Chapter 14

The endocrine system is made up of endocrine glands, which is a group of cells specialised to secrete chemicals known as hormones directly into the bloodstream. Hormones are used to send information about changes in the environment around the body. Endocrine glands include:

• Pituitary gland - produces growth hormone, ADH to affect reabsorption of water in the kidneys and gonodatrophins which control sexual development. The pituitary gland is found at the base of the brain, its close proximity to the hypothalamus ensures hormonal and nervous responses are closely linked.
• Pineal gland - produces melatonin which affects reproductvie developement and daily cycles.
• Thyroid gland - produces thyroxine which controls the rate of metabolism and respiration.
• Thymus gland - produces thymosin which promotes production/maturation of neutrophils.
• Adrenal gland - produces adrenaline which increases heart rate and raises blood sugar level.
• Pancreas - produces insulin which converts excess glucose into glycogen in the liver and glucagon which converts glycogen back into glucose in the liver.
• Testis - produce testosterone which controls sperm production and sexual characteristics.
• Ovary - produces oestrogen which controls ovulation and sexual characteristics, and progesterone whcih prepares the uterus lining for recieving and embryo.

Hormones are often referred to as chemical messengers because they carry information from one part of the body to another. They can be proteins, steroids, glycoproteins, polypeptides or amines. Hormones are secreted directly into the blood when a gland is stimulated, which can be due to a change in concentration of a particular substance or as a result of another hormone or nerve impulse. Once secreted the hormones are transported in the blood plasma all over the body. The hormones diffuse out of the blood and bind to specific receptors for that hormone found on the membranes or in the cytoplasm of the cells in the target organs. These are known as target cells. Once bound to their receptors the hormones stimulate the target cells to produce a response. The type of hormone determines the way it causes an effect on a target cell, for example:

• Steroid hormones are lipid soluble and so can pass through the lipid component of the cell membrane and bind to steroid hormone receptors to form a complex. The receptors may be in the cytoplasm or the nucleus. A hormone-receptor complex acts as a transcription factor which will facilitate or inhibit the transcription of a specific gene, for example, oestrogen.
• Non-steroid hormones are hydrophoillic so cannot pass directly through the cell membrane. Instead they bind to receptors on the cell surface of the target cell, which triggers a cascade reaction inside the cell, mediated by second messengers, for example, adrenaline.

As hormones are not released directly onto target cells, this results in a slower, less specific form of communication. However as hormones are not broken down as quickly as neurotransmitters so they have a longer lasting more widespread effect. Hormonal communication uses hormones in the bloodstream that travel to all parts of the body but only bind to receptors where they are present in target organs, response is slow but often long lasting, with permament or irreversible effects. Nervous communication involves electrical impulses which travel to specific parts of the body, the response is localised, rapid but short lived. The effect is temporary and reversible.

The adrenal glands are two small glands which are located on top of each kidney and have two distinct parts. The adrenal cortex which is the outer region and produces hormones vital to life such as cortisol and aldosterone, and the adrenal medulla which is the inner region and produces non essential hormones such as adrenaline which helps the body react to stress. 

Adrenal cortex: The production of hormones by the adrenal cortex itself is controlled by hormones  from the pituitary gland in the brain, there are three main hormones produced:

• Glucocorticoids - these include cortisol which helps regulate metabolism by controlling how the body converts proteins, lipids ad carbohydrates to energy, and also helps to regulate blood pressure and cardiovascular function in response to stress. Another glucocorticoid is corticosterone which worls with cortisol to regulate the immune response and suppress inflammatory reactions. The release of these hormones is controlled by the hypothalamus.
• Mineralocorticoids - the main one is aldosterone which helps control blood pressure by maintaining the balance between salt and water concentrations in the blood and body fluids. Its release is mediated by signals triggered by the kidney.
• Androgens - small amounts of sex hormones are released, which have little effect compared larger amounts of others but are important in women after menopause.

