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Transcript
The Pancreas Glucose homeostasis Pancreatic Hormones, Insulin & Glucagon Regulate Metabolism Actions of insulin and glucagon Insulin Glucagon Signal of feeding. Signal of fasting. Target tissues: liver, adipose skeletal muscle Target tissues: liver, adipose Affects metabolism of: carbohydrates, lipids proteins Affects metabolism of: carbohydrates, lipids Actions are anabolic Actions are catabolic Why keep blood glucose concentration constant? Some tissues only metabolise glucose: CNS, PNS, red blood cells, kidney, eye Metabolise glucose at constant rate. Rate of glucose uptake determined by blood [glucose]. Keep blood [glucose] constant to enable metabolism to proceed at constant rate. Control of insulin & glucagon secretion Factor Nutrients: glucose 5mM glucose 5mM amino acids fatty acids Insulin Glucagon + + + + + 0 Hormones/neurotransmitters: GI tract + adrenaline noradrenaline - 0 + + Preproinsulin A|F1 KTRR|E33 KR|G66 Ins B-chain 110aa Ins A-Chain C-peptide Preproglucagon Q|R1 KR|H33 KR|H72 KR|N64 Glicentin RGRR|D111 R|H78 GRR|H125 Glucagon Oxyntomodulin GLP-1 GLP-2 GLP-1 (7-37amide) Preprosomatostatin G|A25 Q|R89 F|L34 116aa RERK|A103 Antrin ? Somatostatin 28 SS-14 Prepro Pancreatic polypeptide E|P33 Pancreatic polypeptide Islet Prohormones RK160 RPRYGKR|H69 95 aa 180aa Synthesis of insulin - 1 Preproinsulin (110aa) NH2 S S S S HOOC S S ESR10-07 Synthesis of insulin - 2 Proinsulin (86aa) NH2 S S S S HOOC S S ESR10-08 Synthesis of insulin - 3 Insulin (21 + 30aa) HOOC NH2 S S S S HOOC NH2 S - chain - chain S C - peptide (35aa) ESR10-09 Regulation of glucose transport by insulin Binding of insulin to cell-surface receptors Intracellular vesicles containing membrane-imbedded GLUT4 transporters fuse with the plasma membrane GLUT4 transporters in muscle or adipose cell surface increases capacity of the cell to transport glucose. Basal levels of glucose transport are maintained by GLUT1 and GLUT3 forms of the glucose transporter (in most tissues). Activation of glycogen synthase and inactivation of glycogen phosphorylase Binding of insulin by the liver or muscle cell leads to stimulation of protein phosphatase-1 Hydrolysis of phosphate catalyzed by protein phosphatase-1 increases the activity of glycogen synthase but deactivates glycogen phosphorylase. Insulin switches ON glycogen synthetase (GS) Insulin Pi (+) Phosphoprotein phosphatase GS GS Inactive ADP cAMPINDEPENDENT kinase GSK3 (-) Insulin Active ATP ESR10-26 Insulin Inhibition of TAG Degradation in Adipose In high insulin/low glucagon state: cAMP falls in adipose HSL is not phosporylated and is inactive Remember: epinephrine as shown here is a counterregulatory hormone Insulin Action on Cells: Dominates in Fed State Metabolism Stimulation - insulin secretion • Increased [ glucose ] • Increased [ free aa ] Mixed Meal • Increased [ GI hormones ] (gastrin, secretin, CCK, GIP) • Increased [ glucagon ] • Noradrenaline (low [ ]; α-adrenergic receptors) • Acetylcholine ESR10-12 Inhibition - insulin secretion • Decreased [ glucose ] • Increased [ somatostatin ] (pancreatic + gastric) • Noradrenaline (high [ ]; β-adrenergic receptors) • Adrenaline (β-adrenergic receptors) ESR10-13 Hypoglycaemia Blood glucose < 3.0mM Uptake of glucose by glucose-dependent tissues not adequate to maintain tissue function. CNS very sensitive: Impaired vision, slurred speech, staggered walk Mood change – aggressive Confusion, coma, death Stress response (release of adrenaline): Pale Sweating – clammy Diabetes Mellitus Group of metabolic diseases. Affect 1-2% of population in UK. Characterised by: • chronic hyperglycaemia (prolonged elevation of blood glucose) • leading to long-term clinical complications Caused by: • Insulin deficiency – failure to secrete adequate amounts of insulin from -cells. and/or • Insulin resistance – tissues become insensitive to insulin. Classification of Diabetes Two major types recognised clinically Type 1 – absolute insulin deficiency (loss of -cells). Type 2 – relative insulin deficiency and/or insulin resistance. Also Gestational Diabetes (only occurs during pregnancy). Other pancreatic hormones Glucagon (29aa) - synthesised from preproglucagon • Zn not required for secretion • metal ions decrease clearance Somatostatin (14aa) • physiological role unclear • can suppress insulin and glucagon ESR10-10 Stimulation glucagon secretion • Decreased [ glucose ] • Increased [ free aa ]* • Adrenaline Inhibition glucagon secretion • Increased [ glucose ] ESR10-14 Activation of glycogen phosphorylase and inactivation of glycogen synthase Glucagon as a signal of hunger. In its presence, the liver carries out glycogenolysis to provide glucose to the bloodstream and the rest of the body. Epinephrine is a signal of stress. Stimulates muscle glycogenolysis to provide glucose to support contraction and movement 6-phosphofructo-2-kinase/fructose-2,6bisphosphatase (PFK-2/F-2,6-P2ase) Fructose-6-P Glycolysis Gluconeogenesis cAMP-Dependent Protein Kinase Active F-2,6-Pase F-1,6-P2ase Inactive PFK-2 - - P Glucagon Inactive F-2,6-Pase Active PFK-2 Protein Phosphatase-2 Fructose-2,6-P2 Fructose-1,6-P2 + PFK-1 Glucagon switches OFF glycogen synthetase (GS) Glucagon (+) Glycogen phosphorylase a (-) Pi Phosphoprotein phosphatase GS GS Inactive cAMPdependent kinase ADP (+) Glucagon Active ATP ESR10-25 HSL and futile cycling Glycerol Cytosolic Acetyl CoA TAG FA Mitochondrial Acetyl CoA Glycerol HSL Insulin (-) (+) (+) Glucocorticoids cAMPdependent kinase Glucagon (+) ESR10-32 Somatostatin (somatotropin release-inhibiting factor, SRIF) • Secreted by hypothalamic anterior periventricular region and by d cells of the pancreatic islets • Secretion by GH, IGF-I, thyroid hormones • Chemistr S S y: Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys A single peptide of 14 amino acids A 28-amino acid form is found in the gut Stimulation somatostatin secretion • Carbohydrates • Proteins • Fats Mixed Meal • Decreased pH in duodenum (by gastric acid - bulbogastrone mechanism) ESR10-15 Somatostatin • Actions: • Inhibits GH secretion but not its synthesis • • • Inhibits basal and TRH-stimulated TSH secretion Inhibits secretion of GI peptide hormones: insulin, glucagon, VIP, gastrin, and others • Mechanism of action: • Gi protein-coupled receptors with tissue-specific • expression Reduces cAMP production and Ca2+