Physiology - Chapter 24: Pancreas PDF

Chapter 24 Pancreas By: Scienti c A ociation fi ss Chapter 24 Pancreas Introduction There are four polypeptides with regulatory activit...

Chapter 24 Pancreas By: Scienti c A ociation fi ss Chapter 24 Pancreas Introduction There are four polypeptides with regulatory activity are secreted by the islets of Langerhans in the pancreas. 1.insulin and glucagon: are hormones and have important functions in the regulation of the intermediary metabolism of carbohydrates, proteins, and fats. 2.Somatostatin: plays a role in the regulation of islet cell secretion 3.pancreatic polypeptide: is probably concerned primarily with the regulation of ion transport in the intestine. cells of islets of Langerhans: The cells in the islets can be divided into types on the basis of their staining properties and morphology. Humans have at least four distinct cell types: A, B, D, and F cells. A, B, and D cells are also called α, β, and δ cells. Islets make up about 2% of the volume of the gland exocrine portion of the pancreas makes up 80% and ducts and blood vessels make up the remainder. Humans have 1 to 2 million islets. A cells secrete glucagon B cells secrete insulin D cells secrete somatostatin F cells secrete pancreatic polypeptide. B cells, most common and account for 60–75% of the cells in the islets located in center of each islet. B cells tend to be surrounded by the A cells A cells make up 20% of total less common D and F cells By: Scienti c A ociation fi ss Chapter 24 Pancreas STRUCTURE, BIOSYNTHESIS, & SECRETION OF INSULIN Insulin is a polypeptide containing two chains of amino acids linked by disul de bridges. Insulin is synthesized in the rough endoplasmic reticulum of B cells then transported to Golgi apparatus, where it is packaged into membrane-bound granules. granules move to plasma membrane by process involving microtubules and their contents are expelled by exocytosis FATE OF SECRETED INSULIN: METABOLISM half-life of insulin in the circulation in humans is about 5 min. Insulin binds to insulin receptors, and some is interna ized. It is destroyed by proteases in the endosomes formed by the endocytotic process. EFFECTS OF INSULIN: The physiologic effects of insulin are far-reaching and co plex. They are conveniently divided into rapid, intermediate, and delayed actions ‫جدول‬ insulin has many actions on adipose tissue skeletal. M Cardiac. M Smooth. M Liver By: Scienti c A ociation fi ss l­ m­ fi Chapter 24 Pancreas In general insulin increase cell growth, but also has speci c action on : adipose tissue: ↑ glucose entry ↑ fatty acid synthesis ↑ glycerol phosphate synthesis ↑ triglyceride deposition activation of lipoprotein lipase? ‫الي يدخل الدهون لالنسجة الدهنية‬ inhibition of hormone-sensitive lipase ? ‫اللي يطلع الدهون للدم‬ ↑ K+ uptake. Muscle: ↑ glucose entry ↑ glycogen synthesis ↑ amino acid uptake ↑ protein synthesis in ribosomes ↑ ketone & K+ uptake ↓ protein catabolism & release of gluconeogenic amino acids. Liver : ↑ protein & lipid synthesis ↓ ketogenesis ↓ gluconeogenesis ↓ glucose output due to decreased gluconeogenesis ↑ glycogen synthesis ↑ glycolysis. ‫اكو جدول مال تأثير االنسولني‬ Glucose Transporters: 1-enters cells by facilitated diffusion (GLUTs) 2-in intestine + kidneys by secondary active tran port with Na+ (SGLTs) in muscle + adipose (not liver) insulin stimulates glucose entry into cells by increasing number of (GLUT -4) in cell membranes By: Scienti c A ociation fi ss s­ fi  Chapter 24 Pancreas GLUTs that are responsible for facilitated diffusion of glucose across cell membranes are a family of closely related proteins that span the cell membrane 12 times and have their amino and carboxyl terminals inside the cell. Insulin also increases the entry of glucose into liver cells, but it does not exert this effect by increasing the nu ber of GLUT-4 transporters in the cell membranes. Instead, it induces glucokinase, and this increases the phosphorylation of glucose, so that the intracellular free glucose concentration stays low, facilitating the entry of glucose into the cell. Mechanism of Action Insulin Receptors insulin receptor, is tetramer made up of two α and two β glycoprotein subunits. α subunits bind insulin and are extrace lular β subunits span membrane Consequences of Insulin De ciency: In humans, insulin de ciency is a common pathologic condition. In animals, it can be produced by pancreatectomy; by 1-administration many of toxins that in cause selective destruction of B cells of pancreatic islets 2-by administration of drugs that inhibit insulin secretion 3-by administration of anti-insulin antibodies Effects of Hyperglycemia hyperosmolality gl cosuria osmotic diuresis polydi sia hyperosmolality of the blood gl cosuria because the renal