ANATOMY AND PHYSIOLOGY

The pancreas is an elongated retroperitoneal gland that lies in the upper portion of the posterior abdominal wall. It resembles a fish, with its head and neck lying in the C-shaped curved of the duodenum, its body extending horizontally behind the stomach, and its tail touching the spleen. The head is at the level of the second lumbar vertebra, makes up about 30% of the gland, and lies within the concavity of the duodenum. The neck, the narrowed portion between the head and the body, joins to the body, which accounts for the largest portion of the gland. The tail tapers off from the body. The pancreas is firm, and has a characteristics lobular appearance with a light yellow and slightly pink coloration.

In the adult, the total length of the pancreas varies between 12 and 20 cm, with a width of 3 to 5 cm. and a maximal thickness of 2 to 3 cm. its weight is between 60 and 140 g.

The endocrine portion of the pancreas, the islets of Langerhans, is embedded between exocrine units like small islands. The islets contain four types of cells: the alpha (A), beta (B), delta, and pancreatic polypeptide. These types composed 20%, 70%, 5% to 10%, and 1% to 2% of islet cell population, respectively. All of these cells empty their secretions into the blood stream. Alpha cells secrete glucagons, Beta cells secrete insulin, and Delta cells contain secretory granules that secrete gastrin, or somatostatin. The PP cells have small dark granules, and are present on the islets and the exocrine pancreas. The PP cells secrete a unique pancreatic polypeptide that causes gastrointestinal effects of gallbladder contraction and inhibition of pancreatic enzyme secretion. No metabolic effects by pancreatic polypeptide on glucose, fat, or amino acids have been established. Studies have revealed elevated basal and postprandial PP in lean people who have non-insulin-dependent diabetes mellitus. Although there

are as 2 million islets, 20 to 30m, in diameter, the endocrine portion composes only about 1% of the weight of the pancreas.

PHYSIOLOGIC REGULATION OF INSULIN SECRETION

The main function of the endocrine portion of the pancreas is to secrete insulin, a hormone essential for normal carbohydrate metabolism. Insulin also influences the metabolism. Insulin also influences the metabolism of fats and proteins. Therefore, it is prime anabolic hormone and integrates the major metabolic fuels.

Insulin consists of two amino acid chains and is synthesized from a biologically inactive, pro-insulin, by the beta cells. Study indicates that pro-insulin itself is derived from an even larger polypeptide, preproinsulin. The average adult pancreas secretes an estimated 35 to m50 units of insulin daily.

Carbohydrates (primarily glucose), fats and proteins influence insulin output during meals. Insulin is the only known hormone that reduces the circulating glucose levels. Although numerous physiologic may alter insulin secretion, output is regulated by blood glucose level through a negative feedback mechanism. When the glucose in the blood that is perfusing the pancreas

exceeds about 100mg/dl, an immediate beta cell response extrudes the granules contents from the beta cells. When blood glucose levels fall, the rate of insulin secretion also decreases. The release of insulin biphasic-Glucose prompts both an immediate and a sustained release as more insulin is synthesized. The feedback mechanism is rapid-acting, with insulin levels reaching 10 to 20 times the basal rate with blood glucose levels of 300 to 400 mg/dl. The cessation of secretion is equally rapid, occurring within minutes after restoration of blood glucose to fasting level.

Amino acids also can stimulate insulin secretion in varying degrees. The most potent stimulants are arginine, lysine, and phenylalanine. Insulin in turn promotes transport of the amino acids into the tissue cells.

Fats, although weak stimulators of insulin release promote sufficient amount to prevent ketoacidosis. Oral ingestion of fat triggers release of gastrointestinal hormones that augment insulin secretion.

Although insulin secretion is mostly considered in terms of response to nutrients, measurable amounts are secreted at a low rate between meals and during prolonged fasting. The gastrointestinal hormones secretion,

cholecystokinin, gastrin, and gastric-inhibiting peptide which are release by the gastrointestinal tract after a meal, stimulate pancreatic insulin release. These hormones release during digestion, because an anticipatory increase in blood insulin preparatory for the glucose and amino acids absorbed from the meal.

