PANCREATIC SECRETION The pancreas, which lies parallel to and beneath the stomach, is a large compound gland with an internal structure similar to that of the salivary glands. The pancreatic digestive enzymes are secreted by the pancreatic acini, and large volumes of sodium bicarbonate solution are secreted by the small ductules and larger ducts leading from the acini. The combined product of enzymes and sodium bicarbonate then flows through a long pancreatic duct that usually joins the hepatic duct immediately before empties into the duodenum through the papilla of vater, surrounded by the sphincter of oddi. Pancreatic juice is secreted most abundantly in response to the presence of chyme in the upper portions of the small intestine , and the characteristic of the pancreatic juice are determined to some extent by the types of food in the chyme. The pancreas also secrets insulin, but this is not secreted by the same pancreatic tissue that secretes intestinal pancreatic juice. Instead , insulin is secreted into the blood not into the intestine by the B-cells of islets of Langerhans that occur in islet patches throughout the pancreas(Figure: 1). Physiological anatomy of an islet of Langerhans in the pancreas. Regulation Of Pancreatic Secretion: Basic stimuli that cause pancreatic secretion. Three basic stimuli are important in causing pancreatic secretion: 1. Acetylcholine ,which is released from the parasympathetic vagus nerve endings as well as from other cholinergic nerves in the enteric nervous system. 2. Cholecystokinin , which is secreted by the duodenal and upper jejunal mucosa when food enters the small intestine. 3. Secretin , which is secreted by the same duodenal and jejunal mucosa when highly acid food enters the small intestine. Acetylcholine and cholecystokinin, stimulate the acinar cells of the pancreas much more than the ductal cells. Therefore , they cause production of large quantities of pancreatic digestive enzymes but relatively small quantities of fluid to go with the enzymes. Without the fluid , most of the enzymes remain temporarily stored in the acini and ducts until more fluid secretion comes along to wash them into the duodenum. Secretin , in contrast to the other two basic stimuli , mainly stimulates secretion of large quantities of sodium bicarbonate solution by the pancreatic ductal epithelium but is responsible for almost no stimulation of enzymes secretion. Multiplicative effects of the different stimuli. When all the different stimuli of pancreatic secretion occur at once, the secretion is far greater than the sum of the secretions caused by each one separately. Therefore, the various stimuli are said to "multiply" or "potentiate" one another. Thus, pancreatic secretion normally results from the combined effects of the multiple basic stimuli, not from one alone. Insulin, glucagons & diabetes mellitus: The pancreas in addition to its digestive functions, secretes two important hormones, Insulin and Glucagons, that are crucial for normal regulation of glucose, lipid, and protein metabolism. Although the pancreas secretes other hormones, such as Amylin, somatostatin, and pancreatic polypeptide, their functions are not well established. Physiologic Anatomy of the pancreas: The pancreas is composed of two major types of tissues. 1. The acini, which secrete digestive juices into the duodenum, and 2. The islets of Langerhans, which secret insulin and glucagons directly into the blood . The human pancreas has 1 to 2 million islets of Langerhans, each only about 0.3 millimeter in diameter and organized around small capillaries into which its cells secret their hormones. The islets contain three major types of cells, alpha, beta, and delta cells, which are distinguished from one another by their morphological and staining characteristics. The β-cells, constituting about 60 % of all the cells, lie mainly in the middle of each islet and secret insulin and amylin, a hormone that is often secreted in parallel with insulin, although its function is unclear. The α-cells, about 25% of the total, secret glucagon, and the delta cells, about 10% of the total, secret somatostatin. In addition, at least one other type of cell, the PP cell, is present in small numbers in the islets and secretes a hormone of uncertain function called pancreatic polypeptide. Disorder of glucose metabolism diabetes mellitus: The most important upset in glucose metabolism is diabetes mellitus. It is the great frequency of this disease, which affects about 3% of the population, that has stimulated a vast amount of research into the metabolism of glucose, yet even today there are many aspects that are incompletely understood. Glucose is used as a fuel by many of the body’s cells, and is the only substance used by the brain under normal circumstances. Hence the maintenance of a blood glucose level within narrow limits (3.0-5.0 mmol/l or 55-90 mg/dl in the fasting subject) is an important homeostatic mechanism. The blood level is mainly regulated by the balanced production of insulin, which lowers the blood glucose level, and the activity of the liver, which can either store glucose as glycogen or produce glucose from glycogen or non-carbohydrate sources (gluconeogenesis) Glucose balance in the normal human in the postabsorptive, overnight-fasted state. Alanine forms the principal amino acid released from muscle, and is utilized by the liver to form glucose. The muscle can utilize glucose to form alanine, and this constitutes the glucose-alanine cycle analogous to the Cori cycle. In the latter, lactate and pyruvate formed from glucose in the muscle are released into the blood taken up by the liver, and there converted into glucose. Glucose homeostasis: It is best to consider glucose homeostasis under the three headings: 1. Following glucose administration. 