Endocrine System Flashcards
Name the endocrine glands.
Thyroid Parathyroid Pineal Pituitary Adrenal Pancreas Ovaries Testes
Name and describe the 4 main hormones that regulate metabolism.
- Insulin – produced from the pancreas and secreted in the fed state
- Glucagon – produced by the pancreas and signals the starved state
- Adrenaline – produced by the adrenal glands and is secreted in starvation and stress
- Glucocorticoids – produced by adrenal glands and are secreted in starvation and stress
What is hormone signalling?
Hormones are released by cells in these endocrine glands and enter the bloodstream, where they travel to and affect target cells.
Many cells that do not sit within endocrine glands also produce molecules which as hormones.
What are the 4 types of hormones?
- Amines – small molecules derived from amino acids, such as thyroid hormone, the catecholamines, adrenaline and noradrenaline.
- Peptides/polypeptides – larger molecules, products of genes, such as insulin, glucagon and growth hormone.
- Steroids – derived from cholesterol, such as vitamin D, glucocorticoids and the sex hormones.
- Fatty acid derivatives – prostaglandins, leukotrienes and thromboxanes.
Define signal transduction.
The process by which cells can respond to changes in their environment.
What are some general features of hormone signalling?
- Extracellular signalling molecules bind to specific protein receptors and initiate a cascade of signalling events inside the cell.
- An important factor in cell signalling is amplification. This is so that a small amount of hormone can bring about larger changes in the body, such as changes in metabolism, gene expression or changes in cell shape or movement.
- Cells must be able to ‘switch off’ the intracellular signalling events once the signal concentration falls.
How do hydrophilic and hydrophobic hormones bind to receptors to initiate signal transduction?
Hydrophilic/polar hormones cannot cross the plasma membrane s must bind to cell surface receptors that are embedded in the cell membrane. They have a specific binding region to which the hormone binds.
Hydrophobic molecules such as steroid hormones are not water soluble and tend to move around in the circulation, bound to a carrier protein. At their target tissues, they can diffuse across the cell membrane and interact with intracellular receptors.
What are short and long term cellular responses?
Short term – normally brought about by changes to existing cellular proteins that alter their function.
Long term – take minutes or hour to become apparent. Generally, changes in gene expression are involved here. These types of cell signalling responses change the amount of particular proteins inside the cell.
Describe the action of insulin on glucose homeostasis.
- Secreted in response to high blood glucose by the beta cells of the pancreas
- Signals the fed state
- Promotes glucose uptake into tissues and fuel storage
Describe the action of glucagon on glucose homeostasis.
- Secreted in response to low blood glucose by alpha cells of the pancreas
- Signals the fasting state
- Promotes fuel metabolism and glucose release by the liver
Describe the action of adrenaline on glucose homeostasis.
- Secreted in response to low blood glucose and fear via the adrenal medulla
- Stimulates fuel mobilisation, especially in muscle and adipose tissue
Describe the action of glucocorticoids on glucose homeostasis.
- Secreted largely in response to stress but also starvation
- Long term effects on the expression of enzymes involved in fat and carbohydrate metabolism
What range must glucose be regulated within?
3.5 to 6.5 mM
Describe the consequences of hypoglycaemia.
Many tissues are obligate or preferential glucose oxidisers. So anything leading to a precipitous fall in glucose is likely to be life-threatening. This is probably why animals have a number of hormones that work together (glucagon, adrenaline, glucocorticoids) to prevent hypoglycaemia.
Changes to brain function caused, including:
- Palpitations
- Nausea
- Shivering
- Drowsiness
- Unsteadiness
- Confusion
- Coma and death
Describe the consequences of hyperglycaemia.
More damaging in the long term.
- Osmotic diuresis/loss of fluid and electrolytes: dehydration, excessive thirst and diarrhoea.
- Glucose is a chemically active molecule that can covalently modify proteins causing glycosylation. So can manifest itself as microangiopathy/damage to the small blood vessels, such as in the nephron, macroangiopathy/damage to large blood vessels, leading to hypertension.
- Can also cause cataracts, from glucose metabolising to sorbitol that accumulates in the lens, and neuropathy.
How are hormone levels measured?
- Hormones are typically only present in normal animals in the blood at low concentrations.
- Hormone assays have to be very sensitive and specific and they commonly use antibodies made against the hormone of interest.
- ELISAs are frequently used and can also be used to detect pathogens or quantities of drugs.
Describe the brief histology of thyroid tissue.
