Endocrine Pancreas PDF

Endocrine Pancreas Present in all vertebrates. Rabbit no discrete pancreas. Is a mixed gland.  The biological activities of insulin are not highly species specific. The differences in amino acid composition among species are small. Cattle, sheep, horse, dogs and whales differ...

Endocrine Pancreas Present in all vertebrates. Rabbit no discrete pancreas. Is a mixed gland.  The biological activities of insulin are not highly species specific. The differences in amino acid composition among species are small. Cattle, sheep, horse, dogs and whales differ only in positions 8, 9 and 10 of the chain A. Diabetic human are treated with insulin extracted from pig pancreas. 1- Effect of insulin on carbohydrate metabolism Increase rate of glucose transport across the Functions cell membrane of Insulin in muscle and adipose tissue. HOW? GLUT-4 is insulin dependent ??  . It increases the rate of glycolysis through the induction the enzymes such as glucokinase, phosphofructokinase and pyruvate kinase. 1- Effect of . It increases the rate of glycogenesis in insulin on the liver and in the skeletal muscle by increasing glycogen synthase. carbohydrate metabolism . It inhibits the glycogenolysis by inhibiting the glycogen phosphorylase activity. . It decreases the gluconeogenesis due to the stimulation of protein synthesis and decreasing the amounts of amino acids available for gluconeogenesis. 2- Effect of insulin on lipid metabolism 1- It stimulates lipogenesis in the liver and adipose tissue due to activation of lipoprotein lipase enzyme. Liver saturated with glycogen Triglycerides Blood lipoproptein glucose Fat depot Lipoprotein lipase 2- Insulin inhibits lipolysis by inhibiting a hormone sensitive lipase enzyme (an intracellular enzyme in adipose tissues and gonads) Adipose Hormone sensitive Lipoprotein lipase tissue lipase Lipogenesis Lipolysis Glucose  1. It also stimulates the uptake of amino acids, contributing to its overall anabolic effect (protein synthesis). 3- Other Notable 2. Insulin also increases the permeability of many cells to K+, Effects of because it activates Na+/K+ Insulin ATPases causing influx of K+ into cells.  Injection of insulin can kill patients (Why?) because of its ability to acutely suppress plasma The tissues differ in their sensitivity to insulin, for example: 1.Liver, muscle, and adipose tissue are sensitive to insulin. - Muscle and adipose tissue GLUT 4 (facilitated diffusion) 2. Brain, kidney, intestine and erythrocytes show little response to insulin Enteroglucagon  1- Stimulates glycogenolysis in liver by stimulating phosphatase enzymes 2- Inhibits glycogenesis by inhibiting I- Glucagon and glycogen synthase enzyme carbohydrates 3- Stimulates hepatic metabolism gluconeogenesis by activating fructose 2, 6 biphasphatase enzyme 4- Inhibits glycolysis  1- Stimulate lipolysis of triglyceride in adipose tissue by stimulating the intracellular hormone sensitive lipase enzyme, which provide fatty acid fuel to most cells. II- Glucagon 2- Stimulates ketogenesis through some of the biochemical and fat step involved in its stimulation of gluconeogenesis metabolism 3- Glucagon is ketogenic and hyperglycemic hormone  1- Increase gluconeogenesis by increasing transport of amino acids into the liver. III- Glucagon 2- Lower plasma amino and protein acids. metabolism 3- Has calorigenic effect due to increase hepatic deamination of amino acids.  1. Stimulates bile secretion. IV- Other 2. Inhibits gastric acid functions of secretion. glucagon 3. Simulate the secretion of GH, insulin and somatostatin. Control of secretion Glucagon  Growth hormone inhibiting hormone (GHIH) Relationship between cells of islets  most common in dogs most common in cats Adrenal cortex is essential and vital to life (Why?) because it secretes different types of hormones, which they: 1.Helps regulate metabolism and helps the animal body to respond to stress. 2. Control electrolyte balance, which regulate the function of excitable tissues (nerve and muscle cells). 3. Control the acid-base balance for adjusting the functions of its organs. 4. Control the water balance to preserve tissue fluid volume and composition.  Corticosteroids transport Cortisol Transcortin (75%) Circulates bound to Albumen (15%) Free (10%) Aldosterone Transcortin (10%) Circulates bound to Albumen (50%) Free (40%)  I- Mineralocorticoids - Secreted by Zona Glomerulosa. - Involved in the regulation of electrolytes (Na+, K+, Cl-, HCO3-). Aldosterone exerts the 90% of the mineralocorticoid activity. Deoxycorticosterone has mineralocorticoid function.  1- Increase Na+ and water Function of retention and Increase Aldosterone K+ excretion from DCT and collecting ducts of nephron.  On other tissues Rectum K+ Na+ Aldosterone secretion reabsorption H2O Restore ECF volume 2- It stimulates Na+ and water Function of reabsorption from the gut, salivary Aldosterone and sweat glands in exchange for K+.  It stimulates secretion of H+ via Function of the H+/ATPase in the intercalated Aldosterone cells of the cortical collecting tubules.  