Pyramid Science

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Thursday, January 01, 2009


The endocrine and nervous systems both function to achieve and maintain the stability of the internal environment. Each system may work alone or they may all work in concert as a single neuroendocrine system. They perform the same purpose of communication, integration and control and both systems carry out their regulatory function through chemical messengers sent to specific cells. In the nervous system, neurons secrete neurotransmitters to signal nearby cells that have the appropriate receptor molecules. In the endocrine system, secreting cells send out hormone (Greek "hormaein" to excite) molecules by way of the blood stream to signal specific target cells throughout the body. Target tissues and target organs are the tissues and organs that contain the endocrine target cells. As with postsynaptic cells, endocrine target cells must have the appropriate receptor to be influenced by the signalling chemical. Many cells have receptors for neurotransmitters and hormones and can be influenced by both. Neurotransmitters are sent over very short distances across the synaptic junction, but hormones diffuse into the blood to be carried to nearly every point in the body.
The nervous system can control only muscles and glands that are innervated with efferent nerves whereas the endocrine system can regulate most cells of the body. Neurotransmitters are short lived, but work rapidly. Hormones are slower to act, but the effects last considerably longer. The secretion into the blood is directly from ductless glands. This distinguishes between endocrine and exocrine glands: secretions via ducts.

Neurosecretory cells are modified neurons which secrete chemical messengers into the bloodstream rather than across a synapse. The chemical messenger in this case is called a hormone rather than a neurotransmitter. When norepinephrine is released by neurons, it diffuses across the synapse and binds to an adrenergic receptor in a postsynaptic neuron. In this case norepinephrine is a neurotransmitter. On the other hand it is a hormone when it diffuses into the blood (because there is no postsynaptic cell present) and binds to a distant adrenergic receptor in a distant target cell.

Hormones are classified in various ways and are identified as:

In a chemical sense, steroid hormones are manufactured from cholesterol and there are structural similarities. They are lipid (fat) soluble and so easily pass through phospholipid plasma membrane of the target cell. Cortisol, aldosterone, estrogen, progesterone and testosterone are examples of steroid hormones. Non-steroid hormones mostly come from amino acids though some non-steroid hormone are protein hormones (or peptide hormones) and are long, folded chains of amino acids.
Those protein hormones that have carbohydrate groups attached to amino acid chains are often classified as non-steroid glycoprotein hormones.
Follicle stimulating hormone (FSH), luteinising hormone (LH) or prolactin (LTH: luteotropic hormone), thyroid stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) are all tropic hormones (peptide hormones) and are produced and secreted by the basophils of the pars anterior. They have a stimulating effect on the endocrine glands. These hormones stimulate the development of their target glands and tend to stimulate synthesis and secretions of the target hormone. FSH and LH are gonadotropins because they stimulate growth and maintenance of the gonads (ovaries and testes). The adenohypophysis in childhood releases insignificant amounts then a few years before puberty releases gradually increasing amounts until suddenly the output spurts and gonads are stimulated to develop and begin normal functions. A pituitary tumour may result in hypersecretion (too much) of tropic hormones. Early secretion of gonadotropins may lead to abnormally early onset of puberty and abnormal secretions may disrupt reproduction, kidney function, overall metabolism and other processes: hyposecretion (too little) and hypersecretion (too much).

Peptide hormones. Non-steroid category such as oxytocin (OT) and antidiuretic hormone (ADH) smaller than protein hormones and are made from short chain of amino acids. Also, melanocyte-stimulating hormone (MSH), somatostatin, thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GNRH). A further category of non-steroid hormones consists of the amino-acid derivative hormone. Each is derived from a single amino acid molecule.

There are two major subgroups:
  • Amine hormones
    • synthesised by modifying the amino acid tyrosine and are produced by nonsecretory cells (secreted as hormones) and by neurons (secreted as neurotransmitters).
  • Amino acid derivatives
They operate by the lock and key theory and switch on a cell by receptor acceptance. The target cell may have several different receptors and can be affected by many hormones. Different hormones produce a different effect within the same target cell. Chemical reactions within the cell are altered or modified. Some hormone-receptor interactions trigger the activation or inactivation of certain enzymes and others may regulate activity by opening or closing specific ion channels in membranes. Hormones may work together to enhance each other's influence on the target cell. This is synergism. The effect of both working together is greater than each operating individually. They may exhibit permissiveness which is the full effect of a hormone facilitated by the presence of a small amount of another. The first hormone permits the full action of the second hormone or conversely, by antagonism lowers the activity of the second hormone. A feedback mechanism is put in place through this effect.

