insulin treatment Flashcards
conversion of pre-pro-insulin to insulin
- the signal sequence (pre) targets the protein to the endoplasmic reticulum and it is packaged into secretory vesicles
- pre is cleaved off by a protease in the endoplasmic reticulum generating pro-insulin
- disulphide bonds form between chain A and B of pro-insulin
- proteases cleave at either end of chain C
- giving insulin chain A and B joined by disulphide bonds and C peptide
insulin hexamer
- insulin is stored as an inactive hexamer in secretory vesicles
- hexamer is stabilised by Zn2+ ions
- upon release into bloodstream hexamers disassemble
three groups of insulin
animal: not widely used but some people find it works better for them
human: synthetically made via recombinant DNA technology
analogues: human insulin is altered to make it work quicker or last longer
three types of insulin preparations
- short duration with a relatively rapid onset of action; soluble insulin, insulin aspart, insulin glulisine, insulin lispro
- intermediate action; isophane insulin
- slow onset and lasts for long periods; insulin detemir, insulin glargine
biphasic insulin
pre-mixed insulin preparations containing various combinations of short-acting insulin or rapid-acting insulin analogue together with an intermediate-acting insulin
uptake of insulin
- injected insulin has to diffuse across capillary walls to enter circulation
- diffusion is limited by size of insulin
- monomer > dimer > hexamer/aggregates
humulin S
- soluble
- short-acting
humulin I
- isophane
- medium-acting
- contains protamine
protamine
- basic protein (positively charged) that binds to negatively charged insulin and clusters insulin hexamers
- causes clustering of insulin, limiting diffusion through capillary walls
insulin aspart (novorapid)
has proline to aspartate substitution in the B chain which reduces the tendency to form hexamers as a result it is more rapidly transferred from the sub-cutaneous injection site to the bloodstream
insulin lispro (humalog)
- has two substitutions in the B chain which also diminish the tendency of insulin molecules to self-associate
insulin glulisine
has two substitutions in the B chain
asparagine replaced with a lysine and a lysine replaced with a glutamic acid these changes also reduce insulin self association
insulin glargine (lantus)
contains an asparagine to glycine substitution in A chain and also has two arginines added to the carboxyl terminal end of the B chain
these changes make the insulin analogue less soluble at physiological pH which limits absorption from the site of injection
insulin detemir (levemir)
- covalently attached fatty acid (myristic acid) that causes the molecule to bind to albumin in the blood serum
- albumin with the insulin receptor for binding to insulin detemir prolonging its action
- albumin binding also protects insulin detemir from circulating peptidases increasing its stability
insulin degludec (tresiba)
- has a hexadecanedioic acid group added to B chain this mediates albumin binding but also causes formation of multi-hexamers when injected
- monomers are slowly released from these multi-hexamers extending duration of action beyond 40 hours
injection of insulin
- injection is necessary as orally-administered insulin would be degraded by proteases in the stomach and small intestine
- injection is sub-cutaneous
- once injected, insulin diffuses into small blood vessels and enters bloodstream
- injection site: stomach, buttocks, thighs
- injection sites are rotated to avoid lipohypertrophy, accumulation of lumps under skin
- all insulin should be stored below 25 degrees in fridge
insulin treatment of type 2
- insulin used in combination with oral antidiabetic drugs
- basal insulin is usually a suitable first step with once/twice daily intermediate or long acting insulin
- biphasic insulin can be used if diabetic control is particularly poor
- basal-bolus regimen can be introduced if blood glucose remains inadequate
insulin pumps
- alternative to injections
- size of small mobile
- delivers varied dose of rapid acting insulin continually during day/night
- when food is eaten can give an additional bolus dose of insulin by pressing specific buttons
islet cell transplantation
- implanting islet cells from deceased donor
- simple procedure cells injected through catheter in the upper abdomen into the liver
- recipients need to take immunosuppressive drugs to prevent rejection
- lack of suitable organ donors
stem cell-derived beta cells
- produced from pluripotent stem cells
- the cells form islet-like clusters and made insulin when transplanted into mice
- overcomes limitation of acquiring donors
re-purposing of cells in patient
- switching off a single gene GI cells allowed them to produce insulin
- gut endocrine progenitor cells could be differentiated into glucose-responsive insulin-producing cells by ablation of the transcription factor Fox01
insulin sprays
- attaching insulin to carriers that protect from degradation and allow oral delivery
- non-protein insulin substitutes that are able to bind to the insulin receptor and activate intracellular signalling pathways
