contributes to weight loss. They will also appear anxious and on edge and prone to stress. Increased muscle protein expression is seen which increases the contractility of skeletal and GI tract muscles which can result in skeletal tremor and diarrhea as a result of increased gut motility.

What happens in the systemic iron homeostasis?

The peptide hormone hepcidin is produced in the liver in response to elevated iron level. It opposes the release of iron enterocytes and macrophages. The key cellular action of hepcidin appear to be the binding of ferroportin, leading to its internalisation and lysosomal degradation which means it becomes inactive. By an unknown mechanism, erythropoiesis per se seems to suppress hepcidin production independent of iron levels. This can cause problems in patients with excessive but ineffective erythrocytosis (e.g. thalassaemia), in whom profound hepcidin suppression can produce tissue iron overload. Hypoxia also reduce hepcidin production, partly by stimulating erythropoiesis and causing iron deficiency but possibly also directly through HIF. Several inflammatory cytokines, particularly interleukin-6, stimulate hepcidin production by the liver. This may reflect an evolutionary desire to deprive invading microbes of iron and probably explains the anaemia of chronic disease that is commonly seen in inflammatory conditions such as rheumatoid arthritis.

What is thermogenesis and the role of thyroid hormones in it?

Thermogenesis mechanisms keep core body temperature constant with obligatory thermogenesis being the heat loss from regular metabolism and adaptive thermogenesis being extra heal loss to generate more heat such as in the cold. Mammals have brown adipose tissue which undergoes a non-shivering thermogenesis which is activated by the sympathetic nervous system. Thyroid hormones control both obligatory and adaptive thermogenesis. They increase O2 consumption and head production in all tissues except the brain, spleen and testes. Clinical evidence for the role of thyroid in control of BMR in humans is that hyperthyroidism produces heat intolerance while hypothyroidism produces cold intolerance. BMR was also found to be significantly reduced in TR α + β knockout mice. Thyroxine increase Na-K-ATPase mRNA which is a major consumer of ATP and the calcium ATPase is also upregulated in the SR. Thyroid hormones have also been found to reduce the efficiency of ATP synthesis through targets in the mitochondria. Hepatocytes from hyperthyroid rats have twice the respiration rate of controls and their mitochondria have been found to have increase proton permeability suggesting greater uncoupling. Finally T3 has been found to modulate the adrenergic sensitivity of adipose tissue as it induces β3 receptor expression. As a result tissue in hypothyroid animals have reduced responsiveness to adrenergic stimulation. The relationship is however synergistic as noradrenaline induces T3 production from T4 in adipocytes via type 2 deiodinase activation.

What are peroxisome-activated receptors and what is their role in insulin resistance

They are a family of transcription factors activated by a wide range of ligands including unsaturated fatty acids and prostanoids. PPARγ in particular is expressed in adipose tissue and is a major regulator of adipocyte differentiation and direct activator of genes for many enzymes of lipid metabolism. The role of PPARγ in insulin resistance was identified by the study of thizolidenediones (TZDs). These acts as ligands for PPARγ and stimulate adipocyte differentiation and low glucose and free fatty acid concentrations. Use alone or with other oral anti-diabetic drugs to improve insulin sensitivity in type II diabetes however some have been withdrawn from use because of liver and cardiac side effects.

Write short notes on the synthesis and metabolism of thyroxine

Thyroxine is produced by follicular cells of the thyroid glands. The cells have a vascular face with iodide entering along with sodium via the sodium iodide transporter. TSH drives thyroxin production through driving the uptake of iodide. It is produced as the precursor thyroglobulin which is made up of tyrosine and exits into the lumen where it binds with iodine and is then endocytosed into lysosome where it is cleaved by enzymes to produce the active T4. Mutations in TSH receptors can cause hypothyroidism because thyroxin cannot be synthesised See handwritten notes for diagram

What happens in type 1 diabetes?

Type 1 is an insulin-dependent diabetes which involves the immune destruction of β cells. A complete lack of insulin signals starvation and both gluconeogenesis and glycolysis is increased. Ketogenesis is strongly upregulated in the absence of insulin and this leads to decreased plasma pH resulting in hyperventilation as well as confusion, disorientation and loss of consciousness. The peak incidence of the disease is 12-14 years and the precise cause is still not clear with both genetic and environmental factors at play as well as having a family history of autoimmune disease. As insulin levels decline, blood glucose concentration increases but GLUT4 is not activated and glucose cannot enter skeletal and cardiac muscle and adipose tissue. Glucose in circulation is therefore not available for cellular metabolism. The treatment of this disorder is with insulin injections for life.

What happens in type 2 diabetes?

Type 2 diabetes is a non-insulin dependent diabetes. Its onset is in adulthood with an insulin resistance that is associated with obesity. The disease therefore results from a combination of insulin resistance and β cell failure. Individuals usually have enough insulin to prevent ketogenesis but not hyperglycaemia. Patients usually present with polyuria and polydipsia without ketoacidosis. The cause of type two diabetes is a combination of genetics and the environment. Onset is slow and insidious and only when blood glucose concentration exceeds renal threshold for reabsorption at 10mM do symptoms appear. Pre-diabetics have large amounts of insulin but the body cannot respond to it.