The normal pancreas
- 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