Other hormones that either directly increase the secretion of insulin or potentiate glucose stimulation of insulin are glucagon, cortisol, growth hormone, progesterone and estrogen. Prolonged increased amounts of these hormones can lead to exhaustion of beta cells and diabetes. The hormone glucagon, which is synthesized in the pancreatic alpha cells, affects hepatic glucose production and is important in the pathophysiology of diabetes. High pharmacologic doses of

corticosteriods also may induce diabetes, especially in people who have a tendency toward diabetes.

The autonomic nervous system plays a major role in modulating insulin secretion between meals, during times when there is no intake, and in response to stressors. Norepinephrine and acetylcholine, transmitters of the autonomic nervous system, and the adrenomedulary hormone epinephrine influence secretions of alpha, beta, and delta cells of the islets of Langerhans. The Alpha adrenergic activities of the sympathomimetic amines (epinephrine and

norepinephrine) inhibit insulin secretion. Although catecholamine stimulation of beta-adrenergic sites increases insulin secretion, the alpha-adrenergic action of epinephrine predominates.

Other factors, primarily pharmacologic, that stimulate insulin secretion include sulfonylurea drugs and theophyline. In contrast, beta receptor-blocking agents and diazoxide inhibit secretion.

Effect of Insulin on Facilitated Diffusion

Insulin is an influential hormone that affects the biochemical function of every organ in the body. Its most important action is accelerating the transport of glucose across most cell membranes in the body. In the absence of insulin, the rate of transport of glucose into body cells is about one-fourth normal; when an excess is secreted, the rate may increase to five times normal. Carrier mediated transport of the inside of the membrane and its release transport by means of carrier mechanism called facilitated diffusion, or carrier transport. Insulin influences the transport of glucose into the cell by combining with a receptor protein in the cell membrane, a direct action on the cell a receptor protein in the cell membrane. A direct action on the cell membrane is implied, since glucose transport occurs within seconds or minutes. Once the glucose concentrations inside the cell are equal to that on the outside, additional glucose is not

transferred into cell. Insulin is especially effective in facilitating transport of glucose in skeletal and adipose tissue, the liver, and the heart. Adipose and skeletal tissues alone make up 65% of body weight.

Insulin does not enhance glucose transport into the brain, erythrocytes, leukocytes, intestinal mucosa, or epithelium of the kidneys. The brain continues to function normally when insulin deficiency causes hyperglycemia. In erythrocytes and leukocytes, the level of free glucose is close to that in plasma. These cells do not suffer from insulin deficiency, but they cannot survive glucose deficiency.

Metabolic Effects of Insulin

Insulin stimulates reactions that involve fats, carbohydrates, and proteins. Insulin affects carbohydrate metabolism by increasing the rate of glucose metabolism, decreasing blood glucose concentration, and increasing glycogen stores in the muscle and liver. Insulin affects fat metabolism by increasing the rate of glucose transport into fat cells, forming lipids from fatty acids, and promoting storage in adipose tissue. Insulin affects protein by increasing translation of the messenger ribonucleic acid (RNA) code in the ribosomes to form more protein, and by enhancing transcription of deoxyribonucleic acid (DNA) to form more RNA, thereby resulting in additional synthesis.

Insulins diverse effects are integrated so that it is prime synthesis and storage hormone in metabolism. Its actions are focused on three metabolically important tissues-liver, adipose, tissue, and muscle.

In summary, insulin is primarily a storage hormone. Its diverse metabolic actions on various targets demonstrate the integrated and synergistic effect it has

on the metabolism of fats, carbohydrates, and protein. Each molecule of glucose that enters a cell is immediately phosphorylated. Adipose tissue and muscle

take up glucose only under the influence of insulin, phosphorylate it, and either store it in the form of glycogen or convert it to triglycerides (fatty acids). At the same time, the presence of free fatty acids impedes glucose oxidation and decreases the release of amino acids from muscle for hepatic gluconeogenesis. Glucose uptake by muscle is also stimulated, providing fuel to replace fatty acids whose release from adipose tissue is inhibited by insulin. Fat accumulation also in increased by release of fatty acids at the adipose cell from lipoproteins that arrive by way of the circulation from the liver and gastrointestinal tract. The antilipolytic action of insulin on the adipose cell increases fat storage, and thereby inhibits gluconeogenesis in the liver by depriving the liver of fatty acids and cofactors used in gluconeogenesis.

