The normal pancreas

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  • Pancreas consists of 1 million islets of Langerhans
  • Start to develop from week 9-11 gestation
  • Contain exocrine and endocrine components
  • Contain 4 major cell types, b, a, d and PP (pancreatic polypeptide)
  • b cells produce insulin
  • a cells produce glucagons (hyperglycaemic)
  • d cells produce somatostatin which inhibits both insulin and glucagons
  • PP cels contain a unique polypeptide which has gastrointestinal effects including stimulation of gastric acid secretion and inhibition of intestinal motility
  • There are also 2 rare cell types, D1 cells and enterochromaffin cells
  • D1 cells elaborate vasoactive intestinal polypeptide (VIP) – which stimulates hyperglycaemia and glycogenolysis
  • Enterochromaffin cells produce serotonin

Normal insulin physiology

  • Normal glucose homeostasis is tightly regulated by three processes;
  • Liver glucose production
  • Glucose uptake and utilisation in the peripheral tissues
  • Action of hormones such as insulin and glucagon
  • During fasting states low insulin and high glucagon allow hepatic gluconeogenesis and glycogenolysis whilst decreasing glycogen prevents hypoglycaemia
  • Following a menl, insulin levels rise and glucagons falls. Insulin promotes glucose uptake and utilisation in the tissues

Regulation of insulin release

  • Preproinsulin is synthesised in the rough ER and delivered to the golgi
  • It is then cleaved in a series of steps to form insulin and a cleavage peptide, C-peptide
  • C-peptide can be measured in the serum as an assay of insulin secretion
  • Glucose is the most important signal triggering insulin production and release
  • A rise in blood glucose results in glucose uptake into pancreatic cells by an insulin dependant, glucose transporting protein GLUT-2
  • Metabolism of glucose via glycolysis results in an increase in ATP
  • This inhibits the activity of an ATP-sensitive K+ channels leading to membrane depolarisation and the influx of calcium through voltage dependant Ca2+ channels
  • This results in the immediate release of insulin through the action of calcium on stored hormone in the b cell granules
  • If the stimulus persists, a delayed response of active synthesis of insulin occurs
  • Other agents including intestinal hormones and certain amino acids stimulate insulin release but not synthesis

Insulin action and insulin signalling pathways

  • Insulin is the most potent anabolic hormone known
  • Its principle function is to increase the rate of glucose uptake by certain cells, particularly striated muscle cells (including myocardial cells) and to a lesser extent adipocytes
  • Glucose uptake in other tissues including the brain is insulin independent
  • In the muscle glucose is either stored as glycogen or metabolised to ATP
  • In the adipocyte it is stored as lipid
  • Insulin also promotes amino acid uptake and protein synthesis whilst inhibiting protein breakdown
  • The insulin receptor is a tetrameric protein composed of 2 a subunits and 2 b subunits
  • The b subunit cystolic domain contains tyrosine kinase activity
  • Insulin binding to the extracellular domain of the a subunit activates the tyrosine kinase of the b subunit resulting in autophosphorylation of the receptor and phosphorylation of downstream signalling mediators
  • MAPK pathway is responsible for the mitogenic effects of insulin, promoting cellular proliferation and growth
  • PI-3K pathway is responsible for the metabolic effects of insulin e.g. lipid, protein and glycogen synthesis. It also mediates the translocation of GLUT-4 containing vesicles to the cell surface. GLUT-4 increases the rate of glucose influx. PI-3K pathway also promotes cell survival and proliferation

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