Follicles containing colloid - a protein-rich viscous liquid. Follicles are surrounded by follicular/cuboidal epithelium.
Where are thyroid hormones derived?
From the amino acid, tyrosine.
Each follicle contains lots of thyroglobulin, a precursor polymer containing tyrosine. Cleaving the backbone of this molecule, and with the addition of iodines, produces the thyroid hormones.
Describe the process of thyroid hormone synthesis.
- Follicular cell synthesises enzymes and thyroglobulin for colloid.
- Iodide ions are co-transported into the cell with sodium ions and transported into the colloid.
- Enzymes add iodine to thyroglobulin to make T3 with 3 iodines and T4 with 4 iodines.
- Thyroglobulin is taken back into the cell.
- Intracellular enzymes separate T3 and T4 from the protein.
- Free T3 and T4 enter the circulation.
Describe the properties of T3.
- 10% proportion of total hormones released from the thyroid glands
- 5 times more active than T4
- Circulates loosely bound to a protein
- Half life = 1 day
Describe the properties of T4.
- 90% proportion of total hormones released from the thyroid gland
- 5 times less active than T3
- Circulates the blood tightly bound to a protein
- Half life = 6 days
What happens to T4 at tissues?
Most of the physiological effects of thyroid hormones are due to T3.
So, in target tissues, most T4 is deiodinated to T3.
T4 might be ‘pool or reserve’ for T3, so regulation of conversion of T4 to T3 is important.
Describe the action of thyroid hormones at target cells.
- Move around the body until they reach target cells.
- T3/4 enters the target cell.
- Most of T4 is converted to T3 by now.
- T3 enters the nucleus and binds to the thyroid hormone receptor, THR.
- Binding of THR to promotor elements activates gene transcription, which may have many effects of TH in different target cells.
Describe the hypothalamus-pituitary axis.
- Hypothalamus produces thyrotropin releasing hormone, TRH.
- TRH is transported along the hypophyseal portal circulation to the anterior pituitary.
- TRH binds to thyrotroph, cells that release thyroid-stimulating hormone.
- Thyrotrophs release TSH.
- TSH is transported in the bloodstream to the thyroid gland.
- Binds to the follicle cells in the thyroid gland.
- This increases T3 and T4 synthesis, by increasing the activity of the iodine pump, and so also increases the iodination of tyrosine. Increases the size, number and activity of the thyroid cells. This means there is an increase in re-uptake of the colloidal thyroglobulin.
Is TSH tropic or trophic?
Tropic hormones – hormones whose target is another endocrine cell.
Trophic hormone cause an increase in growth or size.
So, TSH is tropic and trophic.
What controls the release of TRH from the hypothalamus?
Sympathetic activation or the cold increase the amount of TRH released. Cortisol and growth hormone decrease TRH release.
In negative feedback, if T3 or T4 are high, TRH and TSH are supressed.
What is the cardiovascular effect of thyroid hormones?
- Thyroid hormone increases the manufacture and incorporation of beta-1 adrenergic receptors.
- This increases responsiveness and sets sensitivity of the heart to adrenaline and noradrenaline.
- Long term sensitivity of cardiac cells is regulated by plasma levels of thyroid hormone.
What is the effect of thyroid hormones on growth and development?
- Essential for normal growth in childhood. Action unclear but possible supporting action on growth hormone.
- Critical to development of the CNS. Lack of T3 and T4 in late foetal early neonatal period, there is irreversible failure of the CNS development in terms of number of neurones and myelination.
What is the effect of thyroid hormones on basal metabolic rate?
Basal metabolic rate – the rate at which the body uses energy to maintain vital functions whilst at rest.
- Oxidative metabolism increased in most cells.
- Stimulates catabolic and anabolic reactions, stimulates the synthesis of enzymes and structural proteins, more glucose made available to meet elevated metabolic demand, and increased lipid metabolism.
- Measured by increased heat production and increased oxygen consumption.
What are the possible causes of hyperthyroidism?
Tumours on follicular cells and Grave’s disease, which is an autoimmune disease.
One of the most common endocrine diseases in older cats, due to benign tumours or follicular disease. Rare in dogs, are dogs are more likely to be able to excrete any excess thyroid hormone.
What is the effect of hyperthyroidism?
Thyroid gland is increased in size (goiter). Cells undergo hyperplasia and hypertrophy (increase in size and number), which increases the rate of thyroid hormone secretion.