The circulatory system is responsible for the transport of water and dissolved materials throughout the body, including oxygen, carbon dioxide, nutrients, and waste. The circulatory system transports oxygen from the lungs and nutrients from the digestive tract to every cell in the body, allowing for the continuation of cell metabolism. The circulatory system also transports the waste products of cell metabolism to the lungs and kidneys where they can be expelled from the body. Without this important function toxic substances would quickly build up in the body. The human circulatory system is organized into two major circulations. Each has its own pump with both pumps being incorporated into a single organthe heart. The two sides of the human heart are separated by partitions, the interatrial septum and the interventricular septum. Both septa are complete so that the two sides are anatomically and functionally separate pumping units. The right side of the heart pumps blood through the pulmonary circulation (the lungs) while the left side of the heart pumps blood through the systemic circulation (the body).

The human heart is a specialized, four-chambered muscle that maintains the blood flow in the circulatory system. It lies immediately behind the sternum, or breastbone, and between the lungs. The apex, or bottom of the heart, is tilted to the left side. At rest, the heart pumps about 59 cc (2 oz) of blood per beat and 5 l (5 qt) per minute. During exercise it pumps 120-220 cc (4-7.3 oz) of blood per beat and 20-30 l (21-32 qt) per minute. The adult human heart is about the size of a fist and weighs about 250-350 gm (9 oz). The human heart begins beating early in fetal life and continues regular beating throughout the life span of the individual. If the heart stops beating for more than 3 or 4 minutes permanent brain damage may occur. Blood flow to the heart muscle itself also depends on the continued beating of the heart and if this flow is stopped for more than a few minutes, as in a heart attack, the heart muscle may be damaged to such a great extent that it may be irreversibly stopped. The heart is made up of two muscle masses. One of these forms the two atria (the upper chambers) of the heart, and the other forms the two ventricles (the lower chambers). Both atria contract or relax at the same time, as do both ventricles. An electrical impulse called an action potential is generated at regular intervals in a specialized region of the right atrium called the sinoauricular (or sinoatrial, or SA) node. Since the two atria form a single muscular unit, the action potential will spread over the atria. A fraction of a second later, having been triggered by the action potential, the atrial muscle contracts. The ventricles form a single muscle mass separate from the atria. When the atrial action potential reaches the juncture of the atria and the ventricles, the atrioventricular or AV node (another specialized region for conduction) conducts the impulse. After a slight delay, the impulse is passed by way of yet another bundle of muscle fibers (the Bundle of His and the Purkinje system.) Contraction of the ventricle quickly follows the onset of its action potential. From this pattern it can be seen that both atria will contract

simultaneously and that both ventricles will contract simultaneously, with a brief delay between the contraction of the two parts of the heart. The electrical stimulus that leads to contraction of the heart muscle thus originates in the heart itself, in the sinoatrial node (SA node), which is also known as the heart's pacemaker. This node, which lies just in front of the opening of the superior vena cava, measures no more than a few millimeters. It consists of heart cells that emit regular impulses. Because of this spontaneous discharge of the sinoatrial node, the heart muscle is automated. A completely isolated heart can contract on its own as long as its metabolic processes remain intact. The rate at which the cells of the SA node discharge is externally influenced through the autonomic nervous system, which sends nerve branches to the heart. Through their stimulatory and inhibitory influences they determine the resultant heart rate. In adults at rest this is between 60 and 74 beats a minute. In infants and young children it may be between 100 and 120 beats a minute. Tension, exertion, or fever may cause the rate of the heart to vary between 55 and 200 beats a minute. The heart's pace maker is the Sinoatrial (SA) Node. The Heart Sounds The closure of the heart valves and the contraction of the heart muscle produce sounds that can be heard through the thoracic wall by the unaided ear, although they can be heard better when amplified by a stethoscope. The sounds of the heart may be represented as lubb-dubb-pause-lubb-dubb-pause. The lubb sound indicates the closing of the valves between the atria and ventricles and the contracting ventricles; the dubb sound indicates the closing of the semilunar valves. In addition, there may also be cardiac murmurs, especially when the valves are abnormal. Some heart murmurs, however, may also occur in healthy persons, mainly during rapid or pronounced cardiac action. The study of heart sounds and murmurs furnishes valuable information to physicians regarding the condition of the heart muscle and valves.

