diabetes therapies (Steve Darby) Flashcards
How does glucose release insulin from the pancreas?
- glucose transported in through glucose transporter
- metabolised by mitochondria and ATP generated
- ATP interferes with K channel, becomes inactivated
- leads to membrane depolarisation
- leads to activation of Ca channel
- Ca causes insulin to be released
How does insulin lower high glucose levels?
- insulin binds to the insulin receptor
- receptor is phosphorylated
- activates cell signaling
- releases GLUT4, transported to the cell surface
- GLUT4 imports glucose into the cell lowering glucose levels
structure of insulin
2 peptide chains A and B
A = 21 AA
B = 30 AA
What links the 2 chains of insulin?
2 disulfide bonds
What are the 2 phases of insulin release?
1st - rapid release of stored insulin, after eating food to stabilise glucose levels
2nd - slow release following synthesis, as food is digested
insulin 2 phase release in T1DM
no release of insulin
damages beta cells
insulin 2 phase release in T2DM
lack of initial spike in insulin
rush of glucose initially
has the 2nd peak in insulin
How is natural insulin cleared?
liver clears 60% of insulin released from pancreas before systemic circulation
kidneys remove 35-40%
half life of insulin
3-5 mins
Why can’t insulin be taken orally?
it is a protein and is destroyed by the GIT
insulin clearance of injected insulin
liver remove 30-40%
kidneys remove 60%
(ratio reversed)
2 substances used in insulin preparation
zinc
protamine
What do insulin and zinc form?
zinc-insulin hexamer
Why is zinc used in insulin preparation?
- increases the stability of insulin
- delays site absorption
What does protamine form with insulin?
insoluble complexes
What type of release does protamine and insulin form?
prolonged release
times until peak/onset of rapid/short/intermediate/long acting insulins
rapid 5-15 mins onset
short 2-3 hrs
intermediate 6-12 hrs
long 10-24 hrs
What is a soluble preparation of insulin called?
neutral insulin
types of short/intermediate/longacting insulins
short - insulin neutral/soluble
intermediate - isophane insulin
long - insulin zinc suspension/protamine zinc insulin
How to make recombinant insulin?
- insert human gene into plasmid at a specific point and ligate them together
- insert the plasmid into bacterium
- bacterial cells produce human insulin gene protein in bulk
- plasmid replicates inside the bacterium and bacteria divide to produce a colony
- purify the protein from culture
How to change the AA sequence of recombinant protein?
use enzymes to cut/change any DNA base you want to change in the AA sequence
3 commercial rapidly acting insulins
lispro
aspart
glulisine
When are rapidly acting insulins taken?
before a meal to elevate glucose levels
onset of rapidly acting insulins
5-15 mins
How does lispro differ from normal human insulin?
AA proline at position B28 is replaced with lysine
lysine at position B29 replaced with proline
Why is lispro recombinated?
it prevents it forming a dimer or hexamer
it only forms monomers
short acting insulin structure
hexamer
When is short acting insulin taken?
30-45 mins before meal
What is short acting insulin especially used for IV?
treatment for diabetic ketoacidosos
What is short acting insulin made from and why?
regular insulin made as a recombinant molecule
it has less immune issues than animal insulin
example of an intermediate acting insulin
neutral protamine hagedorn insulin (NPH)
onset of action of NPH insulin
2-5 hrs
examples of long acting insulin
insulin glargine
insulin detemir
recombinant structure of insulin glargine
insertion of 2 arginine molecules on chain B and substitution of glycine with asparagine at A21 position
solubility of insulin glargine
in acid conditions pH4
What does insulin glargine provide?
low level of continuous insulin
formulation of insulin detemir
myristic acid attaches at B29
increases self aggregation and albumin binding
side effects of insulin
too much - hypoglycaemia, brain damage, cardiac arrest
too little - DKA
insulin allergy (esp animal insulins)
lipodystrophy at site of injection (animal insulins)
cancer risk?
3 strategies of anti-diabetic drugs
- increase cellular sensitivity to insulin
- increase insulin release
- reduce/delay glucose absorption into blood
What effects does insulin have?
increases glucose uptake
increases lipogenesis
increases glycogen synthesis
increases protein synthesis
decreases lipolysis
decreases gluconeogenesis
What group does metformin belong to?
biguanides
How is metformin eliminated?
100% renally eliminated (not metabolised)
What type of drug is metformin?
insulin senstiser
Does metformin affect insulin output?
no, it’s effective in late stage disese where beta cell decline has occurred
How does metformin work in the liver?
it decreases gluconeogenesis
serious clinical consequence of a metformin side effect and how it happens
lactic acidosis
pyruvate is coveted to lactate
there’s increased lactate production
adverse effects of metformin
diarrhoea, dyspepsia
lactic acidosis
metformin and renal function
renl function test required
not prescribed if GFR < 45ml/min
stop if GFR < 30ml/min
results of a kidney funtion test that show impaired kidneys
more orange = high creatinine
high creatinine = impaired kidneys