Steroid hormone mode of action

Steroid hormones are lipids and therefore not particularly soluble in the watery plasma of the blood. They are carried in the blood attached to plasma proteins to confer solubility. They are not freely floating molecules and to be effective must free themselves to reach the target cell receptors. Blood carries hormones throughout the body even where target cells are not present so generally the endocrine glands produce more hormones than are necessary to produce the desired effect. Any excess is either excreted by the kidney or broken down (rendered inactive) by metabolic processes. They pass easily through cell membrane as lipid soluble steroid hormones where receptors are normally found (within the cell rather than on the surface). Once the steroid hormone has diffused into the target cell, it passes into the nucleus and binds to a mobile receptor molecule to form a hormone-receptor complex. Some hormones must be activated by enzymes before they can bind to their receptors. The steroid hormone receptors seem to be free floating in the nucleoplasm so this model has been termed the mobile-receptor hypothesis. Once formed, the hormone-receptor complex activates a certain gene sequence to begin transcription of messenger RNA (mRNA) molecules. These move out of the nucleus into the cytosol (still within the cell) where they associate with ribosomes to begin synthesising specific protein molecules. These would not have been made if the hormone had not been present to act as the trigger.

Steroid hormones regulate cells by controlling the production of certain critical proteins, such as enzymes that effect intracellular reactions or membrane proteins that alter the permeability of the cell. The extracellular hormone in effect initiates the synthesis of the key from within the cell to activate a lock to produce the desired effect. The amount of a hormone will determine the amount of mRNA (via hormone-receptor complexes) formed and hence the level of transcription to form new proteins. So this amount of hormone determines the magnitude of the target cell's response. The time taken can be from 45 minutes to several days for the full effects to be seen.

Non-steroid mode of action

The mechanism of non-steroid hormones is different. This type of hormone typically operates according to the second messenger hypothesis. A non-steroid hormone initially acts as a "first messenger" delivering its chemical message to fixed receptors in the target cell's plasma membrane. This message is then passed into the cell where a "second messenger" triggers the appropriate cellular changes. This concept is called the fixed-membrane-receptor hypothesis. The formation of the hormone-receptor complex causes a membrane protein (G protein) to bind to a nucleotide (guanosine triphosphate - GTP) in turn activating another membrane protein (adenyl cyclase). This enzyme cleaves off two phosphate groups from ATP in the cytosol leaving cyclic adenosine monophosphate (cAMP). This is the "second messenger" within the cell and activates (or inactivates) protein kinases, a set of enzymes that activate other enzymes. The target enzymes are switched on and catalyse the cellular reactions that characterise the target cell's response. The "first messenger" hormone binds to a membrane receptor triggering the formation of an intracellular "second messenger" which activates a cascade of chemical reactions producing the target cell's response. Although most non-steroid hormones use cAMP as second messenger, some use inositol triphosphate (IP3) and cyclic guanosine monophosphate (cGMP).

Others trigger the opening of Ca++ channels in the target cell's membrane through activation of a chain of membrane proteins (G protein and phosphodiesterase, PDE2). Ca++ ions then enter the cytosol and bind to an intracellular molecule (calmodulin). This Ca++ : calmodulin complex then acts as "second messenger" influencing the enzymes that produce the target cell's response. The second messenger mechanism produces target cell effects that differ from steroidal hormone effects in two important ways.
  • The cascade reactions greatly amplify the effects of the hormone and results in a disproportionate effect compared to the amount of non-steroid hormone present.
  • The effect of the steroid hormone is directly proportional to the amount of that hormone present.
The second messenger mechanism also acts very much quicker to reach full effect. Typically seconds or minutes after initial binding to target cell instead of hours or days for steroid hormones. Not all non-steroid hormones operate through this second messenger model. One notable exception is the pair of thyroid hormones thyroxine (T4) and triiodothyronine (T3). These small iodinated amino acids enter the target cell and bind to receptors already associated with a DNA molecule within the nucleus of the target cell. Formation of the hormone-receptor complex triggers transcription of mRNA and the synthesis of new enzymes similar to the steroid mechanism.