- Increased metabolic rate
- Effect on CVS: increased force of contraction and increased rate of contraction
- Effect on CNS: nervousness, irritability and sleeplessness
- Weight loss, fatigue, heat intolerance, sweating, moist skin
Describe what Grave’s disease is and its consequences.
An immunoglobulin/antibody is produced and released by lymphocytes in the body when it shouldn’t be. The immunoglobulin is thyroid stimulating antibody, a long acting thyroid stimulator.
- It can bind to the TSH receptor and cause T3 and T4 release.
- Increased basal metabolic rate, lots of enzyme activity leading to weight loss.
- This feeds backs and reduces the release of TRH and TSH, there is still gland enlargement/goiter and all the other symptoms.
What are some possible causes of hypothyroidism?
Iodine deficiency so T3 and T4 cannot be synthesised, or autoimmune destruction of thyroid cells in Hashimoto’s thyroiditis.
Well recognised in dogs, especially Doberman, Beagles and Golden Retrievers, and only sporadically in other species.
What are the effects of hypothyroidism?
- Decreased basal metabolic rate
- Increased body weight and decreased appetite
- Effect on CVS: decreased cardiac output, decreased force of contraction, decreased rate of contraction
- Effect on CNS: fatigue and mental sluggishness
- Myxoedema, cold intolerance and goiter
No T3 and T4 formation > no negative feedback on TSH and TRH > constantly stimulating thyroglobulin production > gland enlargement.
How can growth be measured?
- Quantitatively – body weight, height, length, amount of muscle mass
- Qualitatively – body proportions and functions. Muscle mass vs intramuscular fat mass
What is growth hormone, how does it travel in the blood and how does it take effect?
Peptide hormone that promotes hypertrophy, hyperplasia and differentiation of some cell types. Causes growth in almost all tissues of the body that can grow.
Binds to growth hormone receptors on target tissues. Released from anterior lobe of the pituitary gland (after stimulation from a hormone from the hypothalamus that travels to the anterior via the hypophyseal portal system in hypothalamus-pituitary-axis).
How does growth hormone travel and why?
Circulates weakly bound to growth hormone binding protein for rapid release into tissues.
Peptide hormones are hydrophobic so do not need to travel with a binding protein, unlike steroid hormones, but can travel with them to maintain their half-life so the body does not break them down as quickly.
What cells release growth hormone?
Somatotrophs release growth hormone into the body to have its effects around the body on different cell types and causing cell growth. Includes liver, bone and muscle growth.
When is growth hormone released?
Growth hormone released in pulsatile release and is released in more concentrated bursts when the animal is going to sleep (diurnal). Under control of neurons in the hypothalamus.
How is the release of growth hormone regulated?
- Hypothalamic peptide, growth hormone releasing hormone, is released in response to hypoglycaemia, sleep, stress, exercise and ghrelin (released in response to hunger). Act on somatotrophs and cause growth hormones release.
- Hypothalamic peptide, somatostatin, which acts on somatotrophs and prevents growth hormones release. Released in response to insulin like growth factor 1, obesity and hyperglycaemia.
- Growth hormones also has a negative feedback system on itself, decreasing its release when its concentration gets too high and vice versa. Is also able to bind to the hypothalamus and cause an increase in somatostatins to decrease growth hormone concentration.
What are the acute effects of growth hormone on metabolism and their collective function?
- Protein metabolism – increased amino acid uptake and utilisation, increased protein synthesis and decreased catabolism
- Lipid metabolism – decreased lipogenesis, so less lipids are stored and more is available for use in the bloodstream.
- Carbohydrate metabolism – decreased glucose uptake and oxidation, increased gluconeogenesis and glycogenolysis. Increased blood glucose so more is available in the blood for use. (Has the opposite effect to insulin so can be called diabetogenic and anti-insulin.)
These effects results in protecting proteins and prevents is breakdown.
Describe insulin-like growth factor-1.
- Mediator if the growth function of growth hormone
- Plasma IGF-1 is GH dependent
- Produced in the liver and locally in tissues similar in structure to insulin
- Bind to IGF-1 binding proteins produced in the liver (to preserve half-life)
- Mediates local growth – differentiation and hyperplasia
What is the effect of insulin-like growth factor-1 on growth hormone?
IGF-1 will have a negative feedback on somatotrophs to prevent growth hormone release and also feedbacks on the hypothalamus to decrease the amount of GHRH and stimulate more somatostatin, reducing growth hormone.
What causes excessive growth hormone production and release?