Control of Aldosterone secretion Low blood volume, I- Renin-Angiotensin-Aldosterone System Dehydration, Hemorrhage The stimulus for renin release is provided by three mechanisms acting together: 1.Reduced distension of the renal afferent arteriole. 2. Tubuloglomerular feedback signaling due to the low glomerular filtration rate and the low renal tubular fluid flow. 3. Stimulation of the renal sympathetic nerves due to activation of the baroreceptor reflex by decreased blood pressure. 2- An increase in plasma K+ concentration  Increase K+ stimulate aldosterone directly through depolarization of the glomerulosa cell membrane potential.  Decrease Na+ stimulate aldosterone indirectly through RAS “Renin Angiotensin system”. Figure 6.12b 3- Atrial natriuretic peptide (ANP): Only known inhibitor of Elevated atrial pressure aldosterone 4- ACTH is a very weak stimulus for aldosterone secretion Aldosterone does not exert any negative feedback control over ACTH secretion.  2- Glucocorticoids Secreted from zona fasiculata in adrenal cortex. The name glucocorticoid (glucose + cortex + steroid) is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure. Most of the glucocorticoid activity in mammals (except rodents) is from cortisol.  Function of cortisol 1- Metabolic functions A- Carbohydrate metabolism (Hyperglycemic action) Glycogen in liver Glycogenolysis Glucose Glycogenesis Gluconeogenesis Amino acids in liver Glucose  1- Metabolic functions B- Protein metabolism  1- Metabolic functions C- Lipid metabolism  Cortisol stimulates the breakdown of lipid stores (lipolysis) (How?). - It has an indirect effect: potentiating the epinephrine effect on the hormone-sensitive lipase. Cortisol Fatty acid Adipose oxidation tissue Lipolysis  The mobilized fatty acids serve as a ready available alternative metabolic fuel for tissues, therefore conserving glucose for the brain  2- ADRENAL DIABTES Increase Steroid Diabetes gluconeogenesis Rise of blood Decrease tissue glucose level utilization of glucose Stimulate secretion of insulin  The increased plasma levels of insulin are not as effective in these conditions as they are under normal conditions (Why?)  Because high levels of glucocorticoids reduce the sensitivity of many tissues, especially skeletal muscle to the stimulatory effects of insulin on glucose uptake and utilization since glucocorticoids inhibits the peripheral use of glucose by decreasing the translocation of (GLUT4) to the cell membrane.  3. PERMISSIVE ACTIONS  Cortisol must be present in sufficient amounts in order for vascular smooth muscles to respond fully to adrenaline and noradrenaline. Therefore, adequate amounts of cortisol is needed to maintain normal blood pressure. Cortisol Adrenaline receptor 4- Anti-inflammatory effect 1. Blocking eicosanoid production (prostaglandins and leukotrienes) which are involved in the inflammatory response. 2. Inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, etc.).  5- Anti-pyretic effect - It reduces the release of both prostaglandins and interleukin-1 from the white blood cells, which is one of the principal excitants to the hypothalamic temperature control system. Cortisol  6- Immuno-suppressive effect 1. Decreasing the function and/or numbers of eosinophils, lymphocytes (both B cells and T cells), monocytes, macrophages. 2. Decreasing capillary permeability. 3. Decreasing the anatomical barrier function of the skin  7- Electrolyte balance effect  Cortisol acts as a diuretic by: 1. Inhibiting ADH activity, increasing water diuresis, glomerular filtration rate, and renal plasma flow from the kidneys.  8- Actions in heart failure  Glucocorticoids could potentiate renal responsiveness to diuretics in patients with heart failure and produce potent diuretic effects.  9- Actions on adrenal medulla  High levels of cortisol are required by the adrenal medulla for: 1. Induction of the enzyme required for adrenaline synthesis pathway. 2. Reduction the activity of COMT, one of the enzymes responsible for inactivating epinephrine. 10- Fetal development  Cortisol stimulates the production of surfactant, which decreases the surface tension in the alveoli.  11- Effects on bone and collagen It reduces bone formation by inhibiting the osteoblast cells. Cortisol stimulates bone resorption by stimulating PTH release, which in turn stimulates the osteoclast cells. It reduces calcium absorption in the intestine. It increases urinary calcium excretion. It causes loss of collagen and connective tissue. Control of glucocorticoid secretion  Catecholamine Synthesis tyrosine tyrosine hydroxylase DOPA(dihydroxyphenylalanine) DOPA decarboxylase dopamine dopamine-B-hydroxylase norepinephrine PNMT phenylethanolamine-N-methyl transferase epinephrine Cortisol   Adrenaline is the major catecholamine secreted by the adrenal medulla of most mammals. Exceptions to this generalization include the dominance of noradrenaline over adrenaline in whales and chicken and in the fetal tissues of all species. Degradation Catechol-O-methyltransferase (COMT) Monoamine oxidase A (MAOA)  Mode of actions Catecholamine Receptors α Receptor β Receptor G protein-coupled receptors α1 adrenergic receptors affect mainly smooth muscles and glands. α2 adrenergic receptors affect presynaptic terminals, pancreatic β cell. β1 receptors affect mainly the heart, JG cells. β2 receptors affect : 1. Smooth muscle present in blood vessels and the wall of the organ as stomach, intestine, urinary bladder, uterus, gall bladder, etc. 2. Intermediary metabolism (glycogenolysis, gluconeogenesis, lipolysis).  