Cell sensitivity

Sensitivity to any particular hormone depends on the number of receptors. These receptors are constantly broken down and replaced with newly synthesised ones as any other cell component. Not only are "new" cell parts made which work properly, but this also allows their number to change with time. If the synthesis of new receptors outstrips their degradation then greater hormone sensitivity will occur: up regulation. Conversely, down regulation leads to less sensitivity. The feedback (endocrine reflex) control the effects of hormones by adjusting levels. The negative feedback loops tend to reverse any deviation of the internal environment away from its stable point. Positive feedback controls the secretion of a hormone. The deviation from the stable point is exaggerated rather than reversed. The simplest mechanism operates when an endocrine cell is sensitive to the physiological changes produced by its target cells. Parathyroid hormone (PTH) produces responses in its target cells that increase Ca++ ion concentration in the blood. When this concentration exceeds a set point value, parathyroid cells sense it and reflexively reduce their output of PTH. (The parathyroid cell monitors extracellular free calcium concentration via an integral membrane protein that functions as a calcium-sensing receptor.) Lactation is caused by prolactin (PRL). This is a lactogenic hormone and, as a pituitary gland hormone, stimulates lactation in pregnant women and consumes Ca++. This reduces blood concentration. The parathyroid glands sense this change and respond by increasing PTH secretions. This in turn stimulates osteoclasts in bone to release more Ca++ from storage in bone tissue into the bloodstream thereby elevating levels. Secretions by many endocrine glands is regulated by a hormone produced by another gland. The pituitary gland (specifically the anterior portion) produces thyroid stimulating hormone (TSH): a non-steroid glycoprotein hormone. The pituitary gland triggers the thyroid to produce its hormone and the pituitary gland reflexively responds to the altering levels and adjusts accordingly by this negative feedback process. Secretions of the pituitary gland can also be controlled by secretions from the hypothalamus (stimulate or inhibit the release of pituitary hormones). A more precise regulation of hormone blood levels is possible by these additional long feedback loops involving the anterior pituitary and hypothalamus. The nervous system can also influence hormone secretions. The posterior pituitary is not regulated by releasing hormones, but by direct nervous input from the hypothalamus. Sympathetic nerve impulses similarly reach the medulla of the adrenal glands and trigger the release of epinephrine and norepinephrine. Many other glands (pancreas) are also influenced to some degree by nervous input. The close functional relationship between these two systems is emphasised by the nervous system operating with the hormonal mechanisms to produce endocrine reflexes. Although these long feedback loops tend to minimise wide fluctuations in secretions, the output of several hormones typically rises and falls dramatically within a short period of time. Insulin concentrations are dependent on blood glucose levels and increases to a high level just after a carbohydrate meal. The insulin level decreases only after blood glucose settles to its set point value. The non-steroid amino acid hormone epinephrine (from the adrenal medulla) can cause a sudden infusion as part of the fight-or-flight response.

Focus on insulin

The pancreas is a mixed endocrine and exocrine gland. Mostly, this involves secretions of digestive enzymes and bicarbonate solution. The endocrine part is the Islet of Langerhans and is one to two million clusters (islets) of cells scattered between the exocrine acinar cells (acini). Each islet is a collection of several different types of cell, each supposedly secreting a particular pancreatic hormone. Alpha cells (A) are less numerous, located peripherally and secrete glucagon. The central beta cells (B) are more in number and secrete insulin. Delta cells (D) cells are more sparse and secrete somatostatin. Insulin and glucagon regulate the metabolism of carbohydrates in tissues and ensure the maintenance of optimal blood glucose levels (normal fasting level between 0-110mg/100ml). Insulin facilitates the transport of glucose across the cell membrane of mostly muscle tissue (heart, skeletal and smooth) and adipose tissue (fat).