capacity for glucose reabsorption is exceeded. By: Scienti c A ociation y­ y­ p­ fi ss m­ fi fi l­  Chapter 24 Pancreas Excretion of the osmotically active glucose mo ecules entails the loss of large amounts of water (osmotic diuresis). resultant dehydration activates the mechanisms regulating water intake, leading to polydi sia When plasma glucose elevated over time, small amounts of hemoglobin A are non- enzymatically gl cated to form HbAIc Careful control of the diabetes with insulin reduces the amount formed and cons quently HbAIc concentration is measured clinically as an int grated index of diabetic control for the 4- to 6-weeks period before the measurement. Effect of hyperglycemia on protein metabolism In diabetes 1-increase catabolized rate of amino acids ———> CO2 and H2O 2-in liver more amino acids are converted to glucose 3-increased glucone genesis because: in absence of insulin, less protein synth sis occurs in muscle and hence blood amino acid levels rise 4-Adrenal glucocorticoids increased gluc neogenesis when they are elevated in severely ill diabetics. Fat Metabolism in Diabetes accelerated lipid catabolism increased formation of ketone bodies decreased synthesis of fatty acids decreased synthesis tr glycerides conversion of glucose to fatty acids is decreased because intr cellular glucose de ciency. Insulin inhibits the hormone-sensitive lipase in adipose tissue, and, in the absence of this hormone, the plasma level of free fatty acids is more than doubled. Thus, the FFA level By: Scienti c A ociation fi p­ fi y­ ss o­ i­ o­ l­ e­ e­ a­ e­  Chapter 24 Pancreas parallels the plasma glucose level in diabetes and in some ways is a better indicator of the severity of the diabetic state. in uncontrolled diabetes, the plasma concentration of tr glycerides and chylomicrons as well as FFA is increased, and the plasma is often lipemic. The rise in these constituents is mainly due to decreased removal of triglycerides into the fat depots. The decreased activity of lipoprotein lipase contributes to this decreased removal. In diabetes, plasma cholesterol level is usually elevated and this plays a role in the accelerated development of the ather sclerotic vascular disease that is a major long-term compl cation of diabetes in humans. The rise in plasma cholesterol level is due to an increase in the plasma concentration of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). These in turn may be due to increased hepatic production of VLDL or decreased removal of VLDL and LDL from the circulation. Regulation of Insulin Secretion The glucose acts directly on pancreatic B cells to increase insulin secretion. response to glucose is biphasic: 1-rapid but short-lived increase in secretion 2-followed by more slowly developing prolonged increase rapid secretion Glucose enters B cells via GLUT-2 transporters and is phosphorylated by glucokinase then metabolized to pyr vate in the cytoplasm. pyruvate enters the mitochondria and is metabolized to CO2 and H2O via the citric acid cycle with the formation of ATP by oxidative pho phorylation. ATP enters the cytoplasm, where it inhibits ATP-sensitive K+ channels, reducing K+ ef ux. This depola izes the B cell, and Ca2+ enters the cell via voltage-gated Ca2+ channels. By: Scienti c A ociation i­ r­ fi ss u­ o­ s­ i­ fl Chapter 24 Pancreas The Ca2+ in ux causes exocytosis of a readily relea able pool of insulin-containing secretory granules, producing the initial spike of insulin secretion. slowly secretion Metabolism of pyruvate via the citric acid cycle also causes an increase in intracellular glutamate. The glutamate appears to act on a second pool of secretory granules, co mitting them to the releasable form. The release of these granules then produces the prolonged second phase of the insulin response to glucose. The feedback control of plasma glucose on insulin secr tion normally operates with great precision so that plasma glucose and insulin levels parallel each other with remarkable consistency. Glucagon is produced by the A cells of the pancr atic islets and the upper gastrointestinal tract. Glucagon is glycogenolytic, gluconeogenic, lipolytic, and ket genic. In the liver, glucagon——> Gs ——> activate adenylyl cyclase and increase intracellular cAMP ——> Activate protein kinase A ——> activation of phosphorylase ——> increased breakdown of glycogen and an increase in plasma glucose. glucagon acts on different glucagon receptors located on the same hepatic cells to activate pho pholipase C, and the resulting increase in cytoplasmic Ca2+ also stimulates glycogenolysis. It increases gluconeogenesis from available amino acids in the liver and elevates the metabolic rate. It increases ketone body formation by decreasing malonyl-CoA levels in the liver. Its lipolytic activity, which leads in turn to increased ketogenesis. By: Scienti c A ociation fl s­ fi ss e­ s­ e­ o­ m­ Chapter 24 Pancreas Regulation of Secretion: The Secretion of glucagon is increased by 1.hypogl cemia and decreased by a rise in plasma glucose. 