Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Metabolic syndrome wikipedia , lookup
Hyperandrogenism wikipedia , lookup
Complications of diabetes mellitus wikipedia , lookup
Epigenetics of diabetes Type 2 wikipedia , lookup
Insulin (medication) wikipedia , lookup
Insulin resistance wikipedia , lookup
Diabetic ketoacidosis wikipedia , lookup
PHYSIOLOGY OF PANCREAS S. Sh. Sadr MD Professor of Tehran University Department of Physiology General Informations W : 50 – 75 gr Langerhans Islet : 0.5 – 1.5 million Histology : α : 20 – 30 % ; Glucagon (around of islet) β : 60 – 80 % ; Insulin (center of islet) δ : 8 % ; Sumatostatin & Gastrin (between α, β) PP or F : variable ; pancreatic polypeptide) Insulin W : 6000 d 51 aa (A chain = 21, B chain = 30) Pro-insulin : 9000 d, 84 aa (= 51+33) C-peptide : 33 aa Store : 4 u/kg (in adult = 200 u) Gene on short arm of Chr. 11 Secretion of Insulin 1- Basal secretion : Continuous, 1 u/h 2- Stimulated secretion : IV Glu. : peak : after 3 – 5 min = 8 – 10 x BS Oral Glu. : peak : after 0.5 – 1 h = 6 – 8 x BS Insulin response to Glu. Infusion shows a rapid first phase of release followed by a fall and a later slower second phase Metabolism of Insulin Half life : 6 min When insulin is secreted into the blood, it circulates almost entirely in an unbound form Each hepatic passage : 40 – 50 % inactivation Mechanism of Action Receptor : W = 300,000 d 2α (extracellular) + 2β(intracellular) Insulin + α subunit → autophosphorilation of β subunit → tyrosine kinase activity ↓ cAMP ↑ Glycogenesis, lipogenesis and Pr. Synthesis ↓ Glycogelolysis, lipolysis, proteolysis, gluconeogenesis and ketogenesis Effects of Insulin Metabolism of Carbohydrates : ↑ Glu. Uptake from plasma Facilitates Glu. entrance into cells ↓ rate of release of Glu. From liver by : By Inhibiting glycogenolysis By Stimulating glycogen synthesis By Stimulating Glu. Uptake By Stimulating glycolysis By indirectly inhibiting glycogenesis via inhibition of fatty acid mobilization from adipose tissue Insulin is necessary for entrance of Glu. Into the most of cells (Except of CNS, intestine epithelium, pancreas cells and renal tubul epithelium) Effects of Insulin Metabolism of Carbohydrates : Effect on Liver: Glu. Uptake from plasma ↑ glycogenesis ↓ glycogenolysis ↓ glyconeogenesis Glu. Converting to fatty acids Effect on Muscles: Most of day time: fatty acid At rest: glu. resistant during sport: needs glu. for providing energy After meal: rapid glu. Transport into muscle cells Effects of Insulin Metabolism of Proteins: ↑ transport of aa into hepatic and muscle cells (unrelated but may be related to Na/K pump activity) Val Leu Ile Tyr Phe ↑ synthesis of protein ↓ proteolysis to glu. transport Effect of Insulin on Protein Metabolism and on Growth Insulin Promotes Protein Synthesis and Storage. 1 . Insulin stimulates transport of many of the amino acids into the cells 2. Insulin increases the translation of messenger RNA 3. Insulin also increases the rate of transcription of selected DNA genetic sequences in the cell nuclei 4. Insulin inhibits the catabolism of proteins 5. In the liver, insulin depresses the rate of gluconeogenesis Insulin Deficiency Causes Protein Depletion and Increased Plasma Amino Acid Insulin and Growth Hormone Interact Synergistically to Promote Growth Effects of Insulin Metabolism of Lipids: ↓ lipolysis ↑ synthesis of fatty acids in liver As a result: Effect on growth: Insulin is an Anabolic Hormone In embryonic life, Insulin is the most important hormone for embryonic growth. Effect on Glucagon: Insulin refuses glucagon secretion The end effects of Insulin 1. Within seconds after insulin binds with its membrane receptors, the membranes of about 80 percent of the body’s cells markedly increase their uptake of glucose. 2. The cell membrane becomes more permeable to many of the amino acids, potassium ions, and phosphate ions,causing increased transport of these substances into the cell 3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more intracellular metabolic enzymes. • 3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more intracellular metabolic enzymes 4. Much slower effects continue to occur for hours and even several days. They result from changed rates of translation of messenger RNAs at the ribosomes to form new proteins and still slower effects from changed rates of transcription of DNA in the cell nucleus Insulin Secretion Increased by Decreased by D-glucose Glucagon-like Fasting Galactose peptide I Gasteric inhibitory polypeptide Secretin Cholecystokinin Vagal activity Acetylcholine β-adrenergic