Lecture 20 - Insulin Treatment of Diabetes Flashcards
When insulin is made where is it targetted?
to the endoplasmic reticulum by a signal sequence
What happens as insulin moves from the endoplasmic reticulum to secretory vesicles?
it undergoes a series of cleavage steps and is packaged into the vesicles from where it can be released in response to high glucose levels
How is insulin made?
as pre-pro-insulin
What happens when insulin arrives at the endoplasmic reticulum?
the pre-sequence is removed to give pro-insulin
What forms between the chains of pro-insulin
disulphide bonds form between chain A and chain B
What happens to chain C?
proteases cleave either end
What arrives as a result of this?
Insulin (chain A and B joined by disulphide bonds) and C peptide
How is insulin stored in secretory vesicles?
as a hexamer
What is an insulin dimer?
two A chains an two B chains
What does an insulin hexamer consist of?
6 insulin molecules
What is a hexamer stabilised by?
Zn2+ molecules, these positive ions interact with the negatively charged amino acids to stabilise the whole structure
What is important about a hexamer?
it is stable but inactive
What happens to the hexamers upon release into the bloostsream?
they disassemble into the monomeric form of insulin
What are the three groups of insulin?
animal, human and analogues
Animal insulin?
not widely used but some people find this works better for them
purified from cows and pigs
Human insulin?
synthetically made via recombinant DNA technology
DNA of human insulin is introduced into a host (bacteria etc) and large amounts of the insulin molecule can be produced
Insulin analogues?
human insulin is altered to make it work quicker or last longer
Short acting insulin?
or rapid acting
short duration with a rapid onset
e.g. soluble insulin or rapid acting insulin analogues such as insulin aspart, insulin glulisine, insulin lispro
Medium acting insulin?
those with an intermediate action
e.g. isophane insulin
Long acting insulin?
those whose action is slower in onset and lasts for long periods
e.g. insulin detemir and insulin glargine
What is a normal insulin profile?
a sharp increase in insulin following increase in blood glucose levels, followed by a more sustained but lower secretion of insulin
What are biphasic insulins?
pre-mixed insulin preparations containing various combinations or short acting insulin or rapid acting insulin analogue together with an intermediate acting insulin (% of short acting varies from 10-15%)
What do biphasic insulins give?
a more physiological profile
What is uptake of insulin affected by?
size
How does insulin enter the general circulation?
they are administered subcutaneously so they have to diffuse across capillary walls
Rates of diffusion of insulin
monomer>dimer>hexamer/aggregates
What can alter the kinetics of insulin?
the composition of human insulin