3. Insulin secretion and action Flashcards
Within what parameters is blood glucose maintained?
3-5mmol/L
Why is the brain so dependent on the extracellular (blood) glucose concentration?
Because it cannot synthesise glucose for use or store glucose in large amounts
Cannot metabolise any substrates other than glucose (apart from ketone bodies)
The brain can also not extract glucose from extracellular fluid at a low concentration
Where is insulin synthesised and from where is it released?
Insulin is synthesised in the beta cells of the islets of Langerhan in the pancreas
Is released from here
Give the different cell types of the pancreas and what is released from here
Alpha cells - glucagon Beta cells - insulin Delta cells - somatostatin PP cells - pancreatic polypeptide Epsilon cells - ghrelin
Give the structure of insulin
Composed of two chains
Alpha chain and a Beta chain
Alpha chain is 21 amino acids long and Beta chain is 30 amino acids long
Give a brief overview of how the two chain amino acid structure is produced
Insulin is initially synthesised as preproinsulin (110 amino acids) in the B cells of the pancreas and the production of this is very very highly controlled
After about 5-10 minutes in the endoplasmic reticulum, the preproinsulin is then cleaved and concerted into proinsulin (86 amino acids)
SO has gone from 110 amino acids to 86 amino acids
Proinsulin is then cleaved to form insulin: from 86 amino acids to 51 plus a 35 amino acid C-peptide
This occurs within the Golgi
body
The insulin is then stored within a vesicle within the B cell and awaits secretion
What is the relation between insulin secretion and insulin synthesis?
These are very independent from each other
Insulin secretion will occur when required according to the blood glucose levels
Insulin synthesis will always occur when the vesicles in the beta cells are used up to constantly maintain a store of insulin vesicles for whenever they are required
Give the mechanism of insulin secretion from the B cells
Glucose enters the B cells through the glucose transporter GLUT1
The increased levels of glucose within the cell is sensed by glucokinase enzyme
When glucose levels exceed 5mm/L, the glucokinase enzyme acts to convert glucose to glucose-6-phosphate and this to pyruvate and this leads to increased levels of ATP as it is produced
The increased ATP/ADP ratio causes the K-channels at the membrane to close and this causes membrane depolarisation
This stimulates VG calcium channels to open and this stimulates insulin secretion via exocytosis
(SO the release of insulin is essentially triggered by rising Ca2+ levels)
What other signals can trigger the release of insulin?
Amino acids arginine and leucine
Fatty acids
Parasympathetic release of acetylcholine
Incretins e.g. glucagon-like peptide 1 (GLP-1)
Describe the structure of the insulin receptor
Transmembrane receptor
Can be activated by many hormones to carry out different cell types
Tyrosine kinase receptor
Alpha chain extracellularly binds to insulin
Beta chain has a tyrosine kinase enzymatic activity
What is the function of insulin at the muscle and adipocytes?
Stimulates glucose uptake into muscles and adipocytes - GLUT4 transporter mediated to the plasma membrane of these cells
Stimulates glycogen synthesis in muscles once the glucose has entered
Stimulates lipogenesis and inhibits lipolysis via the inhibition of hormone sensitive lipase (so inhibition of hydrolysis of triglycerides and release of fatty acids into the circulating blood)
What is the function of insulin at the liver?
Enhances glucose uptake via increased glucokinase activity
Increases glycogen synthesis
Increases lipogenesis
Inhibits gluconeogenesis
What is the function of insulin regarding proteins and amino acids?
Stimulates transport of amino acids into cells
Increases translation of mRNAs for the synthesis of new proteins
Inhibits the catabolism of proteins (decreased release of amino acids from cells)
SO the insulin inhibits gluconeogenesis at the liver (amino acids are the main substrate for the synthesis of glucose)
How is insulin signalling switched off?
When the levels of insulin in the blood falls then this causes a degradation and endocytosis of the receptor
The tyrosine receptor is phosphorylated by tyrosine phosphotases
Give the mechanism of action of insulin at it’s receptor
Insulin binds to the insulin receptor (IR) which has two alpha and two beta units
The insulin binds to the alpha unit and stimulates the activity of tyrosine kinase which acts intracellularly from the beta receptor
This then causes the phosphorylation of numerous intracellular substrates e.g. insulin receptor substrates (IRS) and causes their activation
Downstream signalling molecules are activated - results in the translocation of GLUT4 and action of protein kinase C
This then allows for metabolic actions of insulin to occur e.g. glucose uptake into cell