No matter how much glucose is present in the blood, membranes are impermeable to glucose in the absence of insulin. Insulin enhances the availability of glucose in cells and promotes its utilisation and becomes bound to the insulin receptors in the plasma membrane of target cells. Insulin functions as a hypoglycemic hormone by decreasing blood sugar. Glucagon also enhances carbohydrate utilisation by mobilising glucose from liver (stored as) glycogen. This functions as a hyperglycemic hormone by increasing blood glucose. Somatostatin inhibits the secretion of both insulin and glucagon, the levels of which are influenced by each other: glucagon promotes secretion of both insulin and somatostatin, but insulin inhibits glucagon secretions. An increase in glucose is detected by the beta cells (B) and insulin is released and transported to the tissues promoting glucose uptake and utilisation and so lowering blood sugar levels. The interaction between blood glucose and insulin provides another example of simple hormonal regulation by negative feedback with no nervous system involvement.

A signal is generated in the beta cell (B) resulting in the release of Ca++ ions which interact with secretory vesicles promoting their fusion with the cell membrane. The resulting exocytosis releases insulin into the blood. The Ca++ ions also promote a longer-lasting response (increased synthesis of insulin) at the cytoplasmic level ensuring insulin is available for prolonged secretion (hours) until the hyperglycemia is eliminated. The primary stimulus for glucagon release is a decrease in level of blood sugar below its normal limit. Glucose detectors in the alpha cells (A) of the pancreatic islets sense this and release glucagon, which binds with specific receptors in the membranes of liver cells. This activates the enzyme adenylate cyclase: cyclic adenosine monophosphate (cAMP). This acts as second messenger initiating a cascade of chemical reactions involving the activation of enzymes, but not their synthesis. The amplification mechanism ensures a rapid (within seconds) mobilisation of enzymes to break down liver glycogen through glycogenolysis. Glucagon also stimulates the synthesis of new glucose from amino acids in the liver (gluconeogenesis) when glucose is low. This is a slower process and becomes more important in fasting and starvation. The mobilisation of glucose by the action of glucagon ensures the glucose leaks out into the blood increasing sugar levels and supply for constant users like the brain and heart. Negative feedback on alpha cells (A) decreases glucagon release until the glucose level falls again due to its constant use. Glucagon release is then initiated again. Insulin and glucagon although opposite in their effects: insulin is hypoglycemic causing sugar insufficiency and glucagon is hyperglycemic promoting sugar over-sufficiency. They act in a complementary way to regulate carbohydrate metabolism and provide ample glucose supply for tissues.

Insulin is made up of an A chain and B chain peptide connected at two locations by disulphide (-S-S-) bridging bonds. The beta cells (B) of the endoplasmic reticulum synthesise the larger peptide chain proinsulin but release insulin into the blood. During packaging in the vesicles of the Golgi apparatus, protease (an enzyme) converts proinsulin to insulin by selective peptide hydrolysis. The C chain is attached to one end of A chain and the other end of the B chain is cleaved. The disulphide bridges fold the long peptide chain so the long chain is firstly extended then further modified by bridging.

The C chain can be proposed as a shape assisting moiety which is then discarded. It brings the A and B parts into close proximity for subsequent joining. The two parts (A+B and C chain) are transported together within secretor vesicles, although separated, toward the plasma membrane of the beta cells (B). Near a capillary, the contents of the vesicles are released into the blood by exocytosis of the vesicles. The fate of the C chain is uncertain. Muscle cells normally prefer to use glucose for oxidation and cellular energy metabolism. Once inside a muscle cell glucose is oxidised to provide ATP or is converted to glycogen (rest condition). During activity glycogen is broken down to provide glucose within the cell. Insulin promotes glucose entry into fat cells of adipose tissue where it is not used to provide energy for the fat cell. Instead it is metabolised to form two molecules of glycerol from one glucose unit. Each glycerol molecule combines with three fatty acids to form one triglyceride as the storage form of fat. Fatty acids are usually obtained from the blood (initially from the liver). Insulin also inhibits a lipase enzyme (fat cleavage) which prevents fat breakdown. The direct action of insulin on liver cells does not promote increased transport of glucose because liver cells are normally permeable to glucose. Instead by stimulating the synthesis or actions of specific enzymes, insulin promotes the utilisation of glucose for glycogen, amino acids and proteins and fats, particularly fatty acid, synthesis. These fatty acids are used by adipose tissue to form triglycerides. Insulin does not influence glucose uptake by the brain, kidney tubules and intestinal mucosa mainly because these membranes are permeable to glucose passage. This may be an adaptive response because the nervous tissue relies solely on glucose for its energy needs and a constant and plentiful supply is essential. Alterations in insulin secretions would have major consequences on brain function. A large dose (by injection) of insulin may result in coma or death by causing hypoglycemia and starving the brain of glucose as its energy and fuel source. The special transport functions for glucose by the intestinal mucosa and kidney tubules ( unrelated to its utilisation for energy) preclude their regulation by insulin.

