The Islets of Langerhans and Their Hormones Introduction cid 127 Glucose is a key energy substrate especially for the CNS The majority of hormones released by stressors stimulate an increase in blood glucose concentration The islets of Langerhans act as an endocrine gland cid 127 Glucagon generally acts to increase the blood glucose concentration Insulin actively decreases blood glucose concentration D glucose is a hydrophilic molecule that requires specific transporters GLUT to cross cell membranes cid 127 GLUT1 is found in all plasma cell membranes and is associated with basal uptake of glucose Especially important in erythrocytes endothelium of the blood brain barrier fetal tissues cid 127 GLUT2 is found in the renal tubules hepatocytes liver cells beta cells of the islets of Langerhans cid 127 GLUT3 is found in neurons and the placenta cid 127 GLUT4 is found in skeletal and cardiac muscle as well as adipocytes cid 127 Only transporter that is influenced by insulin cid 127 Glucose undergoes facilitated transport does not require ATP using a high to low concentration gradient The pancreatic islets of Langerhans Anatomy and structure Pancreas is closely associated with the small intestine Derived from the endoderm of the foregut during fetal development cid 127 Most of the pancreas is comprised of lobules of acinar cells the exocrine pancreas Scattered throughout the lobules are the islets of Langerhans Approx 1 million islets in a normal human pancreas 2 of pancreas Blood reaches the pancreas through the superior and inferior pancreatico duodenal arteries Body and tail also receive blood from the splenic artery Veins drain into the portal vessels that pass to the liver Autonomic innervation both sympathetic and parasympathetic Islet is comprised of four cell types alpha glucagon 15 of cells beta insulin 80 of cells delta somatostatin gamma pancreatic polypeptide Pancreatic functions duodenum The beta cells and insulin Synthesis storage secretion and transport of insulin Beta cells synthesize the polypeptide hormone insulin cid 127 Gene located on chromosome 11 Synthesized initially as a precursor molecule single chain of amino acids with 2 disulfide bonds Cleaved by a peptidase in the Golgi body forming insulin and C peptide Stored in secretory granules within the cytoplasm Stimulus for synthesis secretion is increased blood glucose level Enters beta cells via GLUT2 and is immediately phosphorylated to G6P glucose 6 phosphate Key regulatory step in insulin synthesis Enzyme is glucokinase cid 127 When the cell is stimulated pre synthesized insulin is released from the granules ATP closes potassium channels in the cell membrane Transient K increase causes the membrane to depolarize cid 127 Opens voltage dependent Ca channels Influx of Ca causes the granules to move towards the cell membrane Insulin is released via exocytosis Insulin circulates mainly unbound in the bloodstream Insulin receptors and mechanisms of action Receptor tyrosine kinase Family includes the receptors for IGF1 and 2 Producing exocrine secretion enzymes and digestive molecules which enters the pancreatic duct and then moves through the common bile duct into the Producing endocrine secretion polypeptide hormones of the islets of Langerhans which are released into the bloodstream cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 cid 127 Insulin receptor exists as a dimer even in the unstimulated state Activation of the tyrosine kinases is due to auto and cross phosphorylation of tyrosines in the intracellular domain Conformational change occurs with ligand binding Diverse intracellular second messengers Insulin receptor substrates IRS mediate some of these pathways Diverse influences many metabolic processes throughout the body PI kinases cid 127 GF binding protein cid 127 MAPK Actions of insulin Protein metabolism Stimulates amino acid uptake Stimulates protein synthesis genomic Lipid metabolism Stimulates lipogenesis Inhibits lipolysis Ketogenesis Normally in the presence of insulin the formation of ketone bodies is depressed In type 1 diabetes mellitus the concentration of ketones rises in the blood lowering blood pH cid 127 Most important is blood glucose regulation removal from bloodstream Increases GLUT4 mediated glucose uptake striated muscle and cardiac muscle Stimulates glycolysis Stimulates glycogenesis Inhibits gluconeogenesis Inhibits glycogenolysis Inhibits glucagon production Central effects Hypothalamic neurons are very sensitive to changes in glucose concentration in their immediate environment Basal secretion is necessary since some cells are dependent on insulin dependent GLUT4 to receive glucose Likely linked to the neural circuitry that regulates appetite cid 127 Maintains intracellular potassium concentration Control of insulin release Enhanced release with post prandial blood glucose increase Initial increase lasting 10 minutes Second rise which reaches a plateau 2 3 hours later Amino acids glycine alanine arginine directly stimulate insulin release Free fatty acids FFA are generally potent enhancers of glucose stimulated insulin secretion Second messengers include DAG and long chain acyl CoA cid 127 Gastrointestinal hormones cid 127 Oral glucose will have a greater stimulation of insulin release than IV glucose Amplification of the normal stimulatory effect mediated by the GI tract incretin effect cid 127 Gastrin and cholecystokinin glucagon like peptide 1 GLP1 and gastric inhibitory peptide GIP are known as incretins because they stimulate insulin secretion Autonomic nervous system response Islet cell interactions Sympathetic activation is associated with catecholaminergic stimulation of glycogenolysis resulting in increased blood glucose part of fight flight Increased sympathetic and parasympathetic activities are associated with decreased and increased insulin release respectively The beta cells in each islet are more central than the alpha cells and gamma cells Adjacent cells make contact with each other paracrine influences cid 127 Glucagon appears to have a stimulatory effect on insulin release while somatostatin is inhibitory The alpha cells and glucagon Synthesis storage release and transport cid 127 Glucagon is synthesized in the alpha