Coronary Circulation The coronary arteries supply blood to the heart muscle. These vessels originate from the aorta immediately after the aortic valve and branch out through the heart muscle. The coronary veins transport the deoxygenated blood from the heart muscle to the right atrium. The heart's energy supply is almost completely dependent on these coronary vessels. When the coronary vessels become blocked, as in arteriosclerosis or hardening of the arteries, blood flow to the cardiac muscle is compromised. This is when the common "bypass surgery" is performed where the coronary arteries are "bypassed" by replacing them with, for example, a vein from the leg. A "double bypass" is when two coronary arteries are bypassed. A "triple bypass" is when three are bypassed, etc. The Heartbeat The heart muscle pumps the blood through the body by means of rhythmical contractions (systole) and relaxations or dilations (diastole). The heart's left and right halves work almost synchronously. When the ventricles contract (systole), the valves between the atria and the ventricles close as the result of increasing pressure, and the valves to the pulmonary artery and the aorta open. When the ventricles become flaccid during diastole, and the pressure decreases, the reverse process takes place. The Pulmonary Circulation From the right atrium the blood passes to the right ventricle through the tricuspid valve, which consists of three flaps (or cusps) of tissue. The tricuspid valve remains open during diastole, or ventricular filling. When the ventricle contracts, the valve closes, sealing the opening and preventing backflow into the right atrium. Five cords attached to small muscles, called papillary muscles, on the ventricles' inner surface prevent the valves' flaps from being forced backward. From the right ventricle blood is pumped through the pulmonary or semilunar valve, which has three half-moon-shaped flaps, into the pulmonary artery. This valve

prevents backflow from the artery into the right ventricle. From the pulmonary artery blood is pumped to the lungs where it releases carbon dioxide and picks up oxygen.

The Systemic Circulation From the lungs, the blood is returned to the heart through pulmonary veins, two from each lung. From the pulmonary veins the blood enters the left atrium and then passes through the mitral valve to the left ventricle. As the ventricles contract, the mitral valve prevents backflow of blood into the left atrium, and blood is driven through the aortic valve into the aorta, the major artery that supplies blood to the entire body. The aortic valve, like the pulmonary valve, has a semilunar shape. The aorta has many branches, which carry the blood to various parts of the body. Each of these branches in turn has branches, and these branches divide, and so on until there are literally millions of small blood vessels. The smallest of these on the arterial side of the circulation are called arterioles. They contain a great deal of smooth muscle, and because of their ability to constrict or dilate, they play a major role in regulating blood flow through the tissues. The major artery that supplies blood to the body is the aorta.