A pituitary tumour. If this occurs in early life, before the epiphyseal growth plates have closed, it will result in giantism. If this occurs in adulthood, when the epiphyseal growth plates have closed, it can result in acromegaly, which can be seen in domestic animals.
What is acromegaly?
Acromegaly – soft tissue swelling of internal organs, generalised expansion of the skull, pronounced lower jaw protrusion and insulin resistance/diabetes (as growth hormone promotes high blood glucose).
What can cause a deficit of growth hormone?
Pituitary malformation or tumour can cause dwarfism.
GH receptor mutation.
What is glucagon?
Glucagon signals the starved state and is released when glucose levels start to fall. It has a key role is maintaining blood glucose concentrations. It is a small protein that brings about its effects by binding to the glucagon receptor.
Describe the receptors of glucagon.
- Member of a very large family of receptors which all have similar 7-membrane spanning structures, where they are embedded in the plasma membrane and the polypeptide chain crosses the membrane 7 times.
- When activated, these receptors couple to heterotrimeric G proteins and are hence called G protein coupled receptors.
- Glucagon receptors are mainly found in hepatocytes although some are also found in adipose tissue.
What is the effect of glucagon?
Binding to receptor triggers an intracellular signalling pathway which culminates in the stimulation of glycogenolysis and gluconeogenesis in the liver and lipolysis in adipose tissue.
Describe the process of glucagon using cAMP as a secondary messenger to bring about its effects.
- Binding of glucagon to its specific receptor causes a conformational change, which is transmitted to the inside of the cell.
- Allows the receptor to interact with a heterotrimeric G-protein complex, which consists of 3 subunits: alpha, beta and gamma subunits. In the unstimulated state, alpha subunit is bound to GDP. Interaction between the heterotrimeric G-protein and the activated glucagon receptor stimulates the alpha subunit to release the bound GDP. GTP bind sin its place, forming the active state of the alpha subunit.
- GTP bound form of the alpha subunit can now dissociate from the beta and gamma dimers and can diffuse laterally along the intracellular face of the plasma membrane to interact with an enzyme called adenyl cyclase.
- This activates the enzyme and stimulates it to produce cAMP from ATP.
- cAMP activates a protein kinase called cyclic AMP dependent protein kinase or PKA.
- Activated PKA can diffuse into the nucleus via a nuclear pore, where it then phosphorylate and activate a transcription factor known as CREB.
- Phosphorylated CREB can now bind to specific DNA sequences found in the promotor regions of some genes. Can lead to changes in gene transcription and gene expression.
Describe how cAMP stimulates PKA.
In the unstimulated state, PKA exists as a tetramer with 2 regulatory subunits bound to 2 catalytic subunits. As cAMP levels rise in the cell, cAMP binds to the regulatory subunits. This causes a conformational change in the regulatory subunits s that they are no longer able to bind to the catalytic subunits. This releases the catalytic subunits, which are free to go and phosphorylate target proteins.
What are the 3 mechanisms of stopping phosphorylation of enzymes by PKA?
- Phosphodiesterase hydrolyses cAMP to AMP
- Intrinsic GTPase activity of the alpha subunit hydrolyses bound GTP to GDP. Inactive alpha can re-associate with the beta and gamma subunits.
- Receptor is phosphorylated and inactivated by the GCPR kinase. This leads to the binding of arrestin, which blocks further signalling.
What does glucagon activate?
- Glycogen breakdown – phosphorylation and activation of phosphorylase kinase
- Gluconeogenesis – phosphorylation and inactivation of phosphofructokinase 2
- Triglyceride breakdown – phosphorylation ad activation of hormone sensitive lipase
What does glucagon inhibit?
- Glycogen synthesis – phosphorylation and inactivation of glycogen synthase
- Glycolysis – phosphorylation and inactivation of pyruvate kinase
- Fatty acid synthesis – phosphorylation and inactivation of acetyl-CoA carboxylase
Describe the signal amplification that glucagon and adrenaline (in muscle) have in common.
- Stimulate cAMP production
- PKA stimulates another protein kinase called phosphorylase kinase. PKA also phosphorylates and inactivates glycogen synthase.
- Phosphorylase kinase phosphorylate and activates glycogen phosphorylase.
- Glycogen phosphorylase catalyses the breakdown of glycogen, producing glucose-1 phosphate to be converted into glucose.
Where is glucagon produced?
Produced by alpha cells in the pancreatic islets of Langerhans. The transcription and translation of the glucagon gene produces pre-proglucagon. This goes under proteolytic processing to proglucagon and then again to glucagon.