The hormones of the adrenal medullar are released when the symapthetic nervous system is stimulated, which occurs when the body is stressed during the fight or flight response. The hormones secreted by the adrenal medulla are:

• Adrenaline - this increases the heart rate by sending blood quickly to the muscles and brain. It also rapidly raises blood glucose concentration levels by converting glycogen to glucose in the liver.
• Noradrenaline - this hormone works with adrenaline in response to stress and produces effects such as increasing the heart rate, widening of the pupils, widening of the air passages in the lungs, and the narrowing of blood vessels in non essential organs resulting in a higher blood pressure.

The pancreas is found in the upper abdomen behind the stomach and plays a major role in controlling blood glucose concentration and in digestion. It is a glandular organ and its tole is to produce and secrete hormones and digestive enzymes. The pancreas has two main functions in the body, as an exorcine gland to produce enzymes and release them via ducts into the duodenum, and as an endocrine gland to produce hormones and release them into the blood.

Role as an exocrine gland: Most of the the pancreas is made up of exocrine glandular tissue which is responsible for producing enzymes and an alkaline fluid known as pancreatic juice. The enzymes and juice are seceted into ducts which eventually lead to the pancreatic duct and from here they are released into the duodenum (the top part of the small intestine). The pancreas produces three important types of digestive enzyme - amylases, which break down starch into simple sugars, eg pancreatic amylase, proteases, which break down proteins into amino acids, eg trypsin, and lipases which break down lipids into fatty acids and glycerol, eg pancreatic lipase.

Role as an endocrine gland: The pancreas is responsible for producing insulin and glucagon. hese two hormones play an essential role in controlling blood glucose concentration. Within the exocrine tissue there are small regions of exocrine tosue called islets of Langerhans, the cells here are responsible for prodcuing insulin and glucagon and secreting them directly into the bloodstream.

Using standard staining techniques makes it often diffcult to distinguis between the cell types within an islet of Langerhans so differential staining is used. Islets of Langerhans are lightly stained and appear as large, spherical structures and contain two types of cell: Alpha cells which produce and secrete glucagon, and Beta cells which produce and secrete insulin. Alpha cells are larger and more numerous than beta cells within an iselt. Pancreatic acini are the name of the exocrine tissue which appear darker stained and form small berry-like clusters. The white lines between the different types of tissue are capillaries and blood vessels.

Without control of blood glucose concetration it would range from high levels after a meal to very low levels several hours later, so it has to be kept constant. It can increase as a result of:

• Diet - eating carbohydrate rich foods can result in a lot of glucose being released which is then absorbed in the bloodstream, increasing blood glucose concentration.
• Glyogenolysis - glycogen stored in the liver and muscle cells is broken down into glucose which is released into the bloodstream causing the blood glucose concentration to rise.
• Glucogenogenesis - this is the production of gluxose from non carbohydrate sources, for example the liver is able to make glucose from glycerol (form lipids) and amino acids.

Blood glucose concentration can be decreased by:

• Respiration - some of the glucose in the blood is used by cells to respire as a part of normal body function, however during exercise more glucose is needed as the body needs to generate more energy in order for the muscle cells to contract, the higher the level of activity, the higher the demand for oxyegn so the more the blood glucose concentration decreases.
• Glyogenesis - when blood glucose concentration is too high excess glucose taken in through the diet is converted into glycogen which is then stored in the liver.

Insulin is produced by the Beta cells of the islets of Langherhans in the pancreas. If the blood glucose concentration is too high, the Beta cells detect this and respond by secreting insulin directly into the bloodstream. Virtually all body cells have insulin receptors on their cell surface membrane, when insulin binds to its glycoprotein receptor itchanges their  tertiarty structure of the glucose transport channels, causing them to open allowing more glucose to enter the cell. Insulin also activates enzymes within some cells to convert glucose to glycogen and fat. It does this by:

• Increasing the rate of absorption of glucose by cells, in particular skeletal muscle cells.
• Increasing the respiratory rate of cells which increases glucose demand and causes a higher uptake of glucose from the blood.
• Increasing the rate of glycogenesis - insulin stimulates the liver to remove glucose from the blood by turning glucose into glycogen and storing it in the liver and muscle cells.
• Increasing the rate of glucose to fat conversion.
• Inhibiting the release of glucagon from the Alpha cells of the islets of Langerhans.