The blood passing through the arterioles passes through a bed of minute vessels called capillaries, which are a single cell thick. These capillaries are so small that the red blood cells must line up single file to pass through. The exchange of nutrients and waste products takes place between the capillary blood and the tissue fluids. The arterialized blood that enters the capillaries thus becomes venous blood as it passes through them. The capillaries empty the venous blood into collecting tubes called venules, and these in turn empty into small veins, which empty into larger veins, and so on until finally all the blood returns to the heart through two large veins, the superior and inferior vena cavae. These terminate in the right atrium, and the systemic circulation is complete. A one-way flow of blood in this system is maintained by valves located, not only in the heart, but in the veins as well. Some veins also have semilunar valves and the pressure of contracting muscles against the veins works with the action of these valves to increase the venous return to the heart. This is the reason that exercise is so important for the circulation. The kidneys are essentially regulatory organs which maintain the volume and composition of body fluid by filtration of the blood and selective reabsorption or secretion of filtered solutes. The kidneys are retroperitoneal organs (ie located behind the peritoneum) situated on the posterior wall of the abdomen on each side of the vertebral column, at about the level of the twelfth rib. The left kidney is lightly higher in the abdomen than the right, due to the presence of the liver pushing the right kidney down. The kidneys take their blood supply directly from the aorta via the renal arteries; blood is returned to the inferior vena cava via the renal veins. Urine (the filtered product containing waste materials and water) excreted from the kidneys passes down the fibromuscular ureters and collects in the bladder. The bladder muscle (the detrusor muscle) is capable of distending to accept urine without increasing the pressure inside; this means that large volumes can be collected (700-1000ml) without high-pressure damage to the renal system occuring.

When urine is passed, the urethral sphincter at the base of the bladder relaxes, the detrusor contracts, and urine is voided via the urethra.

Structure of the

kidney

On sectioning, the kidney has a pale outer region- the cortex- and a darker inner region- the medulla.The medulla is divided into 8-18 conical regions, called the renal pyramids; the base of each pyramid starts at the corticomedullary border, and the apex ends in the renal papilla which merges to form the renal pelvis and then on to form the ureter. In humans, the renal pelvis is divided into two or three spaces -the major calyces- which in turn divide into further minor calyces. The walls of the calyces, pelvis and ureters are lined with smooth muscle that can contract to force urine towards the bladder by peristalisis. The cortex and the medulla are made up of nephrons; these are the functional units of the kidney, and each kidney contains about 1.3 million of them.

The nephron is the unit of the kidney responsible for ultrafiltration of the blood and reabsorption or excretion of products in the subsequent filtrate. Each nephron is made up of:
y

A filtering unit- the glomerulus. 125ml/min of filtrate is formed by the kidneys as blood is filtered through this sieve-like structure. This filtration is uncontrolled.

The proximal convoluted tubule. Controlled absorption of glucose, sodium, and other solutes goes on in this region.

The loop of Henle. This region is responsible for concentration and dilution of urine by utilising a counter-current multiplying mechanism- basically, it is waterimpermeable but can pump sodium out, which in turn affects the osmolarity of the surrounding tissues and will affect the subsequent movement of water in or out of the water-permeable collecting duct.

The distal convoluted tubule. This region is responsible, along with the collecting duct that it joins, for absorbing water back into the body- simple maths will tell you that the kidney doesn't produce 125ml of urine every minute. 99% of the

water is normally reabsorbed, leaving highly concentrated urine to flow into the collecting duct and then into the renal pelvis.

THE FORMATION OF URINE FIGURATION, REABSORPTION, AND SECRETION Every one of us depends on the process of urination for the removal of certain waste products in the body. The production of urine is vital to the health of the body. Most of us have probably never thought of urine as valuable, but we could not survive if we did not produce it and eliminate it. Urine is composed of water, certain electrolytes, and various waste products that are filtered out of the blood system. Remember, as the blood flows through the body, wastes resulting from the metabolism of foodstuffs in the body cells are deposited into the bloodstream, and this waste must be disposed of in some way. A major part of this "cleaning" of the blood takes place in the kidneys and, in particular, in the nephrons, where the blood is filtered to produce the urine. Both kidneys in the body carry out this essential blood cleansing function. Normally, about 20% of the total blood pumped by the heart each minute will enter the kidneys to undergo filtration. This is called the filtration fraction. The rest of the blood (about 80%) does not go through the filtering portion of the kidney, but flows through the rest of the body to service the various nutritional, respiratory, and other needs that are always present.