How is glucagon secreted?
This is secreted by the alpha cells in response to changes in blood glucose concentration, but the mechanism for this is unclear. A few theories:
- Low glucose concentration > adrenaline release > adrenaline acts in aloha cells > glucagon release is stimulated
- High insulin concentration > inhibits glucagon secretion. So in the absence of glucose, and so insulin, glucagon secretion is uninhibited
What are adrenocortical steroids and some examples?
All generated form cholesterol so have closely related structures but different effects:
- Glucocorticoids – cortisol and corticosterone
- Mineralocorticoids – aldosterone
- Androgens and oestrogens – small amount
How are cholesterol and steroids transported?
Cholesterol is either absorbed from the GI tract and circulating or is synthesised within cells from acetate. Because cholesterol is insoluble in water, it is transported with low density lipoprotein, LDL.
Steroids are not stored in cortical cells and are transported bound to binding proteins. Steroid hormones bind to receptors within cells and affect gene transcription.
What are glucocorticoids?
- Secreted from zona fasciculata
- Equal potency of cortisol and corticosterone and similar effects
- Released in different ratios according to species
How are glucocorticoids released?
- Release is controlled by CRH and ACH in hypothalamus-pituitary-axis
- Released in response to particular rhythms: dogs and cats do not have daily cortisol rhythms. Other species have CRH secretion synchronised with sleep-wake cycle: animals active in the day have high cortisol levels in the day and animals active at night have high cortisol levels at night.
- Stress induced secretion of CRH can cause up to a 20 times increase in glucocorticoids and override any present circadian rhythm.
Describe the process of glucocorticoids release from the adrenal cortex.
- Within the hypothalamus, there are cells that generate circadian rhythm and so control cortisol release.
- Hypothalamus can cause the production of cortisol in response to acute and long-term stress – trauma, heat, cold, pain, fright, disease.
- Hypothalamus produces corticotropin releasing hormone and releases it into the hypophyseal portal system to the anterior pituitary gland, where CRH acts on corticotrophs.
- Corticotrophs release ACTH, adrenocorticotrophic hormone, in response to CRH.
- This is released in the bloodstream and acts on the adrenal cortex at the zona fasciculata to release glucocorticoids.
- Cortisol released into the bloodstream to act on peripheral tissue target cells.
How is glucocorticoid release controlled?
Cortisol can feedback to the anterior pituitary gland and reduce the release of ACTH and can feedback on the hypothalamus to reduce CRH release.
ACTH can also feedback to the hypothalamus and reduce CRH release.
What are the effects of glucocorticoids on metabolism?
Increases blood glucose:
- Carbohydrate – stimulate gluconeogenesis, inhibit effects of insulin by decreasing tissue uptake of glucose
- Protein – stimulate catabolism of proteins for gluconeogenesis (unlike growth hormone protecting proteins)
- Lipid – during stress and starvation, shift in metabolism from glucose to fat. Increased lipolysis and glucose sparing
What are the effects of glucocorticoids on cardiac, skeletal and vascular smooth muscle?
Insufficient glucocorticoids leads to muscle fatigue:
- Cardiac insufficiency and failure
- Loss of vasomotor tone
- General skeletal muscle weakness
What are the effects of glucocorticoids on the nervous system?
Alertness increased:
- Insufficient glucocorticoids affects mental function, leading to lethargy, apathy, inability to concentrate
- Excess glucocorticoids causes hyperactivity, insomnia, euphoria and increased sensory acuity
What are the effects of glucocorticoids on inflammatory and immune responses?
- Anti-inflammatory and immunosuppressive
- Inhibit secretion of cytokines, proliferation of immune cells and synthesis of antibodies
- Increases susceptibility to infection, which is a potential animal welfare issue but is also used therapeutically for skin conditions, for example.
What is an example of a mineralocorticoid, how is it produced and what is its effect?
- Aldosterone is released form the zona glomerulosa
- Has a short half-life so circulates with a carrier protein
- Its release is mediated by renin/RAAS
- Regulate concentration of sodium and potassium in extracellular fluid
- Stimulated by changed in electrolyte levels and water balance
- Major target is epithelial cells of the collecting tubules if the kidney, where they activate sodium-potassium pumps
- Overproduction of mineralocorticoids does not seem to occur in domestic animal.
What is hypoadrenocorticism or Addison’s Disease?