Insulin is broken down by enzymes in the cells of the liver so to maintain its effect is has to be constantly secreted. As the blood glucose concentration returns to normal or falls below it the Beta cells detect this and inhibit insulin produuction via a negatve feedback mechanism.

The mechanism by which insulin is released by Beta cells when they detect that blood glucose concentration is above the set level occurs as follows:

• At normal blood glucose concentration levels, potassium channels in the plasma membrane on the Beta cells are open and potassium ions diffuse out of the cell, and the inside of the cell is at a potential of -70mV with respect to the outside of the cell.
• When the blood glucose concentration tises, glucose enters the cell by a glucose transporter.
• The glucose is metabolised inside the mitochondria resulting in the production of ATP.
• The ATP binds to potassium channels and causes them to close, they are known as ATP sensitive potassium ion channels.
• As potassium ions can no longer diffuse out of the cell the potential difference reduces to around -30mV and depolarisation occurs.
• Depolarisation causes the voltage gated calcium ion channels to open.
• Calcium ions enter the cell the cause thesecretory vesicles to release the insulin they contain into the bloodstream by exocytosis.

Glucagon is produced by the Alpha cells of the islets of Langerhans in the pancreas. If the blood glucose concentration is too low the Alpha cells detect this fall and respond by secreting glucagon directly into the bloodstream. Unlike insulin the only cells which have glucagon receptors are the liver cells anf fat cells, so they are the only cells that respond to glucagon. Glucagon raises blood glucose concentration by:

• Gylcogenolysis - the liver breaks down its glycogen store into glucose and releases it back into the bloodstream.
• Reducing the amount of glucose absorbed by the liver cells.
• Increasing the rate of gluconeogenesis - increasind the conversion of amino acids and glycerol into glucose in the liver.

As blood glucose concentration returns to normal this is detected by thr Alpha cells, when it rises above a set level the Alpha cells reduce their secretion of glucagon, this negative feedbakc mechanism ensures that changes are reversed back to the set level using corrective measures. Blood glucose concentration is not constant but fluctuates around a set point as a result of negative feedback, so the system for maintaing it is sefl regulating as it is the level of glucose in the blood which determines how much insulin and glucagon is released.

If you suffer from diabetes your pancreas either does not produce enough insulin or yout body cannot effectively respond to the insulin that is produced, meaning the blood glucose concentration remains high, and can result in hyperglycamia which can seriously damage many body systems, especially in the nerves and blood vessels. There are two main types of diabetes:

• Type 1 diabetes: Patients with type 1 are unable to produce insulin as the Beta cells in the islets of Langerhans do not produce insulin. Evidence suggests that in many cases the condition arises as a result of an autoimmune response where the body's own immune system attacks the Beta cells. The disease cannot be prevented or cured.
• Type 2 diabetes: Patients with type 2 cannpt effectively use insulin and control their blood sugar levels. This is either because the person's Beta cells do not produce enough insulin or the person's body cells do not respond to insulin properly. The cells lose their responsiveness to insulin and therfore do not take up enough glucose. It is largely as a result of excess body weight and physical activity, symptoms are similar to type 1 but are often less severe and develop more slowly and therfore it is often only diagnosed after complications have already arisen. The risk of developing type 2 diabetes increases with age.

Diabetes is not a curable dieases but it can be controlled succesfully allowing sufferes to lead a normal life. 

