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Management of GI and Endocrine Conditions > Lecture 20 - Insulin Treatment of Diabetes > Flashcards

Lecture 20 - Insulin Treatment of Diabetes Flashcards

1
Q

When insulin is made where is it targetted?

A

to the endoplasmic reticulum by a signal sequence

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2
Q

What happens as insulin moves from the endoplasmic reticulum to secretory vesicles?

A

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

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3
Q

How is insulin made?

A

as pre-pro-insulin

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4
Q

What happens when insulin arrives at the endoplasmic reticulum?

A

the pre-sequence is removed to give pro-insulin

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5
Q

What forms between the chains of pro-insulin

A

disulphide bonds form between chain A and chain B

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6
Q

What happens to chain C?

A

proteases cleave either end

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7
Q

What arrives as a result of this?

A

Insulin (chain A and B joined by disulphide bonds) and C peptide

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8
Q

How is insulin stored in secretory vesicles?

A

as a hexamer

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9
Q

What is an insulin dimer?

A

two A chains an two B chains

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10
Q

What does an insulin hexamer consist of?

A

6 insulin molecules

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11
Q

What is a hexamer stabilised by?

A

Zn2+ molecules, these positive ions interact with the negatively charged amino acids to stabilise the whole structure

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12
Q

What is important about a hexamer?

A

it is stable but inactive

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13
Q

What happens to the hexamers upon release into the bloostsream?

A

they disassemble into the monomeric form of insulin

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14
Q

What are the three groups of insulin?

A

animal, human and analogues

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15
Q

Animal insulin?

A

not widely used but some people find this works better for them

purified from cows and pigs

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16
Q

Human insulin?

A

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

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17
Q

Insulin analogues?

A

human insulin is altered to make it work quicker or last longer

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18
Q

Short acting insulin?

A

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

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19
Q

Medium acting insulin?

A

those with an intermediate action

e.g. isophane insulin

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20
Q

Long acting insulin?

A

those whose action is slower in onset and lasts for long periods

e.g. insulin detemir and insulin glargine

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21
Q

What is a normal insulin profile?

A

a sharp increase in insulin following increase in blood glucose levels, followed by a more sustained but lower secretion of insulin

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22
Q

What are biphasic insulins?

A

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%)

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23
Q

What do biphasic insulins give?

A

a more physiological profile

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24
Q

What is uptake of insulin affected by?

A

size

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25
Q

How does insulin enter the general circulation?

A

they are administered subcutaneously so they have to diffuse across capillary walls

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26
Q

Rates of diffusion of insulin

A

monomer>dimer>hexamer/aggregates

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27
Q

What can alter the kinetics of insulin?

A

the composition of human insulin

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28
Q

Humulin S and Humulin I?

A

humulin S (soluble) is short acting and I (isophane) is medium acting

29
Q

What does humulin I contain?

A

protamine

30
Q

What does protamine do?

A

causes clustering of insulin, limiting the diffusion through capillary walls

31
Q

What is protamine?

A

a basic protein (positively charged) that binds to negatively charged insulin and clusters insulin hexamers

32
Q

Examples of rapid acting insulin analogues?

A

aspart, lispro, glulisine

33
Q

Examples of long acting insulin analogues?

A

detemir, glargine

34
Q

Rapid acting insulin?

A

modified forms of insulin have been produced that affect hexamer formation/stability

35
Q

Insulin aspart?

A

NovoRapid

has a proline to aspartate substitution in the B chain, which reduces tendency to form hexamers

more rapidly transferred from the subcutaneous injection site to the bloodstream

36
Q

Insulin lispro?

A

Humalog

has 2 substitutions in the B chain, which diminishes the tendency of insulin molecules to self associate

position 28&29 there is a proline and a lysine but these switch places

37
Q

Insulin glulisine?

A

has two substitutions in the B chain

asparagine replaced with a lysine, and a lysine replaced with a glutamic acid

these changes reduce insulin self association

38
Q

Insulin glargine?

A

LONG ACTING (Lantus)

contains an asparagine to glycine substitution in the A chain and also has two arginines added to the carboxy terminal end of the B chain

these make the insulin analogue less soluble at physiological pH, which limits absorption from the site of injection

39
Q

Insulin detemir?

A

LONG ACTING (Levemir)

has a covalently attached fatty acid (myristic acid) that causes the molecule to bind to albumin in the blood serum

40
Q

What does albumin do?

A

competes with the insulin receptor for binding to insulin detemir, prolonging its action

albumin binding also protects insulin detemir from circulating peptidases, increasing its stability

41
Q

Insulin degludec?