Insulin deficiency

The range of glucose over sufficiency is from between 2-4 times normal (before-after meal). The hyperglycemia is due to both the decreased glucose uptake by muscle and adipose tissue and increased glucose output by liver. As a result, takes 6-8hrs vs 1-2hrs to fall to premeal levels. Muscle cells are deprived of glucose as it remains in the blood and so other sources of energy are used. Fat and protein reserves are utilised for oxidation resulting in muscle wasting, weakness and weight loss. The weight loss is worsened because not only can glucose fail to enter these cells, but also triglycerides are broken down to form and mobilise free fatty acids. The hormone-sensitive lipase is removed. Diabetics are characteristically thin and fatty acids provide energy for the heart and muscle tissue. Excessive fatty acids production results in formation of keto acids (ketone bodies), particularly in the liver. The ketones enter the blood stream causing ketosis and ketoacidosis, which is a very dangerous condition if left untreated giving rise to metabolic acidosis. The increased blood acidity suppresses the higher nervous centres (coma). Ultimately, depression of the brain respiratory centres leads to death. These ketone bodies are excreted in the urine worsening the osmotic diuresis (excess water in urine) caused by the glucose. Normally, as long as the blood sugar level stays below about 170mg/100ml, plasma glucose is filtered by the Bowman capsule of the kidney nephron and is completely reabsorbed in the proximal tubules. The extra glucose present in the hyperglycemic condition spills over into the urine causing glycosuria (sugar in urine) , a well-recognised sign of diabetes mellitus and insulin deficiency. This has the consequences of polyuria (excess urine production) and polydipsia (excessive drinking of water) due decreased plasma volume and increased plasma osmolarity. Excessive water loss may lead to severe dehydration and osmotic shock, conditions that can also result in irreversible brain damage, coma and death.

Diabetes mellitus

This is a spontaneous disease and is of two types:
  • Type I
    • Juvenile - seen in children and young adults
  • Type II
    • Maturity onset and usually seen in obese individuals over forty
Type I is associated with the lack or serious deficiency of insulin and may be an autoimmune disease probably without genetic or familial traits. If untreated it is often fatal due to ketoacidosis and dehydration shock. This is remedied by an insulin injection. Maturity onset Type II diabetes shows strong familial association and the insulin deficiency is relative, because the absolute amounts in the blood may be even higher than in normal individuals. Due to prolonged obesity a reduction in the number of insulin receptors in target cells occurs (down-regulation), perhaps caused by a steady, but high insulin production. The available insulin is not as effective resulting in a signs similar to insulin deficiency like hyperglycemia, glycosuria, polydipsia and weight loss. Only ketosis does not occur. Extra insulin may be corrective but simple weight reduction will frequently ameliorate the diabetic condition. However, for reasons not completely understood if untreated, this may lead to vascular diseases that can cause blindness, atherosclerosis, heart and kidney diseases and gangrene. The use of exogenous insulin derived from the pancreas of livestock can stop and reverse the pathological chain of events seen in diabetic patients. One complication is that animal insulin is antigenic and gradually becomes ineffective as the body makes antibodies against this foreign protein. Genetic engineering and new methods of molecular biology are now being researched in order to synthesise human insulin. Such material is not antigenic.


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