- Under secretion of glucocorticoids and mineralocorticoids
- Rare
- Primary hypocorticism is atrophy of the adrenal cortex
- Latrogenic hypocorticism is abrupt (careful) withdrawal of steroid therapy
- Symptoms of hyperadrenocorticism: muscle weakness, poor cardiovascular function and low blood pressure
- Therapeutic use of glucocorticoids: anti-inflammatory and anti-allergic effects, immunosuppressant in autoimmune disorders
What are the cells of the adrenal medulla and their function?
Within the adrenal medulla, there are chromaffin cells, which are catecholamine storage granules.
Catecholamines, such as adrenaline and noradrenaline, are secreted from adrenomedullary cells.
What are the effects of catecholamines?
Catecholamines bind to receptors on adipose, cardiovascular, muscular, pancreatic tissue and CNS. Response of cells is related to nature of adrenergic receptors (“emergency hormones”).
Secretion is under control of the sympathetic nervous system (action of acetylcholine to release adrenaline and noradrenaline): depolarisation > calcium influx > granules fuse with chromaffin cell membrane > exocytosis > catecholamine release
What are pheochromocytomas?
Pheochromocytomas – tumours arising from chromaffin cells. Rare and benign but secrete large quantities of catecholamines, causing increased blood pressure and heart rate.
What is adrenaline?
Adrenaline is a small water soluble molecule derived from the amino acid tyrosine. It has effect by binding to cell surface receptors that are members of the G protein coupled receptor family, which are linked to heterotrimeric G proteins.
Name and describe the different adrenaline receptor isoforms.
Beta 1,2 and 3 - alpha-s G protein. Activation of adenylyl cyclase, increasing cAMP. Adipose tissue, skeletal muscle and heart.
Alpha 1 - alpha-q G protein. Activation of phospholipase C, increasing calcium. Liver tissue.
Alpha 2 - alpha-i G protein. Inhibition of adenylyl cyclase, decreasing cAMP. Pancreatic islets of Langerhans.
What factors can affect how much different tissues express different receptor isoforms?
- Age
- Sex
- Dietary status
- Some diseases
- Species
Describe the process of alpha-1 adrenergic receptor signalling.
- Binding of adrenaline to the alpha-1 adrenergic receptor in the liver causes a conformational change that allows the receptor to interact with the heterotrimeric G protein that contains an alpha-q subunit.
- This interaction stimulates the release of GDP from the alpha subunit and GTP binds in its place, activating the alpha subunit.
- Activated alpha subunit diffuses away from the beta-gamma dimer and can interact with an enzyme in the plasma membrane called phospholipase C/PLC.
- PLC catalyses the hydrolysis of a membrane lipid called PIP2/phosphatidyl inositol bisphosphate.
- This produces diacylglycerol, which remains in the membrane, and a water soluble molecule called IP3/inositol trisphosphate, which can diffuse away from the membrane and interact with channels on the endoplasmic reticulum.
- Binding of IP3 opens these channels to allow calcium to flow out of the endoplasmic reticulum and into the cytoplasm.
- This increase in intracellular calcium and the diacylglycerol can activate a protein kinase called PKC. Calcium can also interact with other protein kinases called calcium calmodulin dependent protein kinases.
What are the metabolic effects of adrenaline?
Activates:
• Adipose tissue – triglyceride mobilisation in phosphorylation and activation of hormone sensitive lipase.
• Muscle – glycogen breakdown in phosphorylation ad activation pf phosphorylase kinase.
• Liver – glycogen breakdown in calcium activating phosphorylase kinase.
Inhibits:
• Glycogen synthesis – phosphorylation and inactivation of glycogen synthase.
What stimulates adrenaline release?
Perception or anticipation of • Danger • Fear • Excitement • Trauma • Pain • Intense exercise • Hypoglycaemia
How is adrenaline secreted?
These are sensed by the hypothalamus and lead to a 5-10 times increase in adrenaline. Splanchnic nerve innervates adrenal medulla > cholinergic preganglionic fibres release acetylcholine > acetylcholine stimulates adrenaline release.
Describe the effects of fight or flight response.
Adrenaline helps to mobilise fuel stores to prepare the body for sudden action.
- Glycogen breakdown
- Triglyceride breakdown
- Stimulation of glucagon release
- Inhibition of insulin release
- Increased heart rate and force
- Smooth muscle relaxation of bronchi, skeletal muscle and gut
- Smooth muscle contraction in peripheral organs, like skin and kidney
All of these allow increased oxygen delivery to peripheral tissues.