activity Sulfounylurea drugs Exercise Mannose Glyceraldehyde Protein: Arg, Lys, Leu, Ala Ketoacids Free fatty acids Potassium Calcium Glucagon Endurance training Somatostatin Galanin Pancreastatin Interleukine I α2-adrenergic activity Prostaglandin E2 Diazoxide Glucagon Single chain polypeptide 29 aa 3485 d α cells Entro-glucagon: Larger molecule Half life = 6 min Hepatic and renal metabolizing Glomerule infiltration Effects of Glucagon (Completely against Insulin effects) Metabolism of Carbohydrates : ↑ glycogenolysis in liver ↑ glyconeogenesis (slow process) Inhibition of glycogen synthesis in liver Metabolism of Lipids : ↑ lipolysis Other effects: β cell stimulation Catecholamine secretion stimulation ↑ heart muscle contractility ↑ bile and calcitonin secreton Glucagon Causes Glycogenolysis and Increased Blood Glucose Factors Influencing Glucagon Release Stimulation Amino acids Gastrointestinal polypeptide hormones Catecholamine (exercise) Growth Hormone Glucocorticoid Inhibition Glucose Insulin Free fatty acids Pancreas Islets Control Effective agents: Metabolites Hormones Neural factors Pancreas Islets Control Metabolites: Glucose: ↑ insulin, ↓ glucagon and hypothalamic effects Amino acids: Arg, lys and Leu aa. amplifies glu. effect on insulin secretion Lipids: Fatty acids and Ketons: inhibitory effects on α cells and stimulatory effect on β cells. Pancreas Islets Control Hormones: GI hormones: oral glu. increases insulin more than IV glu. Gastrin Secretin CCK GIP Entroglucagon Gastrin, CCK and GIP, ↑ glucagon secretion. glucagon Other hormones: GH, Thyroxin, Glucocorticoids, SS Pancreas Islets Control Neural factors: α2 adrenergic: ↓ insulin β adrenergic: ↑ insulin Parasympathetic, dopamine, serotonin and PG : ? Somatostatin δ cells Polypeptide with 14 aa Half life = 2 min All of the factors related to digestion and absorption stimulates SS. secretion: ↑ glu. ↑ aa ↑ fatty acids ↑ GI hormones Effects of Somatostatin Insulin and glucagon secretion inhibition (local effect) ↓ gastric, duodenal and biliary bladder motility ↓ GI secretions and absorption GH inhibitor Blood Sugar Control Normal FBS = 70 – 100 mgr/100cc 1 hour after eating = 120 – 140 mgr/100cc Control Mechanism: Liver Insulin and glucagon Hypoglycemia Early Late Blood Sugar Control ↑ BS: ↑ extracellular osmotic pressure → cellular dehydration Excretion in urine → osmotic dieresis → polydipsia and polyuria signs → dehydration ↓ BS: Cerebral cells, retina and testicular epithelium Diabetes Mellitus (pathophysiology) ↓ insulin : ↓ metabolism of gu. in cells ↑ fatty acids from lipid storages Protein emptying in tissues Abnormalities: Glu. excretion in urine: > 180 mgr/100cc Intra and extra cellular dehydration: shock Acidosis and Coma: metabolism changing from carbohydrate to lipid Chronic High Glucose Concentration Causes Tissue Injury When blood glucose is poorly controlled over long periods in diabetes mellitus, blood vessels in multiple tissues throughout the body begin to function abnormally and undergo structural changes that result in inadequate blood supply to the tissues. This in turn leads to increased risk for heart attack, stroke, end-stage kidney disease, retinopathy and blindness, and ischemia and gangrene of the limbs. Chronic high glucose concentration also causes damage to many other tissues. Peripheral neuropathy, ( which is abnormal function of peripheral nerves) Autonomic nervous system dysfunction These abnormalities can result in impaired cardiovascular reflexes Impaired bladder control Decreased sensation in the extremities Other symptoms of peripheral nerve damage. Hypertension (secondary to renal injury) Atherosclerosis ( secondary to abnormal lipid metabolism) Diabetes Mellitus Causes Increased Utilization of Fats and Metabolic Acidosis. Rapid and deep breathing Clinical Characteristics of DM type I and type II Type I Type II Age at Beginning Usually under 20 Usually above 40 Body Mass ↓ (Thin) abnormal Obese ↓ or empty Normal to ↑ at beginning Plasma Insulin Plasma Glucagon ↑ it can be suppressed ↑, resistant to suppression ↑ ↑ Insulin Susceptibility Normal ↓ Treatment Insulin ↓ Weight, Insulin, Drugs* Plasma Glucose Insulin Resistance: Causes 1) 2) 3) 4) 5) 6) 7) 8) 9) Obesity and Overweight Glucocorticoid excess (Cushing syndrome) ↑ GH Pregnancy and GDM PCO Lipodystrophy Insulin Receptor Ab Insulin Receptor Mutation Hemochromatosis Metabolic Syndrome Obesity Insulin Resistance Fasting Hyperglycemia Lipid Disorders (↑ TG and ↓ HDL) Hypertension Obesity, insulin resistance and metabolic syndrome are usually present before DM II