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PHA223 > diabetes therapies (Steve Darby) > Flashcards

diabetes therapies (Steve Darby) Flashcards

1
Q

How does glucose release insulin from the pancreas?

A
  1. glucose transported in through glucose transporter
  2. metabolised by mitochondria and ATP generated
  3. ATP interferes with K channel, becomes inactivated
  4. leads to membrane depolarisation
  5. leads to activation of Ca channel
  6. Ca causes insulin to be released
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2
Q

How does insulin lower high glucose levels?

A
  1. insulin binds to the insulin receptor
  2. receptor is phosphorylated
  3. activates cell signaling
  4. releases GLUT4, transported to the cell surface
  5. GLUT4 imports glucose into the cell lowering glucose levels
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3
Q

structure of insulin

A

2 peptide chains A and B
A = 21 AA
B = 30 AA

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4
Q

What links the 2 chains of insulin?

A

2 disulfide bonds

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5
Q

What are the 2 phases of insulin release?

A

1st - rapid release of stored insulin, after eating food to stabilise glucose levels
2nd - slow release following synthesis, as food is digested

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6
Q

insulin 2 phase release in T1DM

A

no release of insulin

damages beta cells

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7
Q

insulin 2 phase release in T2DM

A

lack of initial spike in insulin
rush of glucose initially
has the 2nd peak in insulin

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8
Q

How is natural insulin cleared?

A

liver clears 60% of insulin released from pancreas before systemic circulation
kidneys remove 35-40%

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9
Q

half life of insulin

A

3-5 mins

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10
Q

Why can’t insulin be taken orally?

A

it is a protein and is destroyed by the GIT

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11
Q

insulin clearance of injected insulin

A

liver remove 30-40%
kidneys remove 60%
(ratio reversed)

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12
Q

2 substances used in insulin preparation

A

zinc

protamine

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13
Q

What do insulin and zinc form?

A

zinc-insulin hexamer

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14
Q

Why is zinc used in insulin preparation?

A
  • increases the stability of insulin

- delays site absorption

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15
Q

What does protamine form with insulin?

A

insoluble complexes

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16
Q

What type of release does protamine and insulin form?

A

prolonged release

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17
Q

times until peak/onset of rapid/short/intermediate/long acting insulins

A

rapid 5-15 mins onset

short 2-3 hrs

intermediate 6-12 hrs

long 10-24 hrs

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18
Q

What is a soluble preparation of insulin called?

A

neutral insulin

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19
Q

types of short/intermediate/longacting insulins

A

short - insulin neutral/soluble
intermediate - isophane insulin
long - insulin zinc suspension/protamine zinc insulin

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20
Q

How to make recombinant insulin?

A
  1. insert human gene into plasmid at a specific point and ligate them together
  2. insert the plasmid into bacterium
  3. bacterial cells produce human insulin gene protein in bulk
  4. plasmid replicates inside the bacterium and bacteria divide to produce a colony
  5. purify the protein from culture
21
Q

How to change the AA sequence of recombinant protein?

A

use enzymes to cut/change any DNA base you want to change in the AA sequence

22
Q

3 commercial rapidly acting insulins

A

lispro
aspart
glulisine

23
Q

When are rapidly acting insulins taken?

A

before a meal to elevate glucose levels

24
Q

onset of rapidly acting insulins

A

5-15 mins

25
Q

How does lispro differ from normal human insulin?

A

AA proline at position B28 is replaced with lysine

lysine at position B29 replaced with proline

26
Q

Why is lispro recombinated?

A

it prevents it forming a dimer or hexamer

it only forms monomers

27
Q

short acting insulin structure

A

hexamer

28
Q

When is short acting insulin taken?

A

30-45 mins before meal

29
Q

What is short acting insulin especially used for IV?

A

treatment for diabetic ketoacidosos

30
Q

What is short acting insulin made from and why?

A

regular insulin made as a recombinant molecule

it has less immune issues than animal insulin

31
Q

example of an intermediate acting insulin

A

neutral protamine hagedorn insulin (NPH)

32
Q

onset of action of NPH insulin

A

2-5 hrs

33
Q

examples of long acting insulin

A

insulin glargine

insulin detemir

34
Q

recombinant structure of insulin glargine

A

insertion of 2 arginine molecules on chain B and substitution of glycine with asparagine at A21 position

35
Q

solubility of insulin glargine

A

in acid conditions pH4

36
Q

What does insulin glargine provide?

A

low level of continuous insulin

37
Q

formulation of insulin detemir

A

myristic acid attaches at B29

increases self aggregation and albumin binding

38
Q

side effects of insulin

A

too much - hypoglycaemia, brain damage, cardiac arrest

too little - DKA

insulin allergy (esp animal insulins)

lipodystrophy at site of injection (animal insulins)

cancer risk?

39
Q

3 strategies of anti-diabetic drugs

A
  1. increase cellular sensitivity to insulin
  2. increase insulin release
  3. reduce/delay glucose absorption into blood
40
Q

What effects does insulin have?

A

increases glucose uptake
increases lipogenesis
increases glycogen synthesis
increases protein synthesis

decreases lipolysis
decreases gluconeogenesis

41
Q

What group does metformin belong to?

A

biguanides

42
Q

How is metformin eliminated?

A

100% renally eliminated (not metabolised)

43
Q

What type of drug is metformin?

A

insulin senstiser

44
Q

Does metformin affect insulin output?

A

no, it’s effective in late stage disese where beta cell decline has occurred

45
Q

How does metformin work in the liver?

A

it decreases gluconeogenesis

46
Q

serious clinical consequence of a metformin side effect and how it happens

A

lactic acidosis
pyruvate is coveted to lactate
there’s increased lactate production

47
Q

adverse effects of metformin

A

diarrhoea, dyspepsia

lactic acidosis

48
Q

metformin and renal function

A

renl function test required
not prescribed if GFR < 45ml/min
stop if GFR < 30ml/min

49
Q

results of a kidney funtion test that show impaired kidneys

A

more orange = high creatinine

high creatinine = impaired kidneys

PHA223 (43 decks)

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