Download NME2.32 - Insulin and Glucagon

NME2.32: INSULIN AND GLUCAGON
07/03/08
THE ENDOCRINE PANCREAS
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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
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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
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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
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 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
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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
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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
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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