For the production of urine, the kidneys do not simply pick waste products out of the bloodstream and send them along for final disposal. The kidneys' 2 million or more nephrons (about a million in each kidney) form urine by three precisely regulated processes: filtration, reabsorption, and secretion. Filtration Urine formation begins with the process of filtration, which goes on continually in the renal corpuscles. As blood courses through the glomeruli, much of its fluid, containing both useful chemicals and dissolved waste materials, soaks out of the blood through the membranes (by osmosis and diffusion) where it is filtered and then flows into the Bowman's capsule. This process is called glomerular filtration. The water, waste products, salt, glucose, and other chemicals that have been filtered out of the blood are known collectively as glomerular filtrate. The glomerular filtrate consists primarily of water, excess salts (primarily Na+ and K+), glucose, and a waste product of the body called urea. Urea is formed in the body to eliminate the very toxic ammonia products that are formed in the liver from amino acids. Since humans cannot excrete ammonia, it is converted to the less dangerous urea and then filtered out of the blood. Urea is the most abundant of the waste products that must be excreted by the kidneys. The total rate of glomerular filtration (glomerular filtration rate or GFR) for the whole body (i.e., for all of the nephrons in both kidneys) is normally about 125 ml per minute. Reabsorption Reabsorption, by definition, is the movement of substances out of the renal tubules back into the blood capillaries located around the tubules (called the peritubular copillaries). Substances reabsorbed are water, glucose and other nutrients, and sodium (Na+) and other ions. Reabsorption begins in the proximal convoluted tubules and continues in the loop of Henle, distal convoluted tubules, and collecting tubules (Figure 3). Let's discuss for a moment the three main substances that are reabsorbed back into the bloodstream.

Large amounts of water - more than 178 liters per day - are reabsorbed back into the bloodstream from the proximal tubules because the physical forces acting on the water in these tubules actually push most of the water back into the blood capillaries. In other words, about 99% of the 180 liters of water that leave the blood each day by glomerular filtration returns to the blood from the proximal tubule through the process of passive reabsorption. The nutrient glucose (blood sugar) is entirely reabsorbed back into the blood from the proximal tubules. In fact, it is actively transported out of the tubules and into the peritubular capillary blood. None of this valuable nutrient is wasted by being lost in the urine. However, even when the kidneys are operating at peak efficiency, the nephrons can reabsorb only so much sugar and water. Their limitations are dramatically illustrated in cases of diabetes mellitus, a disease which causes the amount of sugar in the blood to rise far above normal. As already mentioned, in ordinary cases all the glucose that seeps out through the glomeruli into the tubules is reabsorbed into the blood. But if too much is present, the tubules reach the limit of their ability to pass the sugar back into the bloodstream, and the tubules retain some of it. It is then carried along in the urine, often providing a doctor with her first clue that a patient has diabetes mellitus. The value of urine as a diagnostic aid has been known to the world of medicine since as far back as the time of Hippocrates. Since then, examination of the urine has become a regular procedure for physicians as well as scientists. Sodium ions (Na+) and other ions are only partially reabsorbed from the renal tubules back into the blood. For the most part, however, sodium ions are actively transported back into blood from the tubular fluid. The amount of sodium reabsorbed varies from time to time; it depends largely on how much salt we take in from the foods that we eat. (As stated earlier, sodium is a major component of table salt, known chemically as sodium chloride.) As a person increases the amount of salt taken into the body, that person's kidneys decrease the amount of sodium reabsorption back into the blood. That is, more sodium is retained in the tubules. Therefore, the amount of salt excreted in the urine increases. The process works the other way as well. The less the

salt intake, the greater the amount of sodium reabsorbed back into the blood, and the amount of salt excreted in the urine decreases. Secretion Secretion is the process by which substances move into the distal and collecting tubules from blood in the capillaries around these tubules (Figure 3). In this respect, secretion is reabsorption in reverse. Whereas reabsorption moves substances out of the tubules and into the blood, secretion moves substances out of the blood and into the tubules where they mix with the water and other wastes and are converted into urine. These substances are secreted through either an active transport mechanism or as a result of diffusion across the membrane. Substances secreted are hydrogen ions (H+), potassium ions (K+), ammonia (NH3), and certain drugs. Kidney tubule secretion plays a crucial role in maintaining the body's acid-base balance, another example of an important body function that the kidney participates in.

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