A

LONG ACTING (Tresiba- developed by Novo Nordisk)

has a hexadecanedioic acid group added to the B chain, this mediates albumin binding but also causes formation of multi hexamers

monomers are slowly released from the multi hexamers, extending duration of action beyond 40 hours

42
Q

What is the duration of action of glargine and detemir?

A

~18-26 hours

43
Q

Why is insulin not orally administered?

A

it would be degraded by proteases in the stomach and small intestine

44
Q

How is insulin administered?

A

subcutaneous injection

45
Q

What happens once insulin is injected?

A

it diffuses into small blood vessels and enters the blood stream

46
Q

what is the injection site of insulin?

A

the stomach, buttocks or thighs

47
Q

Why are injection sites rotated?

A

to avoid lipohypertrophy, accumulation of lumps under the skin - this can lead to problems with absorption of insulin

48
Q

How should insulin be stored?

A

below 25 degrees celcius and ideally in the fridge

49
Q

3 basic regimens for children and young people with type 1 diabetes?

A

multiple daily injection basal bolus injection regimens

continuous subcutaneous insulin infusion (insulin pump)

one, two or three infections per day

50
Q

Basal-bolus insulin regimens?

A

injections of short acting insulin or rapid acting insulin analogue before meals, together with 1 or more separate daily injections of intermediate acting insulin or long acting insulin analogue

51
Q

Insulin pump therapy?

A

a programmable pump and insulin storage device that gives a regular or continuous amount of insulin (usually rapid acting analogue or short acting insulin) by a subcutaneous needle or cannula, and patient activated bolus doses at meal times

52
Q

One, two or three injections per day?

A

these are usually injections of short-acting insulin or rapid acting insulin analogue mixed with intermediate acting insulin

53
Q

Insulin treatment of type 2 diabetes?

A

insulin used in combination with oral antidiabetic drugs

54
Q

What is first step insulin in type 2?

A

basal insulin with once or twice daily intermediate or long acting insulin

55
Q

What can be used if type 2 diabetic control is poor?

A

biphasic insulin

56
Q

What can be introduced if type 2 blood glucose remains inadequate?

A

basal-bolus regimen

57
Q

What are insulin pumps?

A

an alternative to injections

can help to improve overall control of diabetes

58
Q

Design of an insulin pump?

A

about the size of a small mobile phone and delivers a varied dose of rapid acting insulin continually during the day and night (basal rate and is set to the individual)

59
Q

When food is eaten what can be done with the insulin pump?

A

an additional bolus dose can be given by pressing specific buttons

60
Q

What is the artificial pancreas?

A

a closed loop system that continuously monitors glucose levels and uses the information to adjust the amount of insulin being administered by an insulin pump

61
Q

What does the artificial pancreas use?

A

a continuous glucose monitor, where a sensor is inserted just under the skin to measure interstitial glucose levels

measurements are used to determine amount of insulin delivered by a pump

62
Q

What is islet cell transplantation?

A

implants islet cells from a deceased donor, the cells are injected through a catheter placed in the upper abdomen into the liver

63
Q

What is an issue for islet cell transplantation?

A

the lack of suitable organ donors

and patients need to take immunosuppressive drugs to prevent rejection

64
Q

Success rates of islet cell transplantation?

A

70% of adults with T1D free of insulin injections at one year, 50% free at two years and 35% free at 3 years

65
Q

How is islet cell transplantation being improved?

A

islet cells are being encapsulated to build an islet sheet, which can be surgically implanted - this blocks the immune response to transplanted islet cells

66
Q

What are stem cell derived beta cells?

A

are produced fromhuman pluripotent stem cells

these cells formed islet like clusters and made insulin when transplanted into mice

using beta cells derived from stem cells overcomes the limitation of acquiring islet from donors

67
Q

What is repurposing of the cells in the patient?

A

switching off a single gene in the GI cells allowed them to produce insulin

68
Q

What can gut endocrine progenitor cells be differentiated into?

A

glucose responsive insulin producing cells by ablation of the transcription factor Fox01

highlights potential of targeting cells in the body with viral vectors or drugs with the aim of producing insulin secreting cells

69
Q

What are insulin sprays?

A

absorbed by the mouth

attaching insulin to carriers that protect it from degradation and allow oral delivery

non-protein insulin substitutes that are able to bind to the insulin receptor and activate intracellular signalling pathways

Management of GI and Endocrine Conditions (24 decks)

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