What are the 3 domains of cortisol receptors?
- Hormone binding domains – binds to the glucocorticoid molecule
- DNA binding domain – binds to promotor regions of specific genes
- Transactivation domain – binds to the transcriptional machinery to enhance transcription
How does cortisol take effect?
- Cortisol is a hydrophobic molecule so circulates bound to a cortisol binding globulin.
- Upon reaching its target tissues, cortisol can diffuse into cells and interacts with the cortisol receptor inside the cell.
- Once bound to the receptor, cortisol dimerises and binds to DNA at specific sequences called hormone response elements, adjacent to specific genes.
- This can cause upregulation or downregulation of these genes, changing the amounts of specific proteins in the cell, affecting cell function.
What are the metabolic effects of cortisol?
Activates:
- Triglyceride – induction of hormone sensitive lipase
- Gluconeogenesis – induction of phosphoenolpyruvate carboxykinase and glucose-6 phosphatase.
How is cortisol regulated?
- Stress, hypoglycaemia, infection and exercise stimulate the hypothalamus to release cortisol releasing hormone, CRH.
- CRH acts on the anterior lobe of the pituitary gland to release ACTH, which acts on the adrenal gland to release adrenaline.
- Feedback loops prevent excess cortisol secretion.
What is Cushing’s Disease?
Excess cortisol production.
- Affects dogs, cats and horses, though the presentation in horses is different (coat is much shinier and full in contrast)
- 80% of cases are due to pituitary tumours, leading to over production of ACTH
- 20% of cases are due to adrenal gland tumours
- Symptoms: hyperglycaemia, increased appetite, lethargy, thin skin and skin infections, enlarged abdomen
- Can be treated with surgery or drugs to inhibit cortisol production
What is insulin and its structure?
Insulin signals the fed state and promotes fuel storage, it is a protein that consists of 2 polypeptide chains, joined by 3 disulphide bridges between cysteine amino acids. A chain is 21 amino acids and the B chain is 30 amino acids.
Where is insulin secreted from?
Insulin is secreted by the beta cells of the pancreatic islets of Langerhans. 70% of the pancreatic islets of Langerhans are beta cells. 15% are the alpha cells that secrete glucagon and the other 15% are somatostatin secreting cells.
How is insulin synthesised?
Insulin is coded for by a single gene and the mRNA transcript is translated to a single polypeptide called pre-proinsulin. This maturates in the endoplasmic reticulum:
- Signal peptide is proteolytically cleaved to form pro-insulin.
- As pro-insulin moves through the Golgi apparatus, it undergoes additional specific proteolytic cleavage, which removes the C peptide.
- The A and B peptides remain together because they’re attached by disulphide bonds.
- Matured insulin is packed into secretory granules before being released.
What factors affect insulin release?
- Main signal is an increase in blood glucose concentration
- Adrenaline is inhibitory
- Amino acids are stimulatory
- Fatty acids are stimulatory
Secretion is biphasic:
• Initial rapid release of insulin is due to the release of pre-formed insulin
• The second slower phase is due to the synthesis and then the release of new incident molecules, as well as glucose
Describe the process of insulin release.
- Increase in blood glucose leads to glucose entering the pancreatic beta cells and glucose enters via the GLUT-2 glucose transporter. This is a relatively low affinity glucose transporter so only tends to transport significant amounts of glucose into the cell when blood sugar levels start to rise.
- Glucose is metabolised inside the cell and leads to ATP production.
- Increase in ATP levels inhibits an ATP gated potassium channel.
- This decreases the rate at which potassium can leak out of the beta cell.
- Causes membrane depolarisation, which opens a voltage-gated calcium channel to allow calcium into the cell.
- Increase in intracellular calcium due to this and calcium being released from the endoplasmic reticulum, stimulates the movement of the insulin secretion granules to the plasma membrane.
- Granules fuse with the plasma membrane and release their contents into the circulation.
What are sulphonylureas?
Drugs that can inhibit the ATP gated potassium channel and are used to treat some forms of diabetes due to their ability to promote insulin secretion.
What occurs when insulin reaches target cells?
The insulin receptor is a tetramer made up of 2 extracellular alpha subunits and 2 membrane spanning beta subunits, held together by disulphide bridges.
- Binding of insulin to alpha subunits leads to a conformational change which activates these beta subunits.
- Activation of the intrinsic tyrosine kinase activity of the subunits.
- Beta subunits can then phosphorylate themselves and other target proteins on tyrosine amino acid side chains.
