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NME2.32: INSULIN AND GLUCAGON 07/03/08 THE ENDOCRINE PANCREAS The endocrine components of the pancreas are the islets of Langerhans o The pancreas holds several million islets o They are oval or spherical in shape There are at least four types of secretory cells making up the islets: o α cells principally secrete glucagon o β cells principally secrete insulin and proinsulin o δ cells secrete somatostatin o F cells secrete pancreatic polypeptide α and δ cells make up the majority of the periphery β and F cells are more abundant in the centre of the islets LEARNING OUTCOMES Describe the role of insulin and counter-regulation in glucose homeostasis Glucose is essential for life but must be kept within a narrow range of 4-5mM (fasting) o Hypoglycaemia causes confusion, loss of consciousness, coma and ultimately death o Hyperglycaemia causes severe dehydration, osmotic diuresis and vascular damage Insulin and glucagon together control and maintain blood glucose levels INSULIN SYNTHESIS AND SECRETION Insulin is a peptide hormone produced only by β-islet cells in the pancreas o It is primarily responsible for regulating body fuel metabolism during feeding and fasting o It suppresses glycogenolysis, gluconeogenesis and lipolysis o It stimulates glycogen synthesis and carbohydrate/fat/amino acid uptake in peripheral tissues Insulin synthesis begins with the transcription of preproinsulin o In the rough ER the leader sequence of preproinsulin is cleaved leaving proinsulin o Proinsulin consists of three subunits (A, B and C) and is packaged in the Golgi apparatus o Proteases in the Golgi cleave the C peptide leaving the mature insulin molecule The β cells secrete insulin along with proinsulin and C peptide o Proinsulin is roughly 1/20 as potent as insulin an plays a minor role in glucose regulation o C peptide has no biological action but is secreted in a 1:1 ratio to insulin A good clinical marker for insulin secretion Not removed by the liver (unlike insulin – 60% of which is extracted on first pass) Urinary concentration a good guide for insulin secretion capacity Insulin secretion is triggered by depolarisation of β cells o Glucose – primary stimulator of insulin secretion – enters cells via GLUT2 Metabolised producing ATP ATP inhibits K+ leak channels inducing depolarisation o o o Calcium influx stimulates release of secretory granules CCK, GLP and GIP stimulate the PLC pathway to raise intracellular calcium Parasympathetic innervation promotes insulin secretion (e.g. during feeding) Sympathetic innervation of α-adrenoceptors inhibits insulin secretion (e.g. during exercise) PERIPHERAL RESPONSE TO INSULIN Peripheral insulin receptors are tyrosine kinases that induce a dephosphorylation cascade o More than half of secreted insulin is taken up by the liver on first pass o The rest binds to membrane-bound tyrosine kinase receptors on peripheral tissues o The three primary targets for insulin action are the liver, muscle and adipose tissue There are significantly more receptors in the body than are needed for maximum response o Insulin itself down-regulates the number of receptors in tissues it affects reducing sensitivity o The same maximum response can be achieved but only at a higher insulin concentration Insulin acts on the liver by: o Promoting glycogen synthesis through activation of glucokinase and glycogen synthase o Promoting lipogenesis through activation of acetyl-CoA carboxylase and fatty acid synthase o Promoting protein synthesis through unknown mechanisms o Inhibiting gluconeogenesis through deactivation of key gluconeogenic enzymes o Inhibiting glycogenolysis through deactivation of glycogen phosphorylase Insulin acts on muscle (principal site of insulin-mediated glucose disposal) by: o Promoting glycogen synthesis through activation of hexokinase and glycogen synthase o Promoting glucose oxidation through activation of PDH and phosphofructokinase o Promoting protein synthesis through unknown mechanisms o Stimulation of GLUT4 transporters promoting glucose uptake into muscle tissue Insulin acts on adipose tissue by: o Promoting lipogenesis through stimulation of PDH and acetyl-CoA carboxylase o Inhibiting lipolysis through deactivation of hormone-sensitive lipase (HSL) o Stimulation of GLUT4 transporters promoting glucose uptake into adipose tissue GLUCAGON SYNTHESIS AND SECRETION Glucagon is another peptide hormone secreted by α-islet cells in the pancreas o It principally targets the liver o It promotes glycogenolysis, gluconeogenesis and ketogenesis o It often antagonises insulin action Glucagon synthesis begins with the transcription of preproglucagon o In the rough ER the leader sequence of preproglucagon is cleaved leaving proglucagon o Proglucagon is cleaved differently by α cells and intestinal endocrine cells (L-cells) α cells produce glucagon, GRPP and a C-terminal fragment L-cells produce glicentin, GLPs and IP-2 o GLP-1 is a potent insulin secretagogue produced in response to carbohydrate ingestion Glucagon secretion is stimulated only by amino acids o Protein ingestion (leading to production of amino acids) triggers glucagon secretion o Glucose is the major inhibitor of glucagon secretion (and to a lesser extent insulin) PERIPHERAL RESPONSE TO GLUCAGON Glucagon primarily acts on the liver utilising the cAMP/PKA pathway to induce phosphorylation o Glycogenolysis is stimulated through activation of phosphorylase kinase (rapid action) o Gluconeogenesis is stimulated through production of gluconeogenic enzymes (slow action) Describe the factors affecting fuel selection in different circumstances