Type 1 diabetes is controlled by regular injections of insulin and is therefore said to be insulin dependant. People with the condition have to regularily test their blood glucose concentration and based on this the person can work out the dose of insulin they need to inject. The insulin administered increases the amount of glucose absorbed by cells and causees glycogenesis to occur resuling in a reduction of blood glucose concentration. If a person with diabetes injects themself with too much insulin they may experience hypoglycaemia but too low a dose results in hyperglycaemia, so careful monitoring and dose reglation is required.

Type 2 diabetes can be controlled at first by regulating the person's carbohydrate intake through their diet and matching this to their exercise levels. In some cases diet and exercise are not enough to control blood glucose concentration so drugs have to be used such as metformin which either slow down the rate at which the body absorbs glucose from the intestine, or those that stimulate insulin production and ultimately, insulin injections.

Originally, insulin was obtained form the pancreas of cows and pigs, this process was difficult and expensive, depended on the demand for meat, and the insulin extracted could also cause allergic reactions and can be rejected by patients. Now insulin is made by genetically modified bacteria which has several advantages:

• Human insulin is produced in a pure form meaning it is less likely to cause allergic reactions.
• Insulin can be produced in much higher quantities and production costs are much cheaper.
• People's concerns over using animal products in humans are overcome.

For decades researchers having been searching for ways to replace the faulty Beta cells in the pancreatic islets of diabetic sufferers. Transplants can work but their demands far outweighs their availibility, the risk of having the transplant can also be greater than the diabetes itself as immosuppressant drugs are required to ensure the boy accepts the transplantd pancreas, which can leave a person susceptible to infection. Doctors have also attempted to cure diabetes by injecting patients with pancreatic Beta islet cells, but only 8% of transplants have been successful. The immunosuppressant drugs used to prevent the rejection of these cells increases the metabolic demand on insulin-producing cells, which eventually exhausts their capacity to produce insulin.

As type 1 diabetes results from the loss of a single cell type, and there is evidence that a relatively small number of islet cells can restore insulin production, the disease is a perfect candidate for stem cell therapy. Scientists have been researching the best type of totipotent stem cells and the signals required to promote their differentiation into Beta cells either directly in the patient or just before transplant. It is likely these stem cells would be harvested from embryos, but the ones that are usued are usually spare from infertility treatments or from terminated pregancies. Presevred umbilival stem cells could also be used. Stem cells offer many advantages over current therapies:

• Donot availability would not be an issue and stem cells could produce an unlimited source of new Beta cells.
• Reduced likelihood of rejections problems as embryonic stem cells are generally not rejected by the body. Stem cells can also be made by somatic nuclear cell transfer (SCNT).
• People would no longer have to inject themselves with insulin.

However because our availability to control growth and differentiation in stem cells is still limited, a major consideration is whether any precursor or stem-like cells transplanted in the body might induce the formation of tumours as a result of unlimited cell growth.

The fight or flight response is an instinct all mammals posses, when a potentially dangerous situation is detected, the body automatically triggers a series of physical responses, these are intended to help mammals survive by preparing the body either to run or to fight. Once a theat is detected by the autonomic nervous system, the hypthalamus communicates with the sympathetic nervous system which uses neuronal pathways to intitiate body reactions and the adrenal-cortical system which uses hormones in the bloodstream. The combined effects of these result in the fligh or fight response. The synpathetic nervous system sends impules to glands and smooth muscles and signals the adrenal medulla to release adrenaline and noradrenaline. The release of other stress hormones which have longer term action from the adrenal cortex are controlled by hormones produced by the pituitary gland. The hypthalamus stimulates the pituitary gland to secrete ACTH which travels in the bloodstream to the adrenal cortex where it activates the release of hormones that prepare the body to deal with threat. The heart rate increases to increase blood flow, the pupils dilate, the arterioles contract so more blood is directed to the major blood groups of of the brain, heart and lungs. Blood glucose level increases to increase the rate of respiration, the smooth muscle of the airways relaxes to allow more oxygen into the lungs and non essential systems like the digestive system shut down tp focuse energy on emergency resources.