- One of these is IRS-1,which facilitates the binding of phosphoiositide-3 kinase, which is responsible for producing a secondary messenger called PIP3.
- This stimulates a cascade of protein kinases. Cascade leads to metabolic effects, stimulation of protein synthesis and stimulation of transcription.
What does insulin activate in metabolism?
- Glucose uptake into muscle and fat, not liver – induces glucose transporter translocation
- Glycogen synthesis – dephosphorylates and activates glycogen synthase
- Glycolysis – dephosphorylates and activates pyruvate kinase and phosphofructokinase-2
- Pyruvate oxidation – dephosphorylates and activates pyruvate dehydrogenase
- Fatty acid synthesis – phosphorylates and activate acetyl-CoA carboxylase
What does insulin inhibit in metabolism?
- Gluconeogenesis – represses phosphoenolpyruvate carboxykinase
- Fatty acid oxidation – increases malonyl-CoA concentration
- Lipolysis – activates phosphodiesterase > decreases cAMP concentration >less phosphatase activation > dephosphorylation of hormone sensitive lipase
Describe the action of GLUT-4 transporters in the re-uptake of glucose.
- Muscle and adipose cells have GLUT-4 glucose transporters.
- In the unstimulated state, glucose transporters are found in intracellular membrane vesicles. In this intracellular location, they are unable to catalyse the transporter glucose across the cellular membrane. In the absence of insulin, glucose uptake into these cells is relatively low.
- On insulin stimulation, these vesicles move to the cell surface and they fuse with the plasma membrane, delivering the GLUT-4 transporters to the cell surface to transport glucose into the cell.
- Once insulin levels start to drop, these transporter proteins are re-internalise back into the intracellular vesicle pools.
What is diabetes mellitus?
Caused by a malfunction of the regulation of glucose and gat metabolism by insulin.
There are 2 types:
• Type 1 – insulin dependent. Due to failure to produce or to secrete insulin and treated with insulin injections.
• Type 2 – non-insulin dependent. Due to failure to respond to insulin and controlled by diet and by drugs.
What are the differences in diabetes in dogs and cats?
Dogs nearly all insulin dependent and mostly type 1 but not straightforward to divide into type 1 or 2. Treated by insulin injections. Some breeds more susceptible than others.
Cats can be type 1 and 2 but type 2 is more common at 80-95%. Incidence of type 2 is increasing, possibly because of increasing obesity. Type 1 treated with insulin injection. Type 2 managed by altering diet if obese, treating with drugs like sulphonylureas and insulin (attempt to overcome insulin resistance by increasing insulin levels). Some breeds more susceptible than others.
List the symptoms of diabetes.
- Polydasia
- Polyuria
- Increased appetite
- Weight loss
- Cataract formation in dogs
- Poor coat
- Nephropathy
- Increased risk of infections
- Diabetic neuropathy – plantigrade stance in cats due to nerve damage
How can diabetes be diagnosed?
- Hyperglycaemia – but cats often suffer from stress induced hyperglycaemia
- Urine analysis
- Measurement of plasma insulin
- Oral glucose tolerance test (rarely used in animals)
Describe how the oral glucose tolerance test is used to diagnose diabetes.
Patient is starved overnight and then given a sugary drink. Take blood samples at 30 minute intervals, which are analysed for glucose.
Renal threshold for glucose – kidneys reabsorb glucose from the glomerular filtrate but the glucose transport systems involved in this are saturated at glucose concentrations about 12mmolar, so glucose appears in urine.
In a patient with diabetes, even initial concentration is higher at 0 mins. It then rises and remains elevated throughout the test and exceeds the renal threshold. Because glucose appears in the urine, it may predispose animals to urinary tract infections.
What are the metabolic disturbances of diabetes?
As insulin decreases, the effects of glucagon begins to dominate.
- Carbohydrate – decreased glucose uptake by muscle and adipose, increased glycogen breakdown, and increased gluconeogenesis > hyperglycaemia > glucosuria > dehydration
- Triglyceride – increased lipolysis, increased fatty acid oxidation, and increased ketone body production > ketoacidosis
How is diabetes monitored?
- Glucose meter to monitor blood glucose concentration
* Fructosamine levels, which rise in long term blood glucose levels
How is diabetes treated?
- Insulin daily injections of fast or slow acting insulin
- Diet
- Metformin to decrease gluconeogenesis
- Sulphonylureas to increase insulin secretion
- Thiazolidinediones to increase insulin insensitivity