2. In the post absorptive state-following an overnight fast. 3. During exercise. Following glucose administration: Following the oral administration of glucose there is an increase in the amount of insulin released from the pancreas. This promotes the storage and utilization of glucose and prevents an undue rise in the blood glucose level. The oral administration of glucose evokes more insulin release than does a comparable intravenous loading with glucose. This may be due to the stimulation of the islets by a nervous reflex via the vagi, but of greater importance is the release into the blood stream of an intestinal factor or hormone that promotes the pancreatic release of insulin. The nature of this factor is unknown, but secretin, gastrin, cholecystokinin-pancreozymin, vasoactive intestinal poly- peptide, and gastric inhibitory peptide have all been proposed as likely candidates. Following absorption of glucose from the intestine, the rise in blood glucose level stimulates the secretion of insulin from the pancreatic islets by a direct action. Insulin aids the entry of glucose into resting muscle and fat cells: these are the insulin-dependent tissues. Following the ingestion of 100 g of glucose, however, only about 15% enters these tissues along insulin-dependent pathways. An additional 25% escapes from the splanchnic bed, and is utilized to meet the ongoing glucose needs of insulin-independent tissues, especially the brain. From 55 to 60% is retained in the liver, for there is no barrier to the entry of glucose into liver cells, and this organ is well situated anatomically to intercept glucose from the portal vein and prevent it entering the systemic circulation. In the liver the glucose is utilized in the synthesis of glycogen and triglycerides. Two enzymes are involved in the phosphorylation of glucose occurring prior to glycogen synthesis: hexokinase, which is insulin-independent, and glucokinase, which is insulin-dependent. It follows that in the normal person, even after a carbohydrate meal, the blood glucose does not rise above 9 mmol/l (160 mg/dl ); this forms the basis of the glucose tolerance test. In the post absorptive state: If an individual fasts overnight, the liver and the insulin-dependent tissues (resting muscle and fat) show little glucose uptake. The insulin-independent tissues (brain, blood cells, and renal medulla) show a continued glucose uptake at a rate of 150-200 g per day ; the blood glucose level is maintained by the release of glucose from the liver. The liver contains about 70 g of glycogen, which provides an immediate source of glucose by glycogenolysis . The supply, however, lasts less than 1 day, and gluconeogenesis is stimulated; pyruvate, lactate and alanine are used as the main raw materials for this. After 2 to 3 days, gluconeogenesis is more important than glycogenolytic activity. Protein provides the ultimate source for this, a fact reflected in the brisk rate of nitrogen excretion that occurs early in starvation. During exercise: In the resting state the major source of energy for muscular contraction is provided by the oxidation of fatty acids. During exercise the uptake of fatty acid is increased , but in addition there is a marked (up to 20-fold) increase in glucose uptake and oxidation. To compensate for this peripheral utilization, the liver releases glucose into the blood stream, and the blood glucose level shows little change. During short-term exercise the major source of this glucose is liver glycogen (glycogenolysis). During prolonged exercise, gluconeogenesis plays an increasingly important role, because the liver’s supply of glycogen is limited. The mechanisms involved in these changes are not well understood. A reduction in blood insulin level or an increase in blood glucagon level plays some part, but the release of catecholamine is probably of greater importance; these agents stimulate glycogenolysis in the liver. Secretion and actions of insulin: Insulin is synthesized in the B cells of the islets of Langerhans as proinsulin, a polypeptide containing 81-86 amino acid residues. The tail and head of this long polypeptide are joined by two disulphide bonds. By the action of peptidases the middle segment (termed the C peptide) is excised, leaving the two ends of the molecule; to form the A and B chains of the insulin molecules; these remain united by the original disulphide bonds. The formation and excretion of C peptide has been used as a measure of the rate of insulin synthesis. Insulin is formed in the rough endoplasmic reticulum; the product passes into the Golgi complex and is subsequently released as membrane-bound secretory granules. These mature to a crystalline form in the presence of zinc ions, and are finally released by a process of exocytosis. The actual movement and release of these granules is guided by microtubules and effected by the contractile proteins of the microfilaments. Calcium ions are required for this. The major stimulus for both insulin synthesis and release is hyperglycaemia. Adrenocorticotrophic hormone, glucagons, gastrin, and other intestinal hormones also increase insulin secretion, an effect accompanied by a rise in the intracellular level of cyclic AMP. A number of amino acids, particularly leucine, have a similar effect, as does parasympathetic stimulation. It is unlikely, however, that these mechanisms play a major role in normal glucose homeostasis. Sulphonylurea compounds also cause a release of insulin from the islet cells, but unlike the other agents, they do not stimulate insulin synthesis. The target cells of insulin are those of the adipose tissue and muscle, both of which have specific receptors : glucose transport into the cell is enhanced, and glycogen synthesis is increased . Insulin promotes the synthesis of protein from aminacids; it inhibits the breakdown of natural fat (lipolysis). Furthermore, insulin has two important effects on the liver: glycogenolysis is inhibited by small increments in insulin secretion. Larger increments inhibit gluconeogenesis. The net effect of insulin is to lower the blood glucose level; since the half-life of the hormone is from 3 to 4 minutes, the continuous and varying secretion of insulin is the main regulatory mechanism whereby the blood glucose level is normally maintained within narrow limits. Other hormones affecting glucose metabolism: Four other hormones have important effects on glucose metabolism: 1. Glucagons: This hormones is the secretion of the A cells of the islets of Langerhans. It is released whenever the blood glucose level drops below 4.5 mmol/l (80 mg/dl), and its main action is stimulating the liver to break down glycogen into glucose, which is then released into the blood. In the adipose tissue lipolysis is stimulated. It is evident that glucagons opposes the action of insulin. 2. Adrenaline: This raises the blood glucose level by promoting glycogenolysisin the liver and muscles. 3. Pituitary growth hormone: This opposes the actions of insulin, thereby raising the blood glucose level. 4. Adrenal glucocorticoids: These decrease glucose utilization in muscle and fat. Gluconeogenesis in the liver is stimulated, and the blood glucose level rises. |
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Diabetes Mellitus
