Diabetes & Insulin Flashcards
What are the four main types of cells in the islets of the pancreas?
alpha cells: glucagon
beta cells: insulin
delpta cells: somatostain
pp cells: pancreatic polypeptide
Describe the events that lead to the release of insulin from beta cells
At substimulatory glucose concentrations beta cells have a resting membrane potential of -60mV which is maintained by a K+ channels.
Glucose is transported into the beta cell via GLUT2 where is is rapidly phosphorylated by glucokinase for glycolysis.
Metabolism of glucose produces ATP which closes the K+ATP channel. This causes the cell to depolarise and opens VDCC and Calcum ions enter the cell.
Influx of Calcium ions releases more calcium from intracellular stores and promotes the fusion of intracellular vesicles containing insulin with the cell membane.
Insulin is released by exocytosis.
Calcium then activates K+ channels which cause K+ efflux and repolarisation
Function of pancreatic polypeptide
Release is stimulated by protein meals and cholinergic reflexes
Inhibits pancreatic exocrine secretion and affects the MMC and gastric secretion
Function of somatostatin
Release is stimulated by nutrients.
Inhibits the secretion of glucagon and insulin.
Action of sulphonylureas
Acts on the K+/ATP channel and closes it. This promotes depolarisation of the beta cell and the release of insulin.
However the effect wears off as the beta cell mass declines.
Describe the insulin receptor
RTK
Dimer linked by S-S bonds
Define diabetes
A metaboic disorder characterised by chronic hyperglycaemia resulting from the inability to produce insulin or insulin insensitivity.
Common symptoms of diabetes
Polydipsia
Polyuria
Weight loss (fat and protein metabolised)
Lethargy/Fatigue
Also: blurred vision, prone to infections, nausea and vomiting
First-line treatment in someone recently diagnosed with diabetes
Lifestyle changes:
Low calorie diet, low cholesterol and simple sugars
Exercise (increases expression of GLUT4 in muscle and fat)
Weight reduction
What is insulin
An anabolic peptide hormone
Name three modulators of insulin release and describe their mechanism of action
Glucose: ATP produced during glucose metabolism closes a K+-ATP channel depolarising the membrane and opening VDCC. Ca2+ enters the cell and promotes vesicle fusion.
CCK/ACh: bind to GPCR coupled to Gq on the beta cell which stimulates PLC to cleave PIP2 to IP3 and DAG. This results in the activation of PKC which causes protein phosphorylation. This promotes insulin release.
Glucagon: binds a GPCR coupled to Ga. This activates adenylate cyclase, increasing cAMP which activtes PKA. PKA phosphorylates proteins which cause insulin release.
Somatostatin: Binds a GPCR coupled to Gi. This inhibits adenylate cyclase, inhibiting insulin release.
Epinephrine: binds to adrenergic receptors to inhibit insulin release
What factors regulate insulin secretion?
The major factor that stimulates insulin secretion and biosynthesis is when the islets are exposed to glucose.
Amino acids (arginine, lysine) are potent activators of insulin release. Triggered by ATP production during metabolism
Lipids enhance glucose-stimulated insulin secretion. However lond term exposre to lipids impairs this.
Gastrointestinal peptide hormones (CCK, GLP-1, VIP, Gastrin) facilitate the release of insulin following a meal by acting through second messengers.
Glucagon (+), Somatotatin (-) and Insulin (-) regulate secretion
Parasympathetic nerves (ACh) increases insulin secretion. Sympathtetic nerves (epinephrine, norepinephrine) reduce insulin secretion.
Describe the process of insulin biosynthesis
The gene for insulin is synthesised as a large precursor peptide preproinsulin which is then converted to proinsulin.
Proinsulin consists of a signal chain, A chain, B chain and a connecting peptide. This connected segment is cleaved out during the conversion to insulin.
Proinsulin is folded by S-S bonds and transported the golgi apparatus which processes the proinsulin into insulin and stores it into a secretory granule. Cleavage results in the production of insulin and C-peptide which are both secreted from the granule.
Describe the pattern of insulin secretion following a meal
Insulin secretion stimulated by glucose is dose dependent. Insulin spikes occur after meals which show that there is a rapid maximal release of insulin following a meal and then levels decline as the beta cells are repolarised and the released insulin inhibits further release.
Note: If glucose is infused at a constant rate (e.g. iv administration, snacking) then a biphasic response is seen where there is a rapid early insulin peak followed by a second more slowly rising peak.
Describe how insulin increases the uptake of glucose from the blood
Insulin triggers an increase in the presence of GLUT4 receptors on the cell membrane.
GLUT4 receptors are mostly stored in intracellular vesicles. Activation of the insulin receptor triggers vesicle exocytosis and targets the GLUT4 recptors to lipid rafts on the cell surface.
Increases number of receptors helps facilitate the influx of glucose into the cell