6- Endocrine Pancreas.pdf

The Endocrine Pancreas Structure Structure Located posterior to the stomach. It consists of: the rounded head, the middle body, and the thin tail. Pancreatic duct join common bile duct to form ampulla of vator which drain into the duodenum, guarded by sphincter of Oddi. There are two gro...

The Endocrine Pancreas Structure Structure Located posterior to the stomach. It consists of: the rounded head, the middle body, and the thin tail. Pancreatic duct join common bile duct to form ampulla of vator which drain into the duodenum, guarded by sphincter of Oddi. There are two groups of cells within the pancreas: (1) Exocrine cells (acinar cells): secrete enzymes & other products into the digestive tract (2) Endocrine cells found in discrete clusters “islands” called islets of Langerhans (1 – 2 % of total mass): contain three main cell types: a) Alpha (α) cells (25%), secrete glucagon; b) Beta (β) cells (60%), secrete insulin. & amylin Amylin (of unclear function) is also secreted in parallel with insulin. c) Delta (δ) cells (10%), secrete somatostatin d) F (or PP) cells secret pancreatic polypeptide. Insulin Insulin A small protein secreted by β cells, composed of two amino acid chains, connected by disulfide linkages. Synthesized in three steps: A. Preproinsulin: consisting of A, B, C peptides chains, and a terminal signal peptide B. Proinsulin result of cleavage of terminal signal peptide from Preproinsulin in the endoplasmic reticulum. C. Insulin: C peptide is cleaved → A and B chains connected by disulfide linkages. C peptide can be used as an index for insulin production. Secreted insulin circulates in an unbound form. Insulin Actions Mainly concerned with regulation of carbohydrate metabolism. It is also concerned with metabolism of proteins and fats. Mediate its physiological effects through activation of tyrosine kinase and phosphorylation of other intracellular proteins and enzymes Effects of insulin on Carbohydrate Metabolism Insulin is anti-diabetic i.e. reduces the blood sugar level by its following actions: a) ↑Uptake of glucose by the cells; Particularly muscles and adipose tissues. Glucose entry into brain, red blood cells & β pancreatic cells is insulin-independent. b) Promotes peripheral utilization of glucose; oxidation c) Promotes storage of glucose — glycogenesis d) Inhibits formation of glucose ▪ Insulin inhibit glycogen phosphorylase, the enzyme that causes glycogen to split into glucose  Glucose Transporters Glucose enters cells by: A. Facilitated diffusion via glucose transporter: GLUT Seven different GLUTs, named GLUT 1–7, have been discovered. GLUT4 is insulin-dependent, responsible for glucose transport into muscle and adipose cells. Most of the other GLUT are insulin-independent & are widely distributed in different tissues e.g., RBCs. B. Secondary active transport with Na+, via Sodium Glucose Transporter (SGLT) (SGLT-1 and SGLT-2) in the intestine and renal tubules, respectively. On Protein and fat Metabolism On Protein Facilitates the synthesis and storage of proteins. Inhibits the cellular utilization of proteins ➔ ➔ ➔ anabolic effect    Insulin and growth hormone interact synergistically to promote growth. Insulin deficiency causes protein depletion and increased plasma amino acids. On Fat Stimulates the synthesis and storage of fat in the adipose tissue. Insulin deficiency causes lipolysis, release of free fatty acids, ketosis and acidosis. On potassium → insulin causes K+ to enter cells, with a resultant lowering of the extracellular K+ concentration (hypokalemia). Regulation of insulin secretion Secretion is stimulated by: 1. Blood glucose ❑The most important controller of insulin secretion by a feedback effect on the beta cells. ❑↑blood glucose → ↑insulin secretion. 2. Amino acids; have a synergistic effect with glucose in stimulating insulin secretion. 3. Diabetogenic hormones; glucagon, growth hormone, cortisol; stimulate insulin secretion indirectly by ↑ blood glucose level. 4. GIT hormones: called incretins. most importantly GIP (Glucose-dependent insulinotropic peptide, gastric inhibitory peptide) and glucagonlike peptide–1 (GLP-1) released in GIT after a meal to ↑ insulin in preparation for the absorption of glucose & amino acids. 5. Parasympathetic stimulation, acetylcholine. 6. Sulfonylurea drugs (glyburide, tolbutamide). Regulation of insulin secretion Secretion is inhibited by: 1. ↓ blood glucose level. 2. Somatostatin 3. Sympathetic stimulation inhibits insulin secretion by released norepinephrine acting on α2 -adrenergic receptors. ❖However, β-Adrenergic stimulation increases insulin secretion 4. Leptin 5. K+ depletion (e.g. K-losing diuretics, primary hyperaldosteronism) ➔ ↓ insulin secretion, and make diabetes worse. Mechanism of insulin secretion Glucose enters Beta cells through insulin-independent glucose transporters Glucose is phosphorylated to glucose-6-phosphate G6P by glucokinase. G6P is oxidized to form (ATP), which inhibits the ATP- sensitive potassium channels of the cell. Closure of the K+ channels Depolarization of the cell membrane Opening voltage-gated calcium channels → influx of calcium → stimulates: Fusion of the insulin-containing vesicles with the cell membrane and secretion of insulin into the extracellular fluid by exocytosis. Mechanism of insulin secretion Amino acids, can also be metabolized by the beta cells to ↑ intracellular ATP levels and stimulate insulin secretion. A) Glucagon, b) Glucose-dependent insulinotropic peptide (gastric inhibitory peptide; GIP) & C) Acetylcholine, enhance glucose effect by increasing the intracellular Ca through other signaling pathways. Somatostatin and norepinephrine (by activating α- adrenergic receptors), inhibit exocytosis of insulin. Sulfonylurea drugs stimulate insulin secretion by blocking the ATP-sensitive potassium channels activity. Glucagon Glucagon Secreted from A cells or α cells in response to low blood glucose level. ACTIONS Mediated through generation of the second messenger cAMP, which in turn activates protein kinase A, results in the activation or deactivation of a number of enzymes. Its primary effects occur in the liver and are opposite those of insulin: 1. Increases the blood glucose; stimulates glycogenolysis, gluconeogenesis 2. On protein metabolism: catabolic (break down of proteins) 3. On fat metabolism; lipolytic and ketogenic (release of fatty acid and formation of ketone bodies) Regulation of Glucagon Secretion Controlled mainly by blood glucose and amino acid levels. Secretion increased by: 1. Decrease in blood glucose; → the most potent factor 2. Increase in amino acid level This is the same effect that amino acids have in stimulating insulin secretion. After a protein meal, both insulin and glucagon secretion are stimulated. Glucagon tends to increase blood glucose and thus opposes the effects of insulin to cause hypoglycemia. 3. Exercise, fasting and stress: A beneficial effect is to prevent ↓ in blood glucose. The cause of this increase is not well understood. ↑ circulating amino acids, β-adrenergic stimulation may play a role. Secretion inhibited by: Somatostatin: inhibits glucagon and insulin secretion Insulin α-adrenergic stimulation.  Somatostatin Secreted from 1) D cells (δ cells) in the pancreas 2) D cells in stomach and upper part of small intestine. 3) Hypothalamus (growth hormone inhibitory hormone {GHIH} Actions Somatostatin is an inhibitory hormone: 1) Inhibits the secretion of both glucagon and insulin 2) ↓Motility of stomach, duodenum and gallbladder 3) ↓Secretion of GIT hormones gastrin, CCK, GIP and VIP 4) Hypothalamic somatostatin inhibits secretion of GH and TSH from anterior pituitary. Diabetes Mellitus “Why is it so important to maintain a constant blood glucose concentration, particularly most tissues can shift to utilization of fats and proteins for energy in the absence of glucose?” a) It is the only source of energy in brain, retina and gonads. b) Can exert a large amount of osmotic pressure in the ECF & renal tubules → cellular dehydration & osmotic diuresis. c) Long-term ↑ in blood glucose may cause damage to many tissues, especially to blood vessels. Diabetes Mellitus ❑It is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin. ❑There are two general types of diabetes mellitus: 1. Type 1 diabetes (insulin-dependent diabetes mellitus) Caused by lack of insulin secretion due to injury to beta cells as a result of autoimmune disorders, hereditary tendency or viral infections. Age of onset: at any age, commonly at 14 years → juvenile diabetes mellitus. 2. Type 2 diabetes, also called (non–insulin-dependent diabetes mellitus) Caused by decreased sensitivity of target tissues to insulin (insulin resistance) → associated with ↑ plasma insulin (hyperinsulinemia). More common → 90 – 95 % Age of onset: after 30 years, (often between 50 – 60) → adult-onset diabetes. Insulin Resistance Insulin resistance is associated with type II diabetes. Causes of insulin resistance and type 2 diabetes (1) Obesity, especially accumulation of abdominal fat; the main cause. Other factor that can cause insulin resistance and type 2 diabetes: a) Polycystic ovary syndrome; associated with marked ↑ in ovarian androgen & and insulin resistance. b) Cushing’s syndrome → ↑glucocorticoids c) Acromegaly → ↑growth hormone Diabetes Mellitus ❑ Both types of diabetes are associated with a) ↑ blood glucose concentration, b) ↓ cell utilization of glucose c) ↑ utilization of fats and proteins. ❑As a result, the following consequences may occur in diabetic patients. 1. Dehydration (intracellular & Extracellular) ↑ Blood glucose → osmotic gradient in the ECF & renal tubules → cellular dehydration & osmotic diuresis. 2. Tissue injuries 1. Neuropathies; peripheral, autonomic 2. Cardiovascular & atherosclerosis. 3. Retinopathies 4. Renal injury & secondary hypertension. 3. Increased utilization of fats, excess ketoacids and metabolic acidosis. 4. Protein and fat depletion due to failure of to use glucose.  Therapeutic approach to diabetes Type 2 diabetes can be effectively treated in the early stages, with exercise, caloric restriction, and weight reduction Mechanism of action of hypoglycemic agents. 1. ↓liver glucose production, such as metformin, 2. Release of additional insulin, such as sulfonylureas. 3. SGLT2 inhibitors (Gliflozins); inhibits reabsorption of glucose in the kidney. 4. ↑insulin sensitivity; thiazolidinediones. 5. Drugs that mimic the actions of the incretin GLP-1; →↑ secretion of insulin 6. Inhibit the enzyme dipeptidyl peptidase 4 (DPP-4), which inactivates GLP-1 and GIP.