Receptor   Noradrenaline +++++ ++ Adrenaline ++++ ++++ Noradrenaline excites mainly α receptors but excites the β receptors to lesser extent. Conversely, adrenaline excites both types of receptors equally. The effects of noradrenaline and adrenaline on different effector organs are determined by the types and ratio of receptors in the organs.  Functions of catecholamines 1. METABOLIC FUNCTIONS The metabolic effects of catecholamines are mediated mainly by β2 receptors. Because adrenaline is 10 times more potent than noradrenaline with β2 receptors, adrenaline plays a much more important role in the control of intermediary metabolism. Adrenaline increases O2 consumption, so it increases basal metabolic rate. Therefore adrenaline is called calorigenic hormone.  The effects of adrenaline on glucose metabolism are similar to those of glucagon and opposite to those of insulin. Adrenaline (hyperglycemic) 1. It stimulates both hepatic A. glycogenolysis and gluconeogenesis. 2. It also stimulates glycogenolysis in EFFECTS ON skeletal muscles, which in this CARBOHYDRATE situation is in contrast with the action of glucagon, which acts only on liver METABOLISM glycogen. Adrenaline inhibit insulin secretion (through α2 receptors) and stimulates glucagon secretion by pancreas (through β2 receptors) , both actions increase blood glucose concentration   Adrenaline stimulates lipolysis in adipose tissues though the activation of hormone- sensitive B. lipase enzyme resulting in increase EFFECTS ON of free fatty acids in blood. LIPID  Glucocorticoids potentiate the METABOLISM effect of adrenaline on lipolysis  Catechol amines stimulate cardiac function. 2. Both adrenaline and ACTIONS ON noradrenaline interact with CARDIAC β1 receptors to increase the MUSCLE force of cardiac contraction and heart rate.  - Since α1 receptors are present in the smooth muscles of sphincters of hollow organs, while β2 receptors are present in the smooth muscles in their walls, so 3. adrenaline cause excitation ACTIONS ON (contraction) of sphincter muscles, while it inhibits (relaxes) SMOOTH the muscles in the wall of organs. MUSCLE The net results in the different organs: urine retention, constipation, inhibition of gastrointestinal tract movement, eye mydriasis, bronchodilation.  EXOCRINE GLANDS 1. Since catecholamines cause vasoconstriction of blood vessels that supply the glands, so they 4. often reduce rate of secretion of ACTIONS ON exocrine glands except the EXOCRINE sweat glands (Why?)​ AND ENDOCRINE Since sweat glands, they are supplied with sympathetic choli GLANDS -nergic nerve fibers, so sympathetic stimulation leads to secretion of large quantities of sweat.  ENDOCRINE GLANDS 1- Binding to α- 4. adrenergic receptors inhibits ACTIONS ON insulin secretion. EXOCRINE AND 2- β-Adrenergic ENDOCRINE receptor binding stimulates the GLANDS secretion of glucagon, ACTH, and renin.  Adrenaline increases the activity of the brain. Its secretion increases during (fight and flight) reaction after 5. exposure to stress. ACTIONS ON CNS  Regulation of secretion  Factors that stimulate catecholamine release 1- Acute stressors (mainly hypoglycemia- hemorrhage- decrease blood pressure- cold exposure- exercise). 2- Stimulation of sympathetic nervous system. 3- ACTH stimulate synthesis of adrenaline via ……… 4- Adrenaline does not exert negative feedback to down-regulate its own secretion. 5- Its action is terminated with reuptake into nerve terminal endings and metabolism by MAO and COMT.  In case of stimulation of sympathetic nervous system the organs are stimulated in two ways 1- Directly by the sympathetic nerves 2- In directly by medullary hormones The two means support each other, and in most instances, substitute for the other. 1. destruction of the direct sympathetic pathways to the different body organs does not cancel sympathetic excitation of the organs (Why?) because noradrenaline and adrenaline are still released into the circulation and indirectly cause stimulation. 2. loss of the two adrenal medullae usually has little effect on the operation of the sympathetic nervous system (Why?) because the direct pathways can still perform almost all necessary duties.  Melatonin synthesis Tryptophan NAT  Melatonin has important effects in integrating photoperiod and affecting circadian rhythms. FUNCTIONS Consequently, it has a significant effects on reproduction, sleep-wake cycles and other phenomena showing circadian rhythm.