One of adrenaline's main functions during the fight or flight response is to trigger the liver cells to undergo glycogenolysis so that glucose is released into the bloodstream. This allows respiration to increase so more energy is available for muscle contraction. Adrenaline is a hydrophillic hormone and so cannot pass through cell membranes. Adrenaline binds with receptors on the surface of a liver cell membrane and triggers a chain reaction in the cell:

• Adrenaline binds to the receptor site and as a result activates the enzyme adenyly cyclase inside the membrane. The activated enzyme coverts ATP into cyclic AMP (cAMP) which acts a second messengerthat activates other enzymes which in turn convert glycogen to glucose.
• The increases cAMP levels activate specific enzymes called protein kinases which phosphorylate and hence activate other enzymes which trigger the conversion of glycogen to glucose.

This model hormone action is known as the second messenger model, one hormone molecule can cause many cAMP molecules to form and at each stage the number of molecules involved increases so the process is said to have a cascade effect.

The heart rate is involuntary and is controlled by the autonomic nervous system. The medulla oblongata in the brain is responsible for controlling the heart rate and making any necessary changes, There are two centres within the medulla oblongata, linked to the sinoatrial node (SAN) in the heart by motor neurones:

• Once centre increases the heart rate by sending impulses through the sympathetic nervous system, these impulses are transmitted by the accelerator nerve.
• One centre decreases the heart rate by sending impulses through the parasympathetic nervous system, these impulses are transmitted by the vagus nerve.

Which centre is stimulated depends on the information received by receptors in the blood vessels. There are two types of receptors which provide information that affects the heart rate:

• Baroreceptors - these receptors detect changes in blood pressure. For example if a person's blood pressure is low the heart rate needs to increase to prevent fainting. Baroreceptors are found in the aorta, vena cava and carotid arteries.
• Chemoreceptors - thse detect changes in the levels of particular chemicals in the blood such as carbon dioxide. Chemoreceptors are located in the aorta, carotid artery, and the medulla.

Chemoreceptors are sensitive to changes in the pH level of the blood as if the carbon dioxide level in the blood increases, the pH decreases because more carbonic acid will form as a result of more carbon dioxide interacting with water. If the chemoreceptors in the carotid or aorta walls detect a decrease in blood pH as a result of more carbon dioxide being produced due to an increases rate of respiration, the centre in the medulla oblongata will send more impulses along the accelerator nerve to the SAN via the sympathetic nervous system. This will increase the heart rate and as a result more blood will flow to the lungs more quickly so the carbon dioxide can be exhaled, lowering the carbon dioxide level and pH back to its normal level. When the carbon dioxide level in the blood decreases, the pH rises which will be detected by chemoreceptors which results in the reduction in the frequency of nerve impulses being sent to the SAN via the sympathetic nervous system and will increase the frequency of impulses sent along the vagus nerve via the parasympathetic nervous system, resulting the heart rate decreasing back to its normal level, and less carbon dioxide being exhaled per unit of time, decreasing the pH of the blood.

Baroreceptors present in the aorta and carotid artery wall detect changes in pressure. If the blood pressure is too high impulses are sent to the medulla oblongata, which then sends impulses along the parasympathetic neurones to the SAN whoch decreases the rate at which the heart beats, reducing the blood pressure back to normal. If the blood pressure is too low impulses are sent to the medulla oblongata which then increases the frequency of impulses sent along the accelerator nerve via the sympathetic nervous system to the SAN which results in an increase in the heart, increasing the blood pressure back to normal.

Heart rate is also influenced by the presence of hormones. For example in times of stress adrenaline and noradrenaline are released which affect the pacemaker region of the heart itself and speed up the heart rate by increasing the frequency of impules produced by the SAN.