2.stimulation of the symp thetic nerves to the pancreas, and this sympathetic effect is mediated via β-adrenergic receptors and cAMP 3.A protein meal and infusion of various amino acids increase glucagon secretion 4. Cholecystokinin and ga trin increase glucagon secretion, whereas secretin inhibits it. Because CCK and gastrin secretion are both increased by a protein meal, either hormone could be the gastrointestinal mediator of the glucagon response. SOMATOSTATIN Somatostatin 14 (SS 14) somatostatin 28 (SS 28) extended form found in D cells of pa creatic islets. Both forms inhibit secretion of insulin, gl cagon, and pancreatic polypeptide act locally within pancreatic islets in paracrine fashion. SS 28 is more active than SS 14 in inhibiting insulin secretion. secretion of pancreatic somatostatin is increased by same stimuli that increase insulin secretion, such glucose and amino acids. It is also increased by CCK. Pancreatic Polypeptide It is produced by F cells in the islets. closely related to two other amino acid polypeptides 1-polypeptide YY: gastrointestinal peptide 2-neuropeptide Y: found in brain and autonomic nervous system By: Scienti c A ociation y­ fi ss n­ u­ a­ s­  Chapter 24 Pancreas Its secretion is increased by meal containing protein fas ing exercise acute hypoglycemia Secretion is decreased by somatostatin and intravenous glucose Pancreatic pol peptide slows absorption of food in humans. HYPOGLYCEMIA Hypoglycemia “Insulin reactions” are common in type 1 diabetics and occ sional hypoglycemic episodes are the price of good diabetic control in most diabetics. Chronic mild hypoglycemia can cause incoordination and slurred speech, and the condition can be mistaken for drun enness. In functional hypoglycemia, the plasma glucose rise is normal after a test dose of glucose, but the subsequent fall overshoots to hypoglycemic levels, producing symptoms 3–4 h after meals. Diabetes Mellitus The constellation of abnormalities caused by insulin de ciency is called diabetes mellitus. Diabetes is characterized by polyuria (passage of large vo umes of urine) polydipsia (excessive drinking) weight loss in spite of polyphagia (increased appetite) hyperglycemia glyco uria ketosis acidosis coma The fundamental defects to which most of the abnormalities can be traced are (1) reduced entry of gl cose into various “peripheral” tissues (2) increased liberation of glucose into the circulation from the liver. By: Scienti c A ociation t­ s­ fi y­ ss u­ l­ k­ fi a­  Chapter 24 Pancreas extracellular glucose excess and, in many cells, an intracell lar glucose de ciency “starv tion in the midst of plenty.” May be caused microvascular, macrovascular, and neur pathic disease. microvascular abnormalities 1-prolifer tive scarring of the retina (diabetic retinopathy) leading to blindness 2-renal disease (diabetic nephropathy) leading to chronic kidney disease macrovascular abnormalities due to atherosclerosis cause secondary to increased plasma LDL LDL increased stroke and myocardial infarction. The neuropathic abno malities (diabetic neuropathy) involve the autonomic ne vous system and peripheral nerves. Obesity, the Metabolic Syndrome, & Type 2 Diabetes Obesity is increasing in regul tion of food intake and energy balance and overall nutrition As body weight increases, insulin resistance increases, that is, there is a decreased ability of insulin to move glucose into fat and muscle and to shut off glucose release from the liver. Weight reduction decreases insulin resistance. Associated with obesity there is hyperinsulinemia, dysli idemia (characterized by high circulating triglycerides and low high-density lipoprotein [HDL]) ‫والحمد هلل ثم الحمد هلل ثم الحمد هلل وكفى‬ ‫والصالة والسالم بأتمها وأتمه على الرسول املصطفى‬ ‫ وبـع ُد؛ فهـذا خـتام مـادة الفسـلجة الـتي ارتـنا كـيف ابـدع اهلل فـي تـصويـر خـلقه وحـكمة صـنعه ودقـة‬،‫وآلـه االخـيار اولـي الـنهى‬ ‫فعله فجل ربنا عن التصوير وفعله عن االدراك والتقرير والحمد هلل على توفيقه ومنه ورحمته وفضله‬ ،‫كبيرا‬ ً ‫هذا وان الرابطة قد انهت شوطًا وعا ًما دراس ًيا‬ ‫ وان تـبقى عـلى مـنوالـها‬،‫ مـزدانـ ًة بـاملـحبة والـبسمة‬،‫ وعـظيم الـهمة‬،‫ هـو دوام الـنعمة‬،‫ورجـاء رابـطتنا الـكريـمة بـعائـلتها الـعظيمة‬ :‫ وشعارنا الثابت هو قول الشاعر‬،‫فشكرا للمودة وللثقة‬ ً ،‫مع زيادة عطاءها حتى يفتح اهلل عليها على عتبة التخرج‬ ِ ‫للناس عينا‬ ِ ‫بأحسن ما ترى‬ ٍ ‫سعة لدينا‬ ‫قدر ما‬ َ ‫عملنا‬ ‫مشيناها خطىً ُك ِتبت علينا‬ ‫االقدار شئنا ام أبينا‬ ُ ‫هي‬ ‫ومن ُك ِتبَت عليه خطىً مشاها‬ By: Scienti c A ociation a­ a­ a­ fi ss r­ p